Venetoclax, Busulfan, Fludarabine, Azacitidine, Decitabine, and Cedazuridine in Treating Patients with High Risk Acute Myeloid Leukemia, Myelodysplastic Syndrome, and Myelodysplastic/Myeloproliferative Neoplasm Overlap Syndromes Undergoing Donor Stem Cell Transplantation
This phase I trial studies the best dose and side effects of venetoclax when given together with busulfan, fludarabine, azacitidine, decitabine, and cedazuridine in treating patients with high risk acute myeloid leukemia, myelodysplastic syndrome, chronic myelomonocytic leukemia, or myelodysplastic syndrome/myeloproliferative neoplasm undergoing donor hematopoietic stem cell transplantation. Drugs used in chemotherapy, such as venetoclax, busulfan, fludarabine, azacitidine, decitabine, and cedazuridine work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.
Inclusion Criteria
- Age 18 years and older
- Patients must have a prior diagnosis of one of the following: (Note: Mutational and cytogenetic studies performed at sites other than Dana-Farber Cancer Institute or Brigham and Women’s Hospital will require review of the outside cytogenetic and/or molecular pathology reports by the overall principal investigator [PI]) * High-risk MDS, which is defined as one of the following subsets: ** International Prognostic Scoring System (IPSS) Intermediate-2 or higher ** Presence of a mutation in TP53 ** Presence of a mutation in the RAS pathway including NRAS, KRAS, PTPN11, CBL, NF1, RIT1, FLT3, and KIT) OR ** Therapy-related MDS * High-risk AML, which is defined as one of the following subsets: ** AML with adverse risk disease according to European LeukemiaNet (ELN) guidelines including one of the following features: *** A history of mutation in TP53, RUNX1, or ASXL1 *** t(6;9)(p23;q34.1); DEK-NUP214 *** t(v;11q23.3); KMT2A rearranged *** t(9;22)(q34.1;q11.2); BCR-ABL1 *** inv(3)(q21.3q26.2) or t(3;3)(q21.3;26.2); GATA2,MECOM(EVI1) *** -5 or del(5q) *** -7 *** -17/abn(17p) *** Complex karyotype *** Monosomal karyotype *** Wild-type NPM1 and FLT3-ITD^high ** Secondary AML, which is defined as a history of antecedent hematologic disorder (an MPN or MDS), a diagnosis of therapy-related myeloid neoplasm including therapy-related (t)-AML, or AML with myelodysplasia-related changes, OR ** “Secondary-type” AML, which is defined by the presence of a mutation in any of the following eight genes with high specificity for the presence of antecedent myelodysplastic syndrome including SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2 ** Patients with AML with evidence of measurable residual disease by multiparameter flow cytometry (>= 0.1%) despite morphologic remission on the pre-transplant/screening bone marrow biopsy. Review required by overall principal investigator (PI) * High-risk chronic myelomonocytic leukemia (CMML) or MDS/MPN unclassifiable (MDS/MPN-U), which is defined by the presence of trisomy 8, chromosome 7 abnormalities or complex karyotype (3 or more abnormalities); or by the presence of a mutation in ASXL1
- Morphologic measurable disease is not required for eligibility
- Patient is determined to be a suitable candidate for an allo-HCT using a reduced intensity conditioning (RIC) regimen using peripheral blood stem cell as stem cell source
- Patient must have a matched related or an 8/8 unrelated donor option for his/her allo-HCT
- Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status =< 2
- There are no limitations or minimum on the amount of prior therapy for patient’s advanced myeloid malignancy. Prior exposure to venetoclax is allowed
- Total bilirubin =< 2.0 x institutional upper limit of normal. (In patients with Gilbert’s syndrome, total bilirubin >= 2.0 is permitted)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional upper limit of normal
- Creatinine clearance >= 30 mL/min using Cockcroft Gault formula
- For subjects enrolling into Part 4 (PTCy/Tac/MMF), patients must have a left ventricular ejection fraction at least 45% within 3 months of first dose on study
- The effects of venetoclax on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of venetoclax administration. For women who are of child-bearing potential, they must have a negative serum beta-HCG (human chorionic gonadotropin) test to be eligible
- Ability to understand and the willingness to sign a written informed consent document
Exclusion Criteria
- Patients who have had chemotherapy (with the exception of hydroxyurea and/or dexamethasone) or radiotherapy or investigational therapy within 14 days prior to starting treatment on study. Exceptions: Patients already on venetoclax therapy prior to transplant need a three day wash out prior to first treatment dose on study. Patients on BCR-ABL, IDH and FLT3 small molecule inhibitors can stay on this treatment up until 5 days prior to first treatment dose on study
- Patients with > 10% morphologic blasts on bone marrow biopsy if they have a diagnosis of MDS or MDS/MPN. Patients > 5% morphologic blasts on bone marrow biopsy if they have a diagnosis of AML
- Patients recommended to receive a myeloablative conditioning regimen prior to transplantation (since there is a known survival advantage for AML using higher intensity)
- Patients who have a history of prior allogeneic stem cell transplantation
- Symptomatic or untreated known central nervous system (CNS) involvement of disease
- Patients with active heart disease (New York Heart Association class 3-4 as assessed by history and physical exam, or a critical event including unstable angina/stroke/myocardial infarction within the last 6 months prior to first dose on study)
- Patients who have consumed grapefruit, grapefruit products, Seville oranges or starfruit within 3 days prior to study treatment. Patients who a strong or moderate inducer within 7 days prior to the first dose of study drug
- Malabsorption syndrome or other clinically significant condition that would preclude enteral administration
- Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that in the opinion of the investigator may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and/or would make the patient inappropriate for enrollment into this study
- Patients with known active hepatitis B virus (HBV) infection should be excluded because of potential effects on immune function and/or drug interactions. However, if a patient has HBV history with an undetectable HBV load by polymerase chain reaction (PCR), no liver-related complications, and is on definitive HBV therapy that is not contraindicated on this study, then he/she would be eligible for study
- Patients with known active hepatitis C virus (HCV) infection. However, if a patient with a history of HCV infection has received definitive therapy (and is now HCV viral load negative), or if a patient has a reactive HCV antibody test but has an undetectable viral load by PCR, then he/she would be eligible
- Patients with known active human immunodeficiency virus (HIV) infection out of concern for the drug-drug interaction with venetoclax and highly active antiretroviral therapy (HAART) therapy
- Pregnant or breastfeeding women or those intending to become pregnant during the study or within 3 months after the final dose of study treatment are excluded from this study. Women of childbearing potential must have a negative serum pregnancy test resulted during screening and repeated within 7 days prior to study drug (local labs are allowed)
- Vaccination with live, attenuated vaccines within 4 weeks prior to initiation of study treatment or anticipation of need for such a vaccine during the study
- Patients with uncontrolled infection at time of first dose of treatment on study. Patients receiving anti-microbial agents including antibiotics, antiviral and antifungal therapies are allowed if hemodynamically stable
- Part 2, Part 3, and Part 4 only: Patients recommended to receive FLT3 inhibitor therapy or any other anti-leukemic therapy for AML as maintenance post allo-HCT
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT03613532.
Locations matching your search criteria
United States
Massachusetts
Boston
PRIMARY OBJECTIVES:
I. To determine the safety, dose (maximum tolerated dose [MTD] or recommended phase 2 dose (RP2D) and schedule of venetoclax that can be added to a reduced intensity conditioning regimen consisting of busulfan and fludarabine for patients with clonal myeloid malignancies (acute myeloid leukemia [AML], myelodysplastic syndrome [MDS] and MDS/myeloproliferative neoplasm [MPN] overlap syndromes) who are undergoing allogeneic (allo)-hematopoietic cell transplantation (HCT). (Part 1)
II. To determine the safety of venetoclax in combination with azacitidine administered post allo-HCT as maintenance therapy in patients who receive fludarabine (Flu)/busulfan (Bu2)/venetoclax conditioning chemotherapy transplantation. (Part 2)
III. To determine the safety of venetoclax in combination with oral decitabine/cedazuridine administered post allo-HCT as maintenance therapy in patients who receive Flu/Bu2/venetoclax conditioning chemotherapy transplantation. (Part 3)
IV. To determine the safety of adding venetoclax to FluBu2/post-transplant cyclophosphamide/tacrolimus/mycophenolate mofetil for patients undergoing reduced intensity conditioning (RIC) allo-HCT.
SECONDARY OBJECTIVES:
I. To estimate the overall survival at 12 months.
II. To estimate the progression free survival at 12 months.
III. To estimate the best overall response rate (complete remission [CR]) for subjects that enter the study with less than a CR.
IV. To estimate the remission duration from study entry.
V. To estimate the cumulative incidence of disease relapse at 12 months.
VI. To estimate the cumulative incidence of non-relapse mortality at 12 months.
VII. To estimate the cumulative incidence of acute graft versus host disease (GVHD) and chronic GVHD following allo-HCT at 12 months.
VIII. To assess donor granulocyte chimerism at day +28, +100 and at 12 months.
IX. To determine the feasibility of administering the combination of venetoclax and azacitidine or the combination of venetoclax and decitabine/cedazuridine as post allo-HCT maintenance therapy.
X. To compare the cumulative incidence of relapse and non-relapse mortality, overall survival and progression-free survival between patients enrolled in Part 1, Part 2, Part 3, and Parti 4.
EXPLORATORY OBJECTIVES:
I. To assess for biological activity with venetoclax when combined with a fludarabine and busulfan conditioning regimen and with azacitidine maintenance regiment in the peri-transplantation setting with a series of exploratory assays:
Ia. Measure baseline/pre-treatment and changes in the mitochondrial apoptotic priming level of residual morphologic myeloblasts before and after venetoclax therapy using the BH3 profiling assay if there is sufficient measurable disease.
Ib. Measure the changes in mitochondrial apoptotic priming level of immune cell subsets in the post-transplant setting using BH3 profiling.
Ic. Determine the immune cell subsets present (including natural killer [NK] cell and T cell subsets) in the post-transplant setting.
Id. Evaluate the transcriptome of tumor infiltrates at baseline for critical factors that may impact response in patients with clonal myeloid malignancies who receive venetoclax peri-transplant.
Ie. To assess for measurable residual disease clearance in bone marrow by deep sequencing alone in cases of MDS and MDS/MPN and paired with multi-parameter flow cytometry in cases of AML.
OUTLINE: This is a dose-escalation study of venetoclax. Patients are assigned to 1 of 4 Parts.
PART I: Patients receive venetoclax orally (PO) on days -8 to -3 or -2, and fludarabine phosphate intravenously (IV) over 30 minutes once daily (QD) and busulfan IV over 3 hours twice daily (BID) on days -5 to -2. Patients also receive tacrolimus PO BID beginning on day -3 for 6-9 months, then undergo allogeneic hematopoietic stem cell transplantation on day 0. Patients then receive methotrexate IV over 15 minutes on days 1, 3, 6, and 11. Patients undergo echocardiography (ECHO) or multi-gated acquisition scan (MUGA) and chest X-ray during screening. Patients undergo bone marrow biopsy and aspiration during screening, on day 100, at 6 and 12 months, and at the end of the study. Patients undergo collection of blood samples during screening, after 3 doses of venetoclax, on day 28, at 2 months, on day 100, at 3, 6, 9, and 12 months, and at the end of the study.
PART II: Patients receive venetoclax PO on days -8 to -2, and fludarabine phosphate IV over 30 minutes QD and busulfan IV over 3 hours BID on days -5 to -2. Patients also receive tacrolimus PO BID beginning on day -3 for 6-9 months, then undergo allogeneic hematopoietic stem cell transplantation on day 0. Patients then receive methotrexate IV over 15 minutes on days 1, 3, 6, and 11. Patients then move to maintenance therapy between days 42-90.
PART II, MAINTENANCE: Patients receive venetoclax PO on days 1-14 and azacitidine IV or subcutaneously (SC) on days 1-5. Cycles repeat every 28 or 42 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO or MUGA and chest X-ray during screening. Patients undergo bone marrow biopsy and aspiration during screening, between days 28 and 90, on day 100, at 6 and 12 months, and at the end of the study. Patients undergo collection of blood samples during screening, after 3 doses of venetoclax, on day 28, at 2 months, on day 100, at 3, 6, 9, and 12 months, and at the end of the study.
PART III: Patients receive venetoclax PO on days -8 to -2, and fludarabine phosphate IV over 30 minutes QD and busulfan IV over 3 hours BID on days -5 to -2. Patients also receive tacrolimus PO BID beginning on day -3 for 6-9 months, then undergo allogeneic hematopoietic stem cell transplantation on day 0. Patients then receive methotrexate IV over 15 minutes on days 1, 3, 6, and 11. Patients then move to maintenance therapy between days 42-90.
PART III, MAINTENANCE: Patients receive venetoclax PO on days 1-14, decitabine/cedazuridine PO on days 1, 3, and 5. Cycles repeat every 42 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO or MUGA and chest X-ray during screening. Patients undergo bone marrow biopsy and aspiration during screening, between days 28 and 90, on day 100, at 6 and 12 months, and at the end of the study. Patients undergo collection of blood samples during screening, after 3 doses of venetoclax, on day 28, at 2 months, on day 100, at 3, 6, 9, and 12 months, and at the end of the study.
PART IV: Patients receive venetoclax PO on days -8 to -2, fludarabine phosphate IV over 30 minutes QD and busulfan IV over 3 hours BID on days -5 to -2, then undergo allogeneic hematopoietic stem cell transplantation on day 0. Patients also receive cyclophosphamide IV over 2 hours QD on days 3-4, tacrolimus PO BID beginning on day 5 until day 180, and mycophenolate mofetil PO three times daily (TID) on days 5-28. Patients then move to maintenance therapy between days 42-90.
PART IV, MAINTENANCE: Patients receive venetoclax PO on days 1-14 and azacitidine IV or SC on days 1-5. Cycles repeat every 42 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO or MUGA and chest X-ray during screening. Patients undergo bone marrow biopsy and aspiration during screening, between days 28 and 90, on day 100, at 6 and 12 months, and at the end of the study. Patients undergo collection of blood samples during screening, after 3 doses of venetoclax, on day 28, at 2 months, on day 100, at 3, 6, 9, and 12 months, and at the end of the study.
After completion of study treatment, patients are followed up at 30-45, 46-61, 62-77, and 100 days, and at 6 and 12 months.
Trial PhasePhase I
Trial Typetreatment
Lead OrganizationDana-Farber Harvard Cancer Center
Principal InvestigatorJacqueline Suen Garcia
- Primary ID18-283
- Secondary IDsNCI-2018-02454
- ClinicalTrials.gov IDNCT03613532