Venetoclax in Combination With 5 Days Azacitidine in Untreated AML Patients, Not Eligible for Standard Induction Therapy

Study Overview
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Brief Summary
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Acute myeloid leukemia (AML): continuous oral Venetoclax (VEN) and 7 days of s.c. Azacitidine (AZA) per 28-day cycle = standard of care for intensive induction therapy ineligible AML patients in Germany The VENAZA-5S pilot trial: AZA administration reduced to 5 days within each cycle to improve tolerability and treatment adherence due to less neutropenic infections, less treatment interruptions and less hospitalizations.

Detailed Description
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Acute myeloid leukemia (AML) is a uniformly fatal disease if untreated. The combination of continuous oral Venetoclax (VEN) and 7 days of s.c. Azacitidine (AZA) per 28-day cycle has recently emerged as the new standard of care for AML patient who are ineligible for intensive induction therapy, and has been widely adopted in Germany. The VENAZA-5S pilot trial aims to reduce the reported hematological toxicity profile of this currently approved combination, while preserving efficacy, by modifying AZA administration to 5 days within each cycle. The hypothesis is that this modification will not interfere with the response rates achieved by the combination, but will rather improve tolerability and treatment adherence due to less neutropenic infections, less treatment interruptions and hospitalizations, and thus result in better quality of life and favorable long-term outcomes in elderly or comorbid AML patients. This single-arm pilot study is intended to generate first data on the efficacy and toxicity of 5 days AZA + VEN, which will be compared to a historical control cohort treated with the current standard of 7 days AZA + VEN.

Official Title
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A Single-arm, Pilot Study of Venetoclax in Combination With 5 Days Azacitidine in Treatment-naïve Subjects With Acute Myelogenous Leukemia Who Are ≥18 Years of Age and Not Eligible for Standard Induction Therapy (VENAZA-5S PILOT TRIAL)

Conditions
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Acute Myeloid Leukemia (AML)

Intervention / Treatment
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* Drug: VEN+AZA-5


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Confirmed diagnosis of AML by World Health Organization (WHO) criteria 2016 Ineligible for treatment with a standard cytarabine and anthracycline induction regimen due to age or comorbidities Age ≥ 18 years Life expectancy of at least 12 weeks Key Exclusion Criteria: Prior treatment for AML or myelodysplastic syndrome (MDS) with one of the following: Hypomethylating agent (HMA) Chemotherapeutic agent Chimeric Antigen Receptor (CAR)-T cell therapy Experimental therapies Note: Prior use of hydroxyurea is allowed History of myeloproliferative neoplasm (MPN) Diagnosis of acute promyelocytic leukemia (APL) Presence of favorable-risk karyotype abnormalities: t(15;17), t(8;21), inv(16) or t(16;16)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: VEN+AZA-5<br>Azacitidine (AZA) 75 mg/m2, d1-5 of each 28 day cycle (SC) in combination with Venetoclax (VEN): 400 mg daily (orally) | Drug: VEN+AZA-5<br>* Up to 6 cycles: Azacitidine (AZA) 75 mg/m2, d1-5 of each 28 day cycle (SC) in combination with Venetoclax (VEN): 400 mg daily (orally)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary outcome measure is the response rate defined as the rate of CR/CRi after up to 6 cycles of therapy (best response). | Bone marrow assessments will be performed at least at screening, at the end of cycle 1, after cycle 4 and after cycle 6 resp. end of treatment (EOT). Criteria for disease status / response assessment follow the ELN-2022 recommendations . | best response after up to 6 cycles (each cycle is 28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of CR or CRi by the Initiation of Cycle 2 | Rate of CR or CRi by the Initiation of Cycle 2. Criteria for disease status / response assessment follow the European LeukemiaNet (ELN) - 2022 recommendations. | At the end of Cycle 1 (each cycle is 28 days) | 
| Rate of CR with partial hematologic recovery (CRh) after up to 6 cycles of therapy | Rate of CR with partial hematologic recovery (CRh) after up to 6 cycles of therapy. Criteria for disease status / response assessment follow the ELN-2022 recommendations. | after up to 6 cycles (each cycle is 28 days) | 
| Time from initiation of treatment (C1D1) until achievement of CR or CRi | Time from initiation of treatment (C1D1) until achievement of CR or CRi. Criteria for disease status / response assessment follow the ELN-2022 recommendations. | from start of treatment (C1D1) until up to 6 cycles (each cycle is 28 days) | 
| Objective response rate | Objective response rate (CR, CRh, CRi, MLFS). Criteria for disease status / response assessment follow the ELN-2022 recommendations. | at EOT, after up to 6 cycles therapy (each cycle is 28 days) | 
| Event free survival (EFS) | Event free survival (EFS), defined as the number of days from start of treatment to the date of relapse from CR or CRi, treatment failure (i.e., no CR or CRi after 6 cycles (each cycle is 28 days) of therapy or disease progression requiring treatment discontinuation), or death from any cause. | From start of treatment to the date of relapse from CR or CRi, treatment failure (i.e., no CR or CRi after up to 6 cycles (each cycle is 28 days) of therapy or disease progression requiring treatment discontinuation), or death from any cause. | 
| Overall survival (OS) | Overall survival (OS), defined as the number of days from start of treatment to death from any cause. After EOT, patients will be further followed up for survival until the end of the trial is reached (= last patient out, i.e. when the last surviving patient has reached the 3-month follow-up visit after EOT). Therefore, the duration of follow-up can differ between patients but is at least 3 months after EOT. | From start of treatment to date of death from any cause. OS will be assessed until 3 months after end of treatment of the last patient on study. | 
| Descriptive assessment of measurable residual disease (MRD) levels on study treatment, determined by quantitative PCR or targeted next-generation sequencing | Determined by quantitative PCR or targeted next-generation sequencing. Molecular profiling and MRD assessment of all patients will be carried out centrally (Hämatologisches Diagnostiklabor, Universitätsklinikum Leipzig), at least at screening, at the end of cycle 1, after cycle 4 and after cycle 6 resp. end of treatment (EOT). | From Screening until EOT (after up to 6 cycles (each cycle is 28 days)) | 
| Time to treatment discontinuation | Time to treatment discontinuation, defined as the number of days from start of treatment to premature stop of treatment. The stop date is the date the first cycle that was not given should have started as scheduled. This endpoint will be analyzed with death and progression or relapse as competing risk. | From start of treatment to day of treatment discontinuation (within up to 6 cycles (each cycle is 28 days)) | 
| Rate of patients with at least one treatment interruption | Rate of patients with at least one treatment interruption, i.e. a delay of the next cycle, and duration of treatment interruptions. | From start of treatment until EOT (after up to 6 cycles (each cycle is 28 days)) | 
| Delay of subsequent cycles, dose reductions or shortening/interruption of study drug administration | Delay of subsequent cycles, dose reductions or shortening/interruption of study drug administration | From start of treatment until EOT (after up to 6 cycles (each cycle is 28 days)) | 
| Duration of patient hospitalization | Duration of patient hospitalization, defined as days in hospital from start of treatment until EOT. | From start of treatment until EOT (after up to 6 cycles (each cycle is 28 days)) | 
| Quality of life (QoL) | The established cancer-specific Core Quality of Life questionnaire QLQ-C30 from the EORTC (European Organisation for Research) will be used for QoL measurement, at screening and at the beginning of each cycle and at EOT. | From Screening until EOT (after up to 6 cycles (each cycle is 28 days)) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Venclyxto, Venetoclax, Azacitidine, Hematologic Diseases, Acute Myelogenous Leukemia