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

Institut de Recherches Internationales Servier12 sites in 2 countries174 target enrollmentMarch 1, 2014

ConditionsCholangiocarcinoma Chondrosarcoma Glioma Other Advanced Solid Tumors

InterventionsAG-120

DrugsAG-120

Overview

Phase: Phase 1
Intervention: AG-120
Conditions: Cholangiocarcinoma
Sponsor: Institut de Recherches Internationales Servier
Enrollment: 174
Locations: 12
Primary Endpoint: Safety/tolerability: incidence of adverse events
Status: Completed
Last Updated: 2 months ago

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Sites Similar Trials

Overview

Brief Summary

The purpose of this Phase I, multicenter study is to evaluate the safety, pharmacokinetics, pharmacodynamics and clinical activity of AG-120 in advanced solid tumors, including glioma, that harbor an IDH1 mutation. The first portion of the study is a dose escalation phase where cohorts of patients will receive ascending oral doses of AG-120 to determine maximum tolerated dose (MTD) and/or the recommended Phase II dose. The second portion of the study is a dose expansion phase where four arms of patients will receive AG-120 to further evaluate the safety, tolerability, and clinical activity of the recommended Phase II dose. Anticipated time on study treatment is until disease progression, unacceptable toxicity occurs or at Investigator discretion.

Registry

clinicaltrials.gov

Start Date

March 1, 2014

End Date

January 4, 2024

Last Updated

2 months ago

Study Type

Interventional

Study Design

Single Group

Sex

All

Investigators

Sponsor

Institut de Recherches Internationales Servier

Responsible Party

Sponsor

Eligibility Criteria

Inclusion Criteria

•Dose Escalation
•Subjects must have histologically or cytologically confirmed, IDH1 gene-mutated advanced solid tumors, including glioma, that have recurred or progressed following standard therapy, or that have not responded to standard therapy.
•Subjects must have evaluable disease by RECIST v1.1 for subjects without glioma or by RANO criteria for subjects with glioma.
•Dose Expansion: Cholangiocarcinoma
•Subjects must have histologically-confirmed diagnosis of IDH1 gene-mutated cholangiocarcinoma Stage II, III, or IV (intra-hepatic, extra-hepatic and perihilar) that is not eligible for curative resection, transplantation, or ablative therapies. Tumors of mixed histology are not allowed.
•Cholangiocarcinoma subjects must have progressed following gemcitabine-based regimen.
•Cholangiocarcinoma subjects must have radiographically measurable disease in at least one site not previously treated with radiation, chemoembolization, radioembolization, or other local ablative procedures; a new area of tumor progression within or adjacent to a previously-treated lesion, if clearly measurable by a radiologist, is acceptable.
•Dose Expansion: Chondrosarcoma
•a. Subjects must have IDH1 gene-mutated chondrosarcoma that is either locally advanced or metastatic and not amenable to complete surgical excision.
•Dose Expansion: Non-enhancing Glioma

Exclusion Criteria

•Subjects who received systemic anticancer therapy or radiotherapy \<21 days prior to their first day of study drug administration.
•Subjects who received an investigational agent \<14 days prior to their first day of study drug administration. In addition, the first dose of AG-120 should not occur before a period ≥5 half-lives of the investigational agent has elapsed.
•Subjects taking the following sensitive cytochrome P450 (CYP) 3A4 substrate medications are excluded from the study unless they can be transferred to other medications prior to enrolling: alfentanil, aprepitant, budesonide, buspirone, conivaptan, darifenacin, darunavir, dronedarone, eletriptan, eplerenone, felodipine, indinavir, fluticasone, lopinavir, lovastatin, lurasidone, maraviroc, midazolam, nisoldipine, quetiapine, saquinavir, sildenafil, simvastatin, tolvaptan, tipranavir, triazolam, ticagrelor, vardenafil and/or the CYP2B6 substrates: bupropion, efavirenz.
•Subjects taking the following P-glycoprotein (P-gp) transporter-sensitive substrate medications are excluded from the study unless they can be transferred to other medications prior to enrolling: aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, fexofenadine, maraviroc, posaconazole, ranolazine, saxagliptin, sitagliptin, talinolol, and tolvaptan.
•Subjects for whom potentially curative anticancer therapy is available.
•Subjects who are pregnant or breast feeding.
•Subjects with an active severe infection that required anti-infective therapy or with an unexplained fever \>38.5°C during screening visits or on their first day of study drug administration (at the discretion of the Investigator, subjects with tumor fever may be enrolled).
•Subjects with known hypersensitivity to any of the components of AG-
•Subjects with New York Heart Association (NYHA) Class III or IV congestive heart failure or LVEF \<40% by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan within approximately 28 days of C1D
•Subjects with a history of myocardial infarction within the last 6 months.

Arms & Interventions

AG-120

AG-120 administered continuously as a single agent dosed orally on Days 1 to 28 of a 28-day cycle. Subjects may continue treatment with AG-120 until disease progression, development of other unacceptable toxicity or Investigator discretion.

Intervention: AG-120

Outcomes

Primary Outcomes

Safety/tolerability: incidence of adverse events

Time Frame: Up to 26 weeks, on average

Maximum Tolerated Dose and/or the recommended Phase II dose of AG-120 in subjects with advanced solid tumors, including glioma

Time Frame: Up to 26 weeks, on average

Secondary Outcomes

Dose Limiting Toxicities of AG-120 in subjects with advanced solid tumors, including glioma(Up to 26 weeks, on average)
Pharmacokinetics of AG-120 in subjects with advanced solid tumors, including glioma(Up to 26 weeks, on average)
Pharmacodynamic relationship of AG-120 and 2-HG(Up to 26 weeks, on average)
Clinical Activity associated with AG-120 in subjects with advanced solid tumors, including glioma(Up to 26 weeks, on average)