Venetoclax and Azacitidine for the Treatment of High-Risk Recurrent or Refractory Myelodysplastic Syndrome

Sponsor

M.D. Anderson Cancer Center (Other)

Overall Status

Recruiting

CT.gov ID

NCT04160052

Collaborator

National Cancer Institute (NCI) (NIH)

116

Enrollment

Location

Arm

Anticipated Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Chronic Myelomonocytic Leukemia Myelodysplastic Syndrome Recurrent Myelodysplastic Syndrome Refractory Myelodysplastic Syndrome Therapy-Related Myelodysplastic Syndrome	Drug: Azacitidine Drug: Venetoclax	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVE:

To determine the safety and tolerability (phase 1) and overall response rate (ORR) (phase

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:

Rate of complete remission (CR). II. Rate of marrow/morphologic complete remission (mCR).
Rate of hematologic improvement (HI; erythroid/platelet/neutrophil responses).
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:

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

116 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase I/II of Venetoclax in Combination With Azacitidine in Treatment Naïve and Relapse Refractory High Risk MDS Individuals"

Actual Study Start Date :

Oct 1, 2019

Anticipated Primary Completion Date :

Dec 31, 2022

Anticipated Study Completion Date :

Dec 31, 2022

Arms and Interventions

Arm	Intervention/Treatment
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.	Drug: Azacitidine Given SC or IV Other Names: 5 AZC 5-AC 5-Azacytidine 5-AZC Azacytidine Azacytidine, 5- Ladakamycin Mylosar Onureg U-18496 Vidaza Drug: Venetoclax Given PO Other Names: ABT-0199 ABT-199 ABT199 GDC-0199 RG7601 Venclexta Venclyxto

Arm

Intervention/Treatment

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.

Drug: Azacitidine

Given SC or IV

Other Names:

5 AZC

5-AC

5-Azacytidine

5-AZC

Azacytidine

Azacytidine, 5-

Ladakamycin

Mylosar

Onureg

U-18496

Vidaza

Drug: Venetoclax

Given PO

Other Names:

ABT-0199

ABT-199

ABT199

GDC-0199

RG7601

Venclexta

Venclyxto

Outcome Measures

Primary Outcome Measures

Maximum tolerated dose (MTD) of the combination regimen of venetoclax and azacitidine (Phase I) [Up to 8 weeks]
The MTD is the highest dose level in which < 2 patients of 6 develop first cycle dose-limiting toxicity.
Incidence of adverse events (Phase I) [Up to 5 years]
Safety data will be summarized by category, severity, and frequency.

Secondary Outcome Measures

Overall response rate (Phase 2) [Up to 5 years]
Will be defined as the proportion of patients who had complete remission (CR), partial remission (PR), marrow complete remission, or hematologic improvement lasting at least 4 weeks. Will estimate the overall response rate for the combination treatment, along with the 95% confidence interval.
Rate of CR [Up to 5 years]
The association between response and patient's clinical characteristics will be examined by Wilcoxon's rank sum test or Fisher's exact test, as appropriate.
Rate of marrow/morphologic CR [Up to 5 years]
The association between response and patient's clinical characteristics will be examined by Wilcoxon's rank sum test or Fisher's exact test, as appropriate.
Rate of hematologic improvement [Up to 5 years]
The association between response and patient's clinical characteristics will be examined by Wilcoxon's rank sum test or Fisher's exact test, as appropriate.
Rate of red blood cell transfusion independence [Up to 5 years]
Rate of platelet transfusion independence [Up to 5 years]
The association between response and patient's clinical characteristics will be examined by Wilcoxon's rank sum test or Fisher's exact test, as appropriate.
Rate of cytogenetic response [Up to 5 years]
The association between response and patient's clinical characteristics will be examined by Wilcoxon's rank sum test or Fisher's exact test, as appropriate.
Rate of bone marrow blast response [Up to 5 years]
The association between response and patient's clinical characteristics will be examined by Wilcoxon's rank sum test or Fisher's exact test, as appropriate.
Time to transformation to acute myeloid leukemia [Up to 5 years]
Will be estimated using the method of Kaplan and Meier. Comparisons of time-to-event endpoints by important subgroups will be made using the log-rank tests.
Duration of response [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]
Will be estimated using the method of Kaplan and Meier. Comparisons of time-to-event endpoints by important subgroups will be made using the log-rank tests.
Overall survival [From treatment start till death or last follow-up, assessed up to 5 years]
Will be estimated using the method of Kaplan and Meier. Comparisons of time-to-event endpoints by important subgroups will be made using the log-rank tests.
Progression-free survival [From treatment to progression or last follow-up, assessed up to 5 years]
Will be estimated using the method of Kaplan and Meier. Comparisons of time-to-event endpoints by important subgroups will be made using the log-rank tests.
Time to next myelodysplastic syndrome treatment [Up to 5 years]
Will be estimated using the method of Kaplan and Meier. Comparisons of time-to-event endpoints by important subgroups will be made using the log-rank tests.
Event-free survival [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]
Will be estimated using the method of Kaplan and Meier. Comparisons of time-to-event endpoints by important subgroups will be made using the log-rank tests.

Other Outcome Measures

Effects of therapy on myelodysplastic syndrome [Up to 5 years]
Biological markers of response [Up to 5 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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
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