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

Study ID
STU 062013-037

Cancer Related
Yes

Healthy Volunteers
No

Study Sites

Contact
Joyce Bolluyt
214-648-7007
joyce.bolluyt@utsouthwestern.edu

Principal Investigator
Arthur Frankel

Summary

This is a Phase 1, multicenter, open-label, dose-escalation, safety, PK/PD, and clinical activity evaluationof 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. The dose escalation phase will utilize a standard [Quote]3 + 3[Quote] design. During the dose escalation phase, consented eligible subjects will be enrolled into sequential cohorts of increasing doses of aG-221. each dose cohort will plan to enroll a minimum of 3 subjects. The first 3 subjects in each cohort enrolled in the dose escalation phase will initially receive a single dose of aG-221 on Day -3 (i.e., 3 days prior to the start of twice daily dosing) to evaluate concentrations of aG-221, its metabolite, and 2-HG levels; safety also will be assessed.

once or twice (every 12 or 24 hours) daily dosing will begin on Cycle 1, Day 1 (C1D1). if there are multiple subjects in the screening process at the time the third subject within a cohort begins treatment, up to 2 additional subjects may be enrolled, for a maximum of 5 subjects per cohort, with approval of the Medical Monitor.

Study aG221-C-001 is an ascending multiple dose clinical trial. it is primarily intended to evaluate the safety and tolerability of aG-221 when administered orally once or twice daily (approximately every 12 - 24 hours) to subjects with specific iDH2-mutated hematologic malignancies. This study will also evaluate the PK/PD profiles of multiple dose administration of aG-221. it is anticipated that this study will provide evidence of biologic activity at one or more
dose levels by demonstration of effects on cellular differentiation and associated clinical antitumor activity. The safety, tolerability, and PK/PD findings in this study will form the basis for subsequent clinical development of aG-221.

aG-221 will be administered orally once or twice daily (approximately every 12 or 24 hours) on Days 1 to 28 in 28-day cycles. Starting with C1D1, dosing is continuous; there are no inter-cycle rest periods.

Subjects will be dispensed the appropriate number of tablets for 28 days of dosing (plus an
additional 2-day supply to allow for scheduling of visits) on Day 1 of each cycle. Subjects are to
return all unused tablets (or the empty bottles) on Day 1 of each treatment cycle.

Safety Measures and endpoints
Safety will be evaluated by:
* 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
The PK and PD profile of aG-221 will be evaluated by:
* Serial blood sampling at specified time points for determination of plasma concentration-time profiles and PK parameters of aG-221 and its metabolite aGi-16903.
* urine sampling at specified time points for determination of urinary excretion of aG-221 and its metabolite aGi-16903.
* Blood, bone marrow, and urine sampling at specified time points for determination of 2-HG levels to characterize the PD effects of aG-221.

Clinical activity Measures and endpoints
Clinical activity of aG-221 will be evaluated by:
* Serial blood and bone marrow sampling to determine response to treatment based on modified international Working Group (iWG) Response Criteria in aML (Cheson, et al. 2006)

exploratory endpoints
* Blood and bone marrow samples to explore early clinical activity and the prognostic relationship of PD markers

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.
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.