Venetoclax and Azacitidine for the Treatment of Relapsed or Refractory High-Risk Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia

Sponsor

M.D. Anderson Cancer Center (Other)

Overall Status

Recruiting

CT.gov ID

NCT04550442

Collaborator

National Cancer Institute (NCI) (NIH), Genentech, Inc. (Industry)

Enrollment

Location

Arm

32.2

Anticipated Duration (Months)

1.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This phase I/II trial investigates the side effects and best dose of venetoclax when given together with azacitidine and to see how well it works in treating patients with high-risk myelodysplastic syndrome or chronic myelomonocytic leukemia that has come back (relapsed) or has not responded to treatment (refractory). Venetoclax may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as 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. Giving venetoclax and azacitidine together may help to control myelodysplastic syndrome or chronic myelomonocytic leukemia.

Condition or Disease	Intervention/Treatment	Phase
Recurrent Chronic Myelomonocytic Leukemia Recurrent Myelodysplastic Syndrome Refractory Chronic Myelomonocytic Leukemia 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 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:

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) 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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

58 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase I/II Study of Venetoclax in Combination With Azacitidine in Relapsed/Refractory High-Risk Myelodysplastic Syndrome (MDS) or Chronic Myelomonocytic Leukemia (CMML)

Actual Study Start Date :

Sep 4, 2020

Anticipated Primary Completion Date :

May 11, 2023

Anticipated Study Completion Date :

May 11, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (venetoclax, azacitidine) Patients receive venetoclax PO daily on days 1-14 and azacitidine IV over 15 minutes or SC on days 1-5. Cycles repeat every 4-8 weeks in the absence of disease progression or unacceptable toxicity.	Drug: Azacitidine Given IV or SC Other Names: 5 AZC 5-AC 5-Azacytidine 5-AZC Azacytidine Azacytidine, 5- Ladakamycin Mylosar 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 PO daily on days 1-14 and azacitidine IV over 15 minutes or SC on days 1-5. Cycles repeat every 4-8 weeks in the absence of disease progression or unacceptable toxicity.

Drug: Azacitidine

Given IV or SC

Other Names:

5 AZC

5-AC

5-Azacytidine

5-AZC

Azacytidine

Azacytidine, 5-

Ladakamycin

Mylosar

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) (Phase I) [Up to 28 days]
The MTD is the highest dose level in which < 2 patients of 6 develop first cycle dose-limiting toxicity (DLT).
Overall response rate (ORR) (Phase II) [Up to 5 years post-treatment]
ORR is defined as the proportion of patients who had complete remission (CR), partial remission (PR) or marrow CR (mCR) lasting at least 4 weeks, or hematologic improvement (HI) lasting at least 8 weeks. Will estimate the overall response rate for the combination treatment, along with the 95% credible interval.

Secondary Outcome Measures

Rate of CR [Up to 5 years post-treatment]
The association between CR and patient's clinical characteristics will be examined by Wilcoxon's rank sum test or Fisher's exact test, as appropriate.
Rate of mCR [Up to 5 years post-treatment]
The association between mCR 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 post-treatment]
Rate of platelet transfusion independence [Up to 5 years post-treatment]
Rate of red blood cell transfusion independence [Up to 5 years post-treatment]
Rate of cytogenetic response [Up to 5 years post-treatment]
The correlation between cytogenetic 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 post-treatment]
The correlation between bone marrow blast response and patient's clinical characteristics will be examined by Wilcoxon's rank sum test or Fisher's exact test, as appropriate.
Duration of response [The number of days 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 post-treatment]
Will be estimated using the method of Kaplan and Meier. Comparisons by important subgroups will be made using the log-rank tests.
Event-free survival [The number of days 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 post-treatment]
Will be estimated using the method of Kaplan and Meier. Comparisons by important subgroups will be made using the log-rank tests.
Overall survival [The time from treatment start till death or last follow-up, assessed up to 5 years post-treatment]
Will be estimated using the method of Kaplan and Meier. Comparisons by important subgroups will be made using the log-rank tests.
Progression free survival [The time from treatment to progression or last follow-up, assessed up to 5 years post-treatment]
Will be estimated using the method of Kaplan and Meier. Comparisons by important subgroups will be made using the log-rank tests.
Time to transformation to acute myeloid leukemia (AML) [The time from treatment till transformation of AML or last follow-up, assessed up to 5 years post-treatment]
Will be estimated using the method of Kaplan and Meier. Comparisons by important subgroups will be made using the log-rank tests.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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 >

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)