A Phase 1/2, Multicenter, Open-Label, Dose-Escalation and Expansion, Safety, Pharmacokinetic, Pharmacodynamic, and Clinical Activity Study of Orally Administered AG-221 in Subjects With Advanced Hematologic Malignancies With an IDH2 Mutation
Study AG221-C-001 is a Phase 1/2, multicenter, open-label, dose-escalation, safety, PK/PD, and clinical activity evaluation of orally administered AG-221 in subjects with advanced hematologic malignancies that harbor an IDH2 mutation. The study includes a dose escalation phase to determine the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) and an expansion phase to further evaluate the safety, tolerability and clinical activity of AG-221 in select populations.
Stanford is not currently accepting new patients for this trial. You may want to check clinicaltrials.gov to see if other locations are recruiting.
- drug : AG-221
Phase: Phase 1/Phase 2
Ages Eligible For Study:
1. Subject must be greater than or equal to 18 years of age. 2. Subjects must have an advanced hematologic malignancy including: Phase 1/ Dose escalation: 1. Diagnosis of acute myelogenous leukemia (AML) according to World Health Organization (WHO) criteria; - Disease refractory or relapsed (defined as the reappearance of > 5% blasts in the bone marrow). - Untreated AML, greater than or equal to 60 years of age and are not candidates for standard therapy due to age, performance status, and/or adverse risk factors, according to the treating physician and with approval of the Medical Monitor; 2. Diagnosis of Myelodysplastic syndrome (MDS) according to WHO classification with refractory anemia with excess blasts (subtype RAEB-1 or RAEB-2), or considered high-risk by the Revised International Prognostic Scoring System (IPSS-R), that is recurrent or refractory, or the subject is intolerant to established therapy known to provide clinical benefit for their condition (i.e., subjects must not be candidates for regimens known to provide clinical benefit), according to the treating physician and with approval of the Medical Monitor. Phase 1/Part 1 Expansion: Arm 1: Relapsed or refractory AML and age greater than or equal to 60 years or any subject with AML regardless of age who has relapsed following a Bone marrow transplant (BMT). Arm 2: Relapsed or refractory AML and age <60 years, excluding subjects with AML who have relapsed following a BMT. Arm 3: Untreated AML and age greater than or equal to 60 years that decline standard of care chemotherapy. Arm 4: Isocitrate dehydrogenase protein, 2 (IDH2)-mutated advanced hematologic malignancies not eligible for Arms 1 to 3. Phase 2: Diagnosis of AML according to World Health Organization (WHO) criteria and disease relapsed or refractory as defined by: - Subjects who relapse after allogeneic transplantation; - Subjects in second or later relapse; - Subjects who are refractory to initial induction or re-induction treatment - Subjects who relapse within 1 year of initial treatment, excluding patients with favorable-risk status according to NCCN Guidelines (NCCN 2015). Favorable-risk cytogenetics: inv(16), t(16;16), t(8;21), t(15;17) 3. Subjects must have documented IDH2 gene-mutated disease: - For subjects in the dose escalation phase and Part 1 Expansion, IDH2 mutation may be based on local evaluation. (Centralized testing will be performed retrospectively.) - For subjects in the Phase 2 portion of the trial, central testing of IDH2 mutation of bone marrow aspirate and peripheral blood, is required during screening to confirm eligibility 4. Subjects must be amenable to serial bone marrow sampling, peripheral blood sampling and urine sampling during the study. - The diagnosis and evaluation of AML or MDS will be made by bone marrow aspiration and/or biopsy. If an aspirate is unobtainable (i.e., a "dry tap"), the diagnosis may be made from the core biopsy. - Screening bone marrow aspirate and peripheral blood samples are required of all subjects. A bone marrow biopsy must be collected if adequate aspirate is not attainable unless: - A bone marrow aspirate and biopsy was performed as part of the standard of care within 28 days prior to the start of the study treatment; and - Slides of bone marrow aspirate, biopsy and stained peripheral blood smear are available for both local and central pathology reviewers; and - A bone marrow aspirate sample acquired within 28 days prior to the start of study treatment has been sent for cytogenetic analysis. 5. Subjects must be able to understand and willing to sign an informed consent. A legally authorized representative may consent on behalf of a subject who is otherwise unable to provide informed consent, if acceptable to and approved by the site and/or sites Institutional Review Board (IRB)/Independent Ethics Committee (IEC). 6. Subjects must have Eastern Cooperative Oncology Group (ECOG) Performance status (PS) of 0 to 2. 7. Platelet count ?20,000/?L (transfusions to achieve this level are allowed). Subjects with a baseline platelet count of <20,000/?L due to underlying malignancy are eligible with Medical Monitor approval. 8. Subjects must have adequate hepatic function as evidenced by: - Serum total bilirubin ?1.5 × upper limit of normal (ULN), unless considered due to Gilbert's disease, a gene mutation in UGT1A1, or leukemic organ involvement, following approval by the Medical Monitor; - Aspartate aminotransferase (AST), Alanine aminotransferase (ALT) and Alkaline phosphatase (ALP) ?3.0 × ULN (Upper limit of normal), unless considered due to leukemic organ involvement. 9. Subjects must have adequate renal function as evidenced by: ? Serum creatinine ?2.0 × ULN OR ? Creatinine clearance greater than 40 mL/min based on the Cockroft-Gault glomerular filtration rate (GFR) estimation: (140 - Age) x (weight in kg) x (0.85 if female)/72 x serum creatinine 10. Subjects must be recovered from any clinically relevant toxic effects of any prior surgery, radiotherapy, or other therapy intended for the treatment of cancer. (Subjects with residual Grade 1 toxicity, for example Grade 1 peripheral neuropathy or residual alopecia, are allowed with approval of the Medical Monitor.) 11. Female subjects of child-bearing potential must agree to undergo medically supervised pregnancy test prior to starting study drug. The first pregnancy test will be performed at screening (within 7 days prior to first study drug administration), and on the day of the first study drug administration and confirmed negative prior to dosing and Day 1 before dosing all subsequent cycles. 12. Female subjects with reproductive potential must have a negative serum pregnancy test within 7 days prior to the start of therapy. Subjects with reproductive potential are defined as sexually mature women who have not undergone a hysterectomy, bilateral oophorectomy or tubal occlusion or who have not been naturally postmenopausal (i.e., who have not menstruated at all) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). Females of reproductive potential as well as fertile men and their partners who are female of reproductive potential must agree to abstain from sexual intercourse or to use two highly effective forms of contraception from the time of giving informed consent, during the study and for 120 days (females and males) following the last dose of AG-221. A highly effective form of contraception is defined as hormonal oral contraceptives, injectables, patches, intrauterine devices, double-barrier method (e.g., synthetic condoms, diaphragm, or cervical cap with spermicidal foam, cream, or gel), or male partner sterilization. 13. Able to adhere to the study visit schedule (ie, clinic visits at the study sites are mandatory, unless noted otherwise for particular study visits) and other protocol requirements.