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

AML, Adult Clinical Trial

— HO171  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06014489
• Other study ID #: HO171
• Status: Recruiting
• Phase: Phase 2
• Start date: January 17, 2024
• Est. completion date: March 2028

Study information

• Verified date: January 2024
• Source: Stichting Hemato-Oncologie voor Volwassenen Nederland
• Contact: Gerwin Huls, prof
• Phone: +3150 361 2354
• Email: g.huls[@]umcg.nl
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 142
• Est. completion date: March 2028
• Est. primary completion date: March 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 without approval of the (co-) Principal Investigator. 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). Please check with Appendix I.
• Intolerability, contra-indication or allergy to one of the study drugs.

Related Conditions & MeSH terms

• AML, Adult

Intervention

Drug:
• azacitidine
during run-in and extention phase: from Cycle 1 until relapse
• Venetoclax
during run-in and extention phase: from Cycle 1 until relapse
• Cobicistat
during run-in phase: from cycle 2 until relapse during extension phase: from cycle 1 until relapse

Locations

Country	Name	City	State
Netherlands	NL-Amersfoort-MEANDERMC	Amersfoort
Netherlands	NL-Amsterdam-OLVG	Amsterdam
Netherlands	NL-Amsterdam-VUMC	Amsterdam
Netherlands	NL-Arnhem-RIJNSTATE	Arnhem
Netherlands	NL-Breda-AMPHIA	Breda
Netherlands	NL-Den Haag-HAGA	Den Haag
Netherlands	NL-Dordrecht-ASZ	Dordrecht
Netherlands	NL-Eindhoven-CATHARINA	Eindhoven
Netherlands	NL-Eindhoven-MAXIMAMC	Eindhoven
Netherlands	NL-Enschede-MST	Enschede
Netherlands	NL-Groningen-UMCG	Groningen
Netherlands	NL-Leeuwarden-MCL	Leeuwarden
Netherlands	NL-Leiden-LUMC	Leiden
Netherlands	NL-Maastricht-MUMC	Maastricht
Netherlands	NL-Nieuwegein-ANTONIUS	Nieuwegein
Netherlands	NL-Nijmegen-CWZ	Nijmegen
Netherlands	NL-Rotterdam-ERASMUSMC	Rotterdam
Netherlands	NL-Zwolle-ISALA	Zwolle

Sponsors (1)

Lead Sponsor	Collaborator
Stichting Hemato-Oncologie voor Volwassenen Nederland

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Pharmacokinetic equivalence of cobicistat boosted venetoclax and unboosted venetoclax (PK cycle 1 vs PK cycle 2).venetoclax and unboosted venetoclax (PK cycle 1 vs PK cycle 2).	run-in phase	6-8 months
Primary	Overall survival (OS).	extension phase	48 months
Secondary	Venetoclax and cobicistat CL, Cmax, Tmax, Cmin and AUC0-24.	run-in phase	6-8 months
Secondary	Complete remission (CR) rate defined as CR as best response during or at completion of the treatment, as determined by the Investigator, based on the European LeukemiaNet (ELN2022) recommended response criteria (see Appendix B).	extension phase	48 months
Secondary	CR with incomplete hematologic recovery (CRi) rate, based on the European LeukemiaNet (ELN2022) recommended response criteria (see Appendix B).	extension phase	48 months
Secondary	CR and CR with incomplete hematologic recovery (CRi) rate, based on the European LeukemiaNet (ELN2022) recommended response criteria (see Appendix B).	extension phase	48 months
Secondary	CR with partial hematologic recovery (CRh) rate, based on ELN 2022 recommendations.	extension phase	48 months
Secondary	CR and CR with partial hematologic recovery (CRh) rate, based on ELN 2022 recommendations.	extension phase	48 months
Secondary	CR or CR/CRi or CR/CRh without minimal residual disease (flow and or molecular) (CRMRD- or CR/CRiMRD- or CR/CRhMRD-).	extension phase	48 months
Secondary	Morphologic leukemia-free state (MLFS) rate, based on ELN2022 recommendations.	extension phase	48 months
Secondary	Event free survival (EFS).	extension phase	48 months
Secondary	Relapse-free survival (RFS).	extension phase	48 months
Secondary	Incidence and severity of adverse events according to CTCAE version 5.0.	extension phase	48 months
Secondary	Early (30-day and 60-day) mortality (in general, non-leukemic).	extension phase	48 months
Secondary	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
Secondary	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
Secondary	Prognostic/predictive impact of disease-associated genetic changes at diagnosis.	extension phase	48 months
Secondary	Relapse-associated genetic changes (determined at relapse). The average relative dose intensity will be computed and given by categories. The same will be done for treatment deviation.	extension phase	48 months
Secondary	Clonal evolution during treatment.	extension phase	48 months
Secondary	Exposure-response and exposure-toxicity relation of venetoclax in patients with AML.	extension phase	48 months
Secondary	Cost-savings on venetoclax drug costs.	extension phase	48 months
Secondary	Adherence to venetoclax and cobicistat.	extension phase	48 months

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