Evaluation of Venetoclax and Mercaptopurine Combination Therapy in Patients with Relapsed/Refractory Acute Myeloid Leukemia

Trial ID: 2024-510717-15-00
Protocol: 2282
Sponsor: Universitair Ziekenhuis Antwerpen

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Diseases & Conditions

Acute myeloid leukaemia

Objectives

The primary objective of this phase 1 clinical trial is to evaluate the **clinical response** to a novel oral drug combination of venetoclax and 6-mercaptopurine in patients with relapsed or refractory **acute myeloid leukemia** (AML). This is clinically relevant as AML has a poor prognosis, particularly in patients with primary refractory disease or relapse, and current treatment options are limited for those ineligible for reinduction chemotherapy. The trial aims to determine the objective response rate using parameters such as complete remission (CR), complete remission with incomplete hematologic recovery (CRi), complete remission with partial hematologic recovery (CRp), morphologic leukemia-free state (MLFS), and partial remission (PR).

Secondary objectives include assessing the safety of the treatment combination in this patient population. This is crucial for understanding the risk-benefit profile of the combination therapy, which has not been previously tested together in AML, despite preclinical evidence suggesting a potential synergistic effect on inducing apoptosis.

Participants

The clinical trial involves participants diagnosed with **acute myeloid leukemia** (AML), specifically those with relapsed or refractory AML. The study population includes both male and female adults aged 18 years and older. Participants are selected based on their diagnosis according to the 2008 World Health Organization criteria, excluding those with the M3 subtype of AML. The trial does not provide information on the total number of participants. The selection process considers individuals who have relapsed after or are refractory to at least one cycle of intensive chemotherapy or four cycles of hypomethylating agents. Participants must have a WHO performance status of 0-3, with inclusion of those with a status of 3 only if the impairment is primarily due to AML. The trial includes individuals who are venetoclax and PA-naïve, although prior exposure to venetoclax is permissible under certain conditions. Participants with severe renal impairment may be included if the benefits outweigh the risks. The trial population is considered vulnerable, and lifestyle factors such as diet and physical activity are not specified in the available data.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy and safety of a novel oral drug combination for the treatment of **acute myeloid leukemia** (AML) in patients with relapsed or refractory (R/R) disease. This is a Phase 1, non-randomized, non-controlled trial involving the administration of a combination of **venetoclax** and **mercaptopurine**. The trial aims to assess the clinical response, with primary endpoints including complete remission (CR), morphologic complete remission with incomplete blood count recovery (CRi), CR with incomplete platelet recovery (CRp), morphologic leukemia-free state (MLFS), and partial remission (PR). Secondary endpoints focus on the safety profile of the treatment combination.

The trial is expected to run from July 2022 to February 2026. Participants will be involved in the study for the duration of the treatment period, with the possibility of early termination if they experience significant adverse effects or if the disease progresses. The study includes several key visits: an initial screening visit to confirm eligibility based on criteria such as age, performance status, and previous treatment history; regular follow-up visits to monitor response and safety; and an end-of-study visit to assess final outcomes.

Inclusion criteria require participants to have a confirmed diagnosis of AML, be aged 18 years or older, and have a performance status of 0-3. Exclusion criteria are not explicitly detailed in the provided data. Participants must not be refractory to venetoclax and should have a white blood cell count below 25x10^9/L before starting treatment. The trial is conducted under strict ethical guidelines, and participants' health and safety are closely monitored throughout the study.

Treatment

The clinical trial involves the administration of **mercaptopurine**, a chemical compound known for its role as a chemotherapeutic agent. Mercaptopurine is provided in an oral pharmaceutical form, identified by the code PHF00245MIG. The specific dosage and frequency of administration are not detailed in the provided data. Mercaptopurine, also known by synonyms such as 3,7-dihydropurine-6-thione and 6-mercaptopurine, is classified under the ATC code L01BB02. It is utilized in the study for its potential synergistic effects when combined with venetoclax in the treatment of relapsed/refractory acute myeloid leukemia (R/R AML).

**Venetoclax** is the second experimental medication used in this clinical trial. It is also administered orally, with its pharmaceutical form designated as PHF00082MIG. Venetoclax, a BCL-2 inhibitor, is identified by the ATC code L01XX52. The compound is chemically derived and is known by several synonyms, including ABT-199 and GDC-0199. The trial aims to explore the efficacy of venetoclax in combination with mercaptopurine, leveraging its mechanism of action to induce apoptosis in cancer cells. The specific dosing schedule and participant compliance monitoring details are not provided in the data.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are mentioned in the provided information. The trial focuses solely on the combination of venetoclax and mercaptopurine to assess their combined effect on clinical response in patients with R/R AML. The primary objective is to determine the objective response rate, including complete remission (CR), complete remission with incomplete hematologic recovery (CRi), complete remission with partial hematologic recovery (CRp), and partial remission (PR).

Efficacy

The efficacy of the clinical trial will be assessed by evaluating the **clinical response** to the combination of venetoclax and 6-mercaptopurine in patients with relapsed or refractory acute myeloid leukemia (R/R AML). The primary endpoint for efficacy is the objective response rate, which includes several parameters: complete remission (CR), complete remission with incomplete blood count recovery (CRi), complete remission with incomplete platelet recovery (CRp), morphologic leukemia-free state (MLFS), and partial remission (PR). These parameters will be used to determine the clinical response to the treatment regimen.

The clinical response will be measured using the following criteria: CR is defined as less than 5% blasts in the bone marrow, absence of Auer rods, no extramedullary disease, neutrophil count greater than 1000/μL, and transfusion independence. CRi involves morphologic complete remission with incomplete blood count recovery, while CRp is CR with incomplete platelet recovery. MLFS is characterized by a morphologic leukemia-free state not meeting the criteria for CR, CRi, or CRp. PR is defined as a decrease of 50% in the blast count.

The secondary endpoint of the trial is to assess the safety of the treatment combination in patients with AML. The trial is designed as a phase 1b, non-randomized, non-controlled study, focusing on the novel combination of venetoclax and 6-mercaptopurine. The trial aims to provide insights into the potential synergistic effects of these drugs in inducing apoptosis in AML cells.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Relapsed or refractory (r/r) AML • Diagnosis of acute myeloid leukemia (AML) according to the 2008 criteria of the World Health Organization (WHO). • All French-American-British (FAB) subtypes, except: M3 (acute promyelocytic leukemia) • Relapsed after or refractory to at least one cycle of intensive chemotherapy (combination of ara-c/anthracyclin) or four cycles of HMA (hypomethylating agents). Relapse and refractory disease will be defined according to the Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia 20 . Relapse is defined as >5% blasts in the bone marrow not attributed by another cause and occurring after initial remission. Refractory disease is defined as persistent AML in peripheral blood or bone marrow (>5%) at least ≥7 days after completion of the initial induction treatment. • Adult AML aged >/= 18 years • WHO performance status: 0-3 at the time of enrollment. Inclusion of a patient with WHO performance status 3 is only allowed if functional impairment is believed to be mainly attributed to the underlying disease (in this case AML). • ABT-199 (venetoclax) and PA-naïve. Patient may be prior exposed but not refractory to venetoclax. In case of previous therapy with venetoclax inclusion is only possible after discussion with the PI. • Prior to initiation of venetoclax, all patients should have a white blood cell count <25x10 9 /µl. Prior cytoreductive treatment might be required (e.g. hydroxyurea) and is permitted in order to lower the WBC count. The WBC should be determined ≥24 hours after the last dose of hydroxyurea. • Patients with severe renal impairment (CrCl ≥ 15 ml/min and < 30 ml/min) can only be included if benefits outweigh risks (after discussion with PI) and will be closely monitored for TLS.

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Exclusion Criteria

Participation in any other interventional clinical trial during the study period • Isolated central nervous system invasion of AML (in the absence of systemic relapse or refractory AML) will be excluded from the study. However, patients with both systemic relapse or refractory disease and central nervous system invasion of AML can be included in the study. Nevertheless, patients who are not able to adhere to the study requirement because of their neurological 11 condition will be excluded from the study. In patients with central nervous system invasion of AML the concomitant use of intrathecal chemotherapy is allowed in addition to the study drugs. • History or concomitant presence of any other malignancy, except for: o non-melanoma skin cancer o carcinoma in situ of the cervix o any other effectively treated malignancy that has been in remission for >5 years or that is highly likely to be cured at the time of enrollment. • Active HIV, hepatitis B or hepatitis C infection • Use of any antitumoral agent within less than 5 times the half-life of the agent prior to the screening bone marrow examination. As described in the inclusion criteria, after the screening bone marrow examination, the use of cytoreductive treatment prior to the initiation of venetoclax is permitted in order to lower the WBC-count to <25 000/µl (e.g. hydroxyurea). An exception is made in case of central nervous system invasion of acute myeloid leukemia in which the use of intrathecal chemotherapy is allowed before and during the study. • Use of G-CSF within less than 4 days prior to the screening bone marrow examination • Medical conditions requiring chronic therapy of moderate or strong CYP3A4 inducers without alternative • Patients with known hypersensitivity to the active substance or to any of the excipients should be excluded. • Pregnant or breastfeeding woman • Active uncontrolled systemic infection