OncoTrials - мониторинг клинических исследований

Описание

This phase II trial tests the effectiveness of golcadomide and rituximab as bridging treatment before chimeric antigen receptor (CAR) T-cell therapy in patients with aggressive B-cell non-Hodgkin lymphoma that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). Patients that are able to receive CAR T-cell therapy have a potential for cure, however, many will not be qualified to receive therapy due to relapse. Bridging therapy is therapy intended to transition a patient from one therapy or medication to another or maintain their health or status until they are a candidate for a therapy or have decided on a therapy. Golcadomide may help block the formation, growth or spread of cancer cells. Rituximab is a monoclonal antibody. It binds to a protein called CD20, which is found on B cells (a type of white blood cell) and some types of cancer cells. This may help the immune system kill cancer cells. Giving golcadomide and rituximab as bridging therapy before CAR T-cell therapy may kill more tumor cells and may improve the chance of proceeding to CAR T-cell therapy in patients with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma.

Критерии включения

• * Age ≥ 18 years
• * Confirmed pathology diagnosis according to 2016 World Health Organization (WHO) classification including patients with diseases listed below with relapsed, progressive and/or refractory disease (Cheson et al. 2014) following treatment with one or two prior lines of standard therapy, no more than two lines of therapy are permitted:
• * Diffuse large B-cell lymphoma not otherwise specified (NOS) including:
• * Transformed lymphoma
• * Germinal center B-cell type
• * Activated B-cell type
• * High-grade B-cell lymphoma (HGBCL), NOS
• * High grade B-cell lymphoma with MYC and BCL2 translocation
• * Primary mediastinal (thymic) large B-cell lymphoma
• * Grade 3B follicular lymphoma
• * T-cell/histiocyte-rich large B-cell lymphoma
• * Large B-cell lymphoma with IRF4 rearrangement
• * Primary cutaneous diffuse large B-cell lymphoma (DLBCL), leg type
• * Epstein-Barr virus (EBV) positive DLBCL, NOS
• * DLBCL associated with chronic inflammation
• * Intravascular large B-cell lymphoma
• * ALK positive large B-cell lymphoma
• * NOTE: Richters transformation patients are excluded
• * Measurable disease by PET-CT with at least one lymph node or other type of lesion that has a size /> 1.5 cm in the transverse diameter, as defined by Lugano classification
• * NOTE: Tumor lesions in a previously irradiated area are not considered measurable disease; Disease that is measurable by physical examination only is not eligible
• * Patient is potentially eligible for CAR-T therapy as determined by treating physician
• * Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2
• * Hemoglobin /> 7.0 g/dL (obtained ≤ 14 days prior to registration)
• * Absolute neutrophil count (ANC) ≥ 1000/mcL (obtained ≤ 14 days prior to registration); growth factor support allowed at physician discretion
• * Platelet count ≥ 75,000/mcL (obtained ≤ 14 days prior to registration)
• * Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (obtained ≤ 14 days prior to registration); if total bilirubin is /> 1.5 ULN, direct bilirubin must be normal
• * Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤ 2.5 x ULN (≤ 5 x ULN if there is evidence of parenchymal liver involvement with lymphoma) (obtained ≤ 14 days prior to registration)
• * Calculated creatinine clearance ≥ 45 ml/min using the Cockcroft-Gault formula (obtained ≤ 14 days prior to registration)
• * Have 2 negative pregnancy tests as verified by the investigator prior to starting CC-99282:
• * A negative serum pregnancy test (sensitivity of at least 25 mIU/mL) at screening (between 10 to 14 days prior to cycle 1 day 1)
• * A negative serum or urine pregnancy test (investigator`s discretion) within 24 hours prior to cycle 1 day 1 of study treatment
• * Provide written informed consent
• * Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study)
• * Subjects must agree not to donate blood while receiving golcadomide, during dose interruptions and for ≥ 28 days following the last dose of golcadomide

Критерии исключения

• * Any of the following because this study involves an investigational agent that has known genotoxic, mutagenic, and teratogenic effects:
• * Pregnant persons
• * Nursing persons
• * Persons of childbearing potential (and persons able to father a child) who are unwilling to employ adequate contraception
• * Persons of childbearing potential (PCBP) unwilling to use two reliable forms of contraception simultaneously or to practice complete abstinence (true abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence /[e.g., calendar, ovulation, symptothermal or postovulation methods/] and withdrawal are not acceptable methods of contraception) from heterosexual contact during the following time periods related to this study:
• * For ≥ 28 days before starting treatment, during treatment and dose interruptions, and for ≥ 28 days after the last dose of golcadomide
• * Examples of highly effective methods of contraception:
• * Intrauterine device (IUD)
• * Hormonal (birth control pills, injections, implants, levonorgestrel-releasing intrauterine system /[IUS/], medroxyprogesterone acetate depot injections, ovulation inhibitory
• * Progesterone-only pills /[e.g., desogestrel/])
• * Tubal ligation
• * Partner`s vasectomy
• * Examples of additional effective methods:
• * Male condom
• * Diaphragm
• * Cervical cap
• * Persons who can father a child unwilling to practice complete abstinence (true abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence /[e.g., calendar, ovulation, symptothermal or post-ovulation methods/] and withdrawal are not acceptable methods of contraception.) or unwilling to use a condom during sexual contact with a pregnant person or a PCBP during treatment and dose interruptions, and for /> 28 days following the last dose of golcadomide, even if they have undergone a successful vasectomy
• * Persons who can father a child and are unwilling to refrain from donating semen or sperm while receiving golcadomide, during dose interruptions, or for ≥ 28 days following the last dose of golcadomide
• * Life expectancy /< 3 months
• * Any of the following prior therapies:
• * Any prior CAR-T or other T-cell targeting treatment (approved or investigational) ≤ 4 weeks prior to registration
• * Any prior systemic anti-cancer treatment (approved or investigational) ≤ 5 half-lives or 4 weeks prior to registration, whichever is shorter
• * Exception: Monoclonal and bispecific antibodies is acceptable
• * Prior therapy with golcadomide ≤ 4 weeks prior to registration
• * Prior autologous stem cell transplantation (SCT) ≤ 3 months prior to registration. If subject had autologous SCT /> 3 months prior to the start of registration, any treatment-related toxicity is unresolved (grade /> 1)
• * Major surgery ≤ 3 weeks prior to registration
• * Chemotherapy ≤ 2 weeks prior to registration
• * Concomitant radiation therapy; local palliative radiotherapy is permitted
• * Co-morbid systemic illnesses or other severe concurrent disease or cancer which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens
• * Impaired cardiac function or clinically significant cardiac diseases including, but not limited to:
• * Symptomatic congestive heart failure
• * History of myocardial infarction ≤ 6 months, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias
• * Unstable angina pectoris
• * Cardiac arrhythmia
• * Uncontrolled intercurrent non-cardiac illness including, but not limited to:
• * Ongoing or active infection
• * Psychiatric illness/social situations
• * Dyspnea at rest due to complications of advanced malignancy or other disease that requires continuous oxygen therapy (such as interstitial lung disease or chronic obstructive pulmonary disease /[COPD/])
• * Any other conditions that would limit compliance with study requirements
• * Subject had prior allogeneic SCT with either standard or reduced intensity conditioning ≤ 6 months prior to registration. If subject had prior allogeneic SCT /> 6 months prior to registration, any treatment-related toxicity is unresolved (grade />1)
• * Immunocompromised patients and patients known to be HIV positive and currently receiving antiretroviral therapy, as there is currently no safety data in HIV positive patients
• * Subject has known chronic active hepatitis B or C virus (HBV/HCV) infection
• * Exception: Patients with HBV and an undetectable viral load who are on suppressive therapy and/or those with HCV and an undetectable viral load are allowed
• * Concurrent administration of strong or moderate CYP3A4/5 inhibitors and inducers within 14 days or 5 half-lives, whichever is longer before the study treatment administration
• * Receiving any other investigational agent which would be considered as a treatment for lymphoma.
• * Exception: Corticosteroids are allowed
• * Active second malignancy requiring treatment that would interfere with the assessment of the response of the primary cancer or interpretation of the safety of this protocol therapy
• * History of deep venous thrombosis/embolism, threatening thromboembolism or known thrombophilia. Patients with a history of deep vein thrombosis (DVT)/pulmonary embolism (PE) or thrombophilia may still participate if they are willing to be on full anticoagulation during treatment. Full anticoagulation is defined as Warfarin, factor X inhibitors, or low molecular weight heparin at therapeutic doses. The rationale for this requirement is that golcadomide therapy is associated with an increased risk of thrombosis. Patients with no history of DVT/PE or thrombophilia are not required to take anticoagulation and/or anti-platelet prophylaxis
• * NOTE: If a patient develops a thrombotic event, they must be able and willing to receive anticoagulation therapy with aspirin 81-325 mg daily prophylaxis, low molecular weight heparin, factor X inhibitors or Warfarin. This is due to an increased risk of thrombosis in patients treated with golcadomide without prophylaxis
• * Live COVID-19 vaccine administered ≤ 28 days prior to registration

Описание

This phase of the protocol (protocol part B), seeks to evaluate the new formulation in healthy normal volunteers to confirm the new formulation provides comparable human dosimetry to which was seen and published in protocol part A. Additionally, the new formulation will be studied utilizing an expanded patient population to include patients with confirmed diagnosis of multiple myeloma (MM), low-grade lymphoma, or MM and lymphoma patients who are status post bone marrow transplant (BMT) with negative imaging and suspected recurrence.

Критерии включения

• Healthy Volunteer:
• * Adult 18 years of age or older
• * Able to give informed consent.
• * Able to comprehend and willing to follow instructions for study procedures as called for by the protocol
• * Capable of lying still and supine within the PET/CT scanner for up to 75 minutes.
• * No illicit drug use or other inhaled drug use (including pharmacologic agents and illicit drugs) within the past year per self-reporting mechanisms.
• * No history of claustrophobia or other condition that has previously or would interfere with completion of protocol specified imaging sessions.
• * Not currently pregnant or nursing: Subject must be surgically sterile (has had a documented bilateral oophorectomy and/or documented hysterectomy), post-menopausal (cessation of menses for more than 1 year), non-lactating, or of childbearing potential for whom a urine pregnancy test (with the test performed within the 24 hour period immediately prior to administration of 64Cu-LLP2A) is negative.
• Inclusion Criteria Hematological Malignancy:
• * Clinical or pathologically defined MM or lymphoma including both newly diagnosed, relapsed or refractory disease:
• * Multiple Myeloma defined in accordance with the International Myeloma Working Group criteria
• * Low-grade lymphoma, including the following subtypes: follicular lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma, small lymphocytic lymphoma/chronic lymphocytic leukemia
• * Adult 18 years of age or older and able to provide informed consent
• * Capable of lying still and supine within the PET/CT scanner for up to 75 minutes.
• * No history of claustrophobia or other condition that has previously or would interfere with completion of protocol specified imaging sessions
• * Not currently pregnant or nursing: Subject must be surgically sterile (has had a documented bilateral oophorectomy and/or documented hysterectomy), post-menopausal (cessation of menses for more than 1 year), non-lactating, or of childbearing potential for whom a urine pregnancy test (with the test performed within the 24 hour period immediately prior to administration of 64Cu-LLP2A) is negative
• * Patients participating in imaging or therapeutic trials with investigational agents are eligible to participate

Критерии исключения

Описание

This phase Ib/II trial evaluates the safety, optimal dose, and efficacy of the combination of epcoritamab and ibrutinib in treating patients with aggressive B-cell non-Hodgkin lymphoma that has come back (relapsed) or responded to previous treatment (refractory). Epcoritamab, a bispecific antibody, binds to two different types of receptors (proteins present on the cell surface) at the same time. The two receptors that epcoritamab binds to are called CD3 and CD20. CD3 is found on T cells, which are important cells of the immune system that help fight cancer and infections. CD20 is found on the surface of most types of aggressive B-cell non-Hodgkin lymphoma cells. By binding to both CD3 and CD20, epcoritamab brings the two cells close together so the T cells can fight and kill the lymphoma B cells. Ibrutinib, a Bruton`s tyrosine kinase (BTK) inhibitor, binds to a protein on B cells, a type of white blood cell from which the lymphoma developed. By doing this it decreases the ability of the lymphoma B cells to survive and grow. Ibrutinib may also improve the health (or fitness) of T cells thus making epcoritamab safer and/or more effective.

Критерии включения

• * One of the following CD20+ B-cell non-Hodgkin lymphoma subtypes (note, documentation of CD20 positivity by flow cytometry and/or immunohistochemistry is based on any representative pathology report)
• * Diffuse large B-cell lymphoma (DLBCL), including DLBCL, not otherwise specified (NOS); T-cell/histiocyte-rich large B-cell lymphoma; and Epstein-Barr virus-positive DLBCL, NOS
• * High-grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 rearrangements (double-hit or triple-hit lymphoma) or HGBL, NOS
• * Primary mediastinal B-cell lymphoma (PMBCL)
• * Follicular lymphoma, grade 3b (also known as follicular large B-cell lymphoma in the 5th edition of World Health Organization /[WHO/] classification of lymphoid neoplasms)
• * Patients with previously diagnosed indolent lymphoma (follicular lymphoma or marginal zone lymphoma but not lymphoplasmacytic lymphoma or small lymphocytic lymphoma/chronic lymphocytic leukemia) who have transformed to any of the above lymphoma subtypes are eligible
• * Patients must have relapsed or refractory aggressive B-cell lymphoma and received prior treatment with an anthracycline in combination with an anti-CD20 monoclonal antibody:
• * ≥ 2 prior systemic lymphoma treatments OR
• * ≥ 1 prior systemic lymphoma treatment in patients with high-risk disease defined as primary refractory or relapsed within 12 months of completing anthracycline-based frontline treatment who are ineligible for chimeric antigen receptor (CAR) T cells per the treating physician. The reason for CAR T-cell treatment ineligibility should be documented
• * Prior treatment with a BTK inhibitor is allowed if stopped due to lymphoma progression or treatment completion but not intolerance
• * Prior treatment with autologous stem cell transplant (ASCT) is allowed if ≥ 100 days prior to enrollment
• * Prior treatment with CAR T cells is allowed if ≥ 30 days prior to enrollment
• * Age ≥ 18 years. Because no dosing or adverse event data are currently available on the use of ibrutinib or epcoritamab in patients /< 18 years of age, children are excluded from this study
• * Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
• * Measurable disease (defined as /> 1.5 cm in diameter) or at least one PET fludeoxyglucose F-18 (FDG) avid area of disease
• * Absolute neutrophil count (ANC) ≥ 1,000/mcL
• * Platelet count ≥ 75,000/mcL. Platelet count ≥ 50,000/mcL is allowed in case of bone marrow involvement and/or splenomegaly
• * Hemoglobin ≥ 8 g/dL
• * Transfusion and/or growth factor support within 7 days (or 14 days in case of long-acting growth factors such as pegylated granulocyte colony-stimulating factor /[G-CSF/]) of enrollment to meet these requirements is not permitted
• * Total bilirubin ≤ 1.5 x the upper limit of the normal range (ULN) (unless due to Gilbert`s disease or hemolysis in which case bilirubin must be /< 3 x ULN)
• * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase /[SGOT/]) /< 3 x institutional ULN
• * Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase /[SGPT/]) /< 3 x institutional ULN
• * Creatinine clearance /> 45 mL/min calculated by Cockcroft-Gault. Patients on dialysis are not eligible
• * The effects of ibrutinib and epcoritamab on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (double barrier method of birth control or abstinence) 2 weeks before initiation of treatment, for the duration of study participation and for 12 months after completing treatment. Should a woman become pregnant or suspect that she is pregnant while she or her partner is participating in this study, she should inform the treating physician immediately. Men must agree to refrain from sperm donation for at least 12 months after the last dose of epcoritamab
• * Women of childbearing potential must have a negative serum (beta-human chorionic gonadotropin /[β-hCG/]) or urine pregnancy test at Screening. Women who are pregnant or breastfeeding are ineligible for this study
• * Patients must have the ability to understand and the willingness to sign a written informed consent document and Health Insurance Portability and Accountability Act (HIPAA) consent document. Voluntary written consent must be given before the performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care

Критерии исключения

• * Prior therapy with a bispecific antibody targeting CD3 and CD20
• * Prior lymphoma therapy should be completed greater than two weeks before the start of protocol therapy, except for corticosteroids used for palliation of symptoms
• * Patients who require immediate cytoreductive therapy for their lymphoma per the treating physician`s assessment are ineligible
• * Patients with a history of allogeneic stem cell transplantation are excluded unless the transplant was /> 180 days before the first scheduled dose of ibrutinib AND the patient does not have evidence of active acute or chronic graft versus host disease AND the patient must not have taken immunosuppressive medications associated with the transplant for at least 1 month before the first scheduled dose of ibrutinib
• * Ongoing systemic treatment with a strong CYP3A inhibitor or inducer. Treatment with any strong CYP3A inhibitor or inducer needs to be stopped for 5 half-lives prior to starting treatment on trial
• * Major surgery within 4 weeks before the start of treatment other than surgery performed for lymphoma diagnosis
• * Known active central nervous system (CNS) involvement by lymphoma. Patients who are enrolled and subsequently identified to have pathologic confirmation of CNS involvement by lymphoma may be continued on the study at the discretion of the principal investigator
• * Active uncontrolled infection or infection requiring intravenous (IV) antibiotic therapy for /> 2 consecutive days within 2 weeks prior to the first dose of study drug
• * Evidence of current uncontrolled or symptomatic cardiovascular conditions, including, uncontrolled cardiac arrhythmias, history of or symptomatic congestive heart failure (New York Heart Association /[NYHA/] class III or greater), unstable angina, or myocardial infarction within the past 6 months. Poorly controlled or clinically significant atherosclerotic vascular disease including angioplasty, cardiac or vascular stenting within 6 months of enrollment
• * Known liver cirrhosis with moderate to severe hepatic impairment (Child-Pugh class B or C)
• * Clinically significant pulmonary disease or history of bronchospasm requiring intubation, or clinically significant active interstitial lung disease or pneumonitis
• * History of cerebrovascular accident or transient ischemic attack within the 6 months before day 1, cycle 1 of treatment
• * Any prior history of intracranial hemorrhage
• * Clinically significant known bleeding diatheses or platelet dysfunction disorders.
• * Receiving treatment with coumadin/warfarin
• * Known gastrointestinal disease or gastrointestinal procedure that will significantly interfere with the oral absorption or tolerance of ibrutinib including the inability to swallow pills/capsules
• * Any serious medical or psychiatric illness that could, in the investigator`s opinion, potentially interfere with the completion of treatment according to this protocol
• * Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent
• * Prior solid organ transplant
• * History of other malignancies that could affect compliance with the protocol or interpretation of results in the opinion of the investigator
• * Participation in other interventional clinical trials, including those with other investigational agents not included in this trial, within 21 days of the first scheduled dose of ibrutinib (cycle 1 day -7)
• * Known history of HIV, active hepatitis C infection (HCV ribonucleic acid /[RNA/] polymerase chain reaction /[PCR/]-positive) and/or active hepatitis B infections (HBV DNA PCR-positive). If hepatitis B core (HBc) antibody is positive, the patient must be evaluated for the presence of HBV DNA by PCR. If HCV antibody is positive, the patient must be evaluated for the presence of HCV RNA by PCR. Patients with positive HBc antibody and negative HBV DNA by PCR are eligible. Patients with positive HCV antibody and negative HCV RNA by PCR are eligible
• * Pregnant or breastfeeding women are excluded from this study. Because there is an unknown, but potential risk for adverse events in nursing infants secondary to treatment of the mother with ibrutinib or epcoritamab, breastfeeding should be discontinued if the mother is treated with ibrutinib or epcoritamab
• * Patients with ongoing clinically significant grade ≥ 2 toxicity from prior therapy

Описание

This study evaluates immune responses after CAR-T therapy to find out if CAR-T therapy reduces the effectiveness of the vaccines (vaccine immunity) against diseases such as measles, mumps and rubella, among others in patients with multiple myeloma and non-Hodgkin lymphoma.

Критерии включения

• * /* Willingness to provide written informed consent before any study-specific procedures or activities are performed
• * Age ≥ 18 years of age, at the time of consent
• * Documented, histologically or cytologically confirmed diagnosis of multiple myeloma (MM), diffuse large B cell lymphoma (DLBCL),follicular lymphoma (FL), mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), or small lymphocytic lymphoma (SLL), or primary mediastinal B cell lymphoma (PMBL). All number of prior lines of therapy are allowed
• * History of prior vaccination against common VPD
• * Approved by managing physician for CAR-T therapy, with preparative conditioning planned within the next 90 days
• * Approved by managing physician for revaccination against Streptococcus pneumoniae or tetanus

Критерии исключения

• * /* Ongoing use of immunosuppressive agents or plans for immunosuppressive therapy that would interfere with interpretation of study endpoints
• * Uncontrolled, intercurrent illness including, but not limited to, systemic infection, symptomatic congestive heart failure, unstable angina pectoris, or psychiatric illness/social situations that would limit compliance with study requirements or make the study procedures unadvisable

Описание

This phase II trial tests the safety, side effects and effectiveness of epcoritamab and tazemetostat in treating patients with grade I-IIIa follicular lymphoma that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). Epcoritamab is a bispecific monoclonal antibody that binds to two different antigens on the surface of cancer cells that may help the body`s immune system attack the cancer and may interfere with the ability of the cancer cells to grow and spread. Tazemetostat, a EZH2 inhibitor, may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving epcoritamab and tazemetostat may be safe, tolerable and/or effective in treating patients with relapsed or refractory grade I-IIIa follicular lymphoma.

Критерии включения

• * Documented informed consent of the participant and/or legally authorized representative
• * Assent, when appropriate, will be obtained per institutional guidelines
• * Agreement to allow the use of archival tissue from diagnostic tumor biopsies
• * If unavailable, exceptions may be granted with study principal investigator (PI) approval
• * Age: ≥ 18 years
• * Eastern Cooperative Oncology Group (ECOG) ≤ 2
• * Histologically confirmed follicular lymphoma, grades 1-3A
• * Relapsed/ refractory disease after at least one line of prior lymphoma therapy
• * Radiologically measurable lymphadenopathy (≥ 1.5 cm) or ≥ 1 measurable extranodal lesion (long axis /> 1.0 cm) on CT scan or magnetic resonance imaging (MRI)
• * Fully recovered from the acute toxic effects (except alopecia) to ≤ grade 1 to prior anti-cancer therapy
• * WITHOUT BONE MARROW INVOLVEMENT: Absolute neutrophil count (ANC) ≥ 1,000/mm/^3 (NOTE: Growth factor use is allowed to reach ANC)
• * WITH BONE MARROW INVOLVEMENT: ANC ≥ 500/mm/^3 (NOTE: Growth factor use is allowed to reach ANC)
• * WITHOUT BONE MARROW INVOLVEMENT: Platelets ≥ 50,000/mm/^3 (NOTE: Platelet transfusions are within 14 days of platelet assessment if thrombocytopenia is secondary to disease involvement)
• * WITH BONE MARROW INVOLVEMENT: Platelets ≥ 25,000/mm/^3 (NOTE: Platelet transfusions are within 14 days of platelet assessment if thrombocytopenia is secondary to disease involvement)
• * Total bilirubin ≤ 2 x upper limit of normal (ULN) (unless has Gilbert`s disease or secondary to disease)
• * Aspartate aminotransferase (AST) ≤ 2.5 x ULN
• * Alanine aminotransferase (ALT) ≤ 2.5 x ULN
• * Creatinine clearance of ≥ 45 mL/min per 24 hour urine test or the Cockcroft-Gault formula
• * If not receiving anticoagulants: International normalized ratio (INR) OR prothrombin (PT) ≤ 1.5 x ULN; If on anticoagulant therapy: PT must be within therapeutic range of intended use of anticoagulants
• * If not receiving anticoagulants: Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN; If on anticoagulant therapy: aPTT must be within therapeutic range of intended use of anticoagulants
• * Fridericia`s formula-corrected QT interval (QTcF) ≤ 480 ms (Note: To be performed within 28 days prior to day 1 of protocol therapy)
• * If seropositive for HIV, hepatitis C virus (HCV) or hepatitis B virus (HBV), nucleic acid quantitation must be performed. Viral load must be undetectable. HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• * Meets other institutional and federal requirements for infectious disease titer requirements (Note Infectious disease testing to be performed within 28 days prior to day 1 of protocol therapy)
• * Women of childbearing potential (WOCBP): negative serum pregnancy test
• * Agreement by females of childbearing potential must agree to either abstain from heterosexual intercourse or to use two effective methods of birth control simultaneously (effective methods described below). The time period for effective contraceptive requirements begins ≥ 28 days prior to initiating tazemetostat and for the course of the study treatment period through at least 6 months after the last dose of tazemetostat, 4 months after the last dose of epcoritamab, or 4 months after the last dose of tocilizumab (if applicable), whichever is longer. Childbearing potential is defined as not being surgically sterilized (men and women) or have not been free from menses for /> 1 year (women only). Two effective methods includes one highly effective method and one barrier method.
• * Highly effective methods:
• * Intrauterine device (IUD)
• * Intrauterine hormone-releasing system (IUS)
• * Hormonal (stopping ovulation with two drugs /[estrogen and progesterone/]: oral, within the vagina, or on/under the skin; stopping ovulation with one drug progesterone-only: oral, injected, or on/under the skin). NOTE: Due to the potential of tazemetostat interference with hormonal contraception methods, use of these method requires that you add a barrier method of contraception (preferably male condom)
• * Bilateral tubal ligation
• * Partner`s vasectomy (if medically confirmed there are no live sperm and sole sexual partner)
• * Barrier methods:
• * Male latex or synthetic condom
• * Diaphragm
• * Cervical cap
• * Agreement by males to either practice complete abstinence or agree to use a latex or synthetic condom, even with a successful vasectomy (medically confirmed azoospermia), during sexual contact with a female of childbearing potential from first dose of study drug, during study treatment (including during dose interruptions), and for 3 months after study drug discontinuation. NOTE: Male subjects must not donate semen or sperm from first dose of tazemetostat, during study treatment (including during dose interruptions), and for 3 months after discontinuation of tazemetostat

Критерии исключения

• * Concurrent enrollment in another therapeutic investigational study
• * Prior bispecific antibodies or tazemetostat
• * Autologous stem cell transplant within 30 days prior to day 1 of protocol therapy
• * Allogeneic stem cell transplant if complicated by active graft versus host disease (GVHD) or if on immunosuppressive agents
• * Chemotherapy, radiation therapy, biological therapy, immunotherapy within 21 days or five half-lives (whichever is shorter for non-radiation therapy) prior to day 1 of protocol therapy
• * Immunosuppressive agents other than prednisolone 20 mg daily or equivalent
• * Major surgery within 4 weeks of first dose of study drug
• * Vaccination with live vaccines within 4 weeks of the first dose of study drug
• * Strong and moderate CYP3A4 inducers/ inhibitors within 14 days prior to day 1 of protocol therapy
• * Current evidence of central nervous system involvement by the lymphoma
• * Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia, or NYHA (New York Heart Association) heart failure class III-IV, or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months of screening
• * History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent
• * History of active human immunodeficiency virus (HIV) or active with hepatitis C virus (HCV) or hepatitis B virus (HBV)
• * Participants who are positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody must have a negative polymerase chain reaction (PCR) result before enrollment. Those who are PCR positive will be excluded
• * Known active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection
• * If a patient has signs/symptoms suggestive of SARS-CoV-2 infection or have had recent known exposure to someone with SARS-CoV-2 infection, the patient must have a negative molecular (e.g., PCR) test, or 2 negative antigen test results at least 24 hours apart, to rule out SARS-CoV-2 infection
• * Note: SARS-CoV-2 diagnostic tests should be applied following local requirements/recommendations
• * Subjects who do not meet SARS-CoV-2 infection eligibility criteria must be screen failed and may only rescreen after they meet the following SARS-CoV-2 infection viral clearance criteria:
• * No signs/symptoms suggestive of active SARS-CoV-2 infection
• * Negative molecular (e.g., PCR) result or 2 negative antigen test results at least 24 hours apart
• * SARS-CoV-2 testing is only required if a patient has signs/symptoms suggestive of SARS-CoV-2 infection or have had recent known exposure to someone with SARS-CoV-2 infection. Patients who fit this description must have a negative molecular (e.g., PCR) test, or 2 negative antigen test results at least 24 hours apart, to rule out SARS-CoV-2 infection
• * Clinically significant uncontrolled illness
• * Uncontrolled active systemic infection
• * Any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or myeloproliferative neoplasm (MPN) or any prior history of T lymphoblastic leukemia (T-LBL)/T acute lymphoblastic leukemia (T-ALL) or B acute lymphoblastic leukemia (B-ALL)
• * Other active malignancy. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. Exceptions are:
• * Malignancy treated with curative intent and no known active disease present for ≥ 3 years prior to initiation of therapy on current study
• * Adequately treated non-melanoma skin cancer or lentigo maligna (melanoma in situ) without evidence of disease
• * Adequately treated in situ carcinomas (e.g., breast, cervical, esophageal, etc.) without evidence of disease
• * Asymptomatic prostate cancer managed with "watch and wait" strategy or hormonal therapy
• * Inability to take oral medication or have malabsorption syndrome or any other uncontrolled gastrointestinal condition (e.g., nausea, diarrhea, vomiting) that might impair the bioavailability of tazemetostat
• * Females only: Pregnant or breastfeeding
• * Any other condition that would, in the investigator`s judgment, contraindicate the patient`s participation in the clinical study due to safety concerns with clinical study procedures
• * Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)

Описание

This study aims to establish and optimize the cluster of differentiation (CD70)-targeted immuno-positron emission tomography/computed tomography (immunoPET/CT) imaging method and its physiological and pathological distribution characteristics, based on which the diagnostic efficacy of the above imaging agents in malignant cancers (renal cancer (especially clear cell renal cell carcinoma), lymphoma, or nasopharyngeal carcinoma (NPC)) will be evaluated.

Критерии включения

• * Aged 18-80 year-old and of either sex；
• * Histologically confirmed diagnosis of renal cancer (especially ccRCC)/lymphoma/NPC or suspected renal cancer/lymphoma/NPC by diagnostic imaging;
• * Capable of giving signed informed consent, including compliance with the requirements and restrictions in the informed consent form (ICF) and this protocol.

Критерии исключения

• * Pregnancy；
• * Severe hepatic and renal insufficiency;
• * Allergic to single-domain antibody radiopharmaceuticals.

Описание

The purpose of this study is to characterise the long-term safety of lisocabtagene maraleucel, focusing on patients treated in the approved follicular lymphoma (FL) indication, and will be part of post-marketing liso-cel pharmacovigilance activities

Критерии включения

• • Participants must have been treated in the post-marketing setting with at least 1 infusion of lisocabtagene maraleucel (liso-cel) used for the treatment of relapsed/refractory (R/R) follicular lymphoma (FL), including FL Grade 1, Grade 2 and Grade 3a, within the FDA-approved indication and dosage per the United States Prescribing Information (USPI) and product specifications approved for commercial release in the USA

Критерии исключения

• * Participants known to be participating in investigational studies at the time of liso-cel, infusion
• * Participants treated with liso-cel for the treatment of R/R FL Grade 3b
• * Participants treated with non-conforming chimeric antigen receptor (CAR) T-cell product

Описание

This is a phase I, interventional, single arm, open label, treatment study designed to evaluate the safety and efficacy of LV20.19 CAR -T cells with pirtobrutinib bridging and maintenance in adult patients with B cell malignancies that have failed prior therapies.

Критерии включения

• To facilitate rapid start of pirtobrutinib, there will be separate inclusion/exclusion for pirtobrutinib and LV20.19 CAR T-cells in addition to the general inclusion as outlined below.
• General inclusion criteria for trial:
• 1. Patients must be aged ≥18 years and /<81 years with relapsed or refractory B-cell non-Hodgkin Lymphoma (NHL).
• 2. Diagnosis of relapsed or refractory B-cell NHL including Follicular Lymphoma, Marginal Zone Lymphoma (splenic, nodal, extranodal), Mantle Cell Lymphoma, Burkitt Lymphoma and DLBCL with associated subtypes (aggressive B-cell lymphoma, high grade B-cell lymphoma, T-cell/histocyte rich B-cell lymphoma, primary mediastinal B-cell lymphoma, Epstein-Barr virus-positive (EBV)+ diffuse large B-cell lymphoma, transformed lymphoma such as transformed follicular or marginal zone, and Richter`s transformation).
• 3. Disease specific criteria as follows:
• 1. DLBCL and associated subtypes (listed above)
• i. Must have received Rituximab or another cluster of differentiation 20 (CD20) antibody with combination anthracycline based chemotherapy regimen and have ONE of the following:
• <!-- -->
• 1. Primary refractory lymphoma or early relapse ≤6 months after one line of therapy.
• 2. For relapse />6.00 months, failure of two different chemotherapy regimens appropriate for their disease and be ineligible to receive autologous transplant.
• ii. Relapse post-autologous transplant. iii. Relapse post-allogeneic transplant. iv. Relapse post-CAR T-cell therapy (maximum 2 patients allowed with this designation).
• b. Mantle Cell Lymphoma
• i. Must have received Rituximab or another CD 20 antibody with one chemotherapy regimen appropriate for this disease (bendamustine or cytarabine, or anthracycline based treatment) and have ONE of the following:
• 1. Relapsed disease after two lines of cytotoxic chemotherapy including administration of anti-CD20 antibody.
• 2. Progressive disease after ≥second line BTK inhibitor.
• 3. Relapse post-autologous transplant.
• 4. Relapse post-allogeneic transplant.
• c. Marginal Zone Lymphoma and Follicular Lymphoma
• i. Must have received Rituximab or another CD20 antibody with chemotherapy regimen appropriate for the disease and have ONE of the following:
• <!-- -->
• 1. Relapsed disease after two lines of therapy including administration of anti-CD20 antibody.
• 2. Relapse post-autologous transplant.
• 3. Relapse post-allogeneic transplant.
• d. Burkitt`s Lymphoma
• i. Must have received Rituximab or another CD20 antibody in combination with anthracycline based chemotherapy regimen and have ONE of the following:
• <!-- -->
• 1. Primary refractory lymphoma.
• 2. Relapse within 6 months.
• 3. For relapse />6 months, failure of two different chemotherapy regimens appropriate for their disease and be ineligible to receive autologous transplant.
• i. Relapse post-autologous transplant. ii. Relapse post-allogeneic transplant.
• 4. Able to provide written informed consent.
• 5. Negative urine or serum pregnancy test in females of childbearing potential at screening.
• 6. Willingness of women of reproductive potential and their partners to observe highly effective birth control methods for duration of treatment and for 1 month following the last dose if study treatment.
• 7. Karnofsky performance score ≥70.
• 8. Expected survival />12 weeks.
• 9. Patient has demonstrated compliance with prior therapies.
• 10. Able to take oral medications.
• 11. Adequate coagulation, defined as activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT) and prothrombin (PT) or (international normalized ratio (INR) not greater than 1.5 x upper limit of normal (ULN).
• 12. Patients are required to have the following washout periods prior to planned Cycle 1 Day 1 (C1D1). In addition, prior treatment-related adverse events (AEs) must have recovered to Grade ≤ 1 with the exception of alopecia and Grade 2 peripheral neuropathy.
• 1. Targeted agents, investigational agents, therapeutic monoclonal antibodies or cytotoxic chemotherapy: 5 half-lives or 2 weeks, whichever is shorter.
• 2. immunoconjugated antibody treatment within 10 weeks prior to randomization.
• 3. broad field radiation (≥ 30% of the bone marrow or whole brain radiotherapy) must be completed 14 days prior to study enrollment.
• 4. palliative limited field radiation must be completed 7 days prior to study enrollment.
• Inclusion Criteria to START Pirtobrutinib Bridging:
• 1. Absolute neutrophil count (ANC) ≥1000 with no G-CSF within 7 days or pegylated G-CSF within 14 days unless patient has biopsy proven bone marrow involvement.
• 2. Platelets≥50,000 with no transfusion within 7 days unless patient has biopsy proven bone marrow involvement.
• 3. Hemoglobin ≥8g/dL (≥80 g/L) /[blood transfusions are allowable to reach this goal/].
• 4. Adequate hepatic function, defined as aspartate aminotransferase (AST) and alanine transaminase (ALT) /<3 x upper limit of normal (ULN) or /< 5 x ULN with documented liver involvement; serum bilirubin /<1.5 x ULN or /<3 x ULN with documented liver involvement , or considered not clinically significant as per the clinical PIs discretion (e.g. Gilbert`s or indirect hyperbilirubinemia) or felt to be due to underlying disease.
• 5. Adequate renal function, defined as creatinine clearance≥50 ml/min.
• 1. No IV hydration within 24 hours of eligibility.
• 2. No dialysis dependent renal failure.
• Inclusion criteria for Pirtobrutinib Maintenance (part B)
• 1. Recovery of neutrophils count after CAR T-cell infusion with ANC ≥1000/dL without G-CSF within the last 7 days.
• 2. Recovery of platelet count after CAR T-cell infusion with platelet count ≥50,000/dL.
• 3. Adequate hepatic function, defined as back to baseline or AST and ALT /<3 x upper limit of normal (ULN); serum bilirubin and alkaline phosphatase /<3 x ULN, or considered not clinically significant as per the clinical PI`s discretion (e.g., Gilbert`s or indirect hyperbilirubinemia) or felt to be due to underlying disease.
• 4. Adequate renal function, defined as creatinine clearance≥40 ml/min.
• 5. Evidence of response or stable disease (complete response/partial response/stable disease) at day 28 after CAR T-cell therapy.
• Inclusion Criteria for Apheresis and LV20.19 CAR T-cells:
• 1. Active Measurable disease must be documented within 4 weeks of lymphodepletion start defined as nodal lesions greater than 15 mm in the long axis or extranodal lesions />10 mm in long and short axis OR bone marrow involvement that is biopsy proven for B-cell NHL.
• 2. Absolute cluster of differentiation (CD) 3 count≥50 mm/^3.
• 3. MRI brain and Lumbar Puncture with cerebrospinal fluid (CSF) analysis by cytology and flow cytometry without evidence of central nervous system (CNS) involvement ONLY in patients with history of CNS involvement or clinical suspicion at the time of enrollment.
• 4. Adequate cardiac function as indicated by New York Heart Association (NYHA) classification I or II AND left ventricular ejection fraction of ≥45% (by echocardiogram (ECHO) or MUGA) and adequate pulmonary function as indicated by room air oxygen saturation of ≥92%.
• 5. No contraindication to central line access.
• 6. ANC≥1000 with no pegylated G-CSF within 14 days unless patient has biopsy proven bone marrow involvement.
• 7. Platelets≥50,000 with no transfusion within 72 hours unless patient has biopsy proven bone marrow involvement.
• 8. Adequate hepatic function, defined as AST and ALT /<3 x upper limit of normal (ULN); serum bilirubin and alkaline phosphatase /<3 x ULN, or considered not clinically significant as per the clinical PIs discretion (e.g. Gilbert`s or indirect hyperbilirubinemia) or felt to be due to underlying disease.
• 9. Adequate renal function, defined as creatinine clearance≥50 ml/min. a. No IV hydration within 24 hours of eligibility. b. No dialysis dependent renal failure.

Критерии исключения

• A potential subject who meets any of the following exclusion criteria is ineligible to participate in the study.
• 1. Positive beta-human chorionic gonadotropin (HCG) in female of child-bearing potential or plan to become pregnant during the study or within 1 month of the last dose of study treatment and women who are current lactating or plan to breastfeed during the study or within 1 week of the last dose of study treatment.
• 2. Known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection based on criteria below:
• 1. HBV: Patients with positive hepatitis B surface antigen (HBsAg) are excluded. Patients with positive hepatitis B core antibody (anti-HBc) and negative HBsAg require hepatitis B polymerase chain reaction (PCR) evaluation before randomization. Patients who are hepatitis B PCR positive will be excluded.
• 2. Hepatitis C virus (HCV): positive hepatitis C antibody. If positive hepatitis C antibody result, patient will need to have a negative result for hepatitis C ribonucleic acid (RNA) before randomization. Patients who are hepatitis C RNA positive will be excluded.
• 3. Known active cytomegalovirus (CMV) infection (Unknown or negative status are eligible).
• 4. History of significant autoimmune disease OR active, uncontrolled autoimmune phenomenon requiring steroid therapy defined as />20 mg of prednisone or equivalent daily.
• 5. Presence of ≥ grade 3 non-hematologic toxicities as per CTCAE version 5.0 from any previous treatment unless it is felt to be due to underlying disease.
• 6. Concurrent use of investigational therapeutic agents or enrollment on another therapeutic clinical trial at any institution. Minimum of 14 days or 5 half-lives of the drug (whichever is shorter) washout prior to apheresis.
• 7. Refusal to participate in the long-term follow-up protocol.
• 8. Patients with active CNS involvement by malignancy on MRI or by lumbar puncture.
• 1. Patients with prior CNS disease that has been effectively treated will be eligible providing treatment was />4 weeks before enrollment and a remission documented within 8 weeks of planned CAR-T cell infusion by MRI brain and CSF analysis.
• 9. Previous recipients of allogeneic hematopoietic stem cell transplantation (AHCT) are excluded if they are /<100 days post-transplant, have evidence of active graft-versus-host-disease (GVHD) of any grade, or are currently on immunosuppression.
• 10. Prior allogeneic CAR T-cell therapy /<100 days from prior CAR T-cell treatment.
• 11. Previous recipients of autologous CAR-T cell therapy directed at either cluster of differentiation 19 (CD19) or CD20 are excluded if they are /<100 days post prior CAR-T cell treatment (does not include re-enrollment) or have />5% residual circulating CAR-T as measured by flow cytometry using a CD19 CAR detection reagent (Miltenyi Biotec).
• a. Patients with prior CAR-T treatment against CD19 or CD20 must have repeat biopsy post-CAR-T cell therapy confirming a minimum of 5% CD19 or CD20 positivity by immunohistochemistry or flow cytometry.
• 12. Anti-CD20 antibody treatment within 4 weeks of cell infusion.
• 13. Anti-CD19 antibody treatment within 4 weeks of cell infusion.
• 14. Cytotoxic chemotherapy treatment within 14 days or steroid treatment (other than replacement dose steroids) within 7 days prior to apheresis collection for CAR-T cells.
• 15. No other oral chemotherapeutic agents or antibody directed treatment after starting pirtobrutinib other than steroids or radiation to a single site in a palliative fashion.
• 16. Patients post solid organ transplant who develop high grade lymphomas or leukemias.
• 17. Concurrent active malignancy other than basal or squamous cell carcinomas of the skin (underlying low-grade lymphoma chronic lymphocytic leukemia/Follicular lymphoma (FL) / Marginal zone lymphoma (MZL) is allowable in patients with transformed large cell lymphoma/Richter`s.
• 18. Patients who experienced a major bleeding event or grade ≥ 3 arrhythmia on prior treatment with a BTK inhibitor.
• 19. History of stroke or intracranial hemorrhage within 6 months of randomization.
• 20. Significant cardiovascular disease defined as myocardial infarction within 6 months of randomization, congestive heart failure with ejection fraction /<30%, active unstable angina, QT prolongation (QTcF)/>470 msec on ECG.
• 21. Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal (GI) absorption of the study drug.
• 22. Patients requiring therapeutic anticoagulation with warfarin or another vitamin K antagonist.
• 23. Patients who had surgery within 4 weeks prior to randomization.
• 24. Patients who have received vaccination with live vaccine within 28 days prior to randomization.
• 25. Patients with known hypersensitivity to any of the excipients of pirtobrutinib.
• Special Criteria Regarding Fertility and Contraception
• Female subjects of reproductive potential (women who have reached menarche or women who have not been post-menopausal for at least 24 consecutive months, i.e., who have had menses within the preceding 24 months, or have not undergone a sterilization procedure /[hysterectomy or bilateral oophorectomy/]) must have a negative serum or urine pregnancy test performed at screening.
• Due to the high-risk level of this study, while enrolled, all subjects must agree not to participate in a conception process (e.g., active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization). Additionally, if participating in sexual activity that could lead to pregnancy, the study subject must agree to use reliable and double barrier methods of contraception during the follow-up period of the protocol.
• Acceptable birth control includes a combination of two of the following methods:
• • Combined estrogen and progestin containing hormonal contraception associated with inhibition of ovulation given orally, intravaginally, or transdermally
• • Progestin-only hormonal contraception associated with inhibition of ovulation given orally, by injection, or by implant
• • Intrauterine device (IUD)
• • Intrauterine hormone-releasing system (IUS)
• • Vasectomized partner
• • Sexual abstinence: considered a highly effective method only if defined as refraining from heterosexual intercourse during an entire period of risk associated with the study treatment. The reliability of sexual abstinence will be evaluated in relation to the duration of the study and to the usual lifestyles of the patient.
• • Female sterilization
• • Fallopian tube implants (if confirmed by hysterosalpingogram) Oocyte donation is prohibited during the duration of participation on this protocol and for 1 month after the last dose of study drug.
• Subjects who are not of reproductive potential (women who are premenarche or have been post-menopausal for at least 24 consecutive months which is non-therapy induced or have undergone hysterectomy tubal ligation, salpingectomy, and/or bilateral oophorectomy or men who have documented azoospermia) are eligible without requiring the use of contraception.

Описание

A prospective collection of data on the treatment of Chinese patients with relapsed/refractory follicular lymphoma (FL) using Axicabtagene Ciloleucel Injection, and evaluation of the efficacy and safety of Axicabtagene Ciloleucel Injection in this treatment.

Критерии включения

• 1. Histologically confirmed follicular lymphoma (FL) grade 1, 2, or 3a according to WHO 2016 classification criteria
• 2. Subjects with relapsed or refractory FL after prior second-line or higher therapy Prior therapy must include: anti-CD20 monoclonal antibody in combination with an alkylating agent (anti-CD20 monoclonal antibody monotherapy is not eligible as a line of therapy for eligibility). Subjects who have had stable disease (no recurrence) for more than 1 year after completion of their last treatment do not meet the enrollment criteria Translated with DeepL.com (free version)
• 3. At least one measurable lesion according to the Lugano 2014 classification (Cheson 2014). Lesions with prior radiotherapy were considered measurable only if definitive progression was confirmed after completion of radiotherapy.
• 4. Patients with FL lymphoma secondary to central may be included in the
• 5. Previous systemic therapy at least 2 weeks or 5 half-lives (whichever is shorter) from the start of leukapheresis, except for immune checkpoint inhibitors/agonists; Systemic immune checkpoint inhibitor/agonist therapy at least 3 half-lives from leukapheresis (e.g., Ipilimumab, Ivolumab, Pembrolizumab, Atezolizumab, OX40 agonist, 4-IBB agonist). Atezolizumab, OX40 agonist, 4-IBB agonist)
• 6. Toxic reactions from prior anti-lymphoma therapy must stabilize and recover to ≤ grade 1 (except for non-clinically significant toxicities such as alopecia/balding)
• 7. ≥ 18 years old
• 8. ECOG physical status score of 0 or 1
• 9. Absolute neutrophil count (ANC) ≥ 1.0×10/^9/L
• 10. Platelet count ≥ 75×10/^9/L
• 11. Absolute lymphocyte count ≥ 0.1×10/^ 9/L
• 12. Adequate renal, hepatic, pulmonary, and cardiac function, defined as: 1) total bilirubin (TBIL) ≤ 1.5 times the upper limit of normal (ULN), except in subjects with Gilbert`s syndrome; 2) alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN 3) serum creatinine (Cr) ≤ 1.5 x ULN or creatinine clearance (CCr) ≥ 60 mL/min, with creatinine clearance estimated based on the cockcroft-Gault formula; 4) cardiac ejection fraction ≥ 50%, absence of pericardial effusion as determined by echocardiography (ECHO), and absence of clinically significant cardiac arrhythmia; 5) baseline transcutaneous oxygen saturation /> 92% under room ventilation; 6) absence of clinically significant chest pain; and ) absence of clinically significant pleural effusion.
• 13. A negative serum pregnancy test is required for women of childbearing potential (women who have been surgically sterilized or who are at least 2 years postmenopausal are not considered to be of childbearing potential).

Критерии исключения

• 1. Converted FL
• 2. Small lymphocytic lymphoma
• 3. The histologic grading of FL was 3b
• 4. lymphoplasmacytic lymphoma
• 5. Subject has had other malignant tumors unless he/she has survived disease-free and has not received antitumor therapy for at least 3 years; except for non-melanoma skin tumors, carcinoma in situ (e.g., cervix, bladder, breast)
• 6. Autologous Hematopoietic Stem Cell Transplantation Within 6 Weeks Prior to Scheduled Infusion of Achille`s Bromide Injection
• 7. Has performed allogeneic hematopoietic stem cell transplants
• 8. Previous CD19-targeted therapy
• 9. Previous chimeric antigen receptor cell therapy or other genetically modified T-cell therapy.
• 10. History of severe rapid-onset hypersensitivity reactions to aminoglycosides
• 11. Presence or suspicion of uncontrolled fungal, bacterial, viral or other infections that require intravenous drug therapy
• 12. Known human immunodeficiency virus (HIV) infection or active acute or chronic hepatitis infection (HBV or HCV). Subjects with a history of hepatitis must undergo standard serologic or genetic testing in accordance with the most recent version of clinical guidelines/institutional protocols to confirm resolution of infection prior to enrollment.
• 13. Known history of lymphoma involving the entire gastric wall
• 14. Presence of any indwelling tube or catheter (e.g., percutaneous nephrostomy tube, indwelling urinary catheter, indwelling biliary drain, or pleural/peritoneal/pericardial catheter). Dedicated central venous access catheters such as Port-a-Cath or Hickman catheters are permitted.
• 15. Patients with primary central nervous system lymphoma (PCNSL)
• 16. Subjects with lymphomatous infiltration of the atria or ventricles
• 17. Myocardial infarction, cardiac angioplasty or stenting, unstable angina pectoris, congestive heart failure class II or worse according to the New York Heart Association cardiac classification, or other clinically significant cardiac disease within 12 months prior to enrollment
• 18. Anticipated emergencies requiring urgent treatment due to rapid tumor progression within 6 weeks of leukapheresis (e.g., tumor mass compression, tumor lysis syndrome)
• 19. End-organ damage due to autoimmune disease (e.g., Crohn`s disease, rheumatoid arthritis, systemic lupus erythematosus) within the past 2 years, or systemic use of immunosuppressive or other systemic disease-control medications. Subjects with a history of autoimmune hypothyroidism who are on a stable dose of thyroid replacement hormone therapy and type I diabetes mellitus on a stable insulin regimen are eligible for enrollment in this study.
• 20. History of symptomatic deep vein thrombosis (DVT) or pulmonary embolism within 6 months prior to enrollment and history of DVT at the end of the upper extremity within 3 months prior to pretreatment chemotherapy
• 21. Any medical condition that may affect the assessment of safety or efficacy
• 22. Has had a severe rapid-onset hypersensitivity reaction to any of the drugs to be used in this study
• 23. Live, attenuated vaccines administered within ≤6 weeks prior to the start of the pretreatment regimen or whose use is expected to be required during the course of the study;
• 24. Women of childbearing age who are breastfeeding
• 25. Male or female subjects who are unwilling to use contraception from the date of signed informed consent until 6 months after completion of pretreatment chemotherapy, or 6 months after completion of an infusion of Aquilensa
• 26. Male or female subjects who are unwilling to use contraception from the date of signed informed consent until 6 months after completion of pretreatment chemotherapy, or 6 months after completion of an infusion of Aquilensa

Описание

The purpose of this study is to determine how effective and safe the combination of epcoritamab, zanubrutinib, and rituximab is in treating participants with relapse or refractory Follicular Lymphoma (FL).

* The names of the study drugs involved in this research study are:
* Epcoritamab (a type of antibody)
* Zanubrutinib (a type of Bruton tyrosine kinase inhibitor)
* Rituximab (a type of monoclonal antibody)

Критерии включения

• * Histologically confirmed diagnosis of CD20+ FL (grade 1-3A) (at time of trial entry) with review of the diagnostic pathology specimen at one of the participating institutions. Patients with current histologic transformation are excluded.
• * Receipt of at least one prior line of therapy for FL (with prior treatment including both a CD20 monoclonal antibody and an alkylating agent).
• * Measurable disease, defined as ≥1 measurable nodal lesion (long axis />1.5 cm or short axis />1.0 cm) or ≥1 measurable extra-nodal lesion (long axis />1.0 cm) on PET, CT, or magnetic resonance imaging (MRI). Disease should be FDG-avid based on PET.
• * Meets at least one criterion to begin treatment based on the modified GELF (Groupe d`Etude des Lymphomes Folliculaires) criteria:
• * Symptomatic adenopathy
• * Organ function impairment due to disease involvement, including cytopenias due to marrow involvement (WBC /<1.5x109/L; absolute neutrophil count /[ANC/] /<1.0x109/L, Hgb /<10g/dL; or platelets /<100x109/L)
• * Constitutional symptoms (defined as persistent fevers />100.4 F, shaking chills, drenching night sweats, or loss of />10% of body weight within a 6 month period)
• * Any nodal or extranodal tumor mass />7 cm in maximum diameter
• --/>3 nodal sites of involvement />3 cm
• * Local compressive symptoms or imminent risk thereof
• * Splenomegaly (craniocaudal diameter /> 16cm on CT imaging)
• * Clinically significant pleural or peritoneal effusion
• * Leukemic phase (/>5x109/L circulating malignant cells)
• * Rapid generalized disease progression
• * Renal infiltration
• * Bone lesions
• * Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. (Appendix A)
• * Age ≥18 years.
• * Adequate hematologic and organ function:
• * Absolute neutrophil count /> 1.0x109/L unless due to marrow involvement by lymphoma in which case ANC must be />0.5x109/L
• * Platelets /> 75 x109/L, unless due to marrow involvement by lymphoma, in which case platelets must be />50 x109/L
• * Estimated CrCl (based on Cockcroft Gault or MDRD) ≥ 45ml/min or ≥45ml/min/1.73m2
• * Total bilirubin /< 1.5 X ULN, unless Gilbert syndrome, in which case direct bilirubin must be /< 1.5 x ULN
• * AST/ALT /< 2.5 X ULN, unless documented liver involvement by lymphoma, in which case AST/ALT must be /<5 x ULN
• * Ability to understand and the willingness to sign a written informed consent document.
• * Willingness to provide a pre-treatment tumor sample by core needle or excisional surgical biopsy. A fresh biopsy is strongly encouraged, but an archival sample is acceptable if it is collected within 90 days and without intervening treatment and the following provisions are met: 1) availability of a tumor-containing formalin-fixed, paraffin-embedded (FFPE) tissue block, 2) if the tumor containing FFPE tissue block cannot be provided in total, sections from this block should be provided that are freshly cut and mounted on positively-charged glass slides. Preferably, 25 slides should be provided; if not possible, a minimum of 15 slides is required. Exceptions to this criterion may be made with approval of the Sponsor-Investigator.
• * Willingness to remain abstinent1 or to use two effective contraceptive methods that result in a failure rate of /<1% per year from screening until: (a) at least 3 months after pre- treatment with rituximab, 12 months after the last dose of epcoritamab, or 3 months after the last dose of zanubrutinib, whichever is longer, if the patient is a male or (b) until at least 18 months after pre-treatment with rituximab, 12 months after the last dose of epcoritamab, or 3 months after the last dose of zanubrutinib, whichever is longer, if patient is a female. Examples of contraceptive methods with a failure rate of /<1% per year include:
• * Tubal ligation, male sterilization, hormonal implants, established proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.
• * Alternatively, two methods (e.g., two barrier methods such as a condom and a cervical cap) may be combined to achieve a failure rate of /<1% per year. Barrier methods must always be supplemented with the use of a spermicide.
• * True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. In contrast, periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.

Критерии исключения

• * Patients who require systemic immunosuppressive therapy for an ongoing medical condition will be excluded. For corticosteroids, patients receiving a prednisone dose of />10 mg daily (or equivalent) will not be eligible. A short course of steroids (up to 14 days) for lymphoma-related symptom palliation or for prophylaxis (i.e., IV contrast allergy) is allowed, in which case patients should be off steroids prior to treatment start.
• * Patients with bulky cervical adenopathy that is compressing the upper airway or could result in significant airway compression during a tumor flare event.
• * Patients, who have had a major surgery or significant traumatic injury within 4 weeks of start of study drug, patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia).
• * Presence of HCV antibody. Patients with presence of HCV antibody are eligible if HCV RNA is undetectable (NOTE: the limit of detection for HCV RNA must have a sensitivity of /< 15 IU/mL). Subjects who received treatment for HCV that was intended to eradicate the virus and who have an undetectable HCV RNA may participate without serial HCV RNA screening. Other patients may participate if they are willing to undergo every 3- month monitoring for HCV reactivation.
• * Presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb). Patients with positive hepatitis B serologies with undetectable HBV DNA (NOTE: the limit of detection for HBV DNA must have a sensitivity of /< 20 IU/mL) are permitted in the trial but should receive prophylactic antiviral therapy (i.e. entecavir) and undergo every 3 month HBV DNA monitoring.
• * Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) requiring antimicrobial therapy at trial enrolment or significant infections within 2 weeks prior to the first dose of epcoritamab.
• * Subject has a known active severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) infection. If a subject has signs/symptoms suggestive of SARS-CoV-2 infection or has had recent known exposure to someone with SARS-CoV-2 infection, the subject must have a negative molecular (e.g., PCR) test, or 2 negative antigen test results at least 24 hours apart, to rule out SARS-CoV-2 infection. Subjects who do not meet SARS- CoV-2 infection eligibility criteria must be screen failed and may only rescreen after they meet the following SARS-CoV-2 infection viral clearance criteria:
• * No signs/symptoms suggestive of active SARS-CoV-2 infection
• * Negative molecular (e.g., PCR) result or 2 negative antigen test results at least 24 hours apart
• * Prior history of another malignancy (except for non-melanoma skin cancer, in situ cervical or breast cancer, or Gleason 6 prostate cancer managed with observation) unless disease free for at least 2 years.
• * Patients should not have received immunization with attenuated live vaccine within one week of study entry or during study period. Vaccination with live vaccines within 28 days of the first dose of study treatment is prohibited.
• * Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study or limit adherence to study requirements.
• * Patients with any one of the following currently on or in the previous 6 months will be excluded: myocardial infarction, congenital long QT syndrome, torsade de pointes, unstable angina, coronary/peripheral artery bypass graft, cardiac arrhythmia (CTCAE grade 3 or higher), or cerebrovascular accident. History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place. Uncontrolled hypertension as indicated by ≥ 2 consecutive blood pressure measurements showing systolic blood pressure /> 170 mm Hg and diastolic blood pressure /> 105 mm Hg at screening.
• * Patients with 1) New York Heart Association Class III or IV heart failure or known ejection fraction of /<45%, 2) MI within 6 months prior to screening, 3) unstable angina within 3 months before screening, or 4) history of clinically significant arrhythmias within 6 months of screening (eg sustained Vtach, Vfib, torsades de pointes).
• * Inability to comply with protocol mandated restrictions.
• * Patients who are pregnant, breast-feeding, or intending to become pregnant during the study.
• * Prior solid organ or allogeneic stem cell transplantation.
• * History of known or suspected hemophagocytic lymphohistiocytosis (HLH).
• * History of clinically significant autoimmune disease, including but not limited to myocarditis, pneumonitis, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener`s granulomatosis, Sjögren`s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis.
• * Patients with a remote history of, or well controlled, autoimmune disease who meet above criteria may be eligible to enroll after consultation with the Sponsor-Investigator.
• * Inability to tolerate anti-CD20 mAb therapy or known allergy or intolerance to any component or excipient of epcoritamab.
• * Known central nervous system involvement
• * Neuropathy /> grade 1(based on CTCAE grading)
• * Treatment with CAR-T therapy within 100 days prior to first dose of epcoritamab.
• * Treatment with an investigational drug within 4 weeks prior to the first dose of study treatment.
• * Chemotherapy and other non-investigational anti-neoplastic agents (except CD20 mAbs) within 4 weeks prior to the first dose of study treatment.
• * Participants who require warfarin or other vitamin K antagonists for anticoagulation. Other anticoagulants including direct oral anticoagulants (i.e. apixaban, rivaroxaban) and low-molecular weight heparin are allowed.
• * Participants who are known at the time of study entry to require concomitant treatment with any medications or substances that are strong CYP3A inducers. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently updated medical reference. As part of the enrollment/informed consent procedures, the participant will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the participant is considering a new over- the-counter medicine or herbal product.
• * Unable to swallow capsules or disease significantly affecting gastrointestinal function, such as malabsorption syndrome.
• * History of severe bleeding disorder such as hemophilia A, hemophilia B, von Willebrand disease, or history of spontaneous bleeding requiring blood transfusions or other medical interventions. Requires ongoing treatment with warfarin or warfarin derivatives.
• * Prior exposure to a BTK inhibitor
• * Screening 12-lead ECG showing a baseline QTcF (Fridericia`s correction) /> 480 msec.
• * History of stroke or intracranial hemorrhage within 6 months before first dose of study drug.
• * Major surgery ≤ 4 weeks before the first dose of study treatment or planned during study.

Описание

This research is being done to see if epcoritamab is effective in treating follicular lymphoma as a second line of treatment.

The name of the study drug in this research study is:

-Epcoritamab (a type of antibody)

Критерии включения

• * Biopsy-confirmed (fresh or archival tissue) follicular lymphoma grade 1-3A that is CD20+ (by immunophenotype or immunohistochemistry) at time of diagnosis. All degrees of CD20 positivity will be accepted. Composite high-grade lymphoma will be excluded.
• * Subjects must have measurable disease at time of enrollment as defined by at least one lymph node with long axis ≥1.5 cm and short axis />1.0 cm and Deauville ≥ 4 seen on baseline PET/CT
• * Stage III/IV at initial diagnosis
• * 1 prior line (at least 3 cycles) of systemic "upfront" or first-line therapy consisting of anti-CD20 antibody (e.g. obinutuzumab or rituximab) combined with chemotherapy (e.g. bendamustine, CHOP, CVP, or lenalidomide). Rituximab monotherapy, rituximab plus radiation, or radiation alone is not sufficient.
• * Subjects need to have achieved a partial response or stable disease as best response following upfront treatment. Subjects with progressive disease will be excluded.
• * Subjects must have completed all prior anti-lymphoma therapy at least 4 weeks (28 days) prior to start of epcoritamab.
• * Age ≥18 years.
• * 3.1.7 Age ≥18 years.
• * ECOG performance status ≤ 2
• * Life expectancy of greater than 2 years
• * Participants must meet the following organ and marrow function as defined below:
• * Absolute neutrophil count ≥1000 cells/mcl (G-CSF allowed if marrow involved with disease)
• * Platelets ≥75,000 cells/mcl (transfusion allowed if marrow involved)
• * Hemoglobin ≥ 8 g/dL (transfusion allowed if marrow involved)
• * Total bilirubin ≤ 1.5 institutional upper limit of normal (ULN). In patients with suspected/known Gilbert`s disease total bilirubin up to 3x ULN will be allowed
• * AST(SGOT)/ALT(SGPT) ≤3× institutional ULN unless suspected/known involvement by follicular lymphoma
• * Creatinine ≤ institutional ULN OR creatinine clearance /> 45 ml/min (by Cockcroft-Gault estimate or 24-hr creatinine clearance measurement)
• * Patients with hepatitis B core antibody positivity with negative PCR on antiviral therapy will be eligible but will be required to receive appropriate antiviral prophylaxis as described in Section 5.4. Patients with Hepatitis C antibody must have undetectable viral load.
• * Participants with a history of prior malignancy will be eligible if all treatment of that malignancy was completed at least 2 years prior to enrollment to this study, the treatment was considered "curable-intent", and there is currently no evidence of disease.
• * Resolution of toxicities from prior therapy to baseline or grade ≤1 (with the exception of grade 2 peripheral neuropathy or any grade alopecia)
• * Ability to understand and the willingness to sign a written informed consent document.
• * Females of childbearing potential must agree to practice a highly effective method of birth control (as defined by the EU Clinical Trial Facilitation Group) consistent with local regulations regarding the use of birth control methods for patients participating in clinical trials:
• * Established use of oral, injected or implanted combined (estradiol and progesterone containing) hormonal contraception;
• * Placement of an intrauterine device (IUD) or intrauterine system (IUS);
• * Male partner sterilization (the vasectomized partner should be the sole partner for that patient)
• * True abstinence (when this is in line with the preferred and usual lifestyle of the patient)
• * Women must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the trial and for 12 months after receiving the last dose of epcoritamab. Men must also not donate sperm during the trial and for 12 months after receiving the last dose of epcoritamab.
• * A man who is sexually active with a woman of childbearing potential must agree to use a barrier method of birth control (i.e. use of condom) during the trial and for 12 months after receiving the last dose of epcoritamab.

Критерии исключения

• * Use of investigational agents incorporated into prior induction therapy
• * Uncontrolled intercurrent active infection requiring hospitalization or intravenous antimicrobial agents within 4 weeks of start of treatment
• * Uncontrolled underlying cardiac conditions including but not limited to congestive heart failure grade III or IV (by NYHA) or EF /<45%, unstable angina pectoris, acute myocardial infarction /< 6 months, cardiac arrhythmia
• * History of uncontrolled neurologic condition including but not limited to seizure disorder, stroke, psychosis, dementia, CNS vasculitis, encephalitis
• * EF /<45% or need for supplemental O2 at rest to maintain SaO2/>89%
• * Immunosuppressive therapy for non-lymphoma-related indication within 28 days (or for lymphoma within 10 days) of initiation of treatment, including systemic corticosteroids 10 mg/day or greater of prednisone or equivalent
• * Patients with known or suspected CNS involvement or leptomeningeal disease are excluded given concern for potentially increased risk of neurologic toxicity with epcoritamab. Patients with history of CNS malignancy from separate malignancy must have completed CNS-directed therapy and must currently have no evidence of disease
• * Pregnant or breastfeeding women or participants unwilling to adhere to institutional guidelines for highly effective contraception for the duration of the therapy are excluded. This is because of the unknown but potential risk of teratogenic or abortifacient effects, as well as potential for adverse events in nursing infants secondary to treatment of the mother, as epcoritamab has not yet been studied in this patient population. A female can be determined to not be of childbearing potential if she meets any of the following criteria:
• * Premenarchal
• * Postmenopausal (/>45 years of age with amenorrhea for at least 12 months or any age with amenorrhea for at least 6 months and a serum follicle stimulating hormone /[FSH/] level />40 IU/L or mIU/mL)
• * Permanently sterilized (e.g., bilateral tubal occlusion /[which includes tubal ligation procedures as consistent with local regulations/], hysterectomy, bilateral salpingectomy, bilateral oophorectomy)
• Note: If the childbearing potential changes after start of the trial (e.g., woman who is not heterosexually active becomes active, premenarchal woman experiences menarche) a woman must begin a highly effective method of birth control, as described under 3.1.15.
• * Known current alcohol or drug abuse, psychiatric illness, or unstable social situation that is likely to limit compliance with study requirements
• * History of allergic reactions attributed to compounds of similar chemical or biologic composition to epcoritamab
• * Exposure to a live or a live attenuated vaccine within 4 weeks
• * Patients with HIV will be excluded

Описание

This is a prospective single-center study designed to assess potential differences in cell composition between bone marrows of patients with follicular lymphoma and those from control subjects.

Follicular lymphoma is the most common indolent lymphoma. It is characterised by systematic relapses and bone marrow dissemination in 70% of patients at the time of diagnosis.

Although relapses are thought to be related to refractory tumour cells nested in a supportive microenvironment in the bone marrow, the mechanisms involved are poorly understood.

To study the specificities of the bone marrow of patients with follicular lymphoma, It is necessary to compare them with control samples.

This study takes advantage of surgeries involving sternotomies to recover lost bone marrow and establish a bone marrow bank of patients without hematological disease.

This bank will be used to set up control cohorts for other clinical trials involving patients with follicular lymphoma.

Критерии включения

• * Major patient
• * Patient hospitalized in the thoracic, cardiac and vascular surgery department for surgery involving a sternotomy
• * Patient with free, informed, written consent
• * Patient covered by a health insurance scheme

Критерии исключения

• * History of haematological malignancy or haemogram disturbance
• * Immunomodulating treatment: immunosuppressants, corticoids, antineoplastics
• * Persons covered by articles L. 1121-5 to L. 1121-8 and L. 1122-1-2 of the French Public Health Code (e.g. minors, protected adults, etc.)/].

Описание

This is a Phase 2 global, multi-center, open-label study to assess the efficacy, safety and tolerability of AZD0486 monotherapy in adult participants with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL) who have received at least two prior lines of therapies. The study has 2 Modules: Module 1 for FL and Module 2 for DLBCL.

Критерии включения

• 1. Key Inclusion Criteria:
• * Aged 18 to 80 years old
• * Histologically confirmed relapsed refractory FL (Module 1) and DLBCL (Module 2) after at least 2 prior lines of therapy
• * ECOG performance status 0 to 2
• * Locally confirmed CD-19 expression in lymphoma cells after progression from last CD 19 directed therapy
• * FDG-avid disease with at least one bi-dimensionally measurable nodal lesion (defined as /> 1.5 cm in its longest dimension), or extranodal lesion (defined as /> 1.0 cm in its longest dimension)
• * Adequate hematological function: ANC ≥ 1000/mm3, platelets
• * 75,000/mm3, hemoglobin ≥ 9 g/dL. Transfusion and/or growth factor are allowed but counts must be stable for at least 72 hours afterwards prior to screening
• * Adequate liver function: total bilirubin /<1.5x ULN, AST/ALT ≤ 3xULN Note: Patients with documented history of Gilbert`s Syndrome and in whom total bilirubin elevations are accompanied by elevated indirect bilirubin are eligible)
• * Adequate renal function: creatinine clearance (CrCl) of ≥ 45 mL/min
• The above is a summary, other inclusion criteria details may apply.
• 2.

Критерии исключения

• * Diagnosis of CLL, Burkitt lymphoma, or Richter`s transformation
• * Active CNS involvement by B-NHL
• * Leukemic presentation of B-NHL
• * History or presence of clinically relevant CNS pathology such as epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson`s disease, cerebellar disease, organic brain syndrome, or psychosis
• * Prior therapy with T-cell engager (TCE) within 8 weeks, CAR T- cell therapy or autologous Hematopoietic Stem Cell Transplantation (HSCT) within 12 weeks, or prior allogeneic HSCT within 24 weeks of first dose of AZD0486
• * Requires chronic immunosuppressive therapy
• * Unresolved non hematological AEs ≥ Grade 2 from prior therapies; history of ≥ Grade 3 CRS or neurotoxicity from prior CAR-T or TCE therapy
• * History of major cardiac abnormalities.
• * If female, participant must not be pregnant or breastfeeding.
• The above is a summary, other exclusion criteria details may apply.

Описание

This was a single center, single arm, phase II study. Patients with previously untreated follicular lymphoma were enrolled from the department of lymphoma, Tianjin Medical University Cancer Institute and Hospital. The bulky disease was received radiation (dose:18～24Gy) before RCHOP. Patients began chemoimmunotherapy 1～2 weeks later than radiation. Treatment included Tiselizumab (200 mg iv d1) plus R-CHOP (rituximab 375 mg/m2 intravenous /[IV/] day 2, cyclophosphamide 750 mg/m2 IV day 3, doxorubicin 50 mg/m2 IV day 3, vincristine 1.4 mg/m2 /[maximum 2.0 mg total/] IV day 3, and prednisone 100 mg oral days 3-7, 21～28 days for one cycle ) for six cycles. Rituximab was given every 2 months to patients who were complete metabolic response /partial metabolic response（CMR/PMR）after first-line chemo until 2 years. Response was assessed by PET/CT scan after cycle 4 and cycle 6.

Критерии включения

• * Histologically confirmed CD20 positive (+) follicular lymphoma, grade 1, 2, or 3a，bulky disease (Mass diameter ≥ 7 cm)
• * Have had no prior systemic treatment for lymphoma
• * Meeting Groupe d`Etude des Lymphomes Folliculaires (GELF) criteria for initiation of treatment
• * Age 18-75 years
• * ECOG Performance Status of 0-2 .Stage II, III, or IV by Ann Arbor staging system.
• * Demonstrate adequate organ function as defined below; all screening labs to be obtained within 28 days prior to registration.
• 1. Hematological: WBC≥3.5×109/L, Platelets ≥ 75×109/L,Absolute Neutrophil Count (ANC) ≥ 1.0×109/L，Hemoglobin (Hgb) ≥ 80 g/L
• 2. Renal: Calculated creatinine clearance ≥ 50 mL/min
• 3. Hepatic: Bilirubin ≤ 1.5 × upper limit of normal (ULN), AST/ALT ≤ 2.5×ULN
• * Females of childbearing potential must be willing to abstain from vaginal intercourse or use an effective method(s) of contraception from the time of informed consent, during the study and for 6 months after the last dose of study drug(s). Males able to father a child must be willing to abstain
• * Life expectancy ≥6 months
• * Sign (or their legally-acceptable representatives must sign) an informed consent document indicating that they understand the purpose of and procedures required for the study, including biomarkers, and are willing to participate in the study

Критерии исключения

• * Known active central nervous system lymphoma or leptomeningeal disease,
• * Evidence of diffuse large B-cell transformation
• * Grade 3b FL
• * Concurrent malignancy or malignancy within the last 3 years (except for ductal breast cancer in situ, non-melanoma skin cancer, prostate cancer not requiring treatment, and cervical carcinoma in situ) whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen are not eligible for this trial
• * Known history of human immunodeficiency virus (HIV), or active hepatitis C Virus, or active hepatitis B Virus infection, or any uncontrolled active significant infection, including suspected or confirmed John Cunningham (JC) virus infection，any class 3 (moderate) or class 4 (severe) cardiac disease as defined by the New York Heart Association functional classification. Or left ventricular ejection fraction /<50%;
• * Known history of human immunodeficiency virus (HIV), or active hepatitis C Virus, or active hepatitis B Virus infection, or any uncontrolled active significant infection
• * Known pneumonia associated with idiopathic pulmonary fibrosis, machine (for example, occlusive bronchiolitis), history of drug induced pneumonia, or screening during the chest computed tomography (CT) showed active pneumonia
• * Have serious neurological or psychiatric history, can`t normal study, including dementia, epilepsy, severe depression and mania
• * Patients who were deemed by the investigator to be ineligible for enrollment

Описание

Non-Hodgkin`s lymphoma (NHL) is a cancer that arises from the transformation of normal B and T lymphocytes (white blood cells). The purpose of this study is to assess the safety, tolerability, pharmacokinetics, and preliminary efficacy of ABBV-291 in adult participants in relapsed or refractory (R/R) NHL, including but not limited to diffuse large b-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and follicular lymphoma (FL). Adverse events will be assessed.

ABBV-291 is an investigational drug being developed for the treatment of NHL. This study will include a dose escalation phase to determine the maximum administered dose (MAD)/Maximum tolerated dose (MTD) of ABBV-291 and a dose expansion/optimization phase to determine the change in disease activity in participants with R/R NHL. Approximately 165 adult participants with multiple NHL subtypes will be enrolled in the study in sites world wide

In the dose escalation phase of the study participants will receive escalating Intravenously (IV) infused doses of ABBV-291, until the MAD/MTD is determined. In the dose expansion/optimization phase of the study participants receive IV infused ABBV-291, as part of the approximately 74 month study duration.

There may be higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the study at an approved institution (hospital or clinic). The effect of the treatment will be frequently checked by medical assessments, blood tests, and side effects.

Критерии включения

• * For dose escalation (Part 1) only: Participants must have documented diagnosis of B-cell malignancies including (but not limited to) the following, with histology based on criteria established by the World Health Organization (WHO), and measurable disease requiring treatment:
• * Mantle cell lymphoma (MCL);
• * Marginal zone lymphoma (MZL);
• * Waldenstrom macroglobulinemia (WM);
• * Diffuse large b-cell lymphoma (DLBCL) (including: germinal center B-cell type, activated B-cell type, primary cutaneous DLBCL /[leg type/], Epstein-Barr virus-positive (EBV+) DLBCL /[not otherwise specified/], DLBCL associated with chronic inflammation, human herpesvirus 8-positive /[HHV8+/] DLBCL /[not otherwise specified/], B cell lymphoma /[unclassifiable/] with features intermediate between DLBCL and classical Hodgkin lymphoma, high-grade B-cell lymphoma /[not otherwise specified/], high-grade B-cell lymphoma /[with MYC (avian myelocytomatosis viral oncogene homolog) and BCL2 and/or BCL6 rearrangements/], DLBCL arising from follicular lymphoma /[FL/] /[transformed FL/]);
• * FL Grades 1 to 3B;
• * For dose expansion (Part 2) only: Participants must have documented diagnosis of one of the following B-cell malignancies, with histology based on criteria established by the WHO, and measurable disease requiring treatment:
• * Part 2a only: DLBCL (including: germinal center B-cell type, activated B-cell type, primary cutaneous DLBCL /[leg type/], EBV+ DLBCL /[not otherwise specified/], DLBCL associated with chronic inflammation, HHV8+ DLBCL /[not otherwise specified/], B-cell lymphoma /[unclassifiable/] with features intermediate between DLBCL and classical Hodgkin lymphoma, high-grade B-cell lymphoma /[not otherwise specified/], high-grade B-cell lymphoma /[with MYC and BCL2 and/or BCL6 rearrangements/], DLBCL arising from FL /[transformed FL/]);
• * Part 2b only: FL Grades 1 to 3B;
• * Part 2c only: Mantle cell lymphoma;
• * For all participants (Parts 1 and 2):
• * Must be considered relapsed or refractory to, or intolerant of, at least 2 or more prior lines of therapy known to provide a clinical benefit for their condition, and for whom there is no appropriate locally available therapy known to provide clinical benefit (e.g., standard chemotherapy or autologous stem cell transplantation /[ASCT/]).
• * Indolent non-Hodkin`s lymphoma (NHL) participants must meet relevant disease specific requirements for treatment (e.g., National Comprehensive Cancer Network /[NCCN/], Groupe d`Etude des Lymphomes Folliculaires /[GELF/]).
• * History of allogeneic stem cell transplantation must be stable off of immunosuppression for at least 3 months.
• * For participants enrolled in backfill cohorts or at dose levels previously cleared, subjects must provide consent to an on-treatment fresh tumor biopsy from the same tumor lesion as the baseline tumor tissue. This requirement may be waived at the discretion of the contract research organization (CRO) Medical Monitor if collecting a biopsy would place the subject at risk of harm or would require a technically complicated procedure based on tumor location as assessed by the investigator or could hinder a subject`s ability to participate in the study.
• * Previously treated with a CD79b-targeting therapy (e.g., CD79b monoclonal antibody) a core or excision tumor biopsy subsequent to the most recent CD79b-targeting therapy must be collected. Tumor biopsy requirements may be modified by Sponsor during the study. This requirement may be waived at the discretion of the contract research organization (CRO) Medical Monitor if collecting a biopsy would place the subject at risk of harm or would require a technically complicated procedure based on tumor location as assessed by the investigator or could hinder a subject`s ability to participate in the study.
• * CD79b expression status will be assessed in all participants.
• * Have an eastern cooperative oncology group (ECOG) Performance Status of 0 or 1.
• * Laboratory values meeting the criteria in the protocol within the screening period prior to the first dose of study drug (if multiple samples are drawn within the screening period, the sample/result immediately prior to Cycle 1 Day 1 is applicable).
• * Availability of representative baseline tumor tissue (most recent archived tumor tissue or fresh biopsy collected during screening phase) suitable for immunohistochemistry (IHC) testing. This requirement may be waived at the discretion of the CRO Medical Monitor if collecting a biopsy at screening would place the participant at risk of harm or would require a technically complicated procedure based on tumor location as assessed by the investigator or could hinder a participant`s ability to participate in the study.

Критерии исключения

• * History of interstitial lung disease (ILD) or pneumonitis that required treatment with systemic steroids, or any evidence of active ILD or pneumonitis.
• * Treatment with any of the following:
• * Anticancer therapy including chemotherapy, radiotherapy, small molecule, investigational, and biologic agents within 14 days (or at least 5 half-lives, whichever is shorter), prior to the first dose of the study treatment;
• * CD79b-directed agents (e.g., CD79b monoclonal antibody therapy) within 4 weeks (or at least 5 half-lives, whichever is shorter) prior to the first dose of study treatment.
• * Prior treatment with an antibody drug conjugate that consists of a topoisomerase I inhibitor.

Описание

This first-in-human (FIH) trial is designed to assess the safety, feasibility and preliminary efficacy of a single intravenous (IV) dose of SynKIR-310 administered to participants with relapsed/refractory B-NHL.

Критерии включения

• * Adult 18 years of age and older.
• * Histologically confirmed diagnosis of B-NHL before enrollment.
• * Must have received prior CAR T or were unwilling/unable to receive prior CAR T.
• * Must have refractory or relapsed disease after receiving 2 prior lines of therapies.
• * If relapsed/refractory post-auto-SCT, then must have undergone auto-SCT at least 6 months prior to enrollment.
• * If relapsed/refractory disease after allogeneic stem cell transplant (allo SCT) then must have undergone allo-SCT at least 6 months prior to enrollment and without evidence of graft versus host disease.
• * Measurable disease at time of enrollment: At least one measurable lesion per Lugano Response Criteria (Cheson et al., 2014).
• * Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1

Критерии исключения

• * Previously treated with any investigational agent within 30 days prior to screening.
• * Adequately treated non-melanoma skin cancer such as basal cell or squamous cell carcinoma
• * Carcinoma-in-situ (e.g., cervix, bladder, breast) treated curatively and without evidence of recurrence for at least 3 years prior to enrollment.
• * Any other malignancy which has been completely treated and remains in complete remission for ≥ 5 years prior to enrollment. Completely treated prostate cancer with prostate-specific antigen (PSA) level /< 1.0 may also be permitted.
• * Known immunodeficiency disease.
• * History or presence of active or clinically relevant primary central nervous system (CNS) disorder, such as seizure, encephalopathy, cerebrovascular ischemia/hemorrhage, cerebellar disease, or any autoimmune disease with CNS involvement. For primary CNS disorders that have recovered or are in remission, participants without recurrence within 2 years of planned study enrollment may be included.
• * Uncontrolled hypertension, history of myocarditis or congestive heart failure, unstable angina, serious uncontrolled cardiac arrhythmia, or myocardial infarction within 6 months prior to study entry.
• * Any active uncontrolled systemic fungal, bacterial or viral infection.
• Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Описание

This phase III trial compares the effectiveness of rituximab to mosunetuzumab in treating patients with follicular lymphoma with a low tumor burden. Rituximab is a monoclonal antibody. It binds to a protein called CD20, which is found on B cells (a type of white blood cell) and some types of cancer cells. This may help the immune system kill cancer cells. Mosunetuzumab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. It is not yet known if giving rituximab or mosunetuzumab works better in treating patients with follicular lymphoma with a low tumor burden.

Критерии включения

• * Participants must have a histologically confirmed diagnosis of classic follicular lymphoma (cFL). cFL was previously categorized as grade 1-3A per World Health Organization (WHO)-HAEM4R, but grading of classic follicular lymphoma (FL) is no longer mandatory.
• * NOTE: Participants with follicular lymphoma with uncommon features (uFL) are eligible, including FL with diffuse growth pattern (dFL). Diagnosis is as per local pathology. Lymphoma fluorescence in situ hybridization (FISH) is not required. Molecular testing is not required.
• * Participants must not have follicular lymphoma with "blastoid" or "large centrocyte" cytological features, or follicular large B-cell lymphoma (FLBL) (previously categorized as follicular lymphoma grade 3B)
• * Participants must have low-tumor burden follicular lymphoma defined as:
• * Nodal or extra-nodal tumor mass with diameter less than 7 cm in its greater diameter
• * Involvement of no more than 3 nodal or extra nodal sites with diameter greater than 3 cm.
• * Absence of B symptoms
• * No symptomatic splenomegaly
• * No compression syndrome (ureteral, orbital, gastrointestinal)
• * No pleural or peritoneal serous effusion related to follicular lymphoma Participants must have Ann Arbor stage II, III, or IV follicular lymphoma. Participants with stage I disease may be included if they do not wish to undergo radiation or are not candidates for radiation
• * Participants must either be experiencing distress due to their disease or would prefer active management of their disease rather than a watch and wait approach
• * Participants must have staging imaging performed within 49 days prior to registration, as follows. PET-CT baseline scans are preferred. If a baseline PET-CT scan cannot be obtained, CT scans of the chest, abdomen, and pelvis, along with a bone marrow biopsy, are acceptable. If CT scans are used for staging at baseline, a CT scan of the neck is recommended. All measurable dominant lesions must be assessed within 49 days prior to registration. Tests to assess non-measurable disease must be performed within 49 days prior to registration. All disease must be assessed and documented on the Baseline Tumor Assessment Form.
• * NOTE: if the initial evaluation is insufficient to detect measurable disease, treating investigators may obtain a CT scan with contrast
• * Participants must have bi-dimensionally measurable disease (at least one lesion with longest diameter /> 1.5 cm)
• * Participants must not have had prior systemic therapy for follicular lymphoma. Radiation therapy for a previous diagnosis of early-stage follicular lymphoma is allowed
• * Participant must be ≥ 18 years of age at the time of registration
• * Participant must have Zubrod performance status of 0-2
• * Participant must have a complete medical history and physical exam within 28 days prior to registration
• * Leukocytes ≥ 3 x 10/^3/uL (within 28 days prior to registration)
• * Hemoglobin /> 9.0 g/dL (within 28 days prior to registration)
• * Absolute neutrophil count ≥ 1.5 x 10/^3/uL (within 28 days prior to registration)
• * Platelets ≥ 100 x 10/^3/uL (within 28 days prior to registration)
• * Total bilirubin ≤ 2 x institutional upper limit of normal (ULN) unless history of Gilbert`s disease. Participants with history of Gilbert`s disease must have total bilirubin ≤ 5 x institutional ULN (within 28 days prior to registration)
• * Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 3 × institutional ULN (within 28 days prior to registration)
• * Lactate dehydrogenase (LDH) /< institutional ULN (within 28 days prior to registration)
• * Participants must have a calculated creatinine clearance ≥ 30 mL/min using the following Cockcroft-Gault Formula. This specimen must have been collected and processed within 28 days prior to registration
• * Participants must not have an active or uncontrolled infection before initiation of study treatment in the opinion of the treating investigators
• * Participants must not have uncontrolled diabetes within 14 days prior to registration in the opinion of the treating investigators
• * Participants must not have uncontrolled blood pressure and hypertension within 14 days prior to registration in the opinion of the treating investigators
• * Participants with known human immunodeficiency virus (HIV)-infection must be on effective anti-retroviral therapy at registration and have undetectable viral load test on the most recent test results obtained within 6 months prior to registration
• * Participants with evidence of chronic hepatitis B virus (HBV) infection must have undetectable HBV viral load while on suppressive therapy on the most recent test results obtained within 6 months prior to registration, if indicated. Participants with a positive total hepatitis (Hep) B core antibody and negative hepatitis B virus surface antigen (HBsAg) at screening are at high risk for reactivation and should receive prophylactic antivirals (e.g., entecavir) before and throughout the treatment
• * Participants must not have active autoimmune disease requiring systemic therapy
• * Participants must not have had undergone organ transplants requiring ongoing systemic immunosuppressive therapy
• * Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. Participants currently being treated for HCV infection must have undetectable HCV viral load test on the most recent test results obtained within 6 months prior to registration, if indicated
• * Participants must not have known chronic active Epstein Barr Virus infection (CAEBV); testing in asymptomatic participants is not required
• * Participants must not have a positive test result for COVID-19 within seven (7) days prior to registration
• * Participants must not have a prior or concurrent malignancy whose natural history or treatment (in the opinion of the treating physician) has the potential to interfere with the safety or efficacy assessment of the investigational regimen
• * Participants must not have a history of confirmed progressive multifocal leukoencephalopathy (PML)
• * Participants must not have received allogeneic stem cell transplantation
• * Participants must not have a history of macrophage activation syndrome (MAS) or hemophagocytic lymphohistiocytosis (HLH)
• * Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, must have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. Participant must not have significant cardiovascular disease such as class III or IV cardiac disease, myocardial infarction within 6 months prior to registration. Participants with unstable arrhythmias, or unstable angina, should be excluded
• * Participants must not be pregnant or nursing (nursing includes breast milk fed to an infant by any means, including from the breast, milk expressed by hand, or pumped). Individuals who are of reproductive potential must have agreed to use an effective contraceptive method with details provided as a part of the consent process. A person who has had menses at any time in the preceding 12 consecutive months or who has semen likely to contain sperm is considered to be of "reproductive potential." In addition to routine contraceptive methods, "effective contraception" also includes refraining from sexual activity that might result in pregnancy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) including hysterectomy, bilateral oophorectomy, bilateral tubal ligation/occlusion, and vasectomy with testing showing no sperm in the semen
• * Participants must be offered the opportunity to participate in specimen banking. With participant consent, specimens must be collected and submitted via the Southwest Oncology Group (SWOG) Specimen Tracking System
• * NOTE: As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution`s identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system.
• * Participants must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines
• * For participants with impaired decision-making capabilities, legally authorized representatives may sign and give informed consent on behalf of study participants in accordance with applicable federal, local, and Central Institutional Review Board (CIRB) regulations

Критерии исключения