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 (1) 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 and (2) to test the safety of combination Venetoclax and azacitidine as "maintenance therapy" after transplant to possibly prevent disease recurrence. - The name of the study drug involved in this study is Venetoclax. - It is expected that about 42 people will take part in this research study.

Related Conditions:
  • Acute Myeloid Leukemia
  • Acute Myeloid Leukemia Arising from Previous Myelodysplastic Syndrome
  • Chronic Myelomonocytic Leukemia
  • Myelodysplastic Syndromes
  • Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable
  • Secondary Acute Myeloid Leukemia
  • Therapy-Related Acute Myeloid Leukemia
  • Therapy-Related Myelodysplastic Syndrome
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 Adding Venetoclax to a Reduced Intensity Conditioning Regimen and to Maintenance in Combination With Azacitidine After Allogeneic Hematopoietic Cell Transplantation for Patients With High Risk 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
VenetoclaxABT199Venetoclax
AzacitidineVenetoclax

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 (1) 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 and (2) to test the safety of combination Venetoclax and azacitidine as "maintenance therapy" after transplant to possibly prevent disease recurrence. - The name of the study drug involved in this study is Venetoclax. - It is expected that about 42 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.

        -  There are two parts to this research study:

             -  Part 1 is to determine a safe dose of the study drug, Venetoclax, when given in
                combination with a standard chemotherapy and Part 2 is to determine the safety of
                post-transplant maintenance therapy with the combination of azacytidine and
                venetoclax. Participants enrolled in Part 1 of this study, will receive Venetoclax
                in combination with conditioning chemotherapy (prior to transplantation).

             -  Participants enrolled in Part 2 of the study, will also receive Venetoclax in
                combination with conditioning chemotherapy (prior to transplantation) and will have
                the opportunity to receive maintenance chemotherapy (after transplantation) for
                potentially a year.

        -  Both Part 1 and Part 2 of this research study will have a Dose-Escalation phase. The
           Dose-Escalation phase is the part of the study where treatment dose and schedule are
           being tested.

             -  In Part 1, the Dose-Escalation phase is when venetoclax will be given at different
                doses until the safest maximum dose has been identified. Part 1 also includes a
                second phase of the study which is called the Dose-Expansion phase, during which
                more participants will be treated at this dose level to obtain additional
                information on safety.

             -  In Part 2, the Dose-Escalation phase is where the combination of venetoclax and
                azacitidine will be given after transplantation at different schedules.

             -  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.
           Participants in Part 1 and Part 2 of this study will receive chemotherapy immediately
           prior to transplantation, which is called the "conditioning regimen." 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 and a common conditioning
                regimen.

             -  In this study, Venetoclax is added to the conditioning regimen (FluBu2) prior to
                transplantation to eliminate leftover blood cancer cells prior to transplant.

             -  Participants in Part 2 of the study will also have the opportunity to receive
                venetoclax plus azacitidine after transplantation. The combination of these two
                drugs is called "maintenance therapy," which is treatment given after transplant to
                potentially reduce the chance of disease relapse. Relapse is a cause of transplant
                failure and can occur when there are leftover blood cancer cells.

        -  The FDA (U.S. Food and Drug Administration) has approved Venetoclax in combination with
           cytarabine, azacitidine or decitabine for the treatment of newly diagnosed acute myeloid
           leukemia, but not for use in with conditioning chemotherapy prior to transplantation or
           after transplant with maintenance chemotherapy. Venetoclax is an oral drug that
           selectively inhibits Bcl-2, which is critical for keeping cancer cells alive.
    

Trial Arms

NameTypeDescriptionInterventions
VenetoclaxExperimentalThis study has three periods: 1) Screening, 2) Treatment including venetoclax + FluBu2 conditioning chemotherapy and transplantation; and 3) Post-Transplant follow up. For Part 1, the post-transplant period will include routine follow-up. For Part 2, the post-transplant period will include investigational therapy with azacitidine and venetoclax and follow-up. Dose escalation in Part 1 will occur using a standard 3+3 dose escalation approach, beginning in dose level I with dose cohorts and rules for escalation/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 Dose escalation in Part 2 will occur using a 10+10 dose escalation approach, beginning in dose level I with dose cohorts and rules for escalation/de-escalation. Venetoclax: 14 doses for 8-12 cycles depending on dose level assigned Azacitidine: 5 doses for 8-12 cycles depending on dose level assigned
  • Venetoclax
  • Fludarabine
  • Busulfan
  • Venetoclax
  • Azacitidine

Eligibility Criteria

        Part 1 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 one of the following subsets:

                         -  IPSS Intermediate-2 or higher

                         -  Presence of a mutation in TP53

                         -  Prescence of mutation in the RAS pathway including NRAS, KRAS, PTPN11,
                            CBL, NF1, RIT1, FLT3, and KIT

                         -  Therapy-related MDS

                    -  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 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 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

               -  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 clearance ≥ 30 mL/min using Cockcroft Gault formula

               -  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

        Part 1 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 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 HIV infection out of concern for the drug-drug interaction
             with venetoclax and 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 only: Patients recommended to receive FLT3 inhibitor therapy or any other
             antileukemic therapy for AML as maintenance post allo-HCT.

        Part 2 Eligibility Criteria:

          -  No DLT event (including delay in neutrophil engraftment) due to the addition of
             venetoclax to conditioning chemotherapy prior to start of maintenance therapy.

          -  No morphologic evidence of relapse (defined as 5% or more morphologic blasts) prior to
             start of maintenance therapy confirmed by bone marrow biopsy after day +28.

          -  ANC ≥ 1.0 K/uL without growth factor support and platelet level ≥ 50 K/uL without
             platelet transfusion within 7 days of starting maintenance therapy. Exception:
             Patients without morphologic evidence of disease relapse but with evidence of
             persistent molecular or cytogenetic residual disease at the time of assessment can
             start maintenance therapy as long as ANC ≥ 0.75 K/uL without growth factor support and
             platelet level ≥ 25 K/uL.

          -  Absence of overall grade II-IV acute GVHD per investigator. Upon acute GVHD
             resolution, patients are eligible. Patients that are on prednisone 0.5 mg/kg daily
             dose or lower are allowed to initiate maintenance.

          -  Total bilirubin less than or equal to 2 x institutional ULN (unless has known
             Gilbert's disease).

          -  AST and ALT less than or equal to 3 x ULN.

          -  Cr Cl ≥ 30 mL/min or higher (Cockgroft Gault formula).

          -  No concurrent illnesses that would prevent taking oral therapy and interfere with
             safety assessment.
      
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
Measure:Number of Maintenance Treatment Cycles Safely Administered
Time Frame:From Initiation of Maintenace Therapy up to 12 months
Safety Issue:
Description:
Measure:Compare Incidences of Mortality and Survival Between Participants in Part 1 and Part 2
Time Frame:12 months
Safety Issue:
Description:Compare cumulative instances of mortality and survival between participants on Part 1 and Part 2

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status: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

January 11, 2021