Phase II Study of Clinical Efficacy of Venetoclax in Combination With Azacitidine in Patients With Therapy Related Myelodysplastic Syndrome (t-MDS)
Overview
- Phase
- Phase 2
- Intervention
- Azacitidine
- Conditions
- Secondary Myelodysplastic Syndrome
- Sponsor
- Uma Borate
- Enrollment
- 33
- Locations
- 3
- Primary Endpoint
- Complete remission (CR)
- Status
- Active, not recruiting
- Last Updated
- last month
Overview
Brief Summary
This phase II trial studies the effect of venetoclax and azacitidine in treating patients with therapy related or secondary myelodysplastic syndrome. Venetoclax may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. 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 in combination with azacitidine may work better in treating patients with therapy related or secondary myelodysplastic syndrome.
Detailed Description
PRIMARY OBJECTIVE: I. Determine the proportion of participants that achieve a complete remission following treatment with azacitidine and venetoclax. SECONDARY OBJECTIVES: I. Assess safety of azacitidine and venetoclax combination therapy. II. Determine the overall response rate (ORR). III. Determine the complete cytogenetic response rate (CCyR). IV. Determine the duration of response (DOR). V. Estimate event-free survival (EFS). VI. Estimate overall survival (OS). VII. Determine combined hematologic improvement rate (HIR). VIII. Determine red blood cell transfusion independence rate. IX. Determine platelet transfusion independence rate. X. Determine proportion of participants whose disease transforms to acute myeloid leukemia (AML). XI. Determine proportion of participants that proceed to allogeneic hematopoietic stem cell transplantation (alloHSCT). XII. Compare response criteria between the 2006 International Working Group (IWG) and 2023 IWG criteria. EXPLORATORY OBJECTIVES: I. Determine baseline frequencies of cytogenetic aberrations and their relationships to response to study therapy. II. Estimate progression-free survival (PFS). III. Obtain quality of life (QoL) information from patient-reported responses to Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form 7a and European Organisation for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) - Core 30 (C30) questionnaires. OUTLINE: Patients receive venetoclax orally (PO) once daily (QD) on days 1-14 and azacitidine intravenously (IV) over 10-40 minutes on days 1-7 or days 1-5 of week 1 and days 1 and 2 of week 2. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days and every 6 months for up to 24 months.
Investigators
Uma Borate
Principal Investigator
Ohio State University Comprehensive Cancer Center
Eligibility Criteria
Inclusion Criteria
- •Ability to understand and the willingness to sign a written informed consent document
- •Age \>= 18 years at time of informed consent. Both men and women and members of all races and ethnic groups will be included
- •Eastern Cooperative Oncology Group (ECOG) performance status of =\< 2
- •Previously untreated therapy related myelodysplastic syndrome (t-MDS) with Revised International Prognostic Scoring System (IPSS-R) risk categories Intermediate, High or Very High (i.e., minimum IPSS-R score of 3.5) and presence of \< 20% bone marrow blasts per bone marrow biopsy/aspirate
- •Patients with t-MDS which is defined as patients who have had prior anti-cancer therapy including chemotherapy and/or radiation therapy
- •Aspartate aminotransferase (AST) \< 3.0 x upper limit of normal (ULN) x upper limit of normal (ULN; local laboratory)
- •Alanine aminotransferase (ALT) \< 3.0 x ULN x ULN
- •Total bilirubin =\< 2 x ULN (except for patients with known Gilbert's syndrome)
- •Creatinine clearance \>= 30 mL/min OR serum creatinine \< 1.5 x the ULN
- •White blood cell (WBC) count =\< 10,000/uL
Exclusion Criteria
- •Participant has received prior therapy with a venetoclax or other BH3 mimetic. Note: Prior supportive care in form of transfusions or growth factors, etc., is not considered prior therapy. Supportive care should be discontinued \>= 14 days prior to the first dose of study drug. Subjects may continue oral corticosteroids for management of conditions other than MDS (e.g., asthma, rheumatoid arthritis) at a stable daily dose equivalent to =\< 10 mg prednisone during screening and study participation
- •Subject has a diagnosis other than previously untreated de novo MDS with IPSS-R risk categories Intermediate, High or Very High, including:
- •MDS with IPSS-R risk categories Very Low or Low (overall IPSS score \< 3)
- •MDS evolving from a pre-existing myeloproliferative neoplasm (MPN)
- •MDS/MPN including chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (CML), juvenile myelomonocytic leukemia (JMML) and unclassifiable MDS/MPN
- •Patients who are suitable for and willing to receive intensive chemotherapy or eligible to proceed to allogeneic stem cell transplantation without additional therapy
- •Known history of testing positive for Human Immunodeficiency Virus (HIV) infections, Hepatitis B, or Hepatitis C. For countries where HIV status is mandatory: testing positive for HIV during screening using a local test.
- •Clinically significant ventricular arrhythmia (e.g., ventricular tachycardia, ventricular fibrillation, or Torsades de pointes)
- •Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, serious cardiac arrhythmia, myocardial infarction within 6 months prior to enrollment, New York Heart Association (NYHA) class III or IV heart failure
- •Patients with uncontrolled infection will not be enrolled until infection is treated and under control
Arms & Interventions
Treatment (venetoclax, azacitidine)
Patients receive venetoclax PO QD on days 1-14 and azacitidine IV over 10-40 minutes on days 1-7 or days 1-5 of week 1 and days 1 and 2 of week 2. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Azacitidine
Treatment (venetoclax, azacitidine)
Patients receive venetoclax PO QD on days 1-14 and azacitidine IV over 10-40 minutes on days 1-7 or days 1-5 of week 1 and days 1 and 2 of week 2. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Quality-of-Life Assessment
Treatment (venetoclax, azacitidine)
Patients receive venetoclax PO QD on days 1-14 and azacitidine IV over 10-40 minutes on days 1-7 or days 1-5 of week 1 and days 1 and 2 of week 2. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Questionnaire Administration
Treatment (venetoclax, azacitidine)
Patients receive venetoclax PO QD on days 1-14 and azacitidine IV over 10-40 minutes on days 1-7 or days 1-5 of week 1 and days 1 and 2 of week 2. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Venetoclax
Outcomes
Primary Outcomes
Complete remission (CR)
Time Frame: At the end of Cycle 4 (each cycle is 28 days) or earlier based on bone marrow results
Defined by 2023 International Working Group (IWG) criteria. A point estimate and 95% exact (i.e., Clopper-Pearson) confidence interval will be computed for the CR rate within the efficacy-evaluable population.
Secondary Outcomes
- Duration of response (DOR)(From earliest occurrence of PR, mCR, or CR to onset of progressive disease, assessed up to 24 months)
- Cytogenetic response rate (CCyR)(At the end of the last cycle of study drug (each cycle is 28 days))
- Overall response rate (ORR)(At the end of the last cycle of study drug (each cycle is 28 days))
- Treatment emergent adverse events (AEs)(Up to 30 days after last dose of study drug)
- Overall survival (OS)(From date of death or the last known alive date for participants who withdraw from or complete the study without dying, assessed up to 24 months)
- Event free survival (EFS)(From event date or date of last clinic visit for participants without an event during the study period, assessed up to 24 months)
- Hematologic improvement rate (HIR)(At the end of the last cycle of study drug (each cycle is 28 days))
- Rates of hematologic improvement-erythrocytes (HI-E)(At the end of the last cycle of study drug (each cycle is 28 days))
- Rates of hematologic improvement-platelets (HI-P)(At the end of the last cycle of study drug (each cycle is 28 days))
- Rates of hematologic improvement-neutrophils (HI-N)(At the end of the last cycle of study drug (each cycle is 28 days))
- Percentage of participants who have disease that transforms to acute myeloid leukemia (AML)(End of study follow-up period (24 months after last dose of study drug))
- Percentage of participants who proceed to allogeneic hematopoietic stem cell transplantation(12 months after last dose of study drug)
- Percentage of patients achieving CR, CR equivalent, CRi, CRh, PR, or HI(From first dose of study drug to end of last cycle of study drug (each cycle is 28 days))