Clinical Trial Finder

Inclusion Criteria:

• - For phase I, patients can be HMA-naive high-risk MDS (Int-2 or high risk by the International Prognostic Scoring System [IPSS] with overall score >= 1.5) with excess blasts > 5%, or relapsed/refractory MDS post-HMA 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) with > 5% blasts.

• - For phase II, patients will be divided into 2 cohorts: Cohort A: patients with HMA-naive high-risk MDS (Int-2 or high risk by the IPSS with overall score >= 1.5) with excess blasts > 5%.

Cohort B: patients with relapsed/refractory MDS post-HMA 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) with > 5% blasts are eligible. Note: Patients with chronic myelomonocytic leukemia (CMML) and therapy-related MDS are eligible. Hydroxyurea is allowed to lower the white cell count =< 10,000/ul prior to initiation of venetoclax.

• - Total bilirubin < 3 x upper limit of normal (ULN) unless increase is due to Gilbert's disease or leukemic involvement.

• - Alanine aminotransferase (ALT) < 4 x ULN unless considered due to leukemic involvement.

• - Creatinine < 2 x ULN unless related to the disease.

• - Signed written informed consent.

Consent may be translated for Non-English Speaking Patients per institutional policy.

• - 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.

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) - Pregnant or breastfeeding.

- Cognitively impaired patients

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 treatment-naive high-risk myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML) with bone marrow excess blasts > 5% and patients 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) once daily (QD) on days 1-7 or 1-14 and azacitidine subcutaneously (SC) or intravenously (IV) over 15 minutes 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 at 30 days and then every 3-6 months for up to 5 years.

Arms

Experimental: Treatment (venetoclax, azacitidine)

Patients receive venetoclax orally PO QD on days 1-7 or 1-14 and azacitidine SC or IV over 15 minutes on days 1-5. Cycles repeat every 4-8 weeks in the absence of disease progression or unacceptable toxicity.

Interventions

Drug: - Azacitidine

Given SC or IV

Drug: - Venetoclax

Given PO