Venetoclax to Improve Outcomes of Fractionated Busulfan Regimen in Patients With High-Risk AML and MDS

Venetoclax to Improve Outcomes of Fractionated Busulfan Regimen in Patients With High-Risk AML and MDS

Venetoclax to Improve Outcomes of Fractionated Busulfan Regimen in Patients With High-Risk AML and MDS

This phase II trial studies the effect of venetoclax together with busulfan, cladribine, and fludarabine in treating patients with high-risk acute myeloid leukemia or myelodysplastic syndrome who are undergoing stem cell transplant. Chemotherapy drugs, such as venetoclax, busulfan, cladribine, and fludarabine, 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. Adding venetoclax to the current standard of care stem cell transplant regimen of busulfan, fludarabine, and cladribine may help to control high-risk acute myeloid leukemia or myelodysplastic syndrome.

PRIMARY OBJECTIVE: I. To obtain preliminary evidence of efficacy as defined by 1-year progression free survival. SECONDARY OBJECTIVES: I.To determine safety of this regimen as per National Cancer Institute (NCI) toxicity criteria. II.To determine time to neutrophil and platelet engraftment. III.To determine incidence of acute and chronic graft versus host disease (GVHD). IV.To determine relapse incidence. V.To determine non-relapse mortality. VI.To determine overall survival. VII.To determine graft versus host disease-relapse free survival (GRFS). OUTLINE: Patients receive venetoclax orally (PO) once daily (QD) on days -22 to -3, busulfan intravenously (IV) over 3 hours on days -20, -13, -6, -5, -4, and -3, and fludarabine phosphate (fludarabine) IV over 1 hour and cladribine IV over 2 hours on days -6 to -3 in the absence of disease progression or unacceptable toxicity. Patients then undergo stem cell transplantation over 1-2 hours on day 0. After completion of study treatment, patients are followed up at 7 days, at engraftment, at 1, 3, 6, and 12 months, then annually for up to 3 years.

Patients receive venetoclax PO QD on days -22 to -3, busulfan IV over 3 hours on days -20, -13, -6, -5, -4, and -3, and fludarabine phosphate IV over 1 hour and cladribine IV over 2 hours on days -6 to -3 in the absence of disease progression or unacceptable toxicity. Patients then undergo stem cell transplantation over 1-2 hours on day 0.

1, 4-Bis[methanesulfonoxy]butane, BUS, Bussulfam, Busulfanum, Busulfex, Busulphan, CB 2041, CB-2041, Glyzophrol, GT 41, GT-41, Joacamine, Methanesulfonic Acid Tetramethylene Ester, Methanesulfonic acid, tetramethylene ester, Mielucin, Misulban, Misulfan, Mitosan, Myeleukon, Myeloleukon, Myelosan, Mylecytan, Myleran, Sulfabutin, Tetramethylene Bis(methanesulfonate), Tetramethylene bis[methanesulfonate], WR-19508

2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586

1,1'',1''''-Phosphinothioylidynetrisaziridine, Girostan, N,N'', N''''-Triethylenethiophosphoramide, Oncotiotepa, STEPA, Tepadina, TESPA, Tespamin, Tespamine, Thio-Tepa, Thiofosfamide, Thiofozil, Thiophosphamide, Thiophosphoramide, Thiotef, Tifosyl, TIO TEF, Tio-tef, Triethylene Thiophosphoramide, Triethylenethiophosphoramide, Tris(1-aziridinyl)phosphine sulfide, TSPA, WR 45312

The proportion of patients who are alive without disease relapse (PFS) at one year will be reported along with the corresponding 95% credible interval. Cox proportional hazards regression will be used to assess the association between PFS and clinical and treatment covariates of interest.

The time to platelet engraftment will be calculated from the time of transplant and estimated by the Kaplan-Meier method.

The time to neutrophil engraftment will be calculated from the time of transplant and estimated by the Kaplan-Meier method.

The cumulative incidence of acute and chronic GvHD with the competing risks of relapse and death will be estimated using the method of Gooley, and the method of Fine and Gray will be used to model the association between both parameters and clinical and treatment characteristics of interest.

The cumulative incidence of non-relapse mortality and relapse will also be assessed in a competing risks framework, with similar analyses performed.

Descriptive statistics will be used to summarize adverse events. The number and proportion of subjects with treatment emergent adverse events will be reported. All other safety parameters will be summarized using descriptive statistics or frequency counts. Graphical summaries will be used where appropriate.

Inclusion Criteria: Non-English speaking patients are eligible. Age ≥ 18 and ≤ 70 years. English and non-English speaking patients are eligible. Patients with acute myeloid leukemia who have previously received induction therapy and one of the following high-risk features: ELN17 adverse risk prognostic group irrespective of remission status (see Appendix 2). Measurable residual disease positive (MRD +) Not in complete remission including complete remission without count recovery (Cri) and/or morphologic leukemia free state (MLFS), primary refractory, or relapsed disease. See Appendix 3 for details. AML secondary to MDS or MPD. Therapy-related AML. Not in complete remission after one course of induction therapy Or Patients with myelodysplastic syndrome or CMML and one of the following high-risk features: Poor or Very poor cytogenetic risk group as per IPSS-R Mutated P53 or Ras pathway genes (CBL, NRAS, KRAS, NF1, PTPN1) or DNMT 3a or ASXL1 or RUNX1 Maximum IPSS-R >3.5 between diagnosis and the start of the preparative regimen. ≥ 5% BM blasts at transplant Therapy-related MDS HLA-identical sibling or a minimum of 7/8 matched unrelated donor, or a haploidentical related donor available Subject must voluntarily sign an informed consent Female subjects of childbearing potential must have negative results for pregnancy test Adequate hepatic and renal function per local laboratory reference range as follows: Aspartate transaminase (AST) and alanine transaminase (ALT) < 3.0X ULN Bilirubin <1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin) Subject must have adequate renal function as demonstrated by a creatinine clearance ≥ 50 mL/min; calculated by the Cockcroft Gault formula or measured by 24 hours urine collection. Exclusion criteria: Subject is known to be positive for HIV. Subject has cognitive impairments and/or is a prisoner. Subject has acute promyelocytic leukemia Subject has known active CNS involvement with AML. Evidence of other clinically significant uncontrolled condition(s) including, but not limited to: Uncontrolled and/or active systemic infection (viral, bacterial or fungal) Chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment. Note: subjects with serologic evidence of prior vaccination to HBV (i.e. hepatitis B surface (HBs) antigen negative-, anti-HBs antibody positive and anti-hepatitis B core (HBc) antibody negative) or positive anti-HBc antibody from intravenous immunoglobulins (IVIG) may participate Cardiac history of CHF requiring treatment or Ejection Fraction < 50% or unstable angina; Corrected DLCO < 65% or FEV1 < 65%; Administration or consumption of any of the following within 3 days prior to the first dose of study drug: grapefruit or grapefruit products Seville oranges (including marmalade containing Seville oranges) star fruit Prior gemtuzumab ozogamicin and/or inotuzumab ozogamicin use Patients with cognitive impairments and/or any serious unstable pre-existing medical condition or psychiatric disorder that can interfere with safety or with obtaining informed consent or compliance with study procedures.