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
This is a Phase 1/2, multicenter, open-label, 3-part (Phase 1 dose-escalation, Phase 1 Part 1 expansion and Phase 2), 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 MTD/MaD and/or RP2D an expansion phase (Part 1) to further evaluate the safety, tolerability and clinical activity aG-221, and a Phase 2 to assess the clincial efficacy of aG-221 and RP2D and to futher evaluate safety in subjects with refreactory adn relapsed aML carrying an iDH2 mutation.
Following determination of the recommended Phase 2 dosing regimen(s), the expansion phase will open. expansion cohorts will be divided into 4 non-randomized arms of 25 subjects per arm with iDH2-mutated hematologic malignancies as follows:
* arm 1: Relapsed or refractory acute myelogenous leukemia (aML) and age [GreaterThanorequalTo]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 [Less Than]60 years, excluding subjects with aML who have relapsed following a BMT.
* arm 3: untreated aML and age [GreaterThanorequalTo]60 years that decline standard of care chemotherapy.
* arm 4: iDH2-mutated advanced hematologic malignancies not eligible for arms 1 to 3.
Subjects enrolled in these cohorts will undergo the same procedures as subjects in the dose escalation cohorts. The Day -3 PK/PD assessments will be obtained for the first 15 subjects enrolled within each expansion arm unless approved by the Medical Monitor to omit the assessment; subsequent subjects enrolled will undergo these procedures based on Medical Monitor evaluation.
Based on continued ongoing demonstration of safety and clinical activity in the dose escalation portion of the study, the Phase 2 portion of the trial will further establish the safety profile and clinical activity of aG-221 in subjects with relapsed or refractory aML that harbor an iDH2 mutation.
The Phase 2 portion of the trial will enroll approximately 125 subjects with iDH2-mutated relapsed or refractory aML defined as follows:
* Subjects who relapse after allogeneic transplantation
* Subjects in second or later relapse
* Subjects who are refractory to second-line induction or re-induction treatment
The Phase 2 portion of the trial will be used to confirm the safety and clinical activity of aG-221 and to explore the relationship with PK/PD and iDH2 mutation for the treatment of subjects with relapsed or refractory aML that harbor an iDH2 mutation.
Safety Measures and endpoints
* Monitoring of adverse events (aes), including determination of DLTs, serious adverse events (Saes), and aes leading to discontinuation. The severity of aes will be assessed by the national Cancer institute Common Terminology Criteria for adverse events (nCi CTCae), version 4.03.
* Monitoring of safety laboratory parameters, physical examination findings, vital signs, 12-lead eCGs, evaluation of left ventricular ejection fraction (LVeF), and eastern Cooperative oncology Group (eCoG) performance status (PS).
Pharmacokinetic and Pharmacodynamic Measures and endpoints
Serial blood sampling for determination of concentration-time profiles of aG-221 and its metabolite aGi-16903. urine sampling for determination of concentrations of aG-221 and its metabolite aGi-16903. Blood, bone marrow, and urine sampling for determination of 2-HG and [RegisteredTM]-KG levels.
Clinical activity Measures
* Serial blood and bone marrow sampling to determine response to treatment based on modified international Working Group (iWG) Response Criteria.
* Blood and bone marrow samples to explore early clinical activity and the prognostic relationship of PD markers.
* Blood samples to assess changes in [RegisteredTM]-KG levels.
* Blood samples for plasma levels of cholesterol and 4[MiCRo-SYMBoL]-oH-cholesterol levels.
Subjects must meet all of the following criteria to be enrolled in the study:
1. Subjects must be >=18 years of age.
2. Subjects must have an advanced hematologic malignancy including:
Phase 1/Dose escalation phase:
* Diagnosis of AML according to (WHO) criteria;
* Disease refractory or relapsed (defined as the reappearance of >5% blasts in teh bone marrow, see Protocol Tables 9 and 10)
* Untreated AML, >=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;
* Diagnosis of Myelodysplastic syndrome (MDS) according to WHO classification with refractory anemia with excess blasts (subtype RAEB-1 or RAEB-2) (see Protocol Appendix 15.2), or considered high-risk by the Revised International Prognostic Scoring System (IPSS-R) (see Protocol Appendix 15.3) 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.
(Subjects with other relapsed and/or primary refractory hematologic cancers, for example CMML, who fulfill the inclusion/excluding criteria may be considered on a case-by case basis, with approval of the Medical Monitor.)
Phase 1/Part 1 Expansion:
* Arm 1: Relapsed or refractory AML (see Protocol Tables 9 and 10) and age >=60 years, or any subject with AML regardless of age who has relapsed following a BMT.
* Arm 2: Relapsed or refractory AML (see Protocol Tables 9 and 10) and age <60 years, excluding subjects with AML who have relapsed following a BMT.
* Arm 3: Untreated AML and age >=60 years that decline standard of care chemotherapy.
* Arm 4: IDH2-mutated advanced hematologic malignancies not eligible for Arms 1 to 3.
AML according to World Health Organization (WHO) criteria: Protocol Appendix 15.1 and disease relapsed or refractory as defined by (see Protocol Tables 9 and 10):
* Subjects who relapse after allogeneic transplantation;
* Subjects in second or later relapse;
* Subjects who are refractory to second-line induction or re-induction treatment.
o 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), +(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 trial, central testing of IDH2 mutation in samples of bone marrow aspirate and peripheral blood, is required during screening to confirm eligibility.
4. Subjects must be amenable to serial bone marrow biopsies, 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 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 for all subjects.
A bone marrow biopsy must be collected if adequate aspirate is not attainable unless:
o 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
o Slides of bone marrow aspirate, biopsy and stained peripheral blood smear are available for both local and central pathology reviewers;
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 site[Single Quote]s Institutional Review Board (IRB)/Independent Ethic Committee (IEC).
6. Subjects must have ECOG Performance Status of 0 to 2.(See protocol Appendix 15.5)
7. Platelet count >=20,000/[MICRO-SYMBOL]L (transfusions to achieve this level are allowed). Subjects with a baseline platelet count of <20,000/[MICRO-SYMBOL]L due to underlying malignancy are eligible with Medical Monitor approval.
8. Subjects must have adequate hepatic function as evidenced by:
a. Serum total bilirubin <=1.5 x upper limit of normal (ULN), unless considered due to Gilbert[Single Quote]s disease, a gene mutation in UGT1A1, or leukemic organ involvement, following approval by the Medical Monitor;
b. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) <=3.0 x ULN, unless considered due to leukemic organ involvement.
9. Subjects must have adequate renal function as evidenced by a serum creatinine <=2.0 x ULN.
Creatinine clearance >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 with reproductive 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