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Trial record 10 of 96 for:    Venetoclax AND marrow

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03613532
Recruitment Status : Recruiting
First Posted : August 3, 2018
Last Update Posted : July 2, 2019
Information provided by (Responsible Party):
Jacqueline Garcia, MD, Dana-Farber Cancer Institute

Brief Summary:

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.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia (AML) Myelodysplastic Syndrome (MDS) Chronic Myelomonocytic Leukemia (CMML) MDS/Myeloproliferative Neoplasm-unclassifiable (MDS/MPN-unclassifiable) Hematopoietic Stem Cell Transplant Drug: Venetoclax Drug: Fludarabine Drug: Busulfan Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 38 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : October 1, 2018
Estimated Primary Completion Date : October 1, 2020
Estimated Study Completion Date : February 1, 2021

Arm Intervention/treatment
Experimental: Venetoclax

This 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
Drug: Venetoclax
6-7 total doses depending on dose level assigned
Other Name: ABT199

Drug: Fludarabine
◦Fludarabine : given once daily for 4 days
Other Name: Fludara

Drug: Busulfan
◦Busulfan: given twice daily for 4 days
Other Names:
  • Busulfex
  • Myleran

Primary Outcome Measures :
  1. MTD of Venetoclax with Busulfan and Fludarabine [ Time Frame: 37 Days ]
    Determine safe dose and schedule of venetoclax

Secondary Outcome Measures :
  1. Overall Survival [ Time Frame: 12 Months ]
    Time from treatment start until death

  2. Progression Free Survival [ Time Frame: 12 Months ]
    Time from treatment start until relapse

  3. Overall Response Rate [ Time Frame: At day 100, 6 months and 12 months ]
    IWG response criteria

  4. Remission Duration Rate [ Time Frame: from start of the treatment until disease relapse (assessed at day 100, 6 months and 12 months) ]
    Duration of remission from treatment start until relapse

  5. Rate of Disease Relapse [ Time Frame: 12 Months ]
    Frequency of disease recurrence on trial

  6. Rate of Non-Relapse Mortality [ Time Frame: 12 Months ]
    Frequency of death that is not due to disease recurrence on trial

  7. Donor granulocyte chimerism percentage [ Time Frame: 28 Days Post-Transplant ]
    Percentage of donor blood cells

  8. Donor granulocyte chimerism percentage [ Time Frame: 100 days Post-Transplant ]
    Percentage of donor blood cells

  9. Donor granulocyte chimerism percentage [ Time Frame: 12 Months Post-Transplant ]
    Percentage of donor blood cells

  10. Cumulative incidence of acute graft versus host disease (GVHD) and chronic GVHD following allo-HCT [ Time Frame: 12 Months ]
    Frequency of GVHD events

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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 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 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

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. 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.
  • 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 either coumadin or 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03613532

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Contact: Jacqueline S. Garcia, MD 617-632-1906

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United States, Massachusetts
Dana-Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Jacqueline S Garcia, MD    617-632-1906   
Principal Investigator: Jacqueline S Garcia, MD         
Sponsors and Collaborators
Jacqueline Garcia, MD
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Principal Investigator: Jacqueline S. Garcia, MD Dana-Farber Cancer Institute

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Responsible Party: Jacqueline Garcia, MD, Principal Investigator, Dana-Farber Cancer Institute Identifier: NCT03613532     History of Changes
Other Study ID Numbers: 18-283
First Posted: August 3, 2018    Key Record Dates
Last Update Posted: July 2, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Jacqueline Garcia, MD, Dana-Farber Cancer Institute:
Acute Myeloid Leukemia (AML)
Myelodysplastic Syndrome (MDS)
Chronic Myelomonocytic Leukemia (CMML)
MDS/myeloproliferative neoplasm-unclassifiable (MDS/MPN-unclassifiable)
Hematopoietic Stem Cell Transplant
Additional relevant MeSH terms:
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Bone Marrow Diseases
Leukemia, Myeloid, Acute
Leukemia, Myelomonocytic, Chronic
Leukemia, Myelomonocytic, Juvenile
Myelodysplastic Syndromes
Myeloproliferative Disorders
Myelodysplastic-Myeloproliferative Diseases
Pathologic Processes
Neoplasms by Histologic Type
Leukemia, Myeloid
Hematologic Diseases
Precancerous Conditions
Fludarabine phosphate
Antineoplastic Agents
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antiviral Agents