OncoTrials - мониторинг клинических исследований

Описание

This phase II trial studies the side effects of an escalated ramp-up of sonrotoclax following initial debulking with zanubrutinib or rituximab in treating patients with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and mantle cell lymphoma (MCL) that is newly diagnosed, has come back after a period of improvement (relapsed) or does not respond to treatment (refractory). Rituximab is a monoclonal antibody that binds to a protein called CD20, which is found on B-cells, and may kill tumor cells. Zanubrutinib may stop the growth of tumor cells by blocking a protein called Bruton`s tyrosine kinase (BTK), which is needed for tumor cell growth. Sonrotoclax works by blocking a protein called B-cell lymphoma-2 (BCL-2). This protein helps certain types of blood tumor cells to survive and grow. When sonrotoclax blocks Bcl-2 it slows down or stops the growth of tumor cells and helps them die. Giving an increased dose of sonrotoclax over a shorter period of time in combination with zanubrutinib or rituximab may be safe and tolerable in treating patients with newly diagnosed, relapsed or refractory CLL, SLL, and MCL.

Критерии включения

• * Provision of signed and dated written informed consent prior to any study specific procedures, sampling, or analyses
• * Age 18 years or older
• * Confirmed diagnosis (per World Health Organization /[WHO/] guidelines, unless otherwise noted) of one of the following:
• * CLL/SLL COHORT: CLL/SLL diagnosis that meets the International Workshop on Chronic Lymphocytic Leukemia criteria:
• * Meeting the following sets of prior treatment criteria:
• * For R/R cohort, disease that relapsed after, or was refractory to, at least 1 prior therapy
• * For the treatment-naïve cohort, patients should have no prior treatment for CLL/SLL (other than 1 aborted regimen /< 2 weeks in duration and /> 4 weeks before enrollment)
• * Requiring treatment per International Workshop on CLL (iwCLL) criteria
• * MCL COHORT: WHO-defined MCL
• * R/R MCL is defined as disease that relapsed after, or was refractory to, at least 1 prior systemic therapy
• * Measurable disease, defined as:
• * CLL/SLL: at least 1 lymph node /> 1.5 cm in longest diameter and measurable in 2 perpendicular dimensions by computed tomography (CT)/magnetic resonance imaging (MRI) or clonal lymphocytes />= 5 x 109/L present on peripheral blood flow cytometry
• * MCL, or SLL: at least 1 lymph node /> 1.5 cm in longest diameter OR 1 extranodal lesion /> 1.0 cm in the longest diameter, measurable in 2 perpendicular dimensions by CT/MRI
• * Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
• * Absolute neutrophil count (ANC) />= 1.0 x 10/^9/L =/< 7 days before first dose of study drug with or without growth factor support. There is an exception for patients with bone marrow involvement, in which case ANC must be />= 0.75 x 10/^9/L before the first dose of study drug
• * Platelets /> 75,000 x 10/^9/L (/> 75,000 cells/mm/^3) =/< 7 days before first dose of study drug without the use of growth factor support or platelet transfusions. Patients with bone marrow involvement will be allowed to have a platelet count /> 50,000 x 10/^9/L (/> 50,000 cells/mm/^3) =/< 7 days before first dose of study drug without the use of growth factor support or platelet transfusions
• * Hemoglobin /> 75 g/L =/< 7 days before first dose of study drug (with or without transfusion)
• * Creatinine clearance or glomerular filtration rate (GFR) />= 50 mL/min as estimated by one of the following:
• * Cockcroft-Gault equation
• * Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation
• * 24-hour urine collection
• * Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase =/< 2 x upper limit of normal (ULN)
• * Alanine aminotransferase (ALT)/serum glutamic-pyruvic transaminase =/< 2 x ULN
• * Total bilirubin level =/< 1.5 x ULN (unless documented Gilbert`s syndrome). For patients with documented Gilbert`s syndrome, total bilirubin may exceed this value, but direct bilirubin must be =/< 1.0 x ULN
• * Serum amylase =/< 1.5 x ULN
• * Serum lipase =/< 1.5 x ULN
• * Women of childbearing potential (WOCBP) must have a negative serum pregnancy test =/< 7 days before the first dose of study drug. In addition, they must use a highly effective method of birth control initiated before the first dose of study drug, for the duration of the study treatment period, and for />= 180 days after the last dose of study drug
• * NOTE: WOCBP is a woman who: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months)
• * NOTE: Highly effective contraceptive methods include the following:
• * Combined (estrogen and progestogen containing) hormonal contraception associated with the inhibition of ovulation. Combined hormonal contraception may be oral, intravaginal, or transdermal
• * Progestogen-only hormonal contraception associated with the inhibition of ovulation. Progesterone-only hormonal contraception may be oral, injectable, or implantable
• * An intrauterine device
• * Intrauterine hormone-releasing system
• * Bilateral tubal
• * Vasectomized partner
• * Sexual abstinence (defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatment, starting the day before the first dose of study treatment, for the duration of the study, and for />= 180 days after the last dose of study drug. Total sexual abstinence should only be used as a contraceptive method if it is in line with the patients` usual and preferred lifestyle. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of exposure to investigational medicinal product, and withdrawal are not acceptable methods of contraception
• * Of note, barrier contraception (including male and female condoms with or without spermicide) is not considered a highly effective method of contraception, and, if used, this method must be used in combination with another acceptable method listed above
• * For patients using hormonal contraceptives such as birth control pills or devices, a second barrier method of contraception (eg, condoms) must be used

Критерии исключения

• * Exposure to a Bcl-2 inhibitor within the last 12 months or a history of disease progression while taking a Bcl-2 inhibitor
• * Prior malignancy (other than the disease under study) within the past 2 years, except for curatively treated basal or squamous skin cancer, melanoma, superficial bladder cancer, carcinoma in situ of the cervix or breast, or localized Gleason score =/< 6 prostate cancer
• * Underlying medical conditions that may render the administration of study drug hazardous or obscure the interpretation of safety or efficacy results
• * Known current central nervous system involvement by lymphoma/leukemia
• * Known plasma cell neoplasm other than a monoclonal gammopathy of undetermined significance (MGUS), prolymphocytic leukemia, or history of or currently suspected Richter`s syndrome
• * Prior autologous stem cell transplant unless />= 3 months after transplant; or prior chimeric antigen receptor T-cell (CAR-T) therapy unless />= 3 months after cell infusion
• * Prior allogeneic stem cell transplant with active graft-versus-host disease (GVHD), or requiring immunosuppressive drugs for treatment of GVHD, or have taken calcineurin inhibitors within 4 weeks prior to consent
• * History of a severe bleeding disorder such as hemophilia A, hemophilia B, von Willebrand disease, or history of spontaneous bleeding requiring blood transfusion or other medical intervention
• * Use of the following substances prior to the first dose of study drug:
• * =/< 28 days before the first dose of study drug:
• * Any biologic and/or immunologic-based therapy(ies) including experimental therapy(ies) for leukemia, lymphoma, or myeloma (including, but not limited to, monoclonal antibody therapy, e.g., rituximab, and/or cancer vaccine therapy)
• * =/< 14 days before the first dose of study drug:
• * Systemic chemotherapy or radiation therapy
• * =/< 7 days before the first dose of study drug:
• * Corticosteroid given with antineoplastic intent
• * =/< 3 days (or 5 half-lives; whichever is shorter) before the first dose of study drug:
• * Bruton`s tyrosine kinase inhibitor (BTKi) or other small molecule inhibitor given with antineoplastic intent
• * Active fungal, bacterial, and/or viral infection requiring systemic therapy
• * Note: oral antibiotics for minor bacterial infections are allowed
• * Major surgery =/< 4 weeks before the first dose of study treatment
• * Toxicity from prior anticancer therapy that has not recovered to grade =/< 1 (except for alopecia, ANC, and platelet count; for ANC and platelet count)
• * Clinically significant cardiovascular disease including the following:
• * Myocardial infarction =/< 6 months before screening
• * Unstable angina =/< 3 months before screening
• * New York Heart Association class III or IV congestive heart failure
• * History of clinically significant arrhythmias (e.g., sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes)
• * Heart rate-corrected QT interval /> 480 milliseconds based on Fridericia`s formula
• * History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place
• * Uncontrolled hypertension as indicated by a minimum of 2 consecutive blood pressure measurements, at screening, showing systolic blood pressure /> 170 mmHg and diastolic blood pressure /> 105 mmHg
• * Known infection with human immunodeficiency virus (HIV) or serologic status reflecting active viral hepatitis B (HBV) or viral hepatitis C (HCV) infection as follows:
• * Presence of viral hepatitis B surface antigen (HBsAg) or viral hepatitis B core antibody (HBcAb)
• * Note: Patients with presence of HBcAb, but absence of HBsAg, are eligible if HBV deoxyribonucleic acid (DNA) is undetectable and if they are willing to undergo monitoring for HBV reactivation
• * Presence of HCV antibody
• * Note: Patients with presence of HCV antibody are eligible if HCV ribonucleic acid (RNA) is undetectable and if they are willing to undergo monitoring for HCV reactivation
• * Pregnant or lactating women
• * Unable to swallow capsules or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, bariatric surgery procedure, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction
• * Inability to comply with study procedures
• * Receiving any treatment with a strong or moderate CYP3A4 inhibitor =/< 14 days (or 5 half-lives, whichever is longer) before first dose of sonrotoclax
• * Unwillingness to stop consumption of grapefruit, grapefruit products, Seville oranges, or starfruit within 3 days before the first dose of sonrotoclax or during the study
• * Receiving any treatment with a strong CYP3A4 inducer =/< 14 days (or 5 half-lives, whichever is longer) before first dose of sonrotoclax
• * History of interstitial lung disease, noninfectious pneumonitis, or uncontrolled lung diseases, including but not limited to pulmonary fibrosis and acute lung diseases
• * Autoimmune anemia and/or thrombocytopenia that is poorly controlled by corticosteroids or other standard therapy
• * Ongoing, drug-induced liver injury, alcoholic liver disease, nonalcoholic steatohepatitis, primary biliary cirrhosis, ongoing extrahepatic obstruction caused by cholelithiasis, cirrhosis of the liver, or portal hypertension
• * Receiving drugs known to prolong the QT/corrected QT (QTc) interval
• * Vaccination with a live vaccine =/< 35 days before first dose of study drug
• * Note: Seasonal vaccines for influenza are generally inactivated vaccines and are allowed. Intranasal vaccines are live vaccines and are not allowed

Описание

The purpose of this study is to investigate the efficacy and safety of BGB-16673 compared with investigator`s choice (idelalisib plus rituximab or bendamustine plus rituximab or venetoclax plus rituximab retreatment) in participants with chronic lymphocytic leukemia (CLL) previously exposed to both BTK inhibitors (BTKi) and BCL2 inhibitors (BCL2i).

Критерии включения

• 1. Confirmed diagnosis of CLL, requiring treatment, based on 2018 international workshop on chronic lymphocytic leukemia (iwCLL) criteria.
• 2. Previously received treatment for CLL with a BTKi and BCL2i.
• 3. Measurable disease by computer tomography/magnetic resonance imaging
• 4. Eastern Cooperative Oncology Group (ECOG) score 0, 1, or 2
• 5. Adequate liver function
• 6. Adequate blood clotting function

Критерии исключения

• 1. Known prolymphocytic leukemia or history of, or currently suspected, Richter`s transformation
• 2. Prior autologous stem cell transplant or chimeric antigen receptor-T cell therapy in the last 3 months
• 3. Known central nervous system involvement
• 4. Prior exposure to any BTK protein degraders
• 5. Active fungal, bacterial and/or viral infection requiring parenteral systemic therapy
• 6. Clinically significant cardiovascular disease
• NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

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

The goal of this clinical trial is to learn if BiTE-EV works to treat relapsed/refractory acute B-cell leukemia in adults. It will also learn about the safety of BiTE-EV. The main questions it aims to answer are:

Can BiTE-EV effectively treat relapsed/refractory acute B-cell lymphoblastic leukemia? What medical problems do participants have when taking BiTE-EV?

Participants will:

Take BiTE-EV every other day for 1 or 2 months Keep a diary of their symptoms during the medication period During the follow-up period, visit the clinic once every 4 weeks for checkups and tests

Критерии включения

• Patients can be enrolled in the group only if they meet all of the following conditions:
• * Patients with acute B lymphocytic leukemia who are clinically diagnosed as relapsed (relapsed after CAR-T treatment or relapsed after transplantation), refractory, or whose T cells cannot be used for the production of CAR-T cells.
• * Tumor cells show positive expression of CD19 detected by flow cytometry or immunohistochemistry.
• * The age is between 18 and 70 years old (inclusive).
• * The expected survival period from the date of signing the informed consent form is greater than 3 months.
• * The Eastern Cooperative Oncology Group (ECOG) performance status score is ≤ 2.
• * The functions of vital organs should meet the following requirements:
• * The ejection fraction (EF) is /> 50%, and there is no significant abnormality in the electrocardiogram.
• * The peripheral oxygen saturation (SpO2) is ≥ 92%.
• * The serum creatinine (Cr) is ≤ 1.5 times the upper limit of normal (ULN).
• * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are ≤ 5 times the upper limit of normal (ULN), and total bilirubin (TBil) is ≤ 3 times the upper limit of normal (ULN).
• * Subjects with pregnancy plans must agree to take contraceptive measures before enrolling in the study and six months after the study. If the subject is pregnant or suspected to be pregnant, they should immediately notify the investigator.
• * The subject or the guardian understands and signs the informed consent form.

Критерии исключения

• If any one of the following conditions is met, the subject cannot be enrolled in the group:
• * Complicated with other diseases that are not effectively controlled, including but not limited to persistent or poorly controlled infections, symptomatic congestive heart failure, unstable angina pectoris, arrhythmia, poorly controlled pulmonary diseases or mental disorders.
• * Having other active malignant tumors.
• * Complicated with severe infections that cannot be effectively controlled.
• * Those who are positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb), and those with peripheral blood hepatitis B virus (HBV) DNA higher than the detection limit need to be excluded; those who are positive for hepatitis C virus (HCV) antibody and positive for peripheral blood HCV RNA need to be excluded; those with positive cytomegalovirus (CMV) DNA detection; those with positive peripheral blood Epstein-Barr virus (EBV) DNA detection.
• * Those who are positive for human immunodeficiency virus (HIV) antibody test or positive for syphilis test.
• * Having a history of severe allergy to biological products (including antibiotics).
• Patients with relapsed after allogeneic hematopoietic stem cell transplantation who have experienced grade 3 - 4 acute graft-versus-host disease (GvHD).
• * Female subjects who are pregnant or in the lactation period.
• * Active autoimmune diseases that require systemic immunosuppressive treatment.
• * Situations that the investigator believes may increase the risk of the subject or interfere with the test results.

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 how well acalabrutinib works in treating patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and evaluates how treatment with acalabrutinib affects heart function. Acalabrutinib is in a class of medications called kinase inhibitors. It blocks a protein called BTK, which is present on B-cell (a type of white blood cells) cancers at abnormal levels. This may help keep cancer cells from growing and spreading. CLL/SLL patients treated with a different BTK inhibitor called ibrutinib often experience cardiac side effects, leading to discontinuation of life-saving therapy. Treatment with acalabrutinib after discontinuing, or even before starting, treatment with ibrutinib may reverse or prevent cardiac side effects and be an effective treatment option for patients with CLL/SLL.

Критерии включения

• * Men and women />= 18 years of age
• * Diagnosis of CLL/SLL meeting criteria as defined by International Workshop on Chronic Lymphocytic Leukemia (iWCLL) 2018 criteria
• * CLL patients cardiac intolerant to current treatment with ibrutinib as defined by AF or other cardiac arrhythmias. Other ibrutinib-related intolerances will be excluded
• * Eastern Cooperative Oncology Group (ECOG) performance status of =/< 2
• * Absolute neutrophil count (ANC) />= 1000/mm/^3 (Independent of growth factor support at screening unless due to marrow involvement by CLL/SLL and/or disease-related immune thrombocytopenia. If cytopenias are due to disease in the bone marrow any degree of cytopenias is allowed. Patients with active uncontrolled autoimmune cytopenias are excluded)
• * Platelets />= 30,000/mm/^3 (Independent of growth factor support at screening unless due to marrow involvement by CLL/SLL and/or disease-related immune thrombocytopenia. If cytopenias are due to disease in the bone marrow any degree of cytopenias is allowed. Patients with active uncontrolled autoimmune cytopenias are excluded)
• * Total bilirubin =/< 1.5 x upper limit of normal (ULN) (excepting Gilbert`s syndrome) (at screening)
• * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =/< 2.5 x ULN (at screening)
• * Creatinine clearance />= 30 mL/min/1.73m/^2 (at screening)
• * Using 24-hour creatinine clearance or modified Cockcroft-Gault equation
• * Woman of childbearing potential (WOCBP) who are sexually active must use highly effective methods of contraception during treatment and for 2 days after the last dose of acalabrutinib
• * Willing and able to participate in all required evaluations and procedures in this study protocol
• * Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information

Критерии исключения

• * Prior exposure to acalabrutinib for primary cohort and prior exposure to BTK inhibitor for pilot cohort
• * Presence of C481S mutation or PCLG2 mutation
• * Disease progression on ibrutinib
• * History of prior malignancy that could affect compliance with the protocol or interpretation of results, except for the following:
• * Curatively treated basal cell carcinoma or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or carcinoma in situ of the prostate at any time prior to study
• * Other cancers not specified above that have been curatively treated by surgery and/or radiation therapy from which subject is disease-free for />= 3 years without further treatment
• * Clinically significant cardiovascular disease such as prior myocarditis, congestive heart failure, prior documented myocardial infarction (i.e., not self-reported), known infiltrative cardiomyopathy (ex. cardiac sarcoidosis, cardiac amyloidosis, etc.) or any class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification. Note: Subjects with controlled, asymptomatic atrial fibrillation can enroll on study
• * Prior allogeneic stem cell transplantation
• * Prior cardiac transplantation
• * Systemic or non-cancer targeted anti-inflammatory medications (i.e., steroids)
• * Contradictions to MRI: non-compatible metal implant, weight /> 300 pounds (lbs.) (MRI scanner limit), severe claustrophobia, advanced or end-stage renal disease (ESRD) (contraindication to gadolinium), pregnancy, cognitive disabilities that may impair ability to comply with instructions or provide informed consent
• * Has difficulty with or is unable to swallow oral medication or has significant. gastrointestinal disease that would limit absorption of oral medication
• * Known history of infection with HIV or any active significant infection (e.g., bacterial, viral, or fungal) including subjects with positive cytomegalovirus /[CMV/] deoxyribonucleic acid /[DNA/] polymerase chain reaction /[PCR/])
• * Known history of hypersensitivity or anaphylaxis to study drug(s) including active product or excipient components
• * Active bleeding or history of bleeding diathesis (e.g., hemophilia or von Willebrand disease)
• * Uncontrolled AIHA (autoimmune hemolytic anemia) or ITP (idiopathic thrombocytopenic purpura)
• * Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening
• * Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer. The use of strong CYP3A inhibitors within 1 week or strong CYP3A inducers within 3 weeks of the first dose of study drug is prohibited
• * Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists
• * Prothrombin time (PT)/international normalized ratio (INR) or activated partial thromboplastin time (aPTT) (in the absence of lupus anticoagulant) /> 2 x ULN
• * Requires treatment with proton pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Note: Subjects receiving proton pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment to this study
• * History of significant cerebrovascular disease/event, including stroke or intracranial hemorrhage, within 6 months before the first dose of study drug
• * Major surgical procedure within 28 days of first dose of study drug. Note: If a subject had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug
• * Received a live virus vaccination within 28 days of first dose of study drug
• * History of or ongoing confirmed progressive multifocal leukoencephalopathy (PML)
• * Received any investigational drug within 30 days or 5 half-lives (whichever is shorter) before first dose of study drug
• * Hepatitis B or C serologic status:
• * Subjects who are hepatitis B core antibody (anti-HBc) positive and who are hepatitis B surface antigen (HBsAg) negative will need to have a negative polymerase chain reaction (PCR) and must be willing to undergo DNA PCR testing during the study to be eligible. Those who are HBsAg positive or hepatitis B PCR positive will be excluded
• * Subjects who are hepatitis C antibody positive will need to have a negative PCR result to be eligible. Those who are hepatitis C PCR positive will be excluded
• * Breastfeeding or pregnant
• * Concurrent participation in another therapeutic clinical trial

Описание

This will be a global Phase IV, open-label, randomised study to evaluate the safety and tolerability of acalabrutinib (monotherapy, 100 mg orally /[po/], twice daily /[bd/]) compared to investigator`s choice of treatment, in patients with CLL (TN or R/R) and moderate to severe cardiac impairment. All patients will have cardiac impairment as defined by LVEF of /< 50%.

Randomisation will be stratified by LVEF /> 40% vs ≤ 40% to stratify for moderate and severe cardiac impairment, which for this study are defined as follows:

Severe cardiac impairment: in those with LVEF ≤ 40% Moderate cardiac impairment: in those with LVEF /> 40% to /< 50%. The study is planned to take place in approximately 20 centres globally. The study will be conducted in centres that have established close collaboration between the Haematology and Cardiology divisions, preferably with a cardio-oncologist on the team.

An IDMC will be responsible for making recommendations for study continuation.

Критерии включения

• 1. Men and women ≥ 18 years of age, at the time of signing the informed consent.
• 2. Eastern Cooperative Oncology Group performance status of 0 to 3
• 3. Left ventricular ejection fraction assessed by ECHO /< 50%.
• 4. Diagnosis of CLL
• 5. Treatment naïve or relapsed/refractory patients who received no more than 2 prior lines of systemic anti-CLL treatment.
• 6. Active disease per iwCLL 2018 criteria that requires treatment.
• 7. Meet the following laboratory parameters:
• 1. Absolute neutrophil count (ANC) ≥ 500 cells/μL (0.50 × 109/L).
• 2. Platelet count ≥ 30,000 cells/μL (30 × 109/L).
• 3. Serum aspartate aminotransferase and ALT ≤ 3.0 × ULN.
• 4. Total bilirubin ≤ 1.5 × ULN unless directly attributable to Gilbert`s syndrome.
• 5. Estimated creatinine clearance (ie, estimated glomerular filtration rate /[eGFR/] using Cockcroft-Gault) ≥ 40 mL/min, or serum creatinine ≤ 2 × ULN.
• 8. Women and men who are sexually active and can bear children must agree to use highly effective forms of contraception while on the study and for 2 days after the last dose of acalabrutinib.
• 9. Patients must be willing and able to adhere to the study visit schedule, understand, and comply with other protocol requirements, and provide written informed consent and authorisation to use protected health information (in accordance with national and local patient privacy regulations). Note: vulnerable patients, as defined in the ICH GCP, are not allowed on this protocol (eg, prisoners or institutionalised patients).

Критерии исключения

• 1. Known active CNS leukaemia, leptomeningeal disease or spinal cord compression. In case of R/R patients with prior history of CNS localisation of leukaemia who received treatment are eligible provided that there is no evidence of CNS involvement at study entry as documented by cerebrospinal fluid (CSF) cytology and/or brain MRI.
• 2. Ongoing Richter`s transformation.
• 3. Prior exposure to a BTKi.
• 4. Major surgery within 30 days before first dose of study treatment.
• 5. Uncontrolled haemolytic anaemia.
• 6. Received any investigational drug within 30 days or 5 half-lives (whichever is shorter) before first dose of study treatment.
• 7. Received a live virus vaccination within 28 days of first dose of study treatment.
• 8. History of or ongoing confirmed PML.
• 9. History of prior malignancy except for the following:
• 1. Prior history of malignancy with no evidence of active disease present for more than
• 3 years before screening or felt to be at low risk for recurrence by treating physician.
• (b) Adequately treated lentigo maligna melanoma without current evidence of disease or adequately resected non-melanomatous skin cancer (ie, basal cell carcinoma or squamous cell carcinoma of the skin). (c) Curatively treated in situ carcinoma of the cervix or carcinoma in situ of the prostate at any time prior to study without current evidence of disease. 10 Unable to swallow tablets or malabsorption syndrome, or disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or gastric bypass, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction.
• 11 Active uncontrolled systemic infection (bacterial, fungal, viral or other) or clinically significant localised infection. 12 Known history of infection with human immunodeficiency virus (HIV). 13 Serologic status reflecting active HepB or HepC infection.
• 1. Patients with HepB core antibody positive who are surface antigen negative or who are HepC antibody positive will need to have a negative polymerase chain reaction (PCR) result before randomisation and must be willing to undergo deoxyribonucleic acid (DNA) PCR testing during the study.
• 2. Patients who are HepB surface antigen positive or HepB PCR positive and those who are HepC PCR positive will be excluded. 14 History of stroke or intracranial haemorrhage within 6 months prior to randomisation.
• 15 History of bleeding diathesis (eg, haemophilia, von Willebrand disease). 16 Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon) within 7 days of first dose of study treatment. Direct anti-X (DOACs) or low molecular weight heparins (LMWH, eg, enoxaparin) on stable dosing schedule is allowed. 17 Requires treatment with a strong cytochrome P450 3A (CYP3A) inhibitor/inducer. The use of strong CYP3A inhibitors within 1 week or strong CYP3A inducers within 3 weeks of the first dose of study treatment is prohibited. 18 Breastfeeding or pregnant. 19 Concurrent participation in another therapeutic clinical trial. 20 Uncontrolled cardiac/cardiovascular disease including the following:
• * Uncontrolled cardiac tachyarrhythmias (sinus, atrial or ventricular) that require new/additional therapy within the last month.
• * Clinically significant outlying QT interval corrected by Fridericia`s formula (QTcF) values; QTcF /> 470 ms or QTcF /< 330 ms.
• * Unstable ischaemic heart disease (IHD), recent (/< 3 months): episode of acute coronary syndrome, including acute myocardial infarction and unstable angina pectoris.
• * Percutaneous coronary intervention, or coronary artery bypass graft within the last month. 21 Uncontrolled hypertension despite optimal management. 22 Current life-threatening illness, medical conditions, organ system dysfunction or lifestyle habits which, in the investigator`s opinion, could compromise the patient`s safety or ability to adhere to the study protocol.

Описание

The purpose of this study is to characterize the long-term safety of lisocabtagene maraleucel (liso-cel), focusing on patients treated in the chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) 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 ≥1 infusion of lisocabtagene maraleucel used for the treatment of relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) within the 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 lisocabtagene maraleucel infusion
• * Patients treated with non-conforming CAR T-cell product

Описание

This is a single arm study to evaluate the safety and efficacy of CAR2219 CAR-T cells in the treatment of relapsed/refractory CD19/CD22 positive B cell Leukemia and Lymphoma.

Критерии включения

• 1. Signed written informed consent;
• 2. Relapsed/refractory CD19/CD22 positive B cell Leukemia or Lymphoma must be assured and meet one of the following conditions: (1) Confirmation for either CD19 or CD22 positivity using immunohistochemistry or flow cytometry; (2) B-cell tumors include the following three categories: ① B-cell acute lymphoblastic leukemia (B-ALL); Indolent B-cell lymphoma (CLL, FL, MZL, LPL, HCL); Aggressive B-cell lymphoma (DLBCL, BL, MCL) (3) Refractory/recurrent B-ALL (include one of the following situations) : ① relapse within 12 months after the first remission; ② The first refractory patients who did not achieve complete remission after 2 cycles of standard chemotherapy regimen; ③ Failure to achieve complete remission or relapse after first-line or multi-line salvage chemotherapy; ④ Recurrence after hematopoietic stem cell transplantation. (4) Refractory/recurrent B-cell lymphoma (meeting the requirements of 1 of the first 4 below plus 5) : ① After 4 courses of chemotherapy prescribed by the standard protocol, the tumor has shrunk by less than 50% or the disease progression(PD); ② CR reached after standard chemotherapy, but relapse occurred within 12 months; ③ Two or more recurrence after CR; ④ Recurrence after hematopoietic stem cell transplantation; ⑤Patients must have received rituximab or another anti-CD20 monoclonal antibody (unless Investigator determines that tumor is CD20-negative) and an anthracycline-containing chemotherapy regimen.
• 3. All genders, ages: 14 to 75 years
• 4. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 2.
• 5. Life expectancy ≥3 months;
• 6. HGB≥70g/L
• 7. Liver,kidney function and cardiopulmonary function meet the following requirements: (1) creatinine ≤1.5×ULN; (2) left ventricular ejection fraction≥50%; (3) Oxygen saturation />90%; (4) Total bilirubin ≤1.5×ULN, ALT and AST≤2.5×ULN;
• 8. Participants agreed to use contraception from the time of informed consent until 1 year after CAR-T cell infusion."

Критерии исключения

• 1. Severe heart failure with left ventricular ejection fraction /<50%;
• 2. A history of severe lung function impairment;
• 3. Combined with other advanced malignant tumors;
• 4. Complicated with severe infection that could not be effectively controlled;
• 5. Severe autoimmune disease or congenital immune deficiency;
• 6. Active hepatitis (hepatitis B virus DNA /[HBV-DNA/] or hepatitis C virus RNA /[HCV-RNA/] test results above the lower limit of detection);
• 7. Human immunodeficiency virus (HIV) infection or known acquired immunodeficiency syndrome (AIDS), or syphilis infection;
• 8. History of severe allergy to biological products (including antibiotics);
• 9. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) patients with acute graft-versus-host reaction (GVHD) one month after immunosuppressant withdrawal;
• 10. Patients with other serious physical or mental illnesses or laboratory abnormalities that could increase the risk of participating in the study or interfere with the results of the study, and those who were deemed by the investigator to be unsuitable for participation in the study.

Описание

The purpose of this study is to assess the safety and efficacy of AZD0486 administered as monotherapy or in combination with other anticancer agents in participants with hematological malignancies.

Критерии включения

• Master Inclusion Criteria applicable to all substudies:
• * Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
• * Contraception during treatment and at least 6 months after final dose.
• * Confirmed CD19 expression if prior anti-CD19 therapy.
• Substudy 1 Specific Inclusion Criteria:
• * Participants with CLL must require treatment according to the international workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria.
• * SLL: at least 1 measurable site per Lugano.
• * Absolute lymphocytes /<10,000.
• * Cohort 1A: at least 2 prior lines of therapy, including a Bruton tyrosine kinase inhibitor (BTKi) and B-cell lymphoma 2 inhibitor (BCL2i).
• * Cohort 1B: at least 1 prior line of therapy and is BTKi-sensitive.
• Substudy 2 Specific Inclusion Criteria:
• * MCL diagnosis per WHO.
• * Clinical Stage II, III, or IV by Ann Arbor Classification.
• * At least 1 measurable site per Lugano
• * ALC /< 10,000.
• * Cohort 2A: Relapse or progressed after 2 or more lines of therapy including BTKi.
• * Cohort 2B: Relapse or progressed after 1 or more line of therapy, not including a BTKi.
• Substudy 3 Specific Inclusion Criteria:
• * Large B-cell lymphoma per WHO 2022.
• * R/R B-NHL after at least 1 prior line of therapy.
• * International Prognostic Index (IPI) 2-5.
• * At least 1 measurable site as per Lugano.
• * Left ventricular ejection fraction (LVEF) />50%.
• * Contraception at least 12 months after last dose of R-CHOP or 6 months after last dose of AZD0486.

Критерии исключения

• Master Exclusion Criteria applicable to all substudies:
• * central nervous system (CNS) lymphoma.
• * Surgery within 14 days of study drug.
• * Clinically significant cardiovascular (CV) disease.
• * Unresolved Grade />2 AEs from prior anticancer therapy (except alopecia or fatigue).
• * Any anticancer therapy within 5 half-lives or 21 days (whichever is shorter) prior to treatment.
• * Radiation therapy within 28 days.
• * Prior CAR-T or auto-haematopoietic stem cell transplant (HSCT) within 12 weeks or prior T-cell engager (TCE) within 8 weeks.
• * Prior Grade /> 3 cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS) event.
• Substudy 1 Specific Exclusion Criteria:
• * CLL transformation to more aggressive lymphoma
• * Cohort 1B: bleeding diathesis, CYP3A inhibitor or inducer, history of ICH or stroke within 6 months, GI malabsorption, receiving vitamin K antagonist
• Substudy 2 Specific Exclusion Criteria:
• * Cohort 2B: bleeding diathesis, CYP3A inhibitor or inducer, history of ICH or stroke within 6 months, GI malabsorption, receiving vitamin K antagonist
• Substudy 3 Specific Exclusion Criteria:
• * Mediastinal grey-zone lymphoma, Burkitt, Richter`s transformation, primary effusion large B-cell lymphoma (LBCL)
• * Cumulative dose of anthracycline />150 mg/m2

Описание

The goal of this observational study is to improve the treatment of hematological patients with secondary immunodeficiency (SID) by developing a patient-reported outcome (PRO) instrument to detect clinically diagnosed infections. The study focuses on adults diagnosed with chronic lymphocytic leukemia (CLL) or multiple myeloma (MM) who are at increased risk of infections due to SID.

The main questions it aims to answer are:

1. Can a newly developed PRO screening tool for infection-related symptoms reliably detect infections in patients with SID?
2. How does the health-related quality of life change over the treatment course

Participants will:

* Complete daily electronic PRO questionnaires (ePRO) to monitor infection-related symptoms
* Complete ePRO health-related quality of life questionnaires every 1.5 months
* Participate in study visits every three months to ensure documentation of clinical data

Критерии включения

• * Adult patient (/>=18 years of age)
• * Access to an internet device (e.g., personal computer or tablet to use a web-based platform, or smartphone where the study app can be installed - all common iOS and Android systems)
• * German-speaking
• * Diagnosis of multiple myeloma or chronic lymphocytic leukemia
• * Secondary immunodeficiency (defined as: recurrent infections, infections requiring inpatient treatment, hypogammaglobulinemia, neutropenia and/or lymphopenia on differential blood cell counts, deficit in lymphocyte subsets as assessed by flow cytometry)

Критерии исключения

Описание

This correlative study aims to understand the pharmacodynamic effects and clonal dynamics in response to epcoritamab by obtaining and analyzing lymph node, bone marrow, and blood samples from subjects enrolled in GCT3013-03 trial sponsored by Genmab at NIH. Samples will be collected before and at multiple time points during treatment with epcoritamab. National Heart, Lung, and Blood Institute (NHLBI) investigators are experienced in testing samples treated with bsAb2,3 including epcoritamab in an ongoing pre-clinical collaboration with Genmab. Addressing the objectives of this correlative study will advance the science and clinical application of epcoritamab specifically as well as T-cell engaging bsAb in general as an emerging class of immunotherapy for cancer.

The study is enrolling by invitation only.

Критерии включения

• * INCLUSION CRITERIA:
• In order to be eligible to participate in this study, an individual must meet all of the following criteria:
• * Must be undergoing screening for GCT3013-03
• * Stated willingness to comply with all study procedures and availability for the duration of the study
• * Ability of subject to understand and the willingness to sign a written informed consent document.

Критерии исключения

• None

Описание

The purpose of this study is to establish the safety of novel dosing and ramp-up schedules for sonrotoclax in participants with hematological malignancies.

Критерии включения

• 1. Stable ECOG Performance Status ≤ 2.
• 2. Adequate organ function and no very recent transfusion or blood growth factor
• 3. Participants of childbearing potential must be willing to use a highly effective method of birth control and refrain from egg donation for the duration of the study and for ≥ 90 days after the last dose of sonrotoclax or ≥ 30 days after the last dose of zanubrutinib, whichever is later.
• 4. Confirmed diagnosis of CLL, based on Hallek et al 2018, and requiring treatment due to certain features of their disease
• 5. At least 1 measurable lesion based on computed tomography (CT)/magnetic resonance imaging (MRI) and no history of prolymphocytic leukemia or Richter`s transformation.

Критерии исключения

• 1. Participants unable to comply with the requirements of the protocol
• 2. Serologic status reflecting active viral HBV or HCV infection
• 3. Positive HIV serology (HIVAb) status unless certain conditions are met.
• 4. Participants with any major surgical procedure ≤ 28 days before first dose of study treatment
• 5. Prior systemic treatment for the CLL
• 6. Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia requiring treatment
• NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Описание

The main purpose of this study is to assess the efficacy and safety of 3 dose levels of Pirtobrutinib in participants with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), who have received 1-3 lines of treatment including a covalent Bruton tyrosine kinase (BTK) inhibitor. The study is expected to last approximately 3 years.

Критерии включения

• * Have confirmed diagnosis of CLL/SLL as defined by these iwCLL 2018 criteria.
• * Have received prior CLL/SLL treatment
• * Have received at least 1, but not more than 3 lines of prior treatment for CLL/SLL
• * Have received a covalent BTK inhibitor
• * Have a requirement for therapy consistent with iwCLL 2018 criteria for initiation of therapy
• * Capable of swallowing oral study medication.
• * Have an Eastern Cooperative Oncology Group Performance Status (ECOG) score of 0 to 2.

Критерии исключения

• * Have received prior treatment with a BTK degrader and a noncovalent BTK inhibitor
• * Have a history of greater than or equal to (/>=) Grade 3 bleeding due to treatment with a BTK inhibitor
• * Have known or suspected Richter`s transformation
• * Have known or suspected history of central nervous system involvement by CLL/SLL
• * Previous or concurrent cancer distinct from CLL/SLL within 3 years before randomization. Exceptions may occur with documented sponsor approval. Examples include:
• * nonmelanoma skin cancer or lentigo maligna melanoma
• * cervical carcinoma in situ
• * localized prostate cancer undergoing active surveillance, and
• * localized (for example, lymph node negative) breast cancer with no evidence of active disease present for more than 3 years. Individual may be receiving adjuvant hormonal therapy

Описание

This is a multicenter, open-label, Phase 1 study of AUR104 in adult patients with select Relapsed/Refractory (R/R) Lymphoid Malignancies. The main objective of the study is to evaluate the safety and tolerability of the study drug AUR104.In this study, safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of AUR104 will be evaluated in dose escalation manner.

Критерии включения

• 1. Males and females ≥ 18 years of age.
• 2. Eastern Cooperative Oncology Group (ECOG) Performance status of 0 or 1.
• 3. Acceptable bone marrow and organ function at screening as described below:
• * ANC ≥ 1000/μL (without WBC growth factor support)
• * Platelet count: For patients with CLL ≥ 50,000/μL, For patients with lymphomas ≥ 75,000/μL without bone marrow involvement and ≥ 50,000/μL with bone marrow involvement. These thresholds should be qualified without current transfusion support.
• * Hemoglobin ≥ 9 g/dL (Transfusion is allowed to achieve this Hb).
• * Total Bilirubin ≤ 1.5 x ULN (Patients with known Gilbert`s syndrome are allowed with a Total Bilirubin ≤ 2.5 x ULN).
• * AST (SGOT) ≤ 3 x ULN (≤ 5 × ULN if known liver metastases).
• * ALT (SGPT) ≤ 3 x ULN (≤ 5 × ULN if known liver metastases).
• * Creatinine clearance (CrCl) ≥ 60 mL/min (either measured or estimated by the Cockcroft-Gault formula). Cockcroft-Gault formula for estimated creatinine clearance (eCrCl):(140 - Age) × Weight (kg) × (0.85 if Female)/(72 × serum creatinine in mg/dL).
• 4. Ability to swallow and retain oral medications.
• 5. Histopathological diagnosis of Non-Hodgkin Lymphoma (NHL) or Chronic Lymphocytic Leukemia (CLL) or Hodgkin disease.
• Note:
• 5a. The lymphoma should be either in Stage III or IV according to Lugano classification at screening.
• 5b. The lymphomas included in this study must fall within one of the following 2017 World Health Organization categories except lymphoma mentioned in Exclusion criterion #5:
• * Mature B-cell neoplasms (excluding plasma cell neoplasms, heavy chain disease, and primary central nervous system /[CNS/] lymphoma).
• * Mature T- and NK-cell neoplasms.
• * Hodgkin lymphomas. 5c. The CLL should be Binet Stage C/Rai stage III or IV, as per the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines.
• 6) In the case of patients who have lymphoid malignancies for which high-dose chemotherapy and autologous stem cell transplantation (HD-ASCT) is considered standard curative therapy, eligibility for this study requires that the disease has relapsed after HD-ASCT, or the subject is not eligible for HD-ASCT, or the subject has refused HD-ASCT.
• 7) In the case of patients who have lymphoid malignancies for which CAR-T therapy is indicated, eligibility for this study requires that the disease has relapsed after CAR-T, or the patient is not eligible for CAR-T, or the patient has refused CAR-T, or the CAR-T is not available locally.
• 8) Evidence of measurable disease as per Lugano Criteria for Lymphoma or evidence of measurable disease as per iwCLL Criteria for CLL.
• Note: Patients with Small Lymphocytic Lymphoma (SLL) alone or in combination with CLL are allowed.
• 9) Standard curative measures do not exist, and the patient must have exhausted all effective therapies available locally. At a minimum, the patients must have relapsed or refractory disease to at least 2 prior lines of systemic therapies for NHL or CLL, or Hodgkin`s disease.
• Note: Any cancer patient with access to any effective therapy locally must not be enrolled.

Критерии исключения

• 1. Systemic anti-cancer therapy, such as chemotherapy, biological therapy, or immunomodulatory drug therapy, received within the past 28 days or 5 half-lives, whichever is longer, from Cycle 1 Day 1 of the study.
• Note: Concomitant use of low-dose prednisone (up to 10 mg/day) is allowed.
• 2. Presence of acute or chronic toxicity resulting from prior anti-cancer treatment, except for alopecia or nail changes that have not resolved to Grade ≤ 1, as determined by NCI CTCAE v 5.0.
• 3. Definitive Radiotherapy within the last 21 days of Cycle 1 Day 1 (limited field palliative radiation is allowed and no restrictions during the screening period or during the trial).
• 4. Use of any investigational agent within 28 days or 5 half-lives (whichever is longer) prior to Cycle 1 Day 1.
• 5. Patients with Burkitt`s lymphoma, Burkitt-like lymphoma, post-transplant lymphoproliferative disease, primary mediastinal large-B cell lymphoma, cutaneous lymphomas, mycosis fungoides (MF), or Sezary syndrome (SS).
• 6. Known symptomatic or untreated or recently treated (≤ 6 months of screening) central nervous system (CNS) lymphoma. Patients with previously treated (more than 6 months of screening) CNS lymphoma and are now stable and asymptomatic, from a CNS perspective, are allowed.
• 7. Patients with lymphoma requiring immediate cytoreductive therapy.
• 8. Patients with low-grade or indolent lymphoma not meeting conventional criteria for treatment.
• 9. Elevated Serum cardiac Troponin I or troponin T more than ULN at screening.
• 10. Serum magnesium and calcium levels more than 1.2 x ULN or less than 0.8 x LLN.
• 11. Serum Potassium more than 1.0 x ULN or less than 1.0 x LLN. Note: Patients experiencing hypokalemia are permitted to undergo treatment to attain normal potassium levels during the screening period.
• 12. Mean Heart Rate less than 60 at screening or Cycle 1 Day 1 (to be recorded at least 3 times at least 5 minutes apart) in ECG.
• 13. Left ventricular ejection fraction (LVEF) less than 50% as determined by an echocardiogram (ECHO) or Multigated Acquisition (MUGA) scan.
• 14. QTcF (Fridericia) interval more than 450 ms for patients on ECG at screening and/or at Cycle 1 Day 1.
• 15. Uncontrolled arterial hypertension defined as supine SBP of ≥ 140 mm Hg AND/OR supine DBP ≥ 90 mmHg on stable doses of three or lesser different classes of antihypertensive drugs.
• Notes:
• * Patients taking 4 or more classes of antihypertensives are excluded. Diuretics (such as furosemide or spironolactone) are considered as one class of anti-hypertensives.
• * The blood pressure has to be recorded 3 times at least 10 minutes apart during Screening and Cycle 1 Day 1 (before dosing) in the supine position. Among these recordings, a single instance of SBP ≥140 mm Hg or DBP ≥ 90 mmHg will exclude the patient. Note: A patient excluded on these criteria can be re-screened after optimal BP management.
• 16. Current or past history of heart failure (NYHA Class 2 or higher)
• 17. Having a history of moderate to severe cardiovascular disease including unstable angina, myocardial infarction, cerebrovascular accident, or transient ischemic attack (TIA), within 1 year prior to Cycle 1 Day 1.
• 18. Ongoing cardiac arrhythmias or conduction blocks.
• 19. History of any ventricular arrhythmia including supraventricular or ventricular premature contractions.
• 20. Patients on drugs which are sensitive substrates of CYP3A4 and cannot be discontinued at least one week prior to Cycle 1 Day 1.
• 21. Use of strong CYP3A4 inhibitors or inducers within 2 weeks prior to Cycle 1 Day 1.
• 22. Concomitant use of any drug which is known to prolong QTc interval or use of such drugs within one week prior to Cycle 1 Day 1.
• 23. Major surgery ≤ 28 days from Cycle 1 Day 1 (major surgery is defined as a procedure requiring general anesthesia)
• 24. Active infection requiring systemic therapy. Note: Prophylactic use of antibiotics is allowed. Any infection detected during the screening period, which is resolved adequately according to the investigator before Cycle 1 Day 1, is allowed.
• 25. Known to be human immunodeficiency virus (HIV) positive or have an acquired immunodeficiency syndrome-related illness.
• 26. Known active or chronic hepatitis B (HBsAg +ve) or hepatitis C infection (HCV antibody +ve).
• 27. Patient expected to require any other form of antineoplastic therapy or targeted therapy while in the study.
• 28. Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or significant gastritis, active bleeding diatheses, presence of any major medical illness (e.g., renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary, or psychiatric illness/social situations or clinically significant laboratory / ECG abnormalities at screening, any or a combination of illnesses, which, in the opinion of the PI, may either put the patient at risk because of participation in the study or influence the results or the patient`s ability to participate in the study
• 29. Current swab-positive or suspected (under investigation) Covid-19 infection or fever and other signs or symptoms suggestive of Covid-19 infection with recent contact of the person(s) with confirmed Covid-19 infection, at screening or Cycle 1 Day 1.
• 30. History of another primary malignancy within 5 years prior to starting the study drug, except for adequately treated basal or squamous cell carcinoma of the skin or cancer of the cervix in situ or cured early-stage (Stage 1 or 2) prostate cancer.
• 31. Positive pregnancy test for women of childbearing potential (WOCBP) at the screening or enrolment visit
• 32. Lactating women or WOCBP who are neither surgically sterilized nor willing to use reliable contraceptive methods (hormonal contraceptive, IUD, or any double combination of male or female condom, spermicidal gel, diaphragm, sponge, cervical cap).

Описание

This is a phase I dose-finding trial of an autologous CD22 targeting chimeric antigen receptor (CAR)-T cell product, called CLIC-2201, for participants with relapsed/refractory B cell malignancies. In the proposed trial, eligible enrolled participants will undergo leukapheresis for autologous T cell collection to enable CLIC-2201 manufacturing, followed by lymphodepletion with cyclophosphamide and fludarabine, then intravenous infusion of the autologous CLIC-2201 product. The trial will use the 3+3 design to escalate or de-escalate the dose level of CLIC-2201 administered. Participants will be monitored for safety and tolerability up to day 365 following CLIC-2201 infusion.

The primary objective is to evaluate the safety and tolerability of CLIC-2201 and estimate the maximum tolerated dose (MTD) of CLIC-2201 in B-cell malignancies.

The secondary objectives are to evaluate the (i) feasibility; (ii) anti-tumour activity of CLIC-2201; (iii) and characterize the pharmacokinetic (PK) profile of CLIC-2201.

Exploratory objectives will include: i) characterizing the cellular and humoral immune responses against CLIC-2201 up to 1 year following infusion of CLIC-2201; (ii) characterizing the phenotype and gene expression profile of CLIC-2201 cells; (iii) evaluating immune and tumour cells at baseline and relapse for biomarkers of response or toxicity; (iv) evaluating serum cytokines, circulating tumour DNA (ctDNA) and B cell aplasia as biomarkers of clinical outcomes; and (v) assessing the quality of life.

Критерии включения

• in Cohort A:
• Participants must meet the following criteria to be enrolled on the trial:
• 1. Participants in the cohort A must be 18 years of age or older of age at time of informed consent.
• 2. Participants must provide written informed consent. The investigator is responsible for obtaining written informed assent/consent for the subject after adequate explanation of the study design, anticipated benefits and the potential risks. Subjects should sign the most current REB approved assent/consent prior to any study specific activity or procedure is performed. (Sites will follow their REB board requirements for consenting).
• 3. Participants must have a relapsed or refractory B cell lymphoma, including one of the following:
• 1. diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS),
• 2. high grade B cell lymphoma NOS,
• 3. high grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements,
• 4. primary mediastinal large B-cell lymphoma (PMBCL),
• 5. aggressive B cell lymphoma transformed from an indolent lymphoma,
• 6. mantle cell lymphoma (MCL),
• 4. Participants must have refractory or relapsed disease, defined as one of the following:
• 1. Relapse or refractory disease after at least 2 lines of therapy, OR
• 2. Any relapse after autologous or allogeneic hematopoietic cell transplantation (HCT), OR
• 3. Any relapse after CAR-T cell therapy.
• 5. Participants must have adequate organ function at enrolment, defined as:
• 1. Left ventricular ejection fraction (LVEF) ≥40%,
• 2. Creatinine clearance using Cockcroft-Gault of /> 30 mL/min, AND
• 3. ALP/ALT /< 5X upper limit of normal (ULN), conjugated bilirubin /< 2X ULN, and no evidence or history of liver cirrhosis.
• 6. Participants must have Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 or Karnofsky Score ≥50%.
• 7. Females of child-bearing potential and sexually active males must agree to use a highly effective contraception method (see section 5.4) through to at least one year following administration of the CLIC-2201 product.
• 8. Participants with accessible disease, willingness to undergo a tumour biopsy at enrolment. For participants with a recent (within 3 months) tumor biopsy, access to the archival biopsy is acceptable.
• Inclusion Criteria in Cohort B:
• 1. Participants in the cohort B must be between 1-21 years of age at the time of consent.
• 2. Parent or legal guardian of the participant signed the informed consent and the participant`s assent/consent is obtained (if applicable). The investigator is responsible for obtaining written informed assent/consent for the subject or legally acceptable representative (e.g. parent, legal guardian) after adequate explanation of the study design, anticipated benefits and the potential risks. Subjects should sign the most current REB approved assent/consent prior to any study specific activity or procedure is performed. (Sites will follow their REB board requirements for consenting).
• 3. Participants must have a relapsed or refractory B cell acute lymphoblastic leukemia (B-ALL).
• 4. Participants must have refractory or relapsed disease, defined as one of the following:
• 1. Relapse or refractory disease after at least 2 lines of therapy, OR
• 2. Any relapse after autologous or allogeneic hematopoietic cell transplantation (HCT), OR
• 3. Any relapse after CAR-T cell therapy.
• 5. Participants in cohort B and/or those who have received CD22 targeted therapy must have documentation of CD22 tumour expression within the 6 months prior to study screening, and after any prior CD22 directed therapy (if applicable).
• 6. Participants must have adequate organ function at enrolment, defined as:
• 1. Left ventricular ejection fraction (LVEF) ≥45%,
• 2. Creatinine clearance using Cockcroft-Gault or Schwartz equation of /> 30 mL/min, AND
• 3. ALP/ALT /< 5X upper limit of normal (ULN), conjugated bilirubin /< 2X ULN, and no evidence or history of liver cirrhosis.
• 7. Participants must have a Karnofsky or Lansky Score ≥50%.
• 8. Participants in reproductive age must agree to use a highly effective contraception method (see section 5.4) through to at least one year following administration of the CLIC-2201 product.
• 9. Participants willingness to undergo a bone marrow biopsy at enrolment.

Критерии исключения

• 1. Any uncontrolled or serious active infection at the time of enrolment.
• 2. Active autoimmune disease requiring immunosuppressive therapy within 4 weeks of enrolment.
• 3. Live vaccine ≤6 weeks prior to enrolment
• 4. Active Graft Versus Host Disease (GVHD) requiring systemic immunosuppressive therapy within 4 weeks of enrolment.
• 5. Treatment with any of the following in the specified time period before leukapheresis:
• 1. Allogeneic HCT within 3 months,
• 2. Autologous HCT within 3 months,
• 3. CD19 CAR-T cell infusion within 3 months,
• 4. Donor lymphocyte infusion (DLI) within 3 months,
• 5. Bendamustine within the last 6 months,
• 6. Any investigational agent within 30 days or 5 half-lives (whichever is shorter),
• 7. Systemic administration of therapeutic dose corticosteroids (/>20 mg/day prednisone or equivalent for adults and ≥ 12 mg/m2/day for paediatric participants) within 7 days prior to leukapheresis.
• 8. Immunosuppressive therapies (i.e., calcineurin inhibitors, methotrexate, mycophenolate, rapamycin) within 4 weeks.
• 9. Oral chemotherapy agents (i.e., venetoclax) within 5 half-lives. An exception to this is that bruton tyrosine kinase (BTK) inhibitors like ibrutinib can be continued in participants with mantle cell lymphoma throughout the trial period.
• 6. Other concurrent malignancy or a prior malignancy treated within the past 2 years, except carcinoma in situ of the skin or cervix treated with curative intent and with no evidence of active disease.
• 7. Concomitant genetic syndrome associated with bone marrow failure such as Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known bone marrow failure or immunodeficiency syndrome.
• 8. Active (confirmed by PCR) hepatitis B or hepatitis C at time of screening confirmed by PCR.
• 9. Any Human Immunodeficiency Virus (HIV) infection at time of screening.
• 10. Hypersensitivity to fludarabine or cyclophosphamide.
• 11. Any allergy to gentamycin or its derivatives
• 12. Pregnant or nursing participants.

Описание

This study is a Phase 1 dose-escalation and dose-confirmation study to evaluate the safety and antitumor activity of UB-VV111. The study will enroll patients with relapsed/refractory large B-cell lymphoma (LBCL) and chronic lymphocytic leukemia (CLL).

Критерии включения

• 1. 18 years or older
• 2. Provides voluntary written informed consent
• 3. Relapsed or refractory large B-cell lymphoma (LBCL) or chronic lymphocytic leukemia (CLL)
• 4. Measurable disease according to Lugano 2014 criteria (LBCL) or iwCLL 2018 (CLL).
• 5. No serious concomitant diseases or active/uncontrolled infections
• 6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• 7. Adequate organ function
• 8. Patients who have previously received CD19-directed therapy must have biopsy confirming CD19 expression following completion of prior CD19-directed therapy.

Критерии исключения

• 1. Women who are pregnant or breastfeeding
• 2. Current isolated central nervous system (CNS) involvement
• 3. Prior allogeneic bone marrow transplant, gene therapy, or adoptive cell transfer (except CAR T-cell therapy in CAR T-exposed subjects)
• 4. History of or active human immunodeficiency virus (HIV)
• 5. Active hepatitis B or C
• 6. Systemic autoimmune or immunodeficiency diseases, except for well-controlled Type I diabetes or thyroid disease
• 7. Ongoing CNS disease that would preclude neurologic assessment
• 8. Uncontrolled angina or other acute heart disease
• 9. Currently receiving treatment in another interventional clinical trial.

Описание

The purpose of this study is to support the registration plan of sonrotoclax plus zanubrutinib treatment in participants with previously untreated CLL. This study is designed to assess the contribution of sonrotoclax to the efficacy outcome of the combination of zanubrutinib and sonrotoclax.

Критерии включения

• 1. Previously untreated adult patient ≥ 18 years with a confirmed diagnosis of CLL.
• 2. CLL requiring treatment as per pre-defined criteria.
• 3. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1, or 2.
• 4. Measurable disease by CT/MRI.
• 5. Adequate marrow function.
• 6. Adequate liver function as indicated by aspartate aminotransferase (AST) alanine aminotransferase (ALT) and serum total bilirubin.
• 7. Adequate renal function.
• 8. Life expectancy /> 6 months.
• 9. Signed informed consent and able to comply with the study protocol in the investigator`s judgment.
• 10. Women of childbearing potential must be willing to use a highly effective method of birth control for the duration of the study and for ≥ 90 days after the last dose of study drug.

Критерии исключения

• 1. Known prolymphocytic leukemia or history of, or currently suspected, Richter`s transformation
• 2. Known central nervous system involvement
• 3. Received previous systemic treatment for CLL
• 4. Clinically significant cardiovascular disease
• 5. Severe or debilitating pulmonary disease
• 6. History of prior malignancy
• 7. Active fungal, bacterial, and/or viral infection requiring systemic therapy
• 8. Positive HIV serology (HIVAb) status or serologic status reflecting active hepatitis B or C infection
• 9. Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia requiring treatment
• 10. History of severe bleeding disorder such as hemophilia A, hemophilia B, von Willebrand disease, or history of spontaneous bleeding requiring blood transfusion or other medical intervention
• 11. History of stroke or intracranial hemorrhage ≤ 6 months before the first dose of study treatment
• 12. Unable to swallow capsules or tablets or diseases significantly affecting GI function
• 13. Hypersensitivity to zanubrutinib, sonrotoclax, or any of its excipients
• 14. Use of investigational agents within the last 4 weeks before screening
• 15. Pregnant and lactating females
• Note: Other protocol defined Inclusion/Exclusion criteria may apply

Описание

This phase II trial tests how well pirtobrutinib (LOXO-305) and venetoclax works in treating patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) that remains despite treatment (resistant) with covalent bruton tyrosine kinase inhibitors (BTKi). Pirtobrutinib is in a class of medications called kinase inhibitors. It works by blocking the action of the a protein that signals cancer cells to multiply. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking BCL-2, a protein needed for cancer cell survival. Giving pirtobrutinib and venetoclax may kill more cancer cells in patients with CLL or SLL that is resistant to covalent BTKi.

Критерии включения

• * Diagnosis of CLL or SLL according to the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 guidelines
• * Detectable CLL on flow cytometry of the blood or marrow at time of enrollment
• * Age ≥ 18 years old
• * Eastern Cooperative Oncology Group (ECOG) performance 0-2
• * Currently taking ibrutinib, acalabrutinib, or zanubrutinib at any daily dose and tolerating it for /> 4 weeks
• * Evidence of progressive disease by iwCLL 2018 criteria for progressive disease or doubling of absolute lymphocyte count (ALC) in ≤ 6 months while on BTK inhibitor provided ALC is /> 5 k/uL
• * Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) ≤ 3 x the upper limit of normal (ULN) or ≤ 5 x ULN with documented liver involvement
• * Bilirubin ≤ 1.5 x ULN or ≤ 3 x ULN with documented liver involvement and/or Gilbert`s disease
• * Creatinine clearance (CrCl) ≥ 30 according to modified Cockcroft-Gault equation
• * Absolute neutrophil count (ANC) ≥ 0.75 k/uL
• * Without transfusion or growth factor administration in the 7 days prior to screening
• * Any values if cytopenias are due to bone marrow involvement with disease
• * Hemoglobin ≥ 8 g/dL
• * Without transfusion or growth factor administration in the 7 days prior to screening
• * Any values if cytopenias are due to bone marrow involvement with disease
• * Platelets ≥ 50 k/uL
• * Without transfusion or growth factor administration in the 7 days prior to screening
• * Any values if cytopenias are due to bone marrow involvement with disease
• * Prothrombin time (PT) and partial thromboplastin time (PTT) ≤ 1.5 x ULN
• * No known inherited qualitative platelet defect (e.g. delta granule storage pool deficiency)
• * Willing and able to complete study activities and treatment
• * Willing and capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol
• * Willingness of men and women of reproductive potential and their partners to observe conventional and highly effective or acceptable birth control methods for the duration of treatment and for 6 months following the last dose of pirtobrutinib or 30 days from the last dose of venetoclax
• * ELIGIBILITY FOR RE-TREATMENT WITH PIRTOBRUTINIB: Discontinued initial study treatment ≤ 12 months ago
• * ELIGIBILITY FOR RE-TREATMENT WITH PIRTOBRUTINIB: Meets iwCLL 2018 criteria for progressive disease

Критерии исключения

• * Inability to tolerate 2 Liters of oral or intravenous (IV) hydration
• * Prior venetoclax exposure /> 13 months or known resistance to venetoclax
• * Known hypersensitivity to any of the excipients of pirtobrutinib or venetoclax
• * Need for treatment with warfarin or other vitamin K antagonist during study treatment
• * History of bleeding diathesis
• * Patients who experienced a major bleeding event or grade ≥ 3 arrhythmia on prior treatment with a BTK inhibitor. Major bleeding is defined as bleeding having one or more of the following features: potentially life-threatening bleeding with signs or symptoms of hemodynamic compromise; bleeding associated with a decrease in the hemoglobin level of at least 2g per deciliter; or bleeding in a critical area or organ (e.g., retroperitoneal, intraarticular, pericardial, epidural, or intracranial bleeding or intramuscular bleeding with compartment syndrome)
• * History of stroke or intracranial hemorrhage within 6 months
• * Inability to take pills or oral medications
• * Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal (GI) absorption of either pirtobrutinib or venetoclax
• * Current known central nervous system involvement with CLL or SLL. Patients with previous treatment for central nervous system (CNS) involvement who are neurologically stable and without evidence of disease may be eligible if a compelling clinical rationale is provided by the investigator and with documented approval by the principal investigator
• * Treatment with the following:
• * Targeted agents, investigational agents, therapeutic monoclonal antibodies, or cytotoxic chemotherapy within 5 half-lives or 2 weeks, whichever is shorter
• * Treatment with immunoconjugated antibody treatment within 10 weeks
• * Receipt of broad field radiation ( ≥ 30% of the bone marrow or whole brain radiotherapy) within 14 days or palliative limited field radiation within 7 days prior to study enrollment
• * Note: Treatment with ibrutinib, acalabrutinib, or zanubrutinib is allowed. Treatment with topical chemotherapy agents for precancerous skin conditions or skin cancers is allowed
• * Unresolved adverse events from prior treatment not resolved to grade ≤ 1 with the exception of alopecia or grade 2 peripheral neuropathy
• * History of allogeneic or autologous stem cell transplant (SCT) or chimeric antigen receptor-modified T cell (CAR-T) therapy within 60 days. Patients with a history of allogeneic stem cell transplant must be stable off all immunosuppression for at least 2 months prior to study screening. Presence of any of the following, regardless of prior SCT and/or CAR-T therapy timing will be exclusionary:
• * Active graft versus host disease (GVHD)
• * Cytopenia from incomplete blood cell count recovery post-transplant
• * Need for anti-cytokine therapy for toxicity from CAR-T therapy and/or residual symptoms of neurotoxicity /> grade 1 from CAR-T therapy
• * Ongoing immunosuppressive therapy
• * Active second malignancy unless in remission and with life expectancy /> 2 years. Adjuvant endocrine therapy for breast or prostate cancer that is expected to be cured is allowed. Non-melanoma skin cancers are permitted if adequately treated
• * Psychiatric illness, or social situations that would limit compliance with study requirements
• * Active uncontrolled auto-immune cytopenia (e.g., autoimmune hemolytic anemia /[AIHA/], idiopathic thrombocytopenic purpura /[ITP/]) for which new therapy was introduced or existing therapy was escalated within the 4 weeks prior to study enrollment to maintain adequate blood counts
• * Evidence of other clinically significant uncontrolled condition(s) including but not limited to, uncontrolled systemic bacterial, viral, fungal or parasitic infection (except for fungal nail infection), or other clinically significant active disease process which in the opinion of the investigator may pose a risk for patient participation. Screening for chronic conditions is not required
• * Significant cardiovascular disease defined as:
• * Unstable angina or acute coronary syndrome within the past 2 months
• * History of myocardial infarction within 3 months
• * Documented left ventricular ejection fraction (LVEF) by any method of ≤ 40% in the 12 months
• * ≥ grade 3 New York Heart Association (NYHA) functional classification system of heart failure
• * Uncontrolled or symptomatic arrhythmias
• * Prolongation of the QT interval corrected for heart rate (Fridericia`s formula-corrected QT interval /[QTcF/]) /> 470 msec. QTcF is calculated using Fridericia`s formula
• * Correction of suspected drug induced QTcF prolongation can be attempted at the investigator¡¦s discretion and only if clinically safe to do so with either discontinuation of the offending drug or switch to another drug not known to be associated with QTcF prolongation
• * Correction for underlying bundle branch block (BBB) allowed
• * Note: Patients with pacemakers are eligible if they have no history of fainting or clinically relevant arrhythmias while using the pacemaker
• * Known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection based on criteria below:
• * Hepatitis B virus (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 inclusion. Patients who are hepatitis B PCR positive will be excluded
• * 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 inclusion. Patients who are hepatitis C RNA positive will be excluded. Patients previously treated for hepatitis C /> 6 months previously with a negative RNA test are eligible
• * Known HIV infection. For patients with unknown HIV status, HIV testing will be performed at screening and result should be negative for enrollment
• * Known active cytomegalovirus (CMV) infection. Unknown or negative status are eligible
• * Treatment with a strong CYP3A inhibitor or inducer and/or strong P-gp inhibitors within 3 days of starting or during study treatment. Treatment with a moderate or strong CYP3A inhibitor or inducer within 7 days prior to first dose of venetoclax or during cycle 2 or 3 of study treatment. Patients may not plan to consume grapefruit or grapefruit products, Seville oranges or products from Seville oranges, or star fruit
• * Pregnancy, lactation, or plan to breastfeed during the study or within 6 months of the last dose of either pirtobrutinib or venetoclax
• * Major surgery within 4 weeks prior to screening
• * Vaccination with live vaccine within 28 days of screening
• * Currently incarcerated
• * History of progressive multifocal leukoencephalopathy (PML) or human polyomavirus 2 (JC virus) infection
• * History of seizure disorder unless controlled without a seizure in the year prior to screening
• * ELIGIBILITY FOR RE-TREATMENT WITH PIRTOBRUTINIB: Has not developed any new medical conditions that would change the safety of treatment with pirtobrutinib

Описание

Chronic lymphocytic leukemia (CLL) is the most common leukemia in Western countries. The purpose of this study is to assess how well ABBV-453 works adult participants with relapsed/refractory (R/R) untreated CLL/small lymphocytic lymphoma (SLL). Adverse events, pharmacokinetics, and change in disease activity will be assessed.

ABBV-453 is an investigational drug for the treatment of CLL and SLL. There are 2 parts to this study. In part A participants will be placed 1 of 5 cohorts with a specific target dose for each cohort and receive obinutuzumab during the debulking period followed escalating doses of ABBV-453, until the appropriate target dose is achieved. In part B participants will be placed in 2 cohorts and receive up to the maximum dose in part A, with cohort 2.1 including a debulking period (obinutuzumab) as in part A. Approximately 80 adult participants with previously R/R CLL/SLL will be enrolled in the study in approximately 40 sites across the world.

Participants in part A will placed into 1 of 5 cohorts with a specific target dose for each cohort and will receive intravenous (IV) obinutuzumab as part of the debulking period, followed by escalating doses of oral ABBV-453 until the appropriate target dose is achieved. Participants in part B will be place in one of 2 cohorts. Participants in cohort 2.1 will receive IV obinutuzumab as part of the debulking period, followed by escalating doses of oral ABBV-453 until the maximum target dose from part A is achieved. Participants in cohort 2.2 will receive no treatment during the the debulking period, followed by escalating doses of oral ABBV-453 until the maximum target dose from part A is achieved. The estimated study duration is 5 years.

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 a hospital or clinic. The effect of the treatment will be checked by medical assessments, blood tests, and checking for side effects.

Критерии включения

• * Relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL) that has received at least 2 prior systemic therapies and have no available (or established) therapies known to provide clinical benefit and to which the participant would consent to receiving.
• * Laboratory values meeting those listed in the protocol.

Критерии исключения

• * QT interval corrected for heart rate (QTc) using Fridericia`s correction of /> 470 msec (females) or /> 450 msec (males), Grade 3 arrythmia, and/or other clinically significant cardiac abnormalities.
• * Known to be B-cell leukemia/lymphoma 2 inhibitor (BCL-2i) refractory or has received a BCL-2i-containing regimen within (6 months) of starting study drug (e.g., venetoclax, lisaftoclax, BGV-11417).
• * Has active human immunodeficiency virus (HIV) infection. HIV testing is not required unless required locally.
• * Recent history (within 6 months) of:
• * Congestive heart failure (defined as New York Heart Association, Class 2 or higher).
• * Ischemic cardiovascular event.
• * Cardiac arrhythmia requiring pharmacological or surgical intervention.
• * Pericardial effusion.
• * Pericarditis.
• * Consumes known moderate or strong inhibitors of cytochrome P450 3A isoform subfamily (CYP3A) within 14 day or 5 half-lives of the drug (whichever is shorter) before the first dose of ABBV-453.