A Phase 3, Multicenter, Open-label, Randomized Study Comparing the Efficacy and Safety of AG-221 (CC-90007) Versus Conventional Care Regimens in Older Subjects With Late Stage Acute Myeloid Leukemia Harboring an Isocitrate Dehydrogenase 2 Mutation
Overview
- Phase
- Phase 3
- Intervention
- AG-221
- Conditions
- Leukemia, Myeloid
- Sponsor
- Celgene
- Enrollment
- 319
- Locations
- 93
- Primary Endpoint
- Overall Survival (OS)
- Status
- Completed
- Last Updated
- 11 months ago
Overview
Brief Summary
This is an international, multicenter, open-label, randomized, Phase 3 study comparing the efficacy and safety of AG-221 versus conventional care regimens (CCRs) in subjects 60 years or older with acute myeloid leukemia (AML) refractory to or relapsed after second- or third-line AML therapy and positive for an isocitrate dehydrogenase (IDH2) mutation.
Detailed Description
Acute myeloid leukaemia (AML) is a form of cancer that is common in older patients. Mutations in the isocitrate dehydrogenase enzyme 2 (IDH2) have been found in approximately 15% of patients with AML. The outcome of first line chemotherapy treatment is poor and many patients fail to attain complete remission (CR, ie refractory) or will eventually relapse. There is no single standard of care for relapsed or refractory AML. Since the prognosis is very poor there is a great need for new therapies. Inhibition of the mutant IDH2 enzyme may represent a promising targeted therapy for AML. AG-221 is a small molecule inhibitor of the IDH2 enzyme, designed to preferentially target the mutant IDH2 variants. Data from the ongoing first-in-human study has shown AG-221 to be generally well tolerated and demonstrated CR in patients with IDH2 mutation positive relapsed or refractory AML. The study purpose is to test the safety and efficacy of AG-221 compared with conventional care regimens (CCR), which include best supportive care (BSC) only, azacitidine plus BSC, low-dose cytarabine plus BSC or intermediate-dose cytarabine plus BSC, in patients with late stage AML refractory to or relapsed after second or third line therapy and positive for the IDH2 mutation. Patients will be randomly assigned to receive open-label tablets of AG-221 or one of the CCR on continuous 28-day treatment cycles. The trial duration is expected to be 78 months which includes 42 months enrollment, approximately 7 months treatment and a follow-up period. Study procedures include: vital signs, physical exams, ECGs, ECHO, urine/blood samples, bone marrow aspirates and/or biopsies and peripheral blood to test for IDH2 and assess treatment response. Bone marrow, blood, cheek swab samples will be used for genetic tests. This study is being sponsored by Celgene Corporation. Approximately 316 participants will take part in the study.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Subjects must satisfy the following criteria to be enrolled in the study:
- •Subject is ≥ 60 years of age at the time of signing the ICF
- •Subject has primary (ie, de novo) or secondary (progression of MDS or myeloproliferative neoplasms (\[MPN\], or therapy-related) AML according to WHO classification (Appendix B)
- •Subject has received second- or third-line of AML therapy (see Appendix G for the definition of prior AML line; note that, for subjects having AML secondary to prior higher risk \[Intermediate-2 or High risk according to the International Prognostic Scoring System\] MDS treated with a hypomethylating agent \[eg, azacitidine or decitabine\], the hypomethylating therapy can be counted as a line if there is disease progression to AML during or shortly \[eg, within 60 days\] after the hypomethylating therapy.)
- •Subject has the following disease status:
- •Refractory to or relapsed after second- or third-line of intensive therapy for AML (eg, the "7 + 3" regimen):
- •at least 5% leukemic blasts in bone marrow (the minimum number of treatment cycles of the intensive therapy is per the investigator's discretion); or
- •Refractory to or relapsed after second- or third-line low-intensity AML therapy (eg, LDAC, azacitidine or decitabine):
- •at least 5% leukemic blasts in bone marrow after at least 2 treatment cycles
- •Subject is eligible for and willing to receive the pre-selected CCR treatment option, according to the investigator's assessment (Note: Subjects with degenerative and toxic encephalopathies, especially after the use of methotrexate or treatment with ionizing radiation, should not receive cytarabine.)
Exclusion Criteria
- •The presence of any of the following will exclude a subject from enrollment:
- •Subject is suspected or proven to have acute promyelocytic leukemia based on morphology, immunophenotype, molecular assay, or karyotype
- •Subject has AML secondary to chronic myelogenous leukemia
- •Subject has received a targeted agent against an IDH2 mutation
- •Subject has received systemic anticancer therapy or radiotherapy \< 14 days prior to the start of study treatment. Note that hydroxyurea is allowed prior to the start of study treatment for the control of leukocytosis (however, hydroxyurea should not be given within 72 hours prior to and after administration of azacitidine).
- •Subject has received non-cytotoxic or investigational agents \< 14 days or 5 half-lives, whichever is longer, prior to the start of study treatment
- •Subject has undergone HSCT within 60 days prior to the start of study treatment, or on immunosuppressive therapy post HSCT at the time of screening, or with clinically significant graft-versus-host disease (GVHD). The use of a stable dose of oral steroid post-HSCT and/or topical steroids for ongoing skin GVHD is permitted.
- •Subject has persistent, clinically significant non-hematologic toxicities from prior therapies
- •Subject 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.
- •Subject has active uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment)
Arms & Interventions
AG-221 plus Best supportive care (BSC)
Continuous 28-day cycles of AG 221 100 mg orally (PO) once a day (QD) for 28 days, plus BSC.
Intervention: AG-221
AG-221 plus Best supportive care (BSC)
Continuous 28-day cycles of AG 221 100 mg orally (PO) once a day (QD) for 28 days, plus BSC.
Intervention: BSC
Conventional care regimen (CCR)
Continuous 28-day cycles of BSC only, azacitidine subcutaneously (SC) plus BSC, low-dose cytarabine (LDAC) SC plus BSC, or intermediate-dose cytarabine (IDAC) intravenously (IV) plus BSC. Subjects will be assigned by the investigator to one of the CCR treatment options based on the investigator's assessment of subjects' eligibility.
Intervention: BSC
Conventional care regimen (CCR)
Continuous 28-day cycles of BSC only, azacitidine subcutaneously (SC) plus BSC, low-dose cytarabine (LDAC) SC plus BSC, or intermediate-dose cytarabine (IDAC) intravenously (IV) plus BSC. Subjects will be assigned by the investigator to one of the CCR treatment options based on the investigator's assessment of subjects' eligibility.
Intervention: Azacitidine
Conventional care regimen (CCR)
Continuous 28-day cycles of BSC only, azacitidine subcutaneously (SC) plus BSC, low-dose cytarabine (LDAC) SC plus BSC, or intermediate-dose cytarabine (IDAC) intravenously (IV) plus BSC. Subjects will be assigned by the investigator to one of the CCR treatment options based on the investigator's assessment of subjects' eligibility.
Intervention: Low-dose cytarabine (LDAC)
Conventional care regimen (CCR)
Continuous 28-day cycles of BSC only, azacitidine subcutaneously (SC) plus BSC, low-dose cytarabine (LDAC) SC plus BSC, or intermediate-dose cytarabine (IDAC) intravenously (IV) plus BSC. Subjects will be assigned by the investigator to one of the CCR treatment options based on the investigator's assessment of subjects' eligibility.
Intervention: Intermediate-dose cytarabine (IDAC)
Outcomes
Primary Outcomes
Overall Survival (OS)
Time Frame: From randomization to death due to any cause (up to approximately 49 months)
The time between randomization and death from any cause. Participants who drop-out or are alive at the end of trial will have their OS times censored at the time of last contact, as appropriate.
Secondary Outcomes
- Overall Response Rate(From randomization up to study completion (approximately 78 months))
- Event-Free Survival(From randomization up to study completion (approximately 78 months))
- Duration of Response(From randomization up to study completion (approximately 78 months))
- Time to Response(From randomization to to first documented MLFS/CR/CRi/CRp/PR (up to approximately 49 months))
- Treatment Mortality at 30 Days(From first dose to 30 days after first dose)
- Treatment Mortality at 60 Days(From first dose to 60 days after first dose)
- One-Year Survival Rate(From randomization up to 1 year post (approximately 12 months))
- Overall Remission Rate(From randomization up to approximately 49 months)
- Complete Remission Rate(From randomization up to approximately 49 months)
- Hematologic Improvement Rate(From randomization up to approximately 49 months)
- The Number of Participants That Underwent Hematopoietic Stem Cell Transplantation (HSCT)(From randomization up to approximately 49 months)
- Time to Treatment Failure(From randomization to discontinuation of study treatment due to any cause (up to approximately 49 months))
- The Number of Participants Experiencing Adverse Events (AEs)(From randomization up to study completion (approximately 78 months))
- The Percent of Participants Experiencing Clinically Significant Laboratory Abnormalities - Serum Chemistry(From first dose up to approximately 49 months)
- The Percent of Participants Experiencing Clinically Significant Laboratory Abnormalities - Hematology(From first dose up to approximately 49 months)
- The Percent of Participants Experiencing Clinically Significant Vital Sign Abnormalities(From first dose up to approximately 49 months)
- The Percentage of Participants Experiencing Clinically Significant Electrocardiogram (ECG) Abnormalities(From first dose up to approximately 49 months)
- Change From Baseline in the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30)(From baseline to cycle 2 day 1 (up to approximately 1 month))
- Change From Baseline in EQ-5D-5L Health Utility Index(From baseline up to cycle 2 day 1 (up to approximately 1 month))