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368 An Australasian Leukemia Lymphoma Group (ALLG) Phase 2 Study to Investigate Novel Triplets to Extend Remission with Venetoclax in Elderly (INTERVENE) Acute Myeloid Leukemia

Program: Oral and Poster Abstracts
Type: Oral
Session: 616. Acute Myeloid Leukemias: Investigational Therapies, Excluding Transplantation and Cellular Immunotherapies: Triplet Combinations of Novel Therapies
Hematology Disease Topics & Pathways:
Clinical Trials, Adults, AML, Clinical Research, Elderly, Diseases, Myeloid Malignancies, Study Population
Sunday, December 12, 2021: 9:45 AM

Chong Chyn Chua, MBBS, FRACP, FRCPA1,2,3, John Reynolds, PhD2,4*, Anoop Kumar Enjeti, MBBS, FRCPA, FRACP, PhD, MD, MRCP2,5, Devendra Hiwase, MBBS, MD, FRACP, FRCPA, PhD2,6, Paula Marlton2,7, Ashish Bajel, MBBS, FRACP, FRCPA2,8,9, Shuh Ying Tan, MBBS2,10*, Edward S. Morris, BMBS, DM2,11, Chun-Kei-Kris Ma, BSc(Med), MBBS, PhD, FRACP, FRCPA2,12*, Carolyn Grove, MBBS, PhD2,13*, Julian Cooney, MBBS, FRACP, FRCPA2,14, Ashanka Beligaswatte, MBBS, FRACP, FRCPA2,15*, Natasha Anstee, PhD3,16*, Stephen B Ting, MBBS, FRACP, FRCPA, PhD2,17*, Travis Perera, MB ChB, FRACP, FRCPA2,18*, Amanda Johnston, MBBS, FRACP, FRCPA2,19, David Ritchie, MB ChB, PhD, FRACP, FRCPA2,9,20 and Andrew H. Wei, MBBS, PhD2,3,16

1The Alfred Hospital & Monash University, Melbourne, VIC, Australia
2Australasian Leukaemia and Lymphoma Group (ALLG), Melbourne, VIC, Australia
3Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia
4The Alfred and Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC, Australia
5Department of Haematology, Calvary Mater Newcastle Hospital, Sydney, NSW, Australia
6Department of Haematology, Royal Adelaide Hospital, Adelaide, SA, Australia
7Princess Alexandra Hospital and University of Queensland, Brisbane, Australia
8Department of Clinical Haematology, Peter MacCallum Cancer Centre and The Royal Melbourne Hospital, Melbourne, Australia
9Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia
10Department of Haematology, St Vincent’s Hospital, Melbourne, VIC, Australia
11Townsville Cancer Centre, Townsville, QLD, Australia
12Department of Haematology, Westmead Hospital, Sydney, NSW, Australia
13Department of Haematology, PathWest & Sir Charles Gairdner Hospital, Department of Health, Nedlands, WA, Australia
14Department of Haematology, Fiona Stanley Hospital, Perth, WA, Australia
15Department of Haematology, Flinders Medical Centre, Adelaide, Australia
16Department of Haematology, The Alfred Hospital, Melbourne, VIC, Australia
17Department of Haematology, Box Hill Hospital and Monash University Eastern Health Clinical School, Melbourne, VIC, Australia
18Wellington Blood and Cancer Centre, Wellington, New Zealand
19Westmead Hospital, Westmead, NSW, Australia
20Clinical Haematology, Peter MacCallum Cancer Centre and The Royal Melbourne Hospital, Melbourne, VIC, Australia

Background:

Adaptive resistance mechanisms leading to treatment failure have been identified in older patients receiving venetoclax (VEN) in combination with either azacitidine or low dose cytarabine (LDAC) as frontline therapy for acute myeloid leukemia (AML). These include the expansion or secondary emergence of kinase activating mutations, including FLT3-ITD in patients with non-adverse karyotype (NON-ADV), as well as TP53 mutations among patients with adverse karyotype (ADV)(DiNardo & Tiong et al, Blood 2020). INTERVENE is a phase 2 study evaluating the safety and efficacy of the “risk-stratified” addition of a novel third agent to VEN-LDAC, delivered in tandem to LDAC to minimize the risk of myelotoxicity (Figure 1A). To mitigate VEN resistance associated with activated kinases in NON-ADV risk AML, midostaurin (MIDO), a FLT3/multi-kinase inhibitor, was incorporated in combination with VEN. To address VEN resistance associated with TP53 defects in ADV risk AML, a HDAC inhibitor pracinostat (PRAN) was incorporated in accordance with pre-clinical studies suggesting synergistic induction of TP53 independent cell death with VEN plus HDAC inhibition (Salmon et al, ASH 2018). We hereby report the results of the dose-finding safety run-in phase of the study.

Methods:

Eligibility: Patients with treatment naïve AML (excluding APL), aged ≥60 years and unfit for intensive chemotherapy were included. Prior hypomethylating agents for antecedent myeloid neoplasms were permitted with a 14-day washout. Patients were stratified according to cytogenetic risk, as per Medical Research Council 2010 criteria.

Treatment: VEN D1-28 (with dose ramp-up in cycle 1) was combined with LDAC (20mg/m2 SC D1-10), with the third agent starting after/on the last day of LDAC (Fig 1A). Each cycle was 28 days. In the NON-ADV stratum (VEN-LDAC-MIDO), 2 dose levels were explored: (L1) VEN 400mg + LDAC + MIDO 50mg BD D11-28; (L2) VEN 600mg + LDAC + MIDO 50mg. In the ADV stratum (VEN-LDAC-PRAN), 3 dose levels were tested: (L1) VEN 400mg + LDAC + PRAN 45mg starting D10 and given 3x/week orally for a total of 9 doses; (L2) VEN 600mg + LDAC + PRAN 45mg; (L3) VEN 600mg + LDAC + PRAN 60mg. Azole antifungals were prohibited in cycle 1 but allowed from cycle 2 with VEN dose modification.

Endpoints (safety run-in): Primary: occurrence of dose-limiting toxicities (DLT) during cycle 1 and determination of recommended phase 2 doses (RP2D) using a Bayesian Logistic Regression Model. Secondary: Preliminary response rates. Molecular studies: Next generation sequencing using a custom 48-gene Roche KAPA HyperCapture myeloid panel and FLT3-ITD targeted amplicon sequencing were performed on baseline bone marrow samples. First patient enrolled: 7SEP2020. Data cut-off: 29JUN2021.

Results:

32 patients were enrolled: 18 in NON-ADV and 14 in ADV strata, respectively. Two patients in the NON-ADV stratum withdrew within the first 7 days due to non-therapy related reasons (1=personal, 1=incidental lung lesion) and were not DLT/response evaluable. Median age was 77 years (68-87; 69% ≥75 years). 43.8% (14/32) had secondary/therapy related AML.

Although gastrointestinal adverse events (AE) during cycle 1 were more common in VEN-LDAC-PRAN arm with nausea (57 vs 17%), vomiting (36% vs 6%) and diarrhea (50% vs 22%), grade 3+ toxicities were uncommon (0-7%)(Table 2). Occurrence of febrile neutropenia was similar between the two arms. 30-day mortality was 0% and 14% (2/14: 1=infection, 1=disease progression) for NON-ADV and ADV strata, respectively. No DLTs were observed in either stratum across all dose levels, thus the RP2D was the highest dose level explored for both triplet combinations.

The intention-to-treat overall response rate CR+CRi+CRh was 72.2% (13/18) in the NON-ADV arm and 57.1% (8/14) in ADV arm. The expanded response rate including PR and MLFS was 77.8% (14/18) and 71.4% (10/14) in the NON-ADV and ADV strata, respectively. Median time to best response was 1 cycle (range 1-6). Updated response and survival outcomes will be presented at the meeting.

Conclusion:

The addition of MIDO or PRAN to VEN-LDAC was tolerable in older/unfit patients with treatment naïve AML. Preliminary efficacy with this risk-stratified approach compared favorably to prior studies with VEN-LDAC alone (Wei et al Blood 2020: CR+CRi 56% in NON-ADV, 28% in ADV). The randomized phase 2 part of this tandem triplet strategy with the goal of preventing adaptive resistance is underway.

Disclosures: Chua: Abbvie: Other: Conference travel and accommodation . Reynolds: Alcon: Current equity holder in publicly-traded company; Abbvie: Research Funding; Novartis AG: Current equity holder in publicly-traded company. Enjeti: Roche: Speakers Bureau; AbbVie: Honoraria; Sanofi: Honoraria; Astra Zeneca: Honoraria; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hiwase: AbbVie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Marlton: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Queensland Health: Current Employment; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bajel: Abbvie, Amgen, Novartis, Pfizer: Honoraria; Amgen: Speakers Bureau. Grove: Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Cooney: Amgen: Other: Travel, accommodation, expenses ; Roche: Other: Travel, accommodation, expenses ; Novartis: Other: Online conference registration . Beligaswatte: Astellas: Membership on an entity's Board of Directors or advisory committees. Anstee: Walter and Eliza Hall Institute: Patents & Royalties: Dr Anstee was a former employee of the Walter and Eliza Hall Institute and is eligible for a fraction of the royalty stream related to Venetoclax. Perera: Abbvie: Speakers Bureau; BMS: Speakers Bureau. Ritchie: Takeda: Research Funding; BMS: Research Funding; Novartis: Honoraria; CRISPR Therapeutics: Research Funding; Amgen Inc: Honoraria, Research Funding; CSL: Honoraria. Wei: Genentech: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees; Macrogenics: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

OffLabel Disclosure: This presentation will focus on the ALLG INTERVENE clinical trial combining venetoclax+LDAC+midostaurin or venetoclax+LDAC+pracinostat. Although venetoclax and midostaurin are individually FDA-approved in some indications, the combinations examined in this clinical trial have not been approved by FDA.

*signifies non-member of ASH