A Phase 1, Multicenter, Open-Label, Dose-Escalation, Safety, Pharmacokinetic, Pharmacodynamic, and Clinical Activity Study of Orally Administered AG-120 in Subjects with Advanced Solid Tumors, Including Glioma, with an IDH1 Mutation

Summary

This is a Phase 1, multicenter, open-label, dose-escalation, safety, PK/PD, and clinical activity evaluation of orally administered aG-120 in subjects with advanced solid tumors, including glioma, that harbor an iDH1 mutation.

The study includes a dose escalation phase to determine maximal tolerated dose (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-120. 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-120 on Day -3 (i.e., 3 days prior to the start of daily dosing) to evaluate concentrations of aG-120 and 2-HG levels. Daily dosing will begin on Cycle 1, Day 1 (C1D1). The initial dosing regimen will be twice daily (approximately every 12 hours). if warranted based on the emerging data, an alternative dosing schedule (e.g., once daily or three times daily), including administration of the same total daily dose using different dosing schedules in concurrent cohorts, may be explored as agreed upon by the Clinical Study Team. 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. For these additional subjects, the Day -3 PK/PD assessments may be considered optional following discussion with the Medical Monitor.

Participant Eligibility

1. Subject must be >=18 years of age.
2. Subjects must have histologically or cytologically confirmed advanced solid tumors, including glioma, that have recurred or progressed following standard therapy, or that have not responded to standard therapy.
3. Subjects must have documented IDH1 gene-mutated disease based on local test evaluation. (Centralized testing will be performed retrospectively.) If not performed prior to screening, gene-mutation analysis should be one of the first screening procedures performed.
4. Subject must have evaluable disease by RECIST v1.1 for subjects without glioma or by RANO criteria for subjects with glioma.
5. Subjects must be amenable to serial peripheral blood sampling, urine sampling, and biopsies during the study.
6. Subject 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's Institutional Review Board (IRB).
7. Subjects must have ECOG PS of 0 to 1.
8. Subjects must have expected survival of >=3 months.
9. Subjects must have adequate bone marrow function as evidenced by: a. Absolute neutrophil count >=1.5 x109/L;
b. Hemoglobin >9 g/dL (Subjects are allowed to be transfused to this level.)
c. Platelets >=75 x 109/L

10. 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 disease involvement following approval by the Medical Monitor;
b. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) <=2.5 x ULN. For subjects with bone metastases and/or suspected disease-related liver or biliary involvement, ALP must be <=5 x ULN.

11. Subjects must have adequate renal function as evidenced by: a. Serum creatinine <=2.0 x ULN


OR
b. 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
12. Subjects must be recovered from any clinically relevant toxic effects of any prior surgery, radiotherapy, or other therapy intended for the treatment of cancer. (For example, subjects with residual Grade 1 toxicity or stable Grade 2 peripheral neuropathy due to prior chemotherapy are allowed with approval of the Medical Monitor.)
13. 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-120.