ITCC-101/APAL2020D: A Randomized Phase 3 Trial of Fludarabine/Cytarabine/Gemtuzumab Ozogamycin with or without Venetoclax in Children with Relapsed Acute Myeloid Leukemia

Background Despite improvements in the therapy of children with acute myeloid leukemia (AML) over the last decades with overall survival (OS) rates approaching 70%, the outcome after relapse remains poor. Outcomes are particularly poor for patients unable to receive anthracyclines due to prior cardiac toxicity or those beyond first relapse, e.g., the AML-Berlin-Frankfurt-Mu¨nster Study Group reported a 5-year OS rate in second relapse of 15+/-4%, and 31+/-9% following hematopoietic stem cell transplantation (HSCT) (n=25/73). Additional therapeutic options for these groups of children are needed.

Venetoclax is a selective, potent, orally bioavailable, small molecule inhibitor of B-cell lymphoma-2 (BCL-2) that restores programmed cell death in cancer cells, and is approved for the treatment of adult patients with newly diagnosed AML in combination with hypomethylating agents or low-dose cytarabine, who are ineligible for intensive chemotherapy (Venetoclax Summary of Product Characteristics and United States Prescribing Information).

The single arm VENAML trial (NCT03194932) assessed the safety and activity of venetoclax in combination with cytarabine and idarubicin in pediatric patients with relapsed or refractory (R/R) AML with encouraging response rates. In 20 evaluable patients treated at the recommended phase II dose (RP2D), there were 13 CRs and 1 CRi. Two additional patients achieved a PR. For patients treated at the RP2D, 10/14 achieved minimal residual disease (MRD) negative (<0.1% by flow cytometry) CR/CRi. Among patients treated at the RP2D, 5/6 patients in untreated first relapse achieved a CR while 9/14 patients beyond first relapse achieved a CR (N=8) or a CRi (N=1).

These encouraging preliminary results in children on the safety and anti-tumor activity of venetoclax led to the development of our study: ITCC-101/APAL2020D trial, within the framework of a Pediatric Investigational Plan and Written Request agreement. The Pediatric Acute Leukemia (PedAL)/European Pediatric Acute Leukemia (EuPAL) initiative is a master protocol with sub-trials with the goal of establishing new standards of care for children with R/R AML in order to improve the outcome and increase the long-term survival of these patients. This is the first sub-trial under the ITCC-101 master protocol in the PedAL/EuPAL project.

Study Design and Methods This is an open-label randomized phase 3 trial of fludarabine, high dose cytarabine (FLA)+gemtuzumab ozogamicin (GO) with or without venetoclax in children with relapsed AML.

This study will enroll children, adolescents, and young adults with AML without FLT3/ITD mutation in second relapse, who are sufficiently fit to undergo intensive chemotherapy, or in first relapse, who cannot tolerate additional anthracycline containing chemotherapy.

There are two cycles of treatments and as backbone chemotherapy, the Cycle 1 consists of FLA+GO and the Cycle 2 FLA. In the experimental arm, venetoclax will be administered at 300 mg adult equivalent dose on Cycle 1 Day 1 and 600 mg adult equivalent dose on subsequent days of each 28 day cycle. Responding patients after the first two cycles can undergo allogeneic HSCT. Patients who have responded to protocol therapy but who cannot tolerate HSCT will receive maintenance therapy consisting of azacitidine or combination azacitidine-venetoclax as per the randomized arm. In maintenance therapy, a lower dose of venetoclax is applied in combination with azacitidine, i.e., 400 mg adult equivalent dose.

The primary objective is to compare the OS of venetoclax in combination with FLA+GO compared with FLA+GO alone. Secondary objectives include the assessment of response, safety, pharmacokinetics and rate of transition to HSCT. A comprehensive study of correlative biomarkers such as BCL-2 homology profiling or venetoclax drug sensitivity will also be carried out. Morphology and MRD by flow cytometry assessments will be centralized.

For statistical analysis, 72 death events need to be observed for which 98 patients will randomized. The primary analysis will be performed approximately 5 years after the first patient is randomized.

Recruitment is ongoing. This trial is registered on clinicaltrials.gov: NCT05183035 and EudraCT Number is 2021-003212-11.

Karol:Servier: Consultancy; Jazz Pharmaceuticals: Consultancy. Sunkersett:AbbVie One Oncology: Current Employment. Onishi:Genentech: Current Employment. Unnebrink:AbbVie Deutschland GmbH & Co. KG: Current Employment. Reinhardt:BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cerus: Membership on an entity's Board of Directors or advisory committees; Medac: Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: Membership on an entity's Board of Directors or advisory committees; BlueBird Bio: Research Funding.

Venetoclax has been approved for the treatment of adult patients with newly diagnosed AML in combination with hypomethylating agents or low-dose cytarabine, who are ineligible for intensive chemotherapy, however, there is no official indication for pediatric patients yet.