Clinical Trials /

Venetoclax Added to Fludarabine + Busulfan Prior to Transplant for AML, MDS, and MDS/MPN

NCT03613532

Description:

This clinical trial involves individuals who have been diagnosed with Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS), Chronic Myelomonocytic Leukemia (CMML), or MDS/myeloproliferative neoplasm-unclassifiable (MDS/MPN-unclassifiable) and are planning to have an allogeneic hematopoietic stem cell transplant ("bone marrow transplant"). The goal of this research study is to test the safety of adding the study drug, Venetoclax, to a standard of care conditioning regimen for bone marrow transplantation, as a possible means of eliminating residual (left-over) disease prior to transplant. - The name of the study drug involved in this study is Venetoclax. - It is expected that about 38 people will take part in this research study.

Related Conditions:
  • Acute Myeloid Leukemia
  • Chronic Myelomonocytic Leukemia
  • Myelodysplastic Syndromes
  • Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Venetoclax Added to Fludarabine + Busulfan Prior to Transplant for AML, MDS, and MDS/MPN
  • Official Title: A Phase 1 Study of Venetoclax Added to Busulfan and Fludarabine Reduced Intensity Conditioning Regimen for AML, MDS, and MDS/MPN Overlap Syndromes

Clinical Trial IDs

  • ORG STUDY ID: 18-283
  • NCT ID: NCT03613532

Conditions

  • Acute Myeloid Leukemia (AML)
  • Myelodysplastic Syndrome (MDS)
  • Chronic Myelomonocytic Leukemia (CMML)
  • MDS/Myeloproliferative Neoplasm-unclassifiable (MDS/MPN-unclassifiable)
  • Hematopoietic Stem Cell Transplant

Interventions

DrugSynonymsArms
VenetoclaxABT199Venetoclax
FludarabineFludaraVenetoclax
BusulfanBusulfex, MyleranVenetoclax

Purpose

This clinical trial involves individuals who have been diagnosed with Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS), Chronic Myelomonocytic Leukemia (CMML), or MDS/myeloproliferative neoplasm-unclassifiable (MDS/MPN-unclassifiable) and are planning to have an allogeneic hematopoietic stem cell transplant ("bone marrow transplant"). The goal of this research study is to test the safety of adding the study drug, Venetoclax, to a standard of care conditioning regimen for bone marrow transplantation, as a possible means of eliminating residual (left-over) disease prior to transplant. - The name of the study drug involved in this study is Venetoclax. - It is expected that about 38 people will take part in this research study.

Detailed Description

      -  This research study is a Phase I clinical trial, which tests the safety of an
           investigational drug and tries to define the appropriate dose and schedule of the
           investigational drug to use for further studies. "Investigational" means that the drug
           is being studied.

        -  In this research study, investigators are trying to determine a safe dose of the study
           drug, Venetoclax, when given in combination with a standard chemotherapy.

        -  There are two phases in this research study:

             -  The first phase of the study is called the Dose-Escalation phase where venetoclax
                will be given in different doses until the safest maximum dose has been identified.

             -  The second phase of the study is call the Dose-Expansion phase where more
                participants will be treated at this dose level to obtain additional information on
                safety. For both the Dose-Escalation or Dose-Expansion phase of this study, there
                will be a screening period, a pre-transplant period, a transplant period, and a
                post-transplant follow up period.

        -  In this research study, participants will receive venetoclax plus chemotherapy. This
           chemotherapy is called the "conditioning regimen", which is treatment required to
           prepare the body for bone marrow transplantation). The conditioning regimen chemotherapy
           will suppress the immune system and may help to destroy cancer cells. During this
           process normal bone marrow cells are destroyed as well, thus making way for donor stem
           cells.

           -- Fludarabine and busulfan (FluBu2) are both chemotherapies that will be given as a
           part of the conditioning regimen.

        -  The FDA (U.S. Food and Drug Administration) has not approved Venetoclax for this
           specific disease, but it is approved for other uses. Venetoclax is an oral drug that
           selectively inhibits Bcl-2, which is critical for keeping cancer cells alive.
    

Trial Arms

NameTypeDescriptionInterventions
VenetoclaxExperimentalThis trial can be divided into three periods: 1) Screening, 2) Treatment including venetoclax + FluBu2 and transplantation; and 3) Post-Transplant follow up. Dose escalation will occur using a standard 3+3 dose escalation approach, beginning in dose level I with dose cohorts and rules for escalation and de-escalation. Venetoclax: 6-7 total doses depending on dose level assigned FLuBu2 Busulfan: given twice daily for 4 days Fludarabine : given once daily for 4 days
  • Venetoclax
  • Fludarabine
  • Busulfan

Eligibility Criteria

        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 PI.)

                    -  High-risk MDS, which is defined as IPSS Intermediate-2, IPSS High, or the
                       presence of a mutation in TP53, JAK2, or those in the RAS pathway including
                       NRAS, KRAS, PTPN11, CBL, NF1, RIT1, FLT3, and KIT

                    -  High-risk AML, which is defined as one of the following subsets:

                         -  AML with adverse risk disease according to 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-ITDhigh

                         -  Secondary AML, which is defined as a history of antecedent hematologic
                            disorder (an MPN or MDS), a diagnosis of therapy-related myeloid
                            neoplasm including t-MDS and 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 including SRSF2, SF3B1, U2AF1, ZRSR2,
                            ASXL1, EZH2, BCOR, or STAG2

                    -  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

               -  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 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.

               -  Patient must have normal organ function as defined below:

                    -  Total bilirubin ≤ 2.0 x institutional upper limit of normal (In patients
                       with Gilbert's Syndrome, Total Bilirubin ≥ 2.0 is permitted.)

                    -  AST(SGOT)/ALT(SGPT) ≤ 3 × institutional upper limit of normal

                    -  Creatinine ≤ 2 mg/dL

               -  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

        Exclusion Criteria:

          -  Patients with > 10% blasts on bone marrow biopsy.

          -  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.

          -  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. Exception: Patients on FLT3 small molecule inhibitors can
             stay on this treatment up until 7 days prior to first treatment dose on study.

          -  Symptomatic or untreated known 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 receive a medication that is a strong or moderate CYP3A inhibitor or
             inducer within 7 days prior to the first dose of study drug. Note: Patients may
             receive these CYP3A agents starting 3 days after the last dose of venetoclax on study
             if clinically necessary.

          -  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 HIV infection out of concern for the drug-drug interaction
             with venetoclax and HAART therapy.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:MTD of Venetoclax with Busulfan and Fludarabine
Time Frame:37 Days
Safety Issue:
Description:Determine safe dose and schedule of venetoclax

Secondary Outcome Measures

Measure:Overall Survival
Time Frame:12 Months
Safety Issue:
Description:Time from treatment start until death
Measure:Progression Free Survival
Time Frame:12 Months
Safety Issue:
Description:Time from treatment start until relapse
Measure:Overall Response Rate
Time Frame:At day 100, 6 months and 12 months
Safety Issue:
Description:IWG response criteria
Measure:Remission Duration Rate
Time Frame:from start of the treatment until disease relapse (assessed at day 100, 6 months and 12 months)
Safety Issue:
Description:Duration of remission from treatment start until relapse
Measure:Rate of Disease Relapse
Time Frame:12 Months
Safety Issue:
Description:Frequency of disease recurrence on trial
Measure:Rate of Non-Relapse Mortality
Time Frame:12 Months
Safety Issue:
Description:Frequency of death that is not due to disease recurrence on trial
Measure:Donor granulocyte chimerism percentage
Time Frame:28 Days Post-Transplant
Safety Issue:
Description:Percentage of donor blood cells
Measure:Donor granulocyte chimerism percentage
Time Frame:100 days Post-Transplant
Safety Issue:
Description:Percentage of donor blood cells
Measure:Donor granulocyte chimerism percentage
Time Frame:12 Months Post-Transplant
Safety Issue:
Description:Percentage of donor blood cells
Measure:Cumulative incidence of acute graft versus host disease (GVHD) and chronic GVHD following allo-HCT
Time Frame:12 Months
Safety Issue:
Description:Frequency of GVHD events

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Jacqueline Garcia, MD

Trial Keywords

  • Acute Myeloid Leukemia (AML)
  • Myelodysplastic Syndrome (MDS)
  • Chronic Myelomonocytic Leukemia (CMML)
  • MDS/myeloproliferative neoplasm-unclassifiable (MDS/MPN-unclassifiable)
  • Hematopoietic Stem Cell Transplant

Last Updated