Clinical Trial: NCT04708054 - My Cancer Genome

NCT04708054

Description:

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.

Related Conditions:

Acute Myeloid Leukemia
Chronic Myelomonocytic Leukemia
Myelodysplastic Syndromes

Recruiting Status:

Not yet recruiting

Phase:

Phase 2

URL:

https://clinicaltrials.gov/show/NCT04708054

Trial Eligibility

Document

Title

Brief Title: Venetoclax, Busulfan, Cladribine, and Fludarabine for the Treatment of High-Risk Acute Myeloid Leukemia or Myelodysplastic Syndrome
Official Title: Venetoclax to Improve Outcomes of Fractionated Busulfan Regimen in Patients With High-Risk AML and MDS

Clinical Trial IDs

ORG STUDY ID: 2020-0790
SECONDARY ID: NCI-2020-13919
SECONDARY ID: 2020-0790
NCT ID: NCT04708054

Conditions

Acute Myeloid Leukemia
Chronic Myelomonocytic Leukemia
Myelodysplastic Syndrome

Interventions

Drug	Synonyms	Arms
Busulfan	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	Treatment (venetoclax, busulfan, fludarabine, cladribine)
Cladribine	2-CdA, 2CDA, CdA, Cladribina, Leustat, Leustatin, Leustatine, RWJ-26251	Treatment (venetoclax, busulfan, fludarabine, cladribine)
Fludarabine Phosphate	2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586	Treatment (venetoclax, busulfan, fludarabine, cladribine)
Thiotepa	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	Treatment (venetoclax, busulfan, fludarabine, cladribine)
Venetoclax	ABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta, Venclyxto	Treatment (venetoclax, busulfan, fludarabine, cladribine)

Purpose

Detailed Description

      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.

Trial Arms

Name	Type	Description	Interventions
Treatment (venetoclax, busulfan, fludarabine, cladribine)	Experimental	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.	Busulfan Cladribine Fludarabine Phosphate Thiotepa Venetoclax

Eligibility Criteria

        Inclusion Criteria:

          -  Age >= 18 and =< 70 years

          -  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

               -  Measurable residual disease positive (MRD +)

               -  Not in complete remission including complete remission without count recovery
                  (Cri), primary refractory, or relapsed disease or

        Patients with myelodysplastic syndrome or chronic myelomonocytic leukemia (CMML) and one of
        the following high-risk features:

          -  Poor or very poor cytogenetic risk group as per Revised International Prognostic
             Scoring System (IPSS-R)

          -  Mutated P53 or Ras pathway genes (CBL, NRAS, KRAS, NF1, PTPN1) or DNMT 3a or ASXL1 or
             RUNX1

          -  IPSS-R > 3.5 at diagnosis

          -  >= 5% bone marrow (BM) blasts at transplant

               -  HLA-identical sibling or a 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

               -  Aspartate transaminase (AST) and alanine transaminase (ALT) < 3.0 x upper limit
                  of normal (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 human immunodeficiency virus (HIV)

          -  Subject has acute promyelocytic leukemia

          -  Subject has known active central nervous system (CNS) involvement with acute
             myeloblastic leukemia (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 (hepatitis C virus [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 congestive heart failure (CHF) requiring treatment or ejection
             fraction < 50% or unstable angina

          -  Corrected diffusion capacity of the lung for carbon monoxide (DLCO) < 65% or forced
             expiratory volume in 1 second (FEV1) < 65%

          -  Treatment with any of the following within 7 days prior to the first dose of study
             drug:

               -  Steroid therapy for anti-neoplastic intent

               -  Moderate or strong cytochrome P450 3A (CYP3A) inhibitors, moderate or strong
                  CYP3A inducers. These agents may be used once venetoclax is discontinued

          -  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

Maximum Eligible Age:	70 Years
Minimum Eligible Age:	18 Years
Eligible Gender:	All
Healthy Volunteers:	No

Primary Outcome Measures

Measure:	1-year progression free survival (PFS)
Time Frame:	At 1 year post-transplant
Safety Issue:
Description:	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.

Secondary Outcome Measures

Measure:	Overall survival (OS)
Time Frame:	Up to 3 years post-transplant
Safety Issue:
Description:	OS will be calculated from the time of transplant by the method of Kaplan and Meier.

Measure:	Graft-versus (vs.)-host disease-free, relapse-free survival (GRFS)
Time Frame:	Up to 3 years post-transplant
Safety Issue:
Description:	GRFS will be calculated from the time of transplant by the method of Kaplan and Meier.

Measure:	Time to platelet engraftment
Time Frame:	From the time of transplant up to 3 years
Safety Issue:
Description:	The time to platelet engraftment will be calculated from the time of transplant and estimated by the Kaplan-Meier method.

Measure:	Time to neutrophil engraftment
Time Frame:	From the time of transplant up to 3 years
Safety Issue:
Description:	The time to neutrophil engraftment will be calculated from the time of transplant and estimated by the Kaplan-Meier method.

Measure:	Incidence of acute and chronic graft-vs.-host disease (GvHD)
Time Frame:	Up to 3 years post-transplant
Safety Issue:
Description:	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.

Measure:	Incidence of relapse and non-relapse mortality
Time Frame:	Up to 3 years post-transplant
Safety Issue:
Description:	The cumulative incidence of non-relapse mortality and relapse will also be assessed in a competing risks framework, with similar analyses performed.

Measure:	Incidence of adverse events
Time Frame:	Up to 3 years post-transplant
Safety Issue:
Description:	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.

Details

Phase:	Phase 2
Primary Purpose:	Interventional
Overall Status:	Not yet recruiting
Lead Sponsor:	M.D. Anderson Cancer Center

Last Updated

January 13, 2021

Clinical Trials /

Venetoclax, Busulfan, Cladribine, and Fludarabine for the Treatment of High-Risk Acute Myeloid Leukemia or Myelodysplastic Syndrome