OncoTrials - мониторинг клинических исследований

Описание

To learn if olutasidenib, when combined with a drug called a hypomethylating agent (HMA) can help to control MDS, CMML, and/or MPN. The safety of the drug combination will also be studied.

Критерии включения

• 1. Pathologically proven higher-risk MDS/CMML or advanced MPN
• 1. MDS/CMML participants must have International Prognostic Scoring System (IPSS) intermediate-2- or high-risk disease or Revised IPSS (IPSS-R) score /> 3.5 or Molecular IPSS (IPSS-M) moderate high-, high-, or very high-risk disease or bone marrow blast percentage.
• 2. Advanced MPN is defined as bone marrow blast percentage />/=10%.
• 3. Participants on the treatment-naive arm must not have received a prior HMA. Agents such as growth factors (e.g. erythropoietin stimulating agents, luspatercept, eltrombopag, granulocyte colony stimulating factors), cyclosporine, and/or hydroxyurea are allowed.
• 2. Participants must have a documented IDH1 mutation
• 3. Participants />/= 18 years old
• 4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 (Appendix A)
• 5. Acceptable liver function
• 1. Bilirubin /</= 2 times upper limit of normal (ULN) or /</= 3 times ULN in participants with Gilbert Syndrome
• 2. Aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase /</= 3 times ULN
• 6. Acceptable renal function with serum creatinine /</= 1.5 times ULN or calculated creatinine clearance />/= 50 mL/min (as assessed by Cockcroft-Gault, MDRD, or CKD-Epi validated measures)
• 7. Negative serum or urine pregnancy test if female of childbearing potential
• 8. For fertile men and women, agreement to use highly effective contraceptive methods for the duration of study participation and 90 days after the last dose of study medication
• 9. Agreement for male participants not to donate sperm and for female participants of childbearing potential not to donate ova during the study and for 90 days after the final dose of study drug
• 10. Ability and willingness to sign informed consent prior to beginning study and undergoing procedures

Критерии исключения

• 1. Participants unable to swallow oral medications, or participants with gastrointestinal conditions (e.g., malabsorption, resection, etc.) deemed by the Investigator to jeopardize intestinal absorption
• 2. Participants with any concurrent uncontrolled clinically significant medical condition, including life-threatening severe infection or psychiatric illness, which could place the participant at unacceptable risk of study treatment
• 3. Known active hepatitis B (HBV) or hepatitis C (HCV) or HIV infection
• 4. Pregnant or nursing women or women of childbearing potential not using highly effective contraception; male participants not using highly effective contraception
• 5. Participants with white blood cell count /> 25 x109/L Note: hydroxyurea use is permitted to meet this criterion
• 6. Unwillingness or inability to comply with procedures either required in this protocol or considered standard of care

Описание

This phase Ib/II trial tests the best dose of axatilimab and effectiveness of axatilimab with or without azacitidine for the treatment of patients with advanced phase myeloproliferative neoplasms (MPN), myeloproliferative neoplasm/myelodysplastic syndrome (MPN/MDS) overlap or high risk chronic myelomonocytic leukemia (CMML). Axatilimab is an antibody that is cloned from a single white blood cell that is known to be able to recognize cancer cells and block a protein on the surface of the white blood cells that may be involved in cancer cell growth. By blocking the proteins, this may slow or halt the growth of the cancer. Azacitidine is in a class of medications called antimetabolites. It works by stopping or slowing the growth of cancer cells. Giving axatilimab with or without azacitidine may be safe and effective in treating patients with advanced phase MPN, MPN/MDS overlap or high risk CMML.

Критерии включения

• * Signed informed consent must be obtained prior to participation in the study
• * Age ≥ 18 years at the date of signing the informed consent form (ICF)
• * Morphologically confirmed diagnosis of the following based on 2016 World Health Organization (WHO) classification (Arber et al 2016): Phase 1b, patients with relapsed or refractory of any of the following; phase 2, patients with newly diagnosed of any of the following:
• * Chronic myelomonocytic leukemia (CMML), classified as intermediate-2, OR high-risk per the CMML Specific Prognostic Scoring System (CPSS) Molecular Model
• * Atypical chronic myelocytic leukemia (aCML)
• * MDS/MPN unclassified (MDS/MPN-U)
• * Myeloproliferative neoplasm accelerated phase (MPN-AP)
• * MPN-AP requires a previous diagnosis of polycythemia vera (PV), essential thrombocythemia (ET), or primary myelofibrosis (PMF) with intermediate-2 or high risk disease according to International Prostate Symptom Score (IPSS) as well as progression on or failure to respond to at least one line of therapy.
• * Myelodysplastic syndrome/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) or MDS/MPN with SF3B1 mutation and thrombocytosis (MDS/MPN-SF3B1-T).
• * Not suitable for immediate myeloablative/intensive chemotherapy based on investigator assessment of age, comorbidities, local guidelines, institutional practice (any or all of these)
• * Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
• * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × upper limit of normal (ULN)
• * Total bilirubin ≤ 1.5 × ULN (except in the setting of isolated Gilbert syndrome)
• * Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73m/^2 (estimation based on Modification of Diet in Renal Disease /[MDRD/] formula, by local laboratory)
• * Patient is able to communicate with the investigator and has the ability to comply with the requirements of the study procedures
• * Women of childbearing potential and men, if not surgically sterilized, should use adequate contraception from 14 days prior to study entry and until 90 days after the last follow-up visit. Adequate contraception is defined as using hormonal contraceptives or an intrauterine device combined with at least 1 of the following forms of contraception: a diaphragm or cervical cap, or a condom

Критерии исключения

• * Previous treatment for MPN or MDS/MPN overlap with chemotherapy or other antineoplastic agents including lenalidomide and hypomethylating agent (HMAs) such as decitabine or azacitidine or INQOVI (oral decitabine) (patients who had up to 2 cycles of hypomethylating agents /[HMAs/] can be included). However, previous treatment with hydroxyurea and/or ruxolitinib is permitted
• * Diagnosis of acute myeloid leukemia (AML) including acute promyelocytic leukemia and extra-medullary AML based on WHO 2016 classification (Arber et al 2016)
• * Patients who are candidates for myeloablative or intensive chemotherapy treatment or who do not provide consent for this treatment
• * History of organ transplant or allogenic hematopoietic stem cell transplant
• * Participants with prior malignancy, except:
• * Participants with history of adequately treated malignancy for which no anticancer systemic therapy (namely chemotherapy, radiotherapy or surgery) is ongoing or required during the course of the study.
• * Participants who are receiving adjuvant therapy such as hormone therapy are eligible. However, participants who developed therapy related neoplasms are not eligible
• * Previous known allergy/sensitivity to components of axatilimab
• * History of acute or chronic pancreatitis
• * History of myositis

Описание

This study is a randomized, controlled, double-blind, multicenter, phase Ⅲ clinical study to evaluate the efficacy of IMM01(timdarpacept) in combination with azacitidine versus placebo in combination with azacitidine in patients with newly diagnosed chronic leukemia monocytic (CMML1-2).Primary endpoint are Complete remission rate and Overall survival.

Критерии включения

• * Age ≥ 18 years old, regardless of gender;
• * Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1.
• * Life expectancy ≥ 12 weeks;
• * Patients with CMML diagnosed according to WHO 2016 criteria, including CMML-1 and CMML-2;
• * White blood cell count ≤ 13×10⁹/L before the first treatment with the study drug (hydroxyurea and leukapheresis are allowed, but not within 3 days prior to the first treatment with the study drug).
• * Patients must be treatment-naïve to any hypomethylating agents (e.g., azacitidine, decitabine), chemotherapy or allogeneic stem cell transplant for CMML. Immunomodulators (thalidomide, lenalidomide), immunosuppressants (antithymocyte globulin, cyclosporine), targeted agents (ruxolitinib), etc. are also excluded, as these agents are considered disease-modifying therapies. Note: During screening and study participation, subjects may continue oral corticosteroids for diseases other than CMML (e.g. asthma) at a stable daily dose equivalent to ≤ 10 mg prednisone. In addition, supportive care in the form of blood transfusions or growth factors is not considered prior therapy in this case and is permitted prior to and as needed during the study.

Критерии исключения

• * Previous treatment with anti-CD47 monoclonal antibody/SIRPα fusion protein;
• * History of allogeneic stem cell transplant and other organ transplants; Patients who have undergone autologous haematopoietic stem cell transplant;
• * No prior diagnosis of: therapy-related myelodysplastic syndrome(t-MDS); MDS evolved from a pre-existing myeloproliferative neoplasm (MPN) ;MDS/MPN including atypical chronic myeloid leukemia (aCML), juvenile myelomonocytic leukemia (JMML) and unclassifiable MDS/MPN. Patients positive for BCR-ABL fusion genes, PDGFRA, PDGFRB, and FGF1 rearrangements need to be excluded;
• * Current or history of central nervous system (CNS) leukemia, extramedullary leukemia, or myeloid sarcoma;
• * Diagnosis of other malignant neoplasms within 5 years prior to the first dose. Exceptions: a. Radically treated cervical carcinoma in situ or non-melanoma skin cancer; b. a second primary cancer that has been curatively treated and has no recurrence within five years

Описание

This phase I trial tests the safety, side effects, and best dose of imetelstat in combination with fludarabine and cytarabine in treating patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) or juvenile myelomonocytic leukemia (JMML) that has not responded to previous treatment (refractory) or that has come back after a period of improvement (recurrent). Imetelstat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as fludarabine and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving imetelstat in combination with fludarabine and cytarabine may work better in treating patients with refractory or recurrent AML, MDS, and JMML.

Критерии включения

• * Patients must be ≥ 1 year and ≤ 18 years of age at the time of study enrollment
• * Patients, with or without down syndrome (DS), and with de novo acute myeloid leukemia, therapy-related AML, MDS or JMML and meet one of the following:
• * Second or greater relapse or refractory AML, including isolated extramedullary disease (EMD), but excluding isolated central nervous system (CNS) or isolated testicular relapse
• * First or greater relapse of MDS
• * First or greater relapse of JMML
• * For flow cytometry, it`s strongly recommended to enroll onto APAL2020SC or to send samples to Hematologics, Inc. Otherwise, assessments must be performed at a College of American Pathologists (CAP)/Clinical Laboratory Improvement Act (CLIA) certified lab that has expertise in AML.
• * For FISH/Karyotype, samples must be sent to a Children`s Oncology Group (COG)-approved Cytogenetics Lab
• * Bone marrow relapse AML:(patients must meet one of the following criteria to be defined as having relapsed disease)
• * A single bone marrow sample showing ≥ 5% leukemic blasts by flow cytometry, fluorescence in situ hybridization (FISH) testing, or other molecular method
• * A single bone marrow with at least two tests showing ≥ 1% leukemic blasts; examples of tests include:
• * Flow cytometry showing ≥ 1% leukemic blasts by multidimensional flow cytometry (MDF)
• * Karyotypic abnormality with at least one metaphase similar or identical to diagnosis
• * Fluorescence in situ hybridization (FISH) abnormality identical to one present at diagnosis
• * Polymerase chain reaction (PCR) or next generation sequencing (NGS)-based demonstration of leukemogenic lesion identical to diagnosis and ≥ 1%
• * In cases where a bone marrow aspirate cannot be obtained because of extensive fibrosis, blast count can be obtained from touch imprints or estimated from an adequate bone marrow core biopsy. A complete blood count documenting the presence of at least 1,000/ uL (i.e., a white blood cell /[WBC/] count ≥ 10,000/uL with ≥ 10% blasts or a WBC count of ≥ 5,000/uL with ≥ 20% blasts) circulating leukemic cells (blasts) can also be used if a bone marrow aspirate or biopsy cannot be performed
• * Extramedullary relapse: Biopsy proven extramedullary disease after documented complete remission
• * Refractory disease AML: Following a re-induction cycle after a second relapse, or refractory to two reinduction attempts after first relapse with:
• * A single bone marrow sample showing ≥5% leukemic blasts by flow cytometry, FISH testing, or other molecular method
• * A single bone marrow with at least two tests showing ≥1% leukemic blasts: examples of tests include:
• * Flow cytometry showing ≥1% leukemic blasts by multidimensional flow cytometry (MDF)
• * Karyotypic abnormality with at least one metaphase similar or identical to diagnosis.
• * FISH abnormality identical to one present at diagnosis
• * Polymerase chain reaction (PCR) or next generation sequencing (NGS)-based demonstration of leukemogenic lesion identical to diagnosis and ≥ 1%
• * In cases where a bone marrow aspirate cannot be obtained because of extensive fibrosis, blast count can be obtained from touch imprints or estimated from an adequate bone marrow core biopsy. A complete blood count documenting the presence of at least 1,000/ uL (i.e., a WBC count ≥ 10,000/uL with ≥ 10% blasts or a WBC count of ≥ 5,000/uL with ≥ 20% blasts) circulating leukemic cells (blasts) can also be used if a bone marrow aspirate or biopsy cannot be performed
• * Extramedullary refractory disease:
• * Biopsy proven persistent extramedullary disease
• * In cases where a bone marrow aspirate cannot be obtained because of extensive fibrosis, blast count can be obtained from touch imprints or estimated from an adequate bone marrow core biopsy. A complete blood count documenting the presence of at least 1,000/ µL (i.e., a WBC count ≥ 10,000/μL with ≥ 10% blasts or a WBC count of ≥ 5,000/μL with ≥ 20% blasts) circulating leukemic cells (blasts) can also be used if a bone marrow aspirate or biopsy cannot be performed
• * Central nervous system disease: Patients with relapsed or refractory disease with central nervous system (CNS) 1 and CNS 2 status are eligible
• * MDS: Bone marrow relapse:(patients must meet one of the following criteria to be defined as having relapsed disease)
• * A single bone marrow sample showing ≥ 5% leukemic blasts by flow cytometry, FISH testing, or other molecular method
• * A single bone marrow with at least two tests showing ≥1% leukemic blasts; examples of tests include:
• * Flow cytometry showing ≥ 1% leukemic blasts by multidimensional flow cytometry (MDF)
• * Karyotypic abnormality with at least one metaphase similar or identical to diagnosis
• * FISH abnormality identical to one present at diagnosis
• * Polymerase chain reaction (PCR) or next generation sequencing (NGS)-based demonstration of MDS associated lesion identical to diagnosis and ≥ 1%
• * In cases where a bone marrow aspirate cannot be obtained because of extensive fibrosis, blast count can be obtained from touch imprints or estimated from an adequate bone marrow core biopsy
• * JMML: Diagnosis: Patients must have had histologic verification of juvenile myelomonocytic leukemia (JMML) at original diagnosis and currently have relapsed or refractory disease. The diagnosis is made based on the following criteria
• * JMML category 1 (all of the following):
• * Splenomegaly
• * /> 1000 (1x10/^9 /uL) circulating monocytes
• * /< 20% Blasts in the bone marrow or peripheral blood
• * Absence of the t(9;22) or BCR/ABL fusion gene
• * The diagnostic criteria must include all features in category 1 andeither (i) one of the features in category 2 or (ii) two features from category 3 to make the diagnosis
• * JMML category 2 (at least one of the following if at least two category 3 criteria are not present):
• * Somatic mutation in RAS or PTPN11
• * Clinical diagnosis of NF1 or NF1 gene mutation
• * Homozygous mutation in CBL
• * Monosomy 7
• * JMML category 3 (at least two of the following if no category 2 criteria are met):
• * Circulating myeloid precursors
• * White blood cell count, />10 000 (10x10/^9 / uL)
• * Increased hemoglobin F for age
• * Clonal cytogenetic abnormality
• * Granulocyte-macrophage-colony-stimulating factor {GM-CSF) hypersensitivity
• * Patients with relapsed JMML must have had at least one cycle of intensive frontline therapy or at least 2 cycles of a deoxyribonucleic acid (DNA) hypomethylating agent with persistence of disease, defined by clinical symptoms or the presence of a clonal abnormality. Frontline therapy is defined as one cycle of intravenous chemotherapy that includes of any of the following agents: fludarabine, cytarabine, or any anthracycline but specifically excludes oral 6-mercaptopurine. Frontline therapy will also include any conditioning regimen as part of a stem cell transplant. Patients who transform to AML at any point with more than 20% blasts are eligible for this trial per the AML specific criteria
• * Patient`s current disease state must be one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life
• * Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2. Use Karnofsky (≥ 50) for patients /> 16 years of age and Lansky for patients ≤ 16 years of age (≥ 50)
• * Patients must have fully recovered (grade /< 2) from the acute toxic effects of all prior anti-cancer therapy and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment. If after the required time frame, the numerical eligibility criteria are met, e.g. blood count criteria, the patient is considered to have recovered adequately
• * Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive: See DVLhomepage on the COG Members site for commercial and investigational agent classifications (https://cogmembers.org/uploadedFiles/Site/Disc/DVL/Documents/TableOfMyelosuppressiveAnti-CancerAgents.pdf). For agents not listed, the duration of this interval must be discussed with the study chair and the study-assigned research coordinator prior to enrollment
• * ≥ 14 days must have elapsed after the completion of other cytotoxic therapy, with the exception of hydroxyurea, for patients not receiving standard maintenance therapy. Additionally, patients must have fully recovered from all acute toxic effects of prior therapy
• * Note: Cytoreduction with hydroxyurea must be discontinued ≥ 24 hours prior to the start of protocol therapy
• * Anti-cancer agents not known to be myelosuppressive (e.g. not associated with reduced platelet or absolute neutrophil (ANC) counts):
• * ≥ 7 days after the last dose of agent. See the DVL homepage on the COG Members site for commercial and investigational agent classifications. For agents not listed, the duration of this interval must be discussed with the study chair and the study-assigned research Ccoordinator prior to enrollment
• * Antibodies: ≥ 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade ≤ 1
• * Hematopoietic growth factors: ≥ 14 days after the last dose of a long-acting growth factor (e.g. pegfilgrastim) or 7 days for short-acting growth factor. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur
• * Interleukins, interferons and cytokines (other than hematopoietic growth factors): ≥ 21 days after the completion of interleukins, interferon, or cytokines (other than hematopoetic growth factors)
• * Stem cell Infusions (with or without total body irradiation /[TBI/]):
• * Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell infusion including donor lymphocyte infusion (DLI) or boost infusion: ≥ 84 days after infusion and no evidence of graft-versus-host disease GVHD
• * Patients must be off calcineurin inhibitors for at least 28 days prior to the date of enrollment. Patients may be on physiological doses of steroids (equivalent to ≤ 10 mg prednisone daily for patients ≥ 18 years or ≤ 10mg/m/^2/day /[up to a maximum of 10 mg/day/] for patients /< 18 years)
• * Autologous stem cell infusion including boost infusion: ≥ 30 days
• * Cellular Therapy: ≥ 30 days after the completion of any type of cellular therapy (eg, modified T cells, NK cells, dendritic cells, etc.)
• * External Beam Radiation (XRT)/external beam irradiation including protons: ≥ 14 days after local XRT; ≥ 150 days after TBI, craniospinal XRT or if radiation to ≥ 50% of the pelvis; ≥ 42 days if other substantial bone marrow (BM) radiation
• * Radiopharmaceutical therapy (eg, radiolabeled antibody, 131I MIBG): ≥ 42 days after systemically administered radiopharmaceutical therapy
• * Patients must not have received prior exposure to imetelstat
• * For patients with leukemia:
• * Platelet count ≥ 25,000/uL (may receive platelet transfusions). These patients must not be known to be refractory to red cell or platelet transfusion
• * Hemoglobin />= 8.0 g/dL at baseline (may receive red blood cell (RBC) transfusions)
• * Adequate renal function defined as:
• * Estimated glomerular filtration rate (GFR) (eGFR) ≥ 70 mL/min/1.73 m/^2 "Bedside" Schwartz formula (2009): eGFR = 0.413 x (height /[cm/] / serum creatinine /[mg/dL/]) OR
• * a 24 hour urine creatinine clearance ≥ 70 mL/min/1.73 m/^2 OR
• * a GFR ≥ 70 mL/min/1.73 m/^2. GFR must be performed using direct measurement with a nuclear blood sampling method OR direct small molecule clearance method (iothalamate or other molecule per institutional standard)
• * Adequate liver function defined as:
• * Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of normal (ULN) for age
• * Serum glutamic-pyruvic transaminase (SGPT) (alanine aminotransferase /[ALT/]) ≤ 3 x ULN, unless attributed to leukemia involvement
• * AST ≤ 3 x ULN, unless attributed to leukemia involvement
• * Albumin ≥ 2 g/dL
• * Shortening fraction of ≥ 27% by echocardiogram, or
• * Ejection fraction of ≥ 50% by gated radionuclide study

Критерии исключения

• * Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies, or because there is yet no available information regarding human fetal or teratogenic toxicities. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use two effective methods of birth control, including a medically accepted barrier or contraceptive method (eg, male or female condom) for the duration of the study. Abstinence is an acceptable method of birth control. Women of childbearing potential must use highly effective contraception in addition to a barrier method during treatment and for at least 1 month after the last dose of imetelstat or longer if required by the institutional guidelines for conventional chemotherapy (fludarabine/cytarabine). Male patients who can father a child should use contraception during treatment and for 3 months after the last dose of imetelstat or longer if required by the institutional guidelines for conventional chemotherapy (fludarabine/cytarabine). Imetelstat should not be administered to nursing mothers
• * Corticosteroids: Patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible. If used to modify immune adverse events related to prior therapy, ≥ 14 days must have elapsed since last dose of corticosteroid
• * Investigational drugs: Patients who are currently receiving another investigational drug are not eligible
• * Anti-cancer Agents: Patients who are currently receiving other anti-cancer agents are not eligible except patients receiving hydroxyurea, which may be continued until 24 hours prior to start of protocol therapy
• * Anti-GVHD agents post-transplant: Patients who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post bone marrow transplant are not eligible for this trial
• * Specific to MDS patients: Low-grade MDS/refractory cytopenia of childhood (RCC) - MDS with less than 2% blasts in peripheral blood (PB) or less than 5% blasts in the bone marrow (BM) by morphology
• * Uncontrolled seizure disorder that is not stabilized with anti-convulsants
• * Patient has undergone surgery that requires general anesthesia within 3 weeks before enrollment (line placement/removal/revision or tissue collection is allowed)
• * Known hypersensitivity to the study drug or excipients of the preparation
• * Patients with acute promyelocytic leukemia (APL) with PML-RARA genetic abnormality according to World Health Organization (WHO) classification or t(15;17) are not eligible
• * Patients known to have a congenital bone marrow failure syndrome where increased risk of toxicity may be expected as judged by the Investigator, for example dyskeratosis congenita, are not eligible
• * Patients with isolated or refractory CNS or isolated or refractory testicular relapse are not eligible
• * Patients who have an uncontrolled infection are not eligible
• * Patients who have received a prior solid organ transplantation are not eligible
• * Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible

Описание

There are 2 possible treatments for the treatment of Acute Myelogenous Leukemia (AML), high-risk myelodysplastic syndromes (HR-MDS) or chronic myelomonocytic leukemia (CMML): intensive curative chemotherapy , and for over-aged or co-morbid patients , non-intensive palliative chemotherapy with a hypomethylating agent (Azacytidine) associated or not with venetoclax.

Pro-inflammatory cytokines and in particular IL-6 (Interleukin 6) seem to play a key role in the chemoresistance of solid cancers and AML : it would be associated with a poor prognosis of AML , would promote the proliferation of leukemic blasts , and would promote the progression of MDS to AML .

In AML treated with intensive chemotherapy, researchers demonstrated that a particular kinetic profile of the FLT3 ligand and IL6 at day 22 could very significantly predict the survival of patients with AML .

It therefore seems interesting to study the plasma cytokine profiles in patients with AML, HR-MDS or CMML treated non-intensively, and to see if researchers observe the same prognostic correlation as during intensive chemotherapy.

Критерии включения

• * Age />=18 years
• * AML or SMD-HR or CMML in first line or in relapse receiving a hypomethylating agent +/- another molecule or a hypomethylating agent in combination with venetoclax +/- another molecule.
• * Patient having agreed to participate in the study (information note signature) and having signed the biocollection consent

Критерии исключения

• * No social security or any other regime
• * Pregnant women or patient unable to take contraception in case of fertility
• * Breastfeeding women
• * Minors
• * Adults under guardianship, curators or safeguard of justice

Описание

This phase I trial tests the safety, side effects, and effectiveness of olutasidenib in preventing the return of disease (relapse) in patients who have undergone donor (allogeneic) hematopoietic cell transplant for acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or chronic myelomonocytic leukemia (CMML) carrying an IDH1 mutation. Olutasidenib is in a class of medications called IDH1 inhibitors. It works by slowing or stopping the growth of cancer cells. Giving olutasidenib may be safe, tolerable and/or effective in preventing relapse in patients with IDH1 mutated AML, MDS or CMML after an allogeneic hematopoietic cell transplant.

Критерии включения

• * Documented informed consent of the participant and/or legally authorized representative
• * 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 or Karnofsky performance status (KPS) ≥ 70
• * Patients who are scheduled to receive or have already undergone allogeneic hematopoietic cell transplantation (alloHCT) from any donor type, any conditioning regimen, and regardless of GVHD prophylaxis will be include
• * Patients must have AML, MDS, or CMML with mIDH1 diagnosis at diagnosis (regardless of time from HCT). Note: Patient with pre-HCT disease relapse will no be included if mIDH1 is not detected after relapse
• * Day 30 marrow post alloHCT should show evidence of morphologic remission with /< 5% bone marrow (BM) blasts. Patients with MRD-positive status either by flow cytometry or IDH1 mutation testing will be eligible
• * Patients with previous therapy with IDH1 inhibitors will be included
• * Absolute neutrophil count (ANC) /> 1000/mm/^3 (within 28 days prior to day 1 of protocol)
• * Hemoglobin ≥ 8.0 gm/dL (within 28 days prior to day 1 of protocol)
• * Platelets ≥ 50,000/mm/^3 (within 28 days prior to day 1 of protocol) Note: Patients with lower counts can enroll if infection cytomegalovirus (CMV)/human herpes virus 6 (HHV6), etc. is being treated actively
• * Bilirubin ≤ 2 x upper limit of normal (ULN) (within 28 days prior to day 1 of protocol) (unless has Gilbert`s disease). Patients with abnormal liver function tests (LFTs) due to active GVHD will not be eligible
• * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase /[SGOT/])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase /[SGPT/]) ≤ 2 x ULN (within 28 days prior to day 1 of protocol). Patients with abnormal LFTs due to active GVHD will not be eligible
• * Creatinine clearance of ≥ 30/min/1.73 m/^2 for participants with creatinine levels above institutional normal per 24 hour urine test or the Cockcroft-Gault formula (within 28 days prior to day 1 of protocol)
• * Corrected QT interval (QTc) ≤ 480 ms (Note: To be performed within 28 days prior to day 1 of protocol therapy)
• * Seronegative for HIV antigen/antibody (Ag/Ab) combo, hepatitis C virus (HCV) (if positive, hepatitis C ribonucleic acid /[RNA/] quantitation must be performed), active hepatitis B virus (HBV) (surface antigen negative), and syphilis (rapid plasma reagin /[RPR/]) (within 28 days prior to day 1 of protocol)
• * Women of childbearing potential (WOCBP): negative urine or serum pregnancy test (within 28 days prior to day 1 of protocol). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
• * Agreement by females and males of childbearing potential, defined as not being surgically sterilized (men and women) or have not been free from menses for /> 1 year (women only), to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 3 months after the last dose of protocol therapy

Критерии исключения

• * Patients with more than one allogeneic HCT
• * History of allergic reactions attributed to compounds of similar chemical or biological composition to study agent
• * Active diarrhea considered clinically significant and may impair oral drug administration
• * Clinically significant uncontrolled illness
• * Uncontrolled infection requiring systemic antimicrobials
• * Active infection: Patients with treated viral, bacterial or fungal infections that are controlled on therapy will be allowed to participate
• * Participant has detectable human immunodeficiency virus (HIV) viral load within the previous 6 months (must have viral load testing prior to study enrollment if participant has a known history of HIV 1/2 antibodies)
• * Active hepatitis B or C, or HIV
• * Other active malignancy. Participants with history of prior malignancy treated with curative intent who achieved CR more than 2 years before study entry are eligible. This exclusion rule does not apply to non-melanoma skin tumors and in-situ cervical cancer
• * Females only: Pregnant or breastfeeding
• * Active grade II-IV acute GVHD per Mount Sinai Acute Graft Versus Host Disease International Consortium (MAGIC) criteria and/or requiring systemic steroids with prednisone dose equivalent of ≥ 0.25 mg/kg at end of 4 weeks. Patients with a mild form of acute GVHD involving skin, gut or liver requiring topical steroid creams or oral beclomethasone (8 mg/day), entocort, (9 mg/day) and/or solumedrol (and equivalent prednisone) will be allowed
• * 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 is a phase 1/2 trial of pacritinib in combination with azacitidine in patients with Chronic Myelomonocytic Leukemia (CMML). Patients will be newly diagnosed or previously treated but could not have received a prior JAK inhibitor. Patients who have previously been treated with a hypomethylating agent (HMA) must have received ≤ 1 cycle. Pacritinib will be initially tested at a dose of 200mg twice daily (dose level 0) in combination with azacitidine 75mg/m2, which can be administered subcutaneously or intravenously, for 7 days in a 28-day cycle. If there are 2 DLTs in the first 6 patients, there will be a dose escalation to pacritinib 100mg twice daily (dose level -1) and an additional 6 patients will be enrolled. Based on the phase 1, 3+3 dose de-escalation design, 6-12 patients will be enrolled in the phase 1 portion. After the completion of phase 1 and identification of the recommended phase 2 dose (RP2D), the trial will then proceed to phase 2 which will employ a Simon two stage design. This portion will include the 6 patients enrolled during the phase 1 portion at the MTD. An interim analysis for futility will occur. If 3 or fewer patients have had a clinical benefit (CB) or better, as defined by 2015 MDS/MPN IWG criteria, the PI and DSMC will meet to discuss the totality of the evidence and determine if the trial shall proceed. In the second stage, an additional 12 patients will be enrolled.

Критерии включения

• * Participants must be ≥18 years of age at time of signing the Informed Consent Form (ICF).
• * Participants must voluntarily sign an ICF.
• * Participants must have a pathologically confirmed diagnosis of chronic myelomonocytic leukemia per World Health Organization (WHO) or International Consensus Classification (ICC)
• * Participants must be JAK inhibitor naïve.
• * Participants may be hypomethylating agent (HMA) naïve or can be treated with up to one prior cycle.
• * Participants must have either proliferative CMML (WBC ≥13 x 109/L) or have intermediate-2 or high risk CMML by the clinical/molecular CMML-specific prognostic scoring system (CPSS-Mol).
• * Participants must have a life expectancy of at least 24 weeks per investigator.
• * ECOG performance status ≤ 3.
• * Females of reproductive potential should use effective contraception during treatment with azacitidine and for 6 months after the last dose and males with female partners of reproductive potential should use effective contraception during treatment with azacitidine and for 3 months after the last dose.
• * Male participants should agree to use an adequate method of contraception starting with the first dose of study therapy through 90 days after the last dose of study therapy.
• * Must have adequate organ function as demonstrated by the following:
• * Serum total bilirubin ≤ 2.0 x upper limit of normal (ULN) unless considered due to leukemic organ involvement, Gilbert`s syndrome, or hemolysis.
• * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x ULN.
• * Creatinine clearance (CrCl) of ≥30 mL/min.
• * PT or INR /<=1.5x ULN and PTT or aPTT /<=1.5x ULN.
• * ANC />= 500 cells/μL.
• * Ability to adhere to the study visit schedule and all protocol requirements.
• * Ability to understand and the willingness to sign a written informed consent.

Критерии исключения

• * Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 2 weeks or within 5 half-lives of the prior investigational agent, whichever is shorter, of the first dose of treatment.
• * Active Graft Versus Host Disease (GVHD), or any GVHD requiring treatment with immunosuppression, with the exception of topical steroids and systemic steroids at a dose equivalent to prednisone 10mg or less and at a stable or decreasing dose. Any GVHD treatment (including calcineurin inhibitors) must be discontinued at least 28 days prior to Day 1 of study treatment.
• * Systemic treatment with a strong CYP3A4 inhibitor or a strong CYP450 inducer within 14 days prior to treatment Day 1 (see Appendix 13.7 and 13.8 for a list of CYP3A4 inhibitors and CYP450 inducers, respectively). Shorter washout periods may be permitted with approval of the Study Chair, provided that the washout period is at least five half-lives of the drug prior to treatment Day 1.
• * Other invasive malignancies within the last 3 years, except curatively treated non-melanoma skin cancer, localized prostate, cervical cancer, and any curatively treated carcinoma in situ.
• * Presence of active serious infection.
• * If a patient is identified to have COVID-19 during the screening period, participants may be considered eligible if in the opinion of the investigator there are no COVID-19 sequlae that may place the patient at a higher risk of receiving investigational treatment.
• * Any serious, unstable medical or psychiatric condition that would prevent, (as judged by the Investigator) the patient from signing the informed consent form or any condition, including the presence of laboratory abnormalities, which places the patient at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study.
• * Known history of uncontrolled human immunodeficiency virus (HIV).
• * Significant recent bleeding history defined as NCI CTCAE grade ≥2 within 3 months prior to treatment Day 1, unless precipitated by an inciting event (e.g., surgery, trauma, or injury).
• * Systemic treatment with medications that increase the risk of bleeding, including anticoagulants, antiplatelet agents (except for aspirin dosages of ≤100 mg per day), anti-vascular endothelial growth factor (anti-VEGF) agents, and daily use of COX-1 inhibiting Non-steroidal anti-inflammatory drugs (NSAIDs) within 14 days prior to treatment Day 1.
• * Any history of CTCAE grade ≥2 cardiac conditions within 6 months prior to treatment Day 1. Patients with asymptomatic grade 2 non-dysrhythmia cardiovascular conditions may be considered for inclusion, with the approval of the Study Chair, if stable and unlikely to affect patient safety.
• * Heart failure other than NYHA class I (asymptomatic, without limitation).
• * QT corrected by the Fridericia method (QTcF) prolongation />480 ms or other factors that increase the risk for QT interval prolongation (e.g., hypokalemia /[defined as serum potassium /<3.0 mEq/L that is persistent and refractory to correction/], or history of long QT interval syndrome).
• * Known active systemic hepatitis B, or C infection requiring therapy or known cirrhosis.
• * Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling, or child) who is investigational site or pharmaceutical sponsor staff directly involved with this trial, unless prospective IRB approval (by chair or designee) is given allowing exception to this criterion for a specific participant.
• * Organ transplant recipients other than bone marrow transplant.
• * Women who are pregnant or lactating.
• * Patient with known gastrointestinal (GI) disease or prior GI procedure that could interfere with the oral absorption or tolerance of pacritinib, including difficulty swallowing, are not eligible.

Описание

This clinical trial will test the safety and efficacy of combining trametinib and azacitidine in patients with juvenile myelomonocytic leukemia (JMML). Newly diagnosed lower-risk JMML patients will receive trametinib and azacitidine. High-risk JMML patients will receive trametinib, azacitidine, fludarabine, and cytarabine.

Критерии включения

• Age
• • Patients must be ≥ 1 month and ≤21 years of age at enrollment.
• Diagnosis • Patients must meet the 2022 International Consensus Classification criteria for JMML. The diagnosis is made based on the following criteria:.
• Clinical and hematologic features (the first 2 features are present in most cases; the last 2 are required):
• * Peripheral blood monocyte count ≥ 1 × 109/L/*
• * Splenomegaly†
• * Blast percentage in PB and BM /< 20%
• * Absence of BCR::ABL1
• * This monocyte threshold is not reached in approximately 7% of cases. †Splenomegaly is absent in 3% of cases at presentation.
• II. Genetic studies (1 finding required):
• * Somatic mutation in PTPN11‡ or KRAS‡ or NRAS‡ or RRAS or RRAS2‡
• * Clinical diagnosis of neurofibromatosis type 1 or germline NF1 mutation and loss of heterozygosity of NF1 or somatic biallelic loss of NF1
• * Germline CBL mutation and loss of heterozygosity of CBL, or somatic mutation(s) in CBL§
• * Germline mutations (indicating Noonan syndrome) need to be excluded. §Occasional cases with heterozygous splice site mutations.
• Performance Level
• * Karnofsky /> 50% for patients ≥ 16 years of age
• * Lansky /> 50% for patients /< 16 years of age.
• Prior Therapy
• * No prior leukemia directed therapy is permitted with the exception of:
• 1. Cytoreduction with hydroxyurea can be initiated and continued for up to 24 hours prior to the start of trametinib.
• 2. Cytoreduction with 6-mercaptopurine (6-MP) 6-MP can be initiated and continued for up to 72 hours prior to the start of trametinib.
• 3. Intrathecal (IT) cytarabine, IT methotrexate or triple IT therapy (cytarabine, methotrexate and hydrocortisone) within 7 days of enrollment as part of a diagnostic evaluation.
• No prior hematopoietic stem cell transplant is permitted.
• Adequate Renal Function Defined as:
• * Patient must have a calculated creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73m2 OR a normal serum creatinine based on age/gender in the chart below:
• Maximum Serum Creatinine (mg/dL):
• * 1 month to /< 6 months old - Male: 0.4, Female 0.4
• * 6 months to /<1 year old - Male 0.5, Female 0.5
• * 1 to /< 2 years old - Male: 0.6, Female: 0.6
• * 2 to /< 6 years old - Male:0.8, Female: 0.8
• * 6 to /< 10 years old - Male: 1, Female: 1
• * 10 to /< 13 years old - Male: 1.2, Female: 1.2
• * 13 to /< 16 years old - Male: 1.5, Female: 1.4
• * ≥ 16 years old - Male: 1.7, Female: 1.4 The threshold creatinine values in this Table were derived from the Schwartz formula for estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing child length and stature data published by the CDC.
• Adequate Liver Function Defined as:
• * Direct bilirubin /< 1.5 x upper limit of normal (ULN) for age or normal, AND alanine transaminase (ALT) /< 5 x ULN for age.
• * The hepatic requirements are waived for patients with known or suspected liver involvement by leukemia and will not be evaluable for hepatotoxicity. This must be reviewed and approved by the study chair or vice chair.
• Adequate Cardiac Function Defined as:
• * Ejection fraction of /> or = to 50% by echocardiogram, OR
• * Ejection fraction of /> or = to 50% by radionuclide angiogram (MUGA).
• Reproductive Function
• * Female patients of childbearing potential must have a negative urine or serum pregnancy test confirmed within 2 weeks prior to enrollment.
• * Female patients with infants must agree not to breastfeed their infants while on this study.
• * Male and female patients of child-bearing potential must agree to use an effective method of contraception approved by the investigator during the study and for a minimum of 6 months after study treatment.

Критерии исключения

• * Patients cannot have a known allergy to any of the drugs used in the study.
• * Patients cannot have a systemic fungal, bacterial, viral, or other infection that is exhibiting ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics or other treatment. The patient needs to be off pressors and have negative blood cultures for 48 hours.
• * Patients cannot have a plan to administer non-protocol chemotherapy, radiation therapy, or immunotherapy during the study period.
• * Patients cannot have significant concurrent disease, illness, psychiatric disorder or social issue that would compromise patient safety or compliance with the protocol treatment or procedures, interfere with consent, study participation, follow up, or interpretation of study results.
• * Patients cannot have a clinical or molecular diagnosis of Noonan syndrome. Note: patients with either neurofibromatosis type 1 or Casitas B-lineage lymphoma (CBL) syndrome (also known as Noonan-like syndrome), are eligible to enroll. Patients with Down syndrome are excluded from the study.
• * Patient cannot have had prior use of hematopoietic growth factors, biologics (anti-neoplastic agent), or XRT.
• * Patients cannot be taking any medications for treatment of left ventricular systolic dysfunction.
• * Patients cannot have a history of or current evidence of retinal vein occlusion (RVO) or central serous retinopathy (CSR).
• * Patients cannot have had prior use of any MEK inhibitor.