- 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
- 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
- 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.
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)
- 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
- "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
- 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
- Patient must have a matched related or an 8/8 unrelated donor option for his/her
- 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
- Ability to understand and the willingness to sign a written informed consent
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
- 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
- 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
- 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
- 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
- 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