Phase II Evaluation of Azacitidine and Venetoclax Combination Therapy in Higher-Risk Chronic Myelomonocytic Leukemia Patients

The primary objective of the AVENHIR trial is to determine the **safety** of the combination of **venetoclax** and **azacitidine** in patients with higher-risk Chronic Myelomonocytic Leukemia (CMML) during the run-in phase, as well as to assess the overall response rate in the phase II portion of the study. This is clinically relevant as it aims to establish a safe and effective treatment regimen for a patient population with limited therapeutic options.

Secondary objectives include: - Description of efficacy in terms of complete response rate, duration of response, and survival, alongside a description of safety. - Exploratory objectives aim at nominating potential biomarkers of the AZA-VEN combination. These objectives are crucial for understanding the broader impact of the treatment and identifying potential predictive markers for treatment response.

The clinical trial involves participants diagnosed with **chronic myelomonocytic leukemia (CMML)**, specifically those who are HMA-naïve and classified as higher-risk according to the CPSS-mol risk intermediate-2 or high criteria. The study population includes both male and female subjects aged 18 and older, with an **ECOG Performance status** of 0-2, indicating a relatively stable general health status. Participants must have adequate organ function, as defined by specific laboratory criteria, and must not have received prior treatment with hypomethylating agents, although prior treatment with erythropoiesis-stimulating agents and hydroxyurea is permissible under certain conditions. The trial population was selected based on these criteria, and all participants are required to provide informed consent and have a negative pregnancy test with adequate contraception if applicable. The sponsor has not provided information regarding the total number of participants. The study includes individuals affiliated with a health insurance system and considers vulnerable populations. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the **safety** and efficacy of a combination therapy involving **azacitidine** and **venetoclax** in patients diagnosed with higher-risk Chronic Myelomonocytic Leukemia (CMML). This is a Phase II study with a safety run-in phase, structured as a randomized, double-blind, controlled trial. The trial is expected to commence on October 4, 2023, and conclude by October 4, 2028, with a total duration of approximately five years.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, CMML diagnosis, risk level, and prior treatment history. The inclusion criteria require participants to be 18 years or older, with a confirmed diagnosis of CMML according to ICC 2022 criteria, and classified as intermediate-2 or high risk per the CPSS-mol scoring system. Adequate organ function and a performance status of 0-2 on the ECOG scale are also required. Following the screening, eligible participants will enter the safety run-in phase, where dose-limiting toxicity will be monitored during the first two cycles of treatment.

Subsequent follow-up visits will occur at regular intervals to evaluate the overall response rate (ORR) after three and six cycles, as well as to monitor safety profiles and other secondary endpoints such as complete remission (CR) rates, overall survival (OS), and progression-free survival (PFS). The end-of-study visit will mark the conclusion of the participant's involvement, where final assessments will be conducted to gather comprehensive data on the treatment's efficacy and safety.

The expected length of participant involvement is up to 24 months, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study include the occurrence of severe adverse events, withdrawal of consent, or any significant protocol deviations. The trial aims to provide valuable insights into the therapeutic potential of the azacitidine and venetoclax combination in managing higher-risk CMML, contributing to the advancement of treatment options for this patient population.

The clinical trial involves the administration of **Vidaza**, a pharmaceutical product containing the active substance **azacitidine**. Vidaza is formulated as a **powder for suspension for injection** and is administered via **subcutaneous use**. The dosage is set at a maximum of 75 mg/m² per day, with a total treatment period not exceeding 24 months. The product is manufactured by Bristol-Myers Squibb Pharma EEIG and is authorized under the marketing authorization number EU/1/08/488/001. The active substance, azacitidine, is of chemical origin and is classified under the ATC code L01BC07. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol.

In addition to Vidaza, the trial includes the administration of **Venetoclax**, a product containing the active substance **venetoclax**. Venetoclax is provided in the form of **film-coated tablets** and is taken orally. The maximum daily dose is 400 mg, with a treatment duration of up to 24 months. Venetoclax is produced by AbbVie Deutschland GmbH & Co. KG and is identified by the sponsor product code ABT-199. The active substance is also of chemical origin. The trial ensures that participants adhere to the prescribed dosing regimen, with regular monitoring to assess compliance and safety.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in this trial. The focus is on evaluating the safety and efficacy of the combination of azacitidine and venetoclax in patients with higher-risk **Chronic Myelomonocytic Leukemia** (CMML). The trial's main objective is to determine the safety of the combination therapy during the run-in phase and to assess the overall response rate in the phase II portion of the study.

The efficacy of the combination of **azacitidine** and **venetoclax** in patients with higher-risk Chronic Myelomonocytic Leukemia (CMML) will be assessed through a series of primary and secondary endpoints. The primary efficacy endpoint for the Phase II portion of the study is the Overall Response Rate (ORR) after 3 and 6 cycles of treatment, evaluated according to protocol-defined criteria modified from the MDS/MPN IWG criteria. This includes assessments of complete remission (CR), partial remission (PR), marrow response (MR), and clinical benefit (CB).

Secondary efficacy endpoints include the CR rate after 3 and 6 cycles, ORR at best response, and ORR after 3 and 6 cycles, as well as at best response according to DACOTA response criteria. Additional secondary endpoints encompass the duration of response, overall survival (OS), AML-free survival (AMLFS), progression-free survival (PFS), and event-free survival (EFS). The study will also evaluate the cumulative incidence of AML, the cumulative risk of death without AML, the cumulative incidence of progressive disease or AML transformation, and the cumulative risk of death without progression or AML transformation. Furthermore, the rate of hematopoietic stem cell transplantation (HSCT) and post-HSCT OS and AMLFS will be assessed, along with OS, AMLFS, and PFS censoring at HSCT and subsequent therapy. The rate and description of subsequent therapy, as well as OS, AMLFS, and PFS censoring at subsequent therapy, will also be evaluated.