A Trial to Assess Cobicistat Boosted Venetoclax in Combination With Azacitidine in Adult Patients With Newly Diagnosed AML

Study Overview
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Brief Summary
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The treatment of older unfit patients with acute myeloid leukemia (AML) is challenging. The hypomethylating agents (HMA) azacitidine and decitabine have relatively mild side effects and have proven to be feasible for the treatment of older patients and patients with co-morbidities. Currently, venetoclax added to an HMA agent is the new standard of treatment. Since this new standard comes with a substantial societal financial burden, there is a rational to optimize the venetoclax dosing schedule. The CYP3A4 inhibitor cobicistat (COBI) can be used to increase venetoclax exposure, thereby allowing to reduce the dose of venetoclax and thus costs substantially.

Official Title
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A Single Arm Phase II Trial to Assess Cobicistat Boosted Venetoclax in Combination With Azacitidine (sc) in Adult Patients With Newly Diagnosed Acute Myeloid Leukaemia (AML) Who Are Not Considered Candidates for Intensive Treatment Regimens

Conditions
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AML, Adult

Intervention / Treatment
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* Drug: azacitidine
* Drug: Venetoclax
* Drug: Cobicistat


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: In order to be eligible to participate in this study, a patient must meet all of the following criteria: Patients with: a diagnosis of AML and related precursor neoplasms according to ICC-2022 classification (excluding acute promyelocytic leukaemia) (appendix A). Patients may have had previous treatment with erythropoiesis stimulating agents (ESA) for an antecedent phase of MDS. ESAs must be stopped at least two weeks before registration. Patients 18 years and older who are considered not fit for intensive chemotherapy or who decline the option of intensive chemotherapy. WHO performance status 0, 1 or 2 (appendix E). Adequate renal and hepatic functions unless clearly disease related as indicated by the following laboratory values: Adequate renal function as demonstrated by a creatinine clearance ≥ 30 mL/min; calculated by the Cockcroft Gault formula or measured by 24 hours urine collection. Serum bilirubin ≤ 3 x upper limit of normal (ULN), unless considered AML-related or due to Gilbert's syndrome. Alanine transaminase (ALT) ≤ 3 x ULN, unless considered AML-related. Male subjects who are sexually active, must agree, from Study Day 1 until at least 90 days after the last dose of study drug, to practice the protocol specified contraception. Male subjects must agree to refrain from sperm donation from initial study drug administration through at least 90 days after the last dose of study drug. Female subjects must be either postmenopausal defined as: Age >55 years with no menses for ≥12 months, without an alternative medical cause. OR willing and able to use adequate contraception during and until 180 days after the last protocol treatment. Written informed consent. Patient is capable of giving informed consent. Patient agrees not to participate in another interventional study while on treatment. Exclusion Criteria: A patient who meets any of the following criteria cannot be included in this study: Acute promyelocytic leukemia. Myelodysplastic syndrome (MDS) Patients previously treated for AML or MDS (any anti-leukemic therapy including investigational agents; excluding: 1) erythropoiesis stimulating agents (ESAs); 2) hydroxyurea (hydroxyurea is allowed for the control of peripheral leukemic blasts in patients with leukocytosis). Diagnosis of any previous or concomitant malignancy is an exclusion criterion: except when the patient successfully completed treatment (chemotherapy and/or surgery and/or radiotherapy) with curative intent for this malignancy at least 24 months prior to registration; except for basal and squamous cell carcinoma of the skin or in situ carcinoma of the cervix Blast crisis of chronic myeloid leukemia. Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, infection, hypertension, pulmonary disease etc.). Cardiac dysfunction as defined by: Myocardial infarction within the last 3 months of study entry, or Reduced left ventricular function with an ejection fraction < 40% as measured by MUGA scan or echocardiogram, or Unstable angina or New York Heart Association (NYHA) grade IV congestive heart failure (see Appendix G), or Unstable cardiac arrhythmias. History of stroke or intracranial haemorrhage within 6 months prior to registration. Symptomatic central nervous system (CNS) leukemia (NO routinely lumbar puncture required to investigate CNS involvement). History of non-compliance to medical regimens or considered unreliable with respect to compliance. Senile dementia, mental impairment or any other psychiatric disorder that prohibits the patient from understanding and giving informed consent. Current concomitant chemotherapy, radiation therapy, or immunotherapy; other than hydroxyurea. Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule. Unreplaceable use of strong inhibitors or inducers of CYP3A or CYP3A/p-GP substrates with a narrow therapeutic window( e.g. cobicistat or ritonavir for HIV treatment) appendix I. Intolerability, contra-indication or allergy to one of the study drugs.

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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: the study consists of a run-in phase and an extension phase
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: single arm arm extension phase<br>prior to the extention phase, there is a run-in phase with (n= 20 patients of 142 total) with the same study scheme, except that cobicistat is added from cycle 2 onwards to the treatment instead of during cycle 1 | Drug: azacitidine<br>* during run-in and extention phase: from Cycle 1 until relapse<br>Drug: Venetoclax<br>* during run-in and extention phase: from Cycle 1 until relapse<br>Drug: Cobicistat<br>* during run-in phase: from cycle 2 until relapse during extension phase: from cycle 1 until relapse<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic (PK) equivalence (Cmax, Tmax, Cmin, AUC0-24) of cobicistat boosted venetoclax and unboosted venetoclax (PK cycle 1 vs PK cycle 2). | run-in phase | 6-8 months | 
| Overall survival (OS). | extension phase | 48 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Venetoclax and cobicistat Clearance (CL). | run-in phase | 6-8 months | 
| Venetoclax and cobicistat Maximum plasma concentration (Cmax). | run-in phase | 6-8 months | 
| Venetoclax and cobicistat Time to maximum plasma concentration (Tmax) | run-in phase | 6-8 months | 
| Venetoclax and cobicistat Trough concentration (Cmin) | run-in phase | 6-8 months | 
| Venetoclax and cobicistat Area under the curve (AUC0-24). | run-in phase | 6-8 months | 
| Response rate (CR, CRi, CR/CRi, CRh, CR/CRh, CRMRD-, CR/CRiMRD-, CR/CRhMRD-, and MLFS). | extension phase | 48 months | 
| Event-free survival (EFS) | extension phase | 48 months | 
| Relapse-free survival (RFS) | extension phase | 48 months | 
| Incidence and severity of adverse events (AEs) according to Common Terminology Criteria for Adverse Events (CTCAE) version v5. | extension phase | 48 months | 
| Early (30-day and 60-day) mortality (in general, non-leukemic). | extension phase | 48 months | 
| Time to next cycle, defined as the time from the start of the cycle until the start of the next cycle | extension phase | 48 months | 
| overal survival (OS) of AZA/VEN/COBI treated patients in comparison with a real-world data cohort treated during the same time period and monitored by the Dutch Cancer registry. | extension phase | 48 months | 
| Prognostic/predictive impact of disease-associated genetic changes (selected molecular subgroups as identified at baseline), by presenting OS, EFS and RFS by the status of the various mutations: positive/negative/ND. | extension phase | 48 months | 
| Relapse-associated genetic changes (determined at relapse). Relapse-associated genetic changes will be identified by cross-tabulation of the molecular characteristics of the patients at baseline and relapse. | extension phase | 48 months | 
| Clonal evolution during treatment. The impact of treatment for selected molecular subgroups (as identified at off protocol) will be investigated. | extension phase | 48 months | 
| Exposure-response and exposure-toxicity relation of venetoclax in patients with AML. The average relative dose intensity will be computed and given by categories. The same will be done for treatment deviation. | extension phase | 48 months | 
| Cost-savings on venetoclax drug costs | extension phase | 48 months | 
| Adherence to venetoclax and cobicistat. Information on deviation, reasons for deviations and relative dose intensity (RDI) will be summarized separately for venetoclax and cobicistat: | extension phase | 48 months |