PRIMARY OBJECTIVE:
I. To determine the safety and tolerability (phase 1) and overall response rate (ORR) (phase
2) of venetoclax in combination with azacitidine in patients with high risk myelodysplastic
syndrome (MDS) or chronic myelomonocytic leukemia (CMML) with bone marrow excess blasts > 5%
that are relapsed/refractory to prior hypomethylating agent (HMA) therapy.
SECONDARY OBJECTIVES:
I. Rate of complete remission (CR). II. Rate of marrow/morphologic complete remission (mCR).
III. Rate of hematologic improvement (HI; erythroid/platelet/neutrophil responses).
IV. Rate of red blood cell (RBC) transfusion independence. V. Rate of platelet (PLT)
transfusion independence. VI. Rate of cytogenetic response. VII. Rate of bone marrow blast
response. VIII. Time to transformation to acute myeloid leukemia (AML). IX. Duration of
response (DOR). X. Overall survival (OS). XI. Progression-free survival (PFS). XII. Time to
next MDS treatment (TTNT). XIII. Event-free survival (EFS).
EXPLORATORY OBJECTIVE:
I. To investigate the effects of therapy on MDS and to identify biological markers of
response to venetoclax and/or its combination with azacitidine.
OUTLINE: This is a phase I, dose-escalation study of venetoclax followed by a phase II study.
Patients receive venetoclax orally (PO) daily on days 1-14 and azacitidine intravenously (IV)
over 15 minutes or subcutaneously (SC) on days 1-5. Cycles repeat every 4-8 weeks in the
absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up within 30 days and then every
3-6 months for up to 5 years.
Inclusion Criteria:
- Patients with post HMA-failure high-risk MDS (intermediate [Int]-2 or high risk by the
International Prognostic Scoring System for Myelodysplastic Syndrome [IPSS] with
overall score >= 1.5) with excess blasts > 5% with failure defined as prior receipt of
4 cycles of HMA therapy with failure to attain a response, or progression of disease
or relapse at any time after prior response to HMA therapy
- Patients with relapsed/refractory chronic myelomonocytic leukemia (CMML) and
therapy-related MDS are also eligible
- Hydroxyurea is allowed to lower the white cell count =< 10,000/ul prior to initiation
of venetoclax
- Total bilirubin =< 2.0 x upper limit of normal (ULN) unless increase is due to
Gilbert's disease or leukemic involvement
- Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) =< 3.0 x ULN unless
considered due to leukemic involvement
- Adequate renal function as calculated using the modified Cockcroft-Gault equation of
>= 30 ml/min, OR creatinine < 2 x ULN, unless related to the disease
- Signed written informed consent
- Females must be surgically or biologically sterile or postmenopausal (amenorrheic for
at least 12 months) or if of childbearing potential, must have a negative serum or
urine pregnancy test within 72 hours before the start of the treatment. Women of
childbearing potential must agree to use an adequate method of contraception during
the study and until 3 months after the last treatment
- Males must be surgically or biologically sterile or agree to use an adequate method of
contraception during the study until 3 months after the last treatment
- Eastern Cooperative Oncology Group (ECOG)/performance status (PS) =< 2
Exclusion Criteria:
- Patients having received any prior BCL2 inhibitor therapy
- Patients with MDS with IPSS risk categories Low or Int-1 (overall IPSS score < 1.5)
- Patient with known human immunodeficiency virus (HIV) infection (due to potential
drug-drug interactions between antiretroviral medications and venetoclax). HIV testing
will be performed at screening, only if required per local guidelines or institutional
standards
- Patient known to be positive for hepatitis B or C infection (hepatitis C virus
antibody [HCV Ab] indicative of a previous or current infection; and/or positive
hepatitis B virus surface antigen [HBs Ag] or detected sensitivity on hepatitis B
virus-deoxyribonucleic acid [HBV-DNA] polymerase chain reaction [PCR] test for
hepatitis B virus core antibody [HBc Ab] and/or hepatitis B virus surface antibody
[HBs Ab] positivity) with the exception of those with an undetectable viral load
within 3 months of screening. (Hepatitis B or C testing is not required). Subjects
with serologic evidence of prior vaccination to HBV [i.e., HBs Ag-, and anti-HBs+] may
participate
- Patient has received strong and/or moderate CYP3A inducers within 7 days prior to the
initiation of study treatment
- Patient has consumed grapefruit, grapefruit products, Seville oranges (including
marmalade containing Seville oranges) or Starfruit within 3 days prior to the
initiation of study treatment
- Patient has a cardiovascular disability status of New York Heart Association class >
2. Class 2 is defined as cardiac disease in which patients are comfortable at rest but
ordinary physical activity results in fatigue, palpitations, dyspnea, or anginal pain
- Patient has chronic respiratory disease that requires continuous oxygen, or
significant history of renal, neurologic, psychiatric, endocrinologic, metabolic,
immunologic, hepatic, cardiovascular disease, any other medical condition or known
hypersensitivity to any of the study medications including excipients of azacitidine
that in the opinion of the investigator would adversely affect his/her participating
in this study
- Patient has a malabsorption syndrome or other condition that precludes enteral route
of administration
- Patient exhibits evidence of other clinically significant uncontrolled systemic
infection requiring therapy (viral, bacterial or fungal)
- Patient has received a live attenuated vaccine within 4 weeks prior to the first dose
of study drug
- Patient has a history of other malignancies within 2 years prior to study entry, with
the exception of:
- Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of
breast
- Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin
- Previous malignancy confined and surgically resected (or treated with other
modalities) with curative intent; requires discussion with TA Doctor of Medicine
(MD)
- Patient has a white blood cell count > 10 x 10^9/L. (Hydroxyurea or leukapheresis are
permitted to meet this criterion)
- Female subject has positive results for pregnancy test
- Patients with (grade > 1) unresolved from prior treatment (including chemotherapy,
targeted therapy, immunotherapy, experimental agents, radiation, or surgery)