Clinical trial NCT04160052: Venetoclax and Azacitidine for the Treatment of High-Risk Recurrent or Refractory Myelodysplastic Syndrome
Official title: Phase I/II of Venetoclax in Combination With Azacitidine in Treatment Naïve and Relapse Refractory High Risk MDS Individuals"
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Chronic Myelomonocytic Leukemia
Myelodysplastic Syndrome
Recurrent Myelodysplastic Syndrome
Refractory Myelodysplastic Syndrome
Therapy-Related Myelodysplastic Syndrome
Lead sponsor: M.D. Anderson Cancer Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2019-11-12
Enrollment: 116
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This phase I/II trial studies the side effects and best dose of venetoclax when given together with azacitidine in treating patients with high-risk myelodysplastic syndrome that has come back (recurrent) or does not respond to treatment (refractory). Drugs used in chemotherapy, such as venetoclax and azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Detailed description: 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.

Eligibility criteria: 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 outcomes:
measure: Maximum tolerated dose (MTD) of the combination regimen of venetoclax and azacitidine (Phase I)
timeFrame: Up to 8 weeks
measure: Incidence of adverse events (Phase I)
timeFrame: Up to 5 years
Secondary outcomes:
measure: Overall response rate (Phase 2)
timeFrame: Up to 5 years
measure: Rate of CR
timeFrame: Up to 5 years
measure: Rate of marrow/morphologic CR
timeFrame: Up to 5 years
measure: Rate of hematologic improvement
timeFrame: Up to 5 years
measure: Rate of red blood cell transfusion independence
timeFrame: Up to 5 years
measure: Rate of platelet transfusion independence
timeFrame: Up to 5 years
measure: Rate of cytogenetic response
timeFrame: Up to 5 years
measure: Rate of bone marrow blast response
timeFrame: Up to 5 years
measure: Time to transformation to acute myeloid leukemia
timeFrame: Up to 5 years
measure: Duration of response
timeFrame: From the date of initial response (PR or better) to the date of first documented disease progression/relapse or death, whichever occurs first, assessed up to 5 years
measure: Overall survival
timeFrame: From treatment start till death or last follow-up, assessed up to 5 years
measure: Progression-free survival
timeFrame: From treatment to progression or last follow-up, assessed up to 5 years
measure: Time to next myelodysplastic syndrome treatment
timeFrame: Up to 5 years
measure: Event-free survival
timeFrame: From the date of treatment initiation to the date of documented treatment failure, relapses from CR, or death from any cause, whichever occurs first, assessed up to 5 years
Other outcomes:
measure: Effects of therapy on myelodysplastic syndrome
timeFrame: Up to 5 years
measure: Biological markers of response
timeFrame: Up to 5 years
Locations:
city: Houston
country: United States
facility: M D Anderson Cancer Center
state: Texas
Study officials:
affiliation: M.D. Anderson Cancer Center
name: Guillermo Garcia-Manero
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bazinet A, Darbaniyan F, Jabbour E, Montalban-Bravo G, Ohanian M, Chien K, Kadia T, Takahashi K, Masarova L, Short N, Alvarado Y, Yilmaz M, Ravandi F, Andreeff M, Kanagal-Shamanna R, Ganan-Gomez I, Colla S, Qiao W, Huang X, McCue D, Mirabella B, Kantarjian H, Garcia-Manero G. Azacitidine plus venetoclax in patients with high-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia: phase 1 results of a single-centre, dose-escalation, dose-expansion, phase 1-2 study. Lancet Haematol. 2022 Oct;9(10):e756-e765. doi: 10.1016/S2352-3026(22)00216-2. Epub 2022 Sep 2.