Phase II Evaluation of Azacitidine, Venetoclax, and Tagraxofusp in Higher-Risk Chronic Myelomonocytic Leukemia Patients
- Trial ID
- 2024-511102-22-00
- Protocol
- PATROL
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase II study is to evaluate the **efficacy** of the combination therapy consisting of azacitidine (AZA), venetoclax (VEN), and tagraxofusp (TAG) in patients with higher-risk chronic myelomonocytic leukemia (CMML). The efficacy will be assessed through complete remission (CR), marrow complete remission (mCR), or partial remission (PR) in the studied patient population. This objective is clinically relevant as it aims to determine the potential of this combination therapy to improve treatment outcomes in a patient group with limited therapeutic options.
Secondary objectives include:
- Assessing the **tolerability** and safety of the combination therapy.
- Evaluating efficacy in terms of overall survival (OS), time to leukemia transformation (TLT), and median duration of response until the end of treatment (EOT).
- Assessing hematologic improvement after three cycles of treatment according to IWG 2018/2023 criteria.
- Evaluating transfusion independence after three cycles of treatment based on IWG 2018/2023 criteria.
- Assessing the quality of life of patients undergoing the treatment.
Participants
The clinical trial involves participants diagnosed with **chronic myelomonocytic leukemia** (CMML), specifically those classified as intermediate-2 or high-risk according to the CPSS criteria. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a performance status of 0-2 on the Eastern Cooperative Oncology Group (ECOG) scale and must demonstrate adequate organ function, including liver, renal, and cardiac health, as well as a serum albumin level of at least 3.2 g/dL. The trial does not include a vulnerable population. Participants must be eligible for and receive azacitidine (AZA) as part of their standard care. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified. The selection criteria emphasize the ability to adhere to the study visit schedule and protocol requirements. Key inclusion criteria include a confirmed CMML diagnosis according to WHO 2022 criteria and the availability of blood counts and transfusion events for the previous eight weeks. The trial does not specify any exclusion criteria in the provided data.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of a combination therapy involving **venetoclax**, azacitidine, and **tagraxofusp** in patients with higher-risk chronic myelomonocytic leukemia (CMML). This is a Phase II, randomized, double-blind, controlled trial. The trial aims to generate data on the efficacy of the treatment combination by assessing complete response (CR), marrow complete response (mCR), or partial response (PR) in the studied patient population. The trial is expected to commence on February 1, 2025, and conclude by November 1, 2029, with an estimated participant involvement of up to 12 months.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, CMML diagnosis, and adequate organ function. Following the screening, participants will be randomized to receive the study treatment. The trial includes multiple follow-up visits to monitor treatment response and safety, with assessments conducted after every three cycles of treatment. The primary outcome measure is the response rate after three cycles, evaluated according to established criteria. Secondary endpoints include adverse events, overall survival, and quality of life changes.
The end-of-study visit will occur after the completion of the treatment period or upon early termination. Conditions that may lead to early termination include significant adverse events or withdrawal of consent. Participants are required to adhere to the study visit schedule and protocol requirements throughout the trial duration. The trial will ensure rigorous monitoring of clinical laboratory values, vital signs, and cardiac function to maintain participant safety and data integrity.
Treatment
The clinical trial involves the administration of **Venetoclax**, a chemical compound provided in the form of a **film-coated tablet**. Venetoclax is manufactured by AbbVie Deutschland GmbH & Co. KG and is identified by the sponsor product code ABT-199. The medication is administered orally. The trial includes three different dosages of Venetoclax: 50 mg, 40 mg, and 400 mg. The maximum daily dose for each formulation is 50 mg, 40 mg, and 400 mg respectively, with a total maximum dose of 8,400 mg, 6,720 mg, and 66,700 mg over a treatment period of up to 12 months. Compliance with the dosing schedule is monitored throughout the trial.
Additionally, the trial includes the administration of **Tagraxofusp**, a protein-based therapeutic agent provided as a concentrate for solution for infusion. This product, marketed under the name ELZONRIS, is produced by Stemline Therapeutics B.V. Tagraxofusp is administered via intravenous infusion. The maximum daily dose is 12 µg/kg, with a total maximum dose of 432 µg/kg over a 12-month treatment period. The administration of Tagraxofusp is carefully monitored to ensure adherence to the dosing regimen.
The study also incorporates the standard-of-care therapy **Azacitidine** (AZA) as a non-experimental treatment. Azacitidine is used in combination with Venetoclax and Tagraxofusp to evaluate the efficacy of the treatment regimen in patients with higher-risk chronic myelomonocytic leukemia (CMML). The trial aims to assess the efficacy of this combination therapy through clinical response rates, including complete remission (CR), marrow complete remission (mCR), or partial remission (PR).
Efficacy
The efficacy of the clinical trial will be assessed through a combination of primary and secondary endpoints. The primary endpoint is the response rate, defined as complete response (CR), marrow complete response (mCR), or partial response (PR) after three cycles of treatment. This response will be evaluated according to the criteria established by Savona et al., 2015. Secondary endpoints include the assessment of adverse events (AEs) and serious adverse events (SAEs), clinical laboratory values, vital signs, electrocardiogram (ECG), and echocardiogram/multigated acquisition scan (ECHO/MUGA) parameters. Additionally, overall survival (OS), time to leukemia transformation (TLT), and median duration of response until the end of treatment (EOT) will be measured.
The trial will also evaluate the proportion of patients achieving hematologic improvement and transfusion independence after three cycles of treatment, based on the International Working Group (IWG) 2018/2023 criteria. Furthermore, changes in quality of life will be assessed after three and twelve cycles of treatment compared to baseline. These efficacy parameters will be collected and analyzed at specified timepoints throughout the trial to provide comprehensive data on the treatment's impact on patients with higher-risk chronic myelomonocytic leukemia (CMML).
Inclusion and Exclusion Criteria
Inclusion Criteria
- Signed written informed consent
- Male and female ≥ 18 years at date of signing informed consent
- Must be able to adhere to the study visit schedule and other protocol requirements
- CMML diagnosis according to WHO 2022 criteria
- CPSS risk intermediate-2 or high2 (HR) CMML at study entry (WBC prior to HY used to compute CPSS at inclusion in HY-exposed patients, see below)
- Patients who are eligible for and will receive azacitidine (AZA) as per standard of care.
- Performance status 0-2 on the Eastern Cooperative Oncology Group (ECOG) Scale
- Adequate organ function including the following: • Liver: o Total bilirubin < 1.5 times upper limit of normal (ULN) (except moderate unconjugated hyperbilirubinemia due to intra medullary hemolysis or due to Gilbert syndrome), AND o Alanine transaminase (ALT) and aspartate transaminase (AST) < 2.5 times ULN • Renal: Creatinine clearance >/= 45 mL/minute • Cardiac o Left ventricular ejection fraction (LVEF) ≥ 50% by multigated acquisition scan (MUGA) or 2-dimensional (2-D) echocardiogram (ECHO) within 28 days prior to the start of therapy o No clinically significant abnormalities on a 12-lead electrocardiogram (ECG) • Albumin: Serum albumin ≥ 3.2 g/dL (note: albumin infusions are not permitted in order to enable eligibility)
- Availability of blood counts and transfusion events for previous 8 weeks
- Women of childbearing potential and practicing a highly effective method of birth control according to the Clinical Trial Facilitation Coordination Group Recommendation (Version 1.1, 2020)3: • combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: o oral o intravaginal o transdermal • progestogen-only hormonal contraception associated with inhibition of ovulation: o oral o injectable o implantable • intrauterine device (IUD) • intrauterine hormone-releasing system (IUS) • bilateral tubal occlusion • vasectomised partner • sexual abstinence For females, these requirements apply during the treatment period and for 6 months after the end of dosing.
- A woman of childbearing potential must have a negative serum (β-human chorionic gonadotropin [β-hCG]) pregnancy test within one week of treatment initiation and agree to be tested (serum or urine) on day 1 of every cycle and at EOT
- A man who is sexually active with a woman of childbearing potential and has not had a vasectomy must agree to use a highly effective method of contraception) and all men must also not donate sperm. Highly effective methods of contraception include double-barrier contraception, total abstinence, vasectomization with confirmed azoospermia, female partner with an intrauterine device, etc.). For males, these requirements apply during the study treatment period and for 3 months after the end of dosing.
Exclusion Criteria
- CMML with t (5 ;12) or PDGFRB rearrangement that may be treated with imatinib
- Myeloproliferative / myelodysplastic neoplasm other than CMML
- Bone marrow or peripheral blood blasts (including promonocytes) ≥ 20%
- Patients with unavailable CPSS at inclusion (WBC prior to HY used to compute CPSS at inclusion in HY-exposed patients) or with a CPSS low or intermediate-1 at study entry
- Patient has received an experimental or investigational drug or used an invasive investigational medical device within 14 days prior to day 1 of C1
- Prior treatment with TAG, VEN and/or HMA treatment, including AZA/CC-486, decitabine (DEC), SGI-110, AST7227. Prior treatment with Erythropoiesis Stimulating Agents (ESA) or hydroxyurea (HY) is acceptable, with a > 15 days washout from ESAs and > 3 days washout from HY
- Patients who previously received an allogeneic stem cell transplantation (HSCT) for CMML or an antecedent hematological malignancy. Those never transplanted but eligible for HSCT are eligible for the trial.
- Major surgery within 4 weeks prior to day 1 of C1 (excluding the placement of vascular access and other minor surgical procedures)
- Prior malignancy (except in situ cervix carcinoma, limited basal cell carcinoma, asymptomatic prostatic cancer not requiring treatment, or other tumors if not active during the last 2 years)
- Serious concomitant systemic disorder, including active bacterial, fungal, psychiatric illness, or viral infection that in the opinion of the investigator, would compromise the safety of the patient and/or his/her ability to complete the study.
- Medical condition requiring therapies with CYP3A inducing activity. All CYP3A inducers should be discontinued 7 days prior to the first dose of study drug
- Patients with known CNS involvement
- Females who are pregnant or are currently breastfeeding or planning to become pregnant while enrolled in this study or within 6 months after the end of dosing
- Patient is a man who plans to father a child while enrolled in this study or within 3 months after the end of dosing
- The patient is receiving immunosuppressive therapy for any reason, with the exception of low-dose prednisone (≤ 10 mg/day) or equivalent
- The patient has persistent clinically significant toxicities Grade ≥ 2 from previous therapies, including cytotoxic chemotherapy, targeted therapies, biological therapies, or immunotherapies, not readily controlled by supportive measures (excluding alopecia, nausea, and fatigue)
- The patient has clinically significant cardiovascular disease (e.g. uncontrolled or any New York Heart Association Class 3 or 4 congestive heart failure, uncontrolled angina, history of myocardial infarction, unstable angina or stroke within 6 months prior to study entry, uncontrolled hypertension or clinically significant arrhythmias not controlled by medication).
- The patient has uncontrolled, clinically significant pulmonary disease (e.g. chronic obstructive pulmonary disease, pulmonary hypertension) that in the opinion of the Investigator would put the patient at significant risk for pulmonary complications during the study.
- The patient has known positive status for human immunodeficiency virus (HIV) or active or chronic Hepatitis B or Hepatitis C.
- Patient is unable to attend site visits as patient is in custody by order of an authority or a court of law
- Participation in another interventional clinical study within the last 3 months prior to signing the ICF or simultaneous participation in other clinical studies
- Previous assignment to treatment during this study
- Close affiliation with the investigator (e.g. a close relative) or persons working at the study site
- Patient is an employee of the sponsor or involved CRO
- Criteria which in the opinion of the investigator preclude participation for scientific reasons, for reasons of compliance, or for reasons of the patient’s safety
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Recruiting | 01 Feb 2025 | 10 |
 Italy | Recruiting | 01 Feb 2025 | 10 |
 Spain | Recruiting | 01 Feb 2025 | 10 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Venetoclax | Test | FILM-COATED TABLET | ORAL | 40 | 12 | PRD2186234 |
ELZONRIS 1 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | IV INFUSION | 12 | 12 | PRD8732455 |
Venetoclax | Test | FILM-COATED TABLET | ORAL | 400 | 12 | PRD2186236 |
Venetoclax | Test | FILM-COATED TABLET | ORAL | 50 | 12 | PRD2186235 |