CPX-351 With or Without Venetoclax in Treating Patients with Relapsed or Refractory High Risk Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia
This phase I trial studies best dose and side effects of liposome-encapsulated daunorubicin-cytarabine (CPX-351) and how well it works in treating patients with high risk myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML) that has come back or has not responded to treatment. Drugs used in chemotherapy, such as liposome-encapsulated daunorubicin-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. 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 CPX-351 with or without venetoclax may be safe and tolerable in treating patients with relapsed or refractory MDS or CMML.
Inclusion Criteria
- Age 18-75 years candidates for intensive therapy
- Diagnosis of MDS or MDS/MPN including chronic myelomonocytic leukemia (CMML) according to World Health Organization (WHO) and
- FOR COHORTS 1 AND 2: * Patients are either not eligible for or choose not to proceed with a stem cell transplant at the time of enrollment * MDS or CMML classified by International Prognostic Scoring System (IPSS) as intermediate-2/high risk with excess blasts > 5% or with 10-19% bone marrow blasts * No response following at least 4 cycles of therapy or relapse after initial CR, partial response (PR) or hematologic improvement (HI) or progression after any number of cycles of either azacitidine, decitabine, guadecitabine or ASTX727 (oral decitabine) as single agents or in combination with other investigational agents
- FOR COHORTS 3-5: * Patients must be deemed eligible for intensive chemotherapy and/or hematopoietic stem-cell transplant at the time of enrollment * Cohorts 3-4: patients with relapsed/refractory higher risk MDS (defined by an IPSS-Revised score ≥ 3.5 or ≥ 10% bone marrow blasts) or MDS/MPN with ≥ 10% bone marrow blasts, after no response to at least 4 cycles of therapy with azacitidine, decitabine, guadecitabine or oral decitabine/cedazuridine or relapse or progression after any number of cycles * Cohort 5: patients with previously untreated higher risk MDS (defined by an IPSS-Revised score ≥ 3.5 or ≥ 10% bone marrow blasts) or MDS/MPN with ≥ 10% bone marrow blasts
- Patient must have signed an informed consent document indicating that the patient understands the purpose of and procedures required for the study and is willing to participate in the study
- Total bilirubin < 3 mg/dL (will allow less than 5 x upper limit of normal [ULN] if Gilbert's at investigator's discretion)
- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 3 x ULN (unless related to disease involvement)
- Serum creatinine clearance > 30 mL/min and no end/stage renal disease
- Hydroxyurea for control of leukocytosis or use of hematopoietic growth factors (e.g., granulocyte-colony stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor [GM-CSF], Procrit, Aranesp, thrombopoietins) is allowed at any time prior to or during study if considered to be in the best interest of the patient
Exclusion Criteria
- New York Heart Association (NYHA) class III or IV congestive heart failure or left ventricular ejection fraction (LVEF) < 50 by echocardiogram or multigated acquisition (MUGA) scan
- FOR COHORTS 3-5: MDS or MDS/MPN with presence of complex and/or monosomal karyotype in the presence of TP53 mutations
- History of myocardial infarction within the last 6 months or unstable/uncontrolled angina pectoris or history of severe and/or uncontrolled ventricular arrhythmias
- Uncontrolled infection not adequately responding to appropriate antibiotics
- Female patients who are pregnant or lactating
- Patients with reproductive potential who are unwilling to following contraception requirements (including condom use for males with sexual partners, and for females: prescription oral contraceptives [birth control pills], contraceptive injections, intrauterine devices [IUD], double-barrier method [spermicidal jelly or foam with condoms or diaphragm], contraceptive patch, or surgical sterilization) throughout the study
- Female patients with reproductive potential who have a positive urine or blood beta-human chorionic gonadotropin (beta HCG) pregnancy test at screening
- Patients receiving any other concurrent investigational agent or chemotherapy, radiotherapy, or immunotherapy (within 14 days of initiating study treatment)
- Prior cumulative anthracycline exposure of > 550 mg/m^2 daunorubicin or equivalent, or > 400 mg/m^2 in patients who received radiation therapy to the mediastinum
Additional locations may be listed on ClinicalTrials.gov for NCT03896269.
Locations matching your search criteria
United States
Texas
Houston
PRIMARY OBJECTIVES:
I. To characterize the safety and tolerability of CPX-351 in patients with intermediate-2 or high-risk myelodysplastic syndrome (MDS). (SINGLE AGENT CPX-351 DOSE ESCALATION STAGE [COHORT 1])
II. To determine the maximum tolerated dose (MTD) of intravenous CPX-351 in patients with intermediate-2 or high-risk MDS. (SINGLE AGENT CPX-351 DOSE ESCALATION STAGE [COHORT 1])
III. To further characterize the safety and tolerability of CPX-351 in patients with intermediate-2 and high-risk MDS. (SINGLE AGENT CPX-351 DOSE-EXPANSION STAGE [COHORT 2])
IV. To evaluate preliminary efficacy of CPX-351 in patients with intermediate-2 or high-risk MDS. (SINGLE AGENT CPX-351 DOSE-EXPANSION STAGE [COHORT 2])
V. Characterize the safety, tolerability and MTD of the combination of CPX-351 and venetoclax in relapsed/refractory higher risk MDS and MDS/MPN. (COMBINATION CPX-351 AND VENETOCLAX STAGE [COHORT 3-4])
VI. Characterize the safety and tolerability of the combination of CPX-351 and venetoclax in previously untreated higher risk MDS and MDS/MPN. (COMBINATION CPX-351 AND VENETOCLAX STAGE [COHORT 5])
SECONDARY OBJECTIVES:
I. To assess overall response (OR) rate, overall survival (OS), duration of response, relapse-free survival (RFS) and safety profile. (SINGLE AGENT CPX-351 DOSE ESCALATION STAGE [COHORT 1])
II. To evaluate percentage of patients transitioning to allogeneic stem-cell transplant after therapy with CPX-351. (SINGLE AGENT CPX-351 DOSE ESCALATION STAGE [COHORT 1])
III. Correlative studies to correlate response outcomes with cytogenetic and mutation profile. (SINGLE AGENT CPX-351 DOSE ESCALATION STAGE [COHORT 1])
VIII. Characterize the clinical activity of CPX-351 in combination with venetoclax defined by International Working Group (IWG) response criteria in relapsed/refractory higher risk MDS and MDS/MPN. (COMBINATION CPX-351 AND VENETOCLAX STAGE [COHORT 3-4])
IX. Characterize the clinical activity of CPX-351 in combination with venetoclax defined by complete response (CR) rate, following IWG response criteria in previously untreated higher risk MDS and MDS/MPN. (COMBINATION CPX-351 AND VENETOCLAX STAGE [COHORT 5])
X. To characterize additional clinical activity outcomes such as duration of response, leukemia-free survival (LFS), relapse-free survival (RFS), and overall survival (OS). (COMBINATION CPX-351 AND VENETOCLAX STAGE)
XI. To evaluate the proportion of patients able to bridge to hematopoietic stem-cell transplant. (COMBINATION CPX-351 AND VENETOCLAX STAGE)
XII. To correlate response with disease subtype and genomic profile. (COMBINATION CPX-351 AND VENETOCLAX STAGE)
XIII. To evaluate changes in clonal composition and variant allele frequency (VAF) of identified mutations with therapy. (COMBINATION CPX-351 AND VENETOCLAX STAGE)
OUTLINE: This is a dose-escalation study followed by a dose expansion study of CPX-351. Patients are assigned to 1 of 2 arms.
ARM I:
INDUCTION THERAPY: Patients receive liposome-encapsulated daunorubicin-cytarabine intravenously (IV) over 90 minutes on days 1, 3, and 5 in the absence of disease progression or unacceptable toxicity. After 2-5 weeks, patients who do not achieve a complete response (CR)/CR with incomplete bone marrow recovery (CRi)/CR with incomplete platelet recovery (CRp), have acceptable or no toxicity, and have stable disease and no disease progression may receive liposome-encapsulated daunorubicin-cytarabine IV over 90 minutes on days 1 and 3 in the absence of disease progression or unacceptable toxicity.
CONSOLIDATION THERAPY: Patients who achieve at least a hematological improvement (HI) response, receive liposome-encapsulated daunorubicin-cytarabine IV over 90 minutes on days 1 and 3. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. After 5-8 weeks, patients who do not show clinically significant disease progression or unacceptable toxicity may receive liposome-encapsulated daunorubicin-cytarabine for up to 12 additional cycles.
Patients undergo echocardiography or multigated acquisition (MUGA) scan during screening and bone marrow aspiration and blood sample collection throughout the study.
ARM II:
INDUCTION THERAPY: Patients receive liposome-encapsulated daunorubicin-cytarabine IV over 90 minutes on days 1, 3, and 5 and venetoclax orally (PO) daily (QD) on days 1-7 in the absence of disease progression or unacceptable toxicity. After 2-5 weeks, patients who do not achieve a CR)/CRi/CRp, have acceptable or no toxicity, and have stable disease and no disease progression may receive liposome-encapsulated daunorubicin-cytarabine IV over 90 minutes on days 1 and 3 and venetoclax PO QD on day 1-7 in the absence of disease progression or unacceptable toxicity.
CONSOLIDATION THERAPY: Patients who achieve at least an HI response, receive liposome-encapsulated daunorubicin-cytarabine IV over 90 minutes on days 1 and 3 and venetoclax PO QD on day 1-7. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. After 5-8 weeks, patients who do not show clinically significant disease progression or unacceptable toxicity may receive liposome-encapsulated daunorubicin-cytarabine and venetoclax for up to 12 additional cycles.
Patients undergo echocardiography or MUGA scan during screening and bone marrow aspiration and blood sample collection throughout the study.
After completion of study treatment, patients are followed up at 30 days and then every 6 months thereafter.
Trial PhasePhase I
Trial Typetreatment
Lead OrganizationM D Anderson Cancer Center
Principal InvestigatorGuillermo Montalban Bravo
- Primary ID2018-0911
- Secondary IDsNCI-2019-01558
- ClinicalTrials.gov IDNCT03896269