Clinical trial NCT02677922: A Study to Assess the Safety and Efficacy of Two Combinations of Isocitrate Dehydrogenase (IDH) Mutant Targeted Therapies Plus Azacitidine in Participants With Newly Diagnosed Acute Myeloid Leukemia (AML) Harboring IDH Mutations Who Are Not Candidates to Receive Intensive Induction Chemotherapy
Official title: A Phase 1b/2 Open-Label, Randomized Study of 2 Combinations of Isocitrate Dehydrogenase (IDH) Mutant Targeted Therapies Plus Azacitidine: Oral AG-120 Plus Subcutaneous Azacitidine and Oral AG-221 Plus SC Azacitidine in Subjects With Newly Diagnosed Acute Myeloid Leukemia Harboring an IDH1 or an IDH2 Mutation, Respectively, Who Are Not Candidates to Receive Intensive Induction Chemotherapy
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Leukemia, Myeloid, Acute
Keywords: Acute Myeloid Leukemia
Leukemia
Azacitidine
AG-120
AG-221
Lead sponsor: Celgene
Sponsor class: INDUSTRY
First posted: 2016-02-09
Enrollment: 130
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study are

1. to determine the recommended combination dose of AG-120 and AG-221 separately when administered with azacitidine and,
2. to investigate the safety, tolerability, and efficacy of the combinations of AG-120 with azacitidine and AG-221 with azacitidine versus with azacitidine alone in participants with acute myeloid leukemia (AML) with the isocitrate dehydrogenase (IDH) enzyme isoforms 1 or 2 mutations, respectively.


Eligibility criteria: Inclusion Criteria:

* Newly diagnosed, primary (ie, de novo) or secondary (progression of Myelodysplastic syndrome \[MDS\] or myeloproliferative neoplasms \[MPN\], or therapy-related) acute myeloid leukemia (AML) according to the WHO classification with ≥ 20% leukemic blasts in the bone marrow
* Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
* Agree to serial bone marrow aspirate/biopsies

Exclusion Criteria:

* Suspected or proven to have acute promyelocytic leukemia based on morphology, immunophenotype, molecular assay, or karyotype
* AML secondary to chronic myelogenous leukemia (CML)
* Received a targeted agent against an isocitrate dehydrogenase 1 (IDH1) or isocitrate dehydrogenase 2 (IDH2) mutation
* Has or is suspected of having central nervous system (CNS) leukemia. Evaluation of cerebrospinal fluid is only required if CNS involvement by leukemia is suspected during screening

Other protocol defined inclusion/exclusion criteria apply

Primary outcomes:
measure: The Number of Participants Experiencing Dose-limiting Toxicities (DLTs): Phase 1B (Dose Finding Stage)
timeFrame: From first dose to 28 days after first dose
measure: The Number of Participants Experiencing Adverse Events: Phase 1B (Dose Finding and Expansion Stage)
timeFrame: From first dose to 28 days after last dose (up to approximately 13 months)
measure: Overall Response Rate: Phase 2 (Randomized Stage)
timeFrame: From first dose up to approximately 26 months
Secondary outcomes:
measure: Overall Response Rate: Phase 1B (Dose Finding and Expansion Stage)
timeFrame: From first dose up to approximately 13 months
measure: Sponsor Derived CR and CRh: Phase 1B (Dose Finding and Expansion Stage)
timeFrame: From first dose up to approximately 13 months
measure: Event-free Survival (EFS): Phase 2 (Randomized Stage)
timeFrame: From randomization to the date of documented relapse, progression, or death due to any cause, whichever occurs first (up to approximately 26 months)
measure: The Number of Participants Experiencing Adverse Events: Phase 2 (Randomized Stage)
timeFrame: From first dose to 28 days after last dose (up to approximately 26 months)
measure: Complete Remission Rate: Phase 2 (Randomized Stage)
timeFrame: From first dose up to approximately 26 months
measure: Hematologic Improvement (HI) Rate: Phase 2 (Randomized Stage)
timeFrame: From first dose up to approximately 26 months
measure: Duration of Response: Phase 2 (Randomized Stage)
timeFrame: From first dose up to approximately 26 months
measure: Time to Response: Phase 2 (Randomized Stage)
timeFrame: From first dose to to first documented MLFS/CR/CRi/CRp/PR (up to approximately 26 months)
measure: Overall Survival: Phase 2 (Randomized Stage)
timeFrame: From randomization to date of death (up to approximately 26 months)
measure: One Year Survival Rate: Phase 2 (Randomized Stage)
timeFrame: From randomization to 1 year after randomization
measure: AUC (0-8)- Area Under the Plasma Concentration-Time Curve: Phase 1B (Expansion Stage)
timeFrame: Pre-dose, 0.5, 2, 3, 4, 6, 8 hours post dose (± 10 minutes) on day 1 of cycle 1 and 2
measure: Cmax- Maximum Observed Plasma Concentration: Phase 1B (Expansion Stage)
timeFrame: Pre-dose, 0.5, 2, 3, 4, 6, 8 hours post dose (± 10 minutes) on day 1 of cycle 1 and 2
measure: Tmax- Time of Maximum Observed Plasma Concentration: Phase 1B (Expansion Stage)
timeFrame: Pre-dose, 0.5, 2, 3, 4, 6, 8 hours post dose (± 10 minutes) on day 1 of cycle 1 and 2
measure: AUC (0-8)- Area Under the Plasma Concentration-Time Curve: Phase 2 (Randomized Stage)
timeFrame: Pre-dose, 2, 3, 4, 6, and 8 hours post dose (± 10 minutes) on day 1 of cycle 2
measure: AUC (0-24)- Area Under the Plasma Concentration-Time Curve: Phase 2 (Randomized Stage)
timeFrame: Pre-dose, 2, 3, 4, 6, 8, and 24 hours post dose (± 10 minutes) on day 1 of cycle 2
measure: Cmax- Maximum Observed Plasma Concentration: Phase 2 (Randomized Stage)
timeFrame: Pre-dose, 2, 3, 4, 6, 8, and 24 hours post dose (± 10 minutes) on day 1 of cycle 2
measure: Tmax- Time of Maximum Observed Plasma Concentration: Phase 2 (Randomized Stage)
timeFrame: Pre-dose, 2, 3, 4, 6, 8, and 24 hours post dose (± 10 minutes) on day 1 of cycle 2
measure: Change From Baseline in Health-related Quality-of-Life Domain Scores of the EORTC QLQ-C30: Phase 2 (Randomized Stage)
timeFrame: Baseline and Day 1 Cycle 5
measure: Change From Baseline in Health Utility Indices of the EQ-5D-5L: Phase 2 (Randomized Stage)
timeFrame: Baseline and Day 1 Cycle 5
measure: Change From Baseline in Visual Analogue Scale (VAS) Scores of the EQ-5D-5L: Phase 2 (Randomized Stage)
timeFrame: Baseline and Day 1 Cycle 5
measure: Sponsor Derived CR: Phase 2 (Randomized Stage)
timeFrame: From first dose to end of study
measure: Sponsor Derived CR and CRh: Phase 2 (Randomized Phase)
timeFrame: From first dose to end of study
measure: Time to Sponsor Derived CR and CRh: Phase 2 (Randomized Phase)
timeFrame: From first dose to end of study
measure: Duration of Sponsor Derived CR/CRh: Phase 2 (Randomized Stage)
timeFrame: From first dose to end of study
Other outcomes:
Locations:
city: Duarte
country: United States
facility: Local Institution - 105
state: California
city: New Haven
country: United States
facility: Local Institution - 107
state: Connecticut
city: Chicago
country: United States
facility: Local Institution - 108
state: Illinois
city: Chicago
country: United States
facility: Local Institution - 103
state: Illinois
city: Boston
country: United States
facility: Local Institution - 102
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Local Institution - 902
state: Massachusetts
city: New York
country: United States
facility: Local Institution - 106
state: New York
city: Dallas
country: United States
facility: Local Institution - 110
state: Texas
city: Adelaide
country: Australia
facility: Local Institution - 178
state: South Australia
city: Melbourne
country: Australia
facility: Local Institution - 175
city: Perth
country: Australia
facility: Local Institution - 177
city: Yvoir
country: Belgium
facility: Local Institution - UNK-121
city: Toronto
country: Canada
facility: Local Institution - 125
state: Ontario
city: Lille
country: France
facility: Local Institution - 205
city: Marseille Cedex 9
country: France
facility: Local Institution - 206
city: Paris Cedex 10
country: France
facility: Local Institution - 200
city: Pessac
country: France
facility: Local Institution - 204
city: Pierre Benite
country: France
facility: Local Institution - 202
city: Toulouse
country: France
facility: Local Institution - 203
city: Villejuif CEDEX
country: France
facility: Local Institution - 201
city: Berlin
country: Germany
facility: Local Institution - 227
city: Dresden
country: Germany
facility: Local Institution - 230
city: Ulm
country: Germany
facility: Local Institution - 225
city: Bologna, Emilia-Romagna
country: Italy
facility: Local Institution - 253
city: Firenze
country: Italy
facility: Local Institution - 252
city: Genova
country: Italy
facility: Local Institution - 256
city: Orbassano
country: Italy
facility: Local Institution - 251
city: Padova
country: Italy
facility: Local Institution - 254
city: Pesaro
country: Italy
facility: Local Institution - 250
city: Roma
country: Italy
facility: Local Institution - 255
city: Seoul
country: Korea, Republic of
facility: Local Institution - 351
city: Seoul
country: Korea, Republic of
facility: Local Institution - 350
city: Utrecht
country: Netherlands
facility: Local Institution - 277
city: Lisboa
country: Portugal
facility: Local Institution - 327
city: Barcelona
country: Spain
facility: Local Institution - 379
city: Barcelona
country: Spain
facility: Local Institution - 375
city: Caceres
country: Spain
facility: Local Institution - 376
city: Madrid
country: Spain
facility: Local Institution - 378
city: Madrid
country: Spain
facility: Local Institution - 381
city: Malaga
country: Spain
facility: Local Institution - 380
city: Valencia
country: Spain
facility: Local Institution - 377
city: Göteborg
country: Sweden
facility: Local Institution - UNK-52
city: Basel
country: Switzerland
facility: Local Institution - 403
city: Zurich
country: Switzerland
facility: Local Institution - 401
city: Birmingham
country: United Kingdom
facility: Local Institution - 429
city: Headington
country: United Kingdom
facility: Local Institution - 427
city: London
country: United Kingdom
facility: Local Institution - 428
city: Sutton (Surrey)
country: United Kingdom
facility: Local Institution - 430
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References:
citation: DiNardo CD, Schuh AC, Stein EM, Montesinos P, Wei AH, de Botton S, Zeidan AM, Fathi AT, Kantarjian HM, Bennett JM, Frattini MG, Martin-Regueira P, Lersch F, Gong J, Hasan M, Vyas P, Dohner H. Enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia (AG221-AML-005): a single-arm, phase 1b and randomised, phase 2 trial. Lancet Oncol. 2021 Nov;22(11):1597-1608. doi: 10.1016/S1470-2045(21)00494-0. Epub 2021 Oct 18.
citation: DiNardo CD, Stein AS, Stein EM, Fathi AT, Frankfurt O, Schuh AC, Dohner H, Martinelli G, Patel PA, Raffoux E, Tan P, Zeidan AM, de Botton S, Kantarjian HM, Stone RM, Frattini MG, Lersch F, Gong J, Gianolio DA, Zhang V, Franovic A, Fan B, Goldwasser M, Daigle S, Choe S, Wu B, Winkler T, Vyas P. Mutant Isocitrate Dehydrogenase 1 Inhibitor Ivosidenib in Combination With Azacitidine for Newly Diagnosed Acute Myeloid Leukemia. J Clin Oncol. 2021 Jan 1;39(1):57-65. doi: 10.1200/JCO.20.01632. Epub 2020 Oct 29.