A Phase 1, Multicenter, Open-Label, Dose-Escalation, Safety, Pharmacokinetic, Pharmacodynamic, and Clinical Activity Study of Orally Administered AG-221 in Subjects with Advanced Hematologic Malignancies with an IDH2 Mutation

Summary

This is a Phase 1, 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 MTD followed by expansion cohorts to further evaluate the safety and tolerability of the MTD and to provide an assessment of its antitumor activity in select populations. The dose escalation phase will utilize a standard [Quote]3 + 3[Quote] design.

increases in the dose of aG-221 for each dose cohort will be guided by an accelerated titration design, where the dose will be doubled (100% increase) from one cohort to the next until aG-221-related nCi CTCae Grade 2 or greater toxicity is observed in any subject within the cohort. Following evaluation by the Clinical Study Team, subsequent increases in dose will be 50% or less until the MTD is determined. The absolute percent increase in the dose will be determined by the Clinical Study Team predicated on the type and severity of any toxicity seen in the prior dose cohorts. The MTD is the highest dose that causes DLTs in [Less Than]2 of 6 subjects. To optimize the number of subjects treated at a potentially clinically relevant dose, intra-subject dose escalation will be permitted with approval of the Medical Monitor.

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.

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.

exploratory endpoints
* 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.

Participant Eligibility

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:

* Relapsed and/or primary refractory AML as defined by WHO criteria; or

* Untreated AML, >=60 years of age and 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.

* Myelodysplastic syndrome with refractory anemia with excess blasts (subtype
RAEB-1 or RAEB-2), or considered high-risk by the International Prognostic Schoring System (IPSS-R), that is recurrent or refractory or the patient is intolerant to established therapy known to provide clinical benefit for their condition (i.e., patients must not be candidates fro 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.)
3. Subjects must have documented IDH2 gene-mutated disease based on local evaluation.
(Centralized testing will be performed retrospectively.) If not performed prior to
screening, gene-mutation analysis should be the first screening procedure performed.
4. Subjects must be amenable to serial bone marrow biopsies, peripheral blood sampling,
and urine sampling during the study.
5. Subjects or their legal representatives must be able to understand and sign an informed consent.
6. Subjects must have ECOG Performance Status of 0 to 2.
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 or leukemic organ involvement;
b. AST, ALT and 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.

OR

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 have a negative serum pregnancy test within 7 days prior to the start of therapy. Subjects with reproductive potential are defined as one who is biologically capable of becoming pregnant. Women of childbearing potential as well as fertile men and their partners must agree to abstain from sexual intercourse or to use an effective form of contraception during the study and for 90 days (females and males) following the last dose of AG-221.