Phase I/II Open-Label Study of Azacitidine and Venetoclax in Untreated Higher-Risk Myelodysplastic Syndromes Ineligible for Allogeneic Transplantation

Trial ID: 2024-514876-41-00
Protocol: GFM-ONUVEN-MDS
Sponsor: Groupe Francophone Des Myelodysplasies

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Diseases & Conditions

Myelodysplastic syndrome

Objectives

The primary objective of this study is to establish the optimal dose and treatment duration of **ONUREG** (CC-486) in combination with **VENETOCLAX** for patients with higher-risk myelodysplastic syndromes who are untreated and ineligible for allogenic transplantation. Determining the optimal dosing regimen is clinically relevant as it aims to maximize therapeutic efficacy while minimizing adverse effects, thereby improving patient outcomes in this high-risk population.

Secondary objectives include: - Assessing the tolerance and efficacy of this two-drug regimen in high-risk myelodysplastic syndromes (MDS) patients, as well as evaluating their quality of life (QoL). - Identifying biomarkers that may predict clinical response, quality of life, and outcome measures of overall survival (OS). These objectives are crucial for understanding the broader impact of the treatment on patient health and for identifying potential predictive markers that could guide personalized treatment strategies.

Participants

The clinical trial involves participants diagnosed with **higher-risk myelodysplastic syndromes** who are untreated and ineligible for allogenic transplantation. The study population includes both male and female subjects aged 18 years and older. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, indicating they are ambulatory and capable of all self-care but unable to carry out any work activities. The trial population was selected based on specific clinical criteria, including adequate liver and renal function, and a total white blood cell count of 10 G/L or less. Participants must not have received prior therapy for myelodysplastic syndromes with any hypomethylating agents, chemotherapy, or experimental agents. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified, but participants must be able to comply with study procedures, including regular blood sampling and clinical assessments. The trial includes a vulnerable population, and both male and female participants must adhere to strict contraceptive measures throughout the study duration and for a specified period after the last dose of treatment.

Plans and Procedures

The clinical trial is designed as a **phase I/II**, open-label, single-arm, multicenter study aimed at assessing the safety and preliminary efficacy of oral **azacitidine** (ONUREG®) in combination with **venetoclax** (VENCLYXTO®) for patients with higher-risk **myelodysplastic syndromes** who are untreated and ineligible for allogenic transplantation. The primary objective is to establish the optimal dose and treatment duration of the combination therapy. The trial is expected to commence recruitment on December 6, 2023, and conclude by December 6, 2028.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and organ function. The trial will include regular follow-up visits to monitor safety, efficacy, and any dose-limiting toxicities, particularly at day 28 of cycle 1. The end-of-study visit will assess the overall response and any long-term effects of the treatment. The expected length of participant involvement will vary depending on individual response and tolerance to the treatment, with the possibility of early termination if significant adverse effects occur or if the participant withdraws consent.

Key elements of the research methodology include the use of modified IWG-MDS 2006 criteria to evaluate primary endpoints such as dose-limiting toxicity and overall response. Secondary endpoints will assess best response, hematological improvement, progression to acute myeloid leukemia, and patient-reported outcomes. The trial will adhere to rigorous ethical standards, requiring informed consent and compliance with study procedures. Participants will be monitored for adverse events, and any significant safety concerns may lead to early discontinuation of the study for affected individuals.

Treatment

The clinical trial involves the administration of **azacitidine**, marketed under the name Onureg, as an experimental medication. Azacitidine is provided in the form of a **tablet** and is intended for **oral use**. The active substance, azacitidine, is a chemical compound produced by Bristol-Myers Squibb International Corporation. The trial aims to determine the optimal dose and treatment duration of azacitidine in combination with another investigational drug. The azacitidine tablets are not formulated for pediatric use, and the administration schedule will be determined based on the study protocol. Participant compliance will be monitored throughout the trial to ensure adherence to the dosing regimen.

In addition to azacitidine, the trial also includes the administration of **venetoclax**, known by the sponsor product code ABT-199. Venetoclax is provided as a **film-coated tablet** for **oral use**. The active substance, venetoclax, is a chemical compound manufactured by AbbVie Deutschland GmbH & Co. KG. Similar to azacitidine, venetoclax is not formulated for pediatric use. The combination of azacitidine and venetoclax is being investigated to assess safety and preliminary efficacy in patients with higher-risk myelodysplastic syndromes who are ineligible for allogenic transplantation. The dosing schedule and administration frequency will be guided by the study protocol, with participant compliance being closely monitored to ensure accurate data collection.

Efficacy

Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoints include **dose-limiting toxicity (DLT)** at day 28 of cycle 1 and overall response (OR) measured at day 28 of cycle 1 according to modified IWG-MDS 2006 criteria. Secondary endpoints encompass a range of measures, including the best response evaluated according to modified IWG-MDS 2006 and IWG-HR-MDS 2023 criteria within the first six cycles, which include complete remission (CR), partial remission (PR), marrow complete response (mCR), and other response categories. Additionally, hematological improvements (HI) such as erythroid HI, neutrophil HI, and platelet HI will be assessed.

Further secondary endpoints include time to response, duration of response, progression to acute myeloid leukemia (AML), time to next treatment, and various survival outcomes such as overall survival (OS), event-free survival (EFS), and progression-free survival (PFS). The trial will also evaluate the duration of transfusion independence and the toxicity profile, including cytopenia duration and infectious complications. Patient-reported outcomes and quality of life (QoL) will be measured using tools such as the FACIT-An, EQ-5D-5L, PGIC, and PGIS, with changes in QoL from baseline assessed through these questionnaires.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Subjects must understand and voluntarily sign and date an informed consent form (ICF) indicating the investigational nature of the study, approved by an independent EC/IRB, prior to the initiation of any screening or study-specific procedures.
Age ≥ 18 years at the date of signing the ICF
Diagnosis of MDS according to the 2016 WHO classification, with presence of < 20% bone marrow blasts per bone marrow aspirate at screening, confirmed by local investigator with HR-MDS, based on the revised International Prognostic Scoring System (IPSS-R) >3 (intermediate, high or very high) and a blast percentage of 5 or more
Previously untreated HR-MDS: no prior therapy for MDS with any HMA (AZA or decitabine) chemotherapy, allo-HSCT or experimental agent. All other treatments are not considered prior therapy.
Not immediately eligible for allo-HSCT or intensive chemotherapy at the time of screening due to individual clinical factors such as age, comorbidities and performance status, donor availability.
Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
Total white blood cell (WBC) count ≤ 10 G/L; Treatment with hydroxyurea is permitted to lower the WBC to reach this inclusion criterion and will be stopped at least 48 hours before treatment initiation.
Adequate liver functions as demonstrated by: Serum alanine transaminase (ALT) < 3.0 × upper limit of normal [ULN] ; Serum aspartate transaminase (AST) < 3.0 × ULN ; Serum total bilirubin ≤ 2.0 × ULN (except in the setting of isolated Gilbert syndrome, where participants may only be included with total bilirubin ≤ 3.0 x ULN).
Adequate renal function with calculated creatinine clearance ≥ 40 mL/min/1.73 m2 (estimation based on Modification of Diet in Renal Disease (MDRD) formula or CKD-EPI, by local laboratory)
Participant is able to communicate with the investigator, and has the ability to comply with the requirements of the study procedures, available for regular blood sampling, study related assessments, including bone marrow aspirates and appropriate clinical management at the treating institution for the duration of the study
Females of childbearing potential (FCBP) is a female who: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy, or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months). FCBP must agree to undergo medically supervised pregnancy test prior to starting study drug, during the course of the study, and after end of study therapy: Have one negative pregnancy test as verified by the Investigator prior to starting study therapy. The first pregnancy test will be performed at screening (within 3 days prior to first study drug administration), and a negative urinary test before starting all subsequent cycles. This applies even if the participant practices true abstinence from heterosexual contact or agree to use, and be able to comply with highly effective contraception without interruption, 28 days prior to starting investigational product, during the study therapy (including dose interruptions), and for 6 months after last dose of Onureg, or at least 1 month after the last dose of venetoclax, whichever is later or longer if required by local regulations. Female patients are either post-menopausal, free from menses for > 2 years, surgically sterilized or willing to use 2 adequate barrier methods of contraception to prevent pregnancy or agree to abstain from becoming pregnant throughout the study, starting with Visit 1. Females of reproductive potential as well as fertile men and their partners who are female of reproductive potential must agree to abstain from sexual intercourse or to use two highly effective forms of contraception from the time of giving informed consent, during the study and for 6 months for females and 3 months for males following the last dose of treatment.
Male participants must practice true abstinence (which must be reviewed on a monthly basis) or agree to use an adequate method of contraception for the duration of the study. Men should be advised not to father a child while receiving treatment and for 3 months post study. Men must agree to learn about the procedures for preservation of sperm before starting treatment.

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Exclusion Criteria

Previous treatment for MDS, any approved or investigational antineoplastic agents or radiotherapy
Previous diagnosis of: MDS evolving from a pre-existing myeloproliferative neoplasm (MPN) ; MDS/MPN including chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), juvenile myelomonocytic leukemia (JMML) and unclassifiable MDS/MPN
Participant has an active, uncontrolled systemic fungal, bacterial, or viral infection. The participant should be afebrile and off antibiotics for at least 72 hours and off antifungals for 7 days. In the case of prior SARS-CoV-2 infection, symptoms must have completely resolved and based on Investigator assessment in consultation with the Medical Monitor, there are no sequelae that would place the patient at a higher risk of receiving investigational treatment.
History of clinically significant medical conditions, laboratory abnormality, psychiatric illness or any other reason that the investigator determines would interfere with the subject's participation in this study, would make the subject an unsuitable candidate to receive study drug or predisposes the participant to high risk of noncompliance with the protocol.
History of active malignancy within the past year prior to screening, with the exception of: Adequately treated carcinoma in situ of the uterine cervix ; Adequately treated basal cell carcinoma or localized squamous cell carcinoma of the skin ; Asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy. Patients with ongoing hormonotherapy could be included.
Participant has received strong or moderate CYP3A inhibitors or inducers or p-gp inhibitors within 7 days prior to initiation of study treatment with prolonged treatment required without therapeutic alternatives. Azols are the only exception and may be permitted after cycle 1 at investigator's discretion and will result in VEN dose reduction.
Consumption of grapefruit products, Seville oranges or starfruit within 3 days prior to first dose of venetoclax
Received live attenuated vaccines prior to initiation of study treatment
History of clinically significant (per investigator's judgment) drug or alcohol abuse within the last 6 months
Conditions that could interfere with drug absorption including short gut syndrome, dysphagia, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally
Participant has uncontrolled hypertension (systolic blood pressure [BP] > 180 mmHg or diastolic BP > 100 mmHg) or has not been stable for at least 1 month prior to treatment
Significant active cardiac disease within the previous 6 months prior to signing the ICF, including: New York Heart Association (NYHA) Class III or IV congestive heart failure ; Unstable angina or angina requiring surgical or medical intervention ; Significant cardiac arrhythmia ; And/or myocardial infarction
Participant is a pregnant or lactating female
Participant has known or suspected to have hypersensitivity to any of the components of the assigned study treatments
Positive test result(s) for human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV). Subjects with serologic evidence of prior vaccination to hepatitis B virus (i.e., hepatitis B surface antigen [HBsAg] negative, anti-hepatitis B surface [HBs] antibody positive and anti-hepatitis B core [HBc] antibody negative) may participate.
Absence of social security affiliation