A study to investigate the effect of adding cobicistat to venetoclax and azacitidine in patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy and have not received previous treatment.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Haemato Oncology Foundation For Adults Netherlands

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

17 Jan 2024 → ongoing

Decision date (initial)

2023-10-25

Transition trial

No

Low-intervention

Yes

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

University Medical Center Groningen

External identifiers

EU CT number

2023-505379-61-00

ClinicalTrials.gov

NCT06014489

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic, Dose response, Efficacy, Pharmacogenetic, Pharmacoeconomic

Run-in phase: To evaluate the pharmacokinetic (PK) equivalence of cobicistat boosted venetoclax and unboosted venetoclax (PK cycle 1 vs PK cycle 2).
Extentension phase: To assess the practical applicability and the therapeutic effect of a defined schedule of cobicistat added to venetoclax and azacitidine (AZA/VEN/COBI) on overall survival (OS) in adult patients with newly diagnosed AML considered ineligible for intensive chemotherapy.

Secondary objectives 9

1. Run-in phase: To assess venetoclax and cobicistat CL, Cmax, Tmax, Cmin, AUC0-24.
2. Extension phase: To determine the efficacy profile: response rate (CR, CRi, CR/CRi, CRh, CR/CRh, CRMRD-, CR/CRiMRD-, CR/CRhMRD-, and MLFS), event-free survival (EFS) and relapse-free survival (RFS) associated with AZA/VEN/COBI.
3. To evaluate safety and toxicity of AZA/VEN/COBI.
4. To assess the impact of cytogenetic and molecular genetic factors on response and survival endpoints.
5. To compare the OS of AZA/VEN/COBI treated patients with a real-world data cohort treated during the same period and monitored by the Dutch Cancer registry.
6. To assess the exposure-response and exposure-toxicity relation of venetoclax in patients with AML.
7. To assess adherence to venetoclax and cobicistat.
8. To assess cost-savings on venetoclax drug costs (corrected for cobicistat costs) compared to the standard dosing schedule.
9. Leukocytes < 30 x 10^9/L

Conditions and MedDRA coding

Acute Myeloid Leukaemia

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Patients with: a diagnosis of AML and related precursor neoplasms according to ICC-2022 classification (excluding acute promyelocytic leukaemia). 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.
2. Patients 18 years and older who are considered not fit for intensive chemotherapy (judged by treating physician) or who decline the option of intensive chemotherapy.
3. WHO performance status 0, 1 or 2.
4. 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.
5. 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.
6. 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.
7. Written informed consent.
8. Patient is capable of giving informed consent.
9. Patient agrees not to participate in another interventional study while on protocol treatment without approval of the (co-) Principal Investigator.

Exclusion criteria 16

1. Acute promyelocytic leukemia.
2. Myelodysplastic syndrome (MDS).
3. Patients previously treated for AML or MDS (any anti-leukemic therapy including investigational agents; excluding: 1) erythropoiesis stimulating agents (ESAs); 2) hydroxyurea (previous treatment with hydroxyurea is allowed for the control of peripheral leukemic blasts in patients with leukocytosis).
4. 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.
5. Blast crisis of chronic myeloid leukemia.
6. Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, infection, hypertension, pulmonary disease etc.).
7. 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; or unstable cardiac arrhythmias.
8. History of stroke or intracranial haemorrhage within 6 months prior to registration.
9. Symptomatic central nervous system (CNS) leukemia (NO routinely lumbar puncture required to investigate CNS involvement).
10. History of non-compliance to medical regimens or considered unreliable with respect to compliance.
11. Senile dementia, mental impairment or any other psychiatric disorder that prohibits the patient from understanding and giving informed consent.
12. Current concomitant chemotherapy, radiation therapy, or immunotherapy; other than hydroxyurea.
13. Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
14. 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).
15. Intolerability, contra-indication or allergy to one of the study drugs.
16. Exclusion for the run-in phase only: Patient with a strong indication for IFD prophylaxis (or treatment)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Run-in phase: Pharmacokinetic equivalence of cobicistat boosted venetoclax and unboosted venetoclax (PK cycle 1 vs PK cycle 2).
2. Extension phase: Overall survival (OS)

Secondary endpoints 14

1. Run-in phase: Venetoclax and cobicistat CL, Cmax, Tmax, Cmin and AUC0-24.
2. Extension phase: Response rate (CR, CRi, CR/CRi, CRh, CR/CRh, CRMRD-, CR/CRiMRD-, CR/CRhMRD-, and MLFS).
3. Event free survival (EFS).
4. Relapse-free survival (RFS).
5. Incidence and severity of adverse events according to CTCAE version 5.0.
6. Early (30-day and 60-day) mortality (in general, non-leukemic).
7. Time to next cycle, defined as the time from the start of the cycle until the start of the next cycle.
8. 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.
9. Prognostic/predictive impact of disease-associated genetic changes at diagnosis.
10. Relapse-associated genetic changes (determined at relapse).
11. Clonal evolution during treatment.
12. Exposure-response and exposure-toxicity relation of venetoclax in patients with AML.
13. Cost-savings on venetoclax drug costs.
14. Adherence to venetoclax and cobicistat.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Haemato Oncology Foundation For Adults Netherlands

Sponsor organisation

Haemato Oncology Foundation For Adults Netherlands

Address

S Gravendijkwal 230

City

Rotterdam

Postcode

3015 CE

Country

Netherlands

Scientific contact point

Organisation

Haemato Oncology Foundation For Adults Netherlands

Contact name

G. Huls

Public contact point

Organisation

Haemato Oncology Foundation For Adults Netherlands

Contact name

HOVON

Third parties 4

Locations

1 EU/EEA country · 19 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Serious breaches 4 · Art. 52 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 16 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications