ABT-199 (Venetoclax) and Purine analogues as Novel Oral Drug Combination for Treatment of Relapsed/Refractory Acute Myeloid Leukemia (ApoAML)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Antwerp University Hospital

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Decision date (initial)

2024-02-13

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-510717-15-00

EudraCT number

2021-006473-35

ClinicalTrials.gov

NCT05506332

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

AML has a poor prognosis, especially in patients with primary refractory disease or relapse. Reinduction with intensive chemotherapy followed by stem cell transplantation is the only potential cure, but is not possible in the majority of patients. For patients who are not eligible for reinduction chemotherapy, standard therapy is lacking. In this interventional phase 1 study, patients with R/R AML will be treated with a combination of venetoclax and 6-mercapopurine. Both venetoclax and mercaptopurine have been used in AML and other hematological malignancies. However the combination of venetoclax and 6-mercaptopurine has not been tested before. There is some preclinical evidence that the combination of venetoclax and 6-mercaptopurine might have a synergistic effect on inducing apoptosis. In this phase I study, we aim to assess the effectivity of the combination of venetoclax and mercaptopurine in R/R AML. The primary objective of this trial is clinical response.

Clinical response: To determine the objective response rate to the combination of
venetoclax/ABT-199 and a PA in R/R AML. The following parameters will be used to assess
clinical response 19 :
• CR/CRi/CRp
• MLFS
• PR

Secondary objectives 1

1. To assess the safety of treatment with a combination of venetoclax and 6-mercaptopurine in patients with AML

Conditions and MedDRA coding

Acute myeloid leukemia

Regulatory references

Scientific advice from competent authorities

Federal Agency For Medicines And Health Products

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. 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.

Exclusion criteria 1

1. 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. clinical response: - CR = complete remission (when all of the following: < 5% blasts in the bone marrow, no Auer rods, no extramedullary disease, neutrophils >1000/μl and transfusion independent). - CRi = morphologic complete remission with incomplete blood count recovery - CRp = CR with incomplete platelet recovery - MLFS = morphologic leukemia free state not meeting criteria for CR, CRi or CRp - PR = Partial remission (decrease of 50% of the blas

Secondary endpoints 1

1. To assess the safety of treatment with a combination of venetoclax and 6-mercaptopurine in patients with AML

Investigational products

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

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Antwerp University Hospital

Sponsor organisation

Antwerp University Hospital

Address

Drie Eikenstraat 655

City

Edegem

Postcode

2650

Country

Belgium

Scientific contact point

Organisation

Antwerp University Hospital

Contact name

Eva Mathilda De Backer

Public contact point

Organisation

Antwerp University Hospital

Contact name

Hematologie

Locations

1 EU/EEA country · 2 investigational sites

By country

Investigational sites

Application history

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