Study of Orally Administered AG-881 in Patients With Advanced Solid Tumors, Including Gliomas, With an IDH1 and/or IDH2 Mutation

Sponsor

Institut de Recherches Internationales Servier (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT02481154

Collaborator

(none)

Enrollment

Locations

Arm

Anticipated Duration (Months)

10.6

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study evaluates the safety, pharmacokinetics, pharmacodynamics and clinical activity of AG-881 in Gliomas, that harbor an IDH1 and/or IDH2 mutation.

Condition or Disease	Intervention/Treatment	Phase
Glioma	Drug: AG881	Phase 1

Detailed Description

The purpose of this Phase I, multicenter study is to evaluate the safety, pharmacokinetics, pharmacodynamics and clinical activity of AG-881 in gliomas, that harbor an IDH1and/or IDH2 mutation. The first portion of the study is a dose escalation phase where cohorts of patients will receive ascending oral doses of AG-881 to determine the maximum tolerated dose (MTD) and/or the recommended Phase II dose. The second portion of the study is a dose expansion phase where patients will receive AG-881 to further evaluate the safety, tolerability, and clinical activity of the recommended Phase II dose. The anticipated time on study treatment is until disease progression, unacceptable toxicity occurs or the patient is removed at the discretion of the investigator

Study Design

Study Type:

Interventional

Anticipated Enrollment :

95 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 1, Multicenter, Open-Label, Dose-Escalation and Expansion, Safety, Pharmacokinetic, Pharmacodynamic, and Clinical Activity Study of Orally Administered AG-881 in Patients With Advanced Solid Tumors, Including Gliomas, With an IDH1 and/or IDH2 Mutation

Actual Study Start Date :

Jun 1, 2015

Anticipated Primary Completion Date :

Jun 1, 2023

Anticipated Study Completion Date :

Jun 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: AG881 AG-881 administered continuously as a single agent dosed orally on Days 1 to 28 of a 28-day cycle. Patients may continue treatment with AG-881 until disease progression, development of other unacceptable toxicity or Investigator discretion	Drug: AG881 AG-881 administered continuously as a single agent dosed orally on Days 1 to 28 of a 28-day cycle. Patients may continue treatment with AG-881 until disease progression or development of other unacceptable toxicity

Arm

Intervention/Treatment

Experimental: AG881

AG-881 administered continuously as a single agent dosed orally on Days 1 to 28 of a 28-day cycle. Patients may continue treatment with AG-881 until disease progression, development of other unacceptable toxicity or Investigator discretion

Drug: AG881

AG-881 administered continuously as a single agent dosed orally on Days 1 to 28 of a 28-day cycle. Patients may continue treatment with AG-881 until disease progression or development of other unacceptable toxicity

Outcome Measures

Primary Outcome Measures

Safety/Tolerability; incidence of adverse events [Up to 26 weeks, on average]
Maximum Tolerated Dose and/or the recommended Phase II dose of AG881 in patients with advance solid tumors, including gliomas [Up to 26 weeks, on average]

Secondary Outcome Measures

Pharmacokinetic profiles including max concentration (Cmax), time to maximum concentration (Tmax), AUC, and elimination half-life [Up to 26 weeks, on average]
Pharmacodynamic levels of AG-881 [Up to 26 weeks, on average]
Pharmacodynamic levels of 2-HG [Up to 26 weeks, on average]
Clinical Activity according to RECIST v 1.1 (2009) for patients with solid tumors, by RANO (2010) criteria for patients with glioma [Up to 26 weeks, on average]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patient must be ≥18 years of age
Patient must have histologically or cytologically confirmed solid tumor, including glioma, with documented IDH1 and/or IDH2 gene-mutation. Patients in the dose escalation phase must have disease that has recurred or progressed following standard therapy and/or therapy with an inhibitor of mutant IDH1 and/or IDH2, or that has not responded to this therapy. Patients in the expansion phase may have previously untreated disease
Patient must have evaluable disease by RECIST v1.1 for patients without glioma or by RANO or RANO LGG criteria for patients with glioma
Patients with glioma must have a baseline brain MRI scan
Patient must have archived primary tumor biopsies or surgical specimens, or biopsies of recurrent or metastatic samples
Patient must be amenable to serial peripheral blood sampling, urine sampling, and tumor biopsies during the study
Patient must be able to understand and willing to sign an informed consent
Patient must have ECOG PS of 0 to 2
Patient must have expected survival of ≥3 months
Patient must have adequate bone marrow function as evidenced by absolute neutrophil count ≥1.5 ×10^{9/L; hemoglobin >9 g/dL (Patients are allowed to be transfused to this
level); platelets ≥75 × 10}9/L
Patient must have adequate hepatic function as evidenced by: Serum total bilirubin ≤1.5 × upper limit of normal (ULN), unless considered due to Gilbert's disease or disease involvement; Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤2.5 × ULN. For patients with bone metastases and/or suspected disease-related liver or biliary involvement, AST, ALT and ALP must be ≤5 × ULN
Patient must have adequate renal function as evidenced by: Serum creatinine ≤2.0 × ULN or Creatinine clearance >40 mL/min based on the Cockroft-Gault glomerular filtration rate (GFR) estimated: (140-Age) x (weight in kg) x (0.85 if female)/72 x serum creatinine
Patient must be recovered from any clinically relevant toxic effects of any prior surgery, radiotherapy, or other therapy intended for the treatment of cancer
Female patients with reproductive potential must have a negative serum pregnancy test within 7 days prior to first study drug administration. Patients with reproductive potential are defined as sexually mature women who have not undergone a hysterectomy, bilateral oophorectomy or tubal occlusion or who have not experienced natural menopause (i.e., who have not menstruated at all) for at least 24 consecutive months (i.e., have had menses at any time in the preceding 24 consecutive months). Women with reproductive potential as well as fertile men and their partners who are female with 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 90 days (females and males) following the last dose of AG 881

Exclusion Criteria:

Patients who received systemic anticancer therapy or radiotherapy <21 days prior to their first day of study drug administration
Patients who received an investigational agent (including AG-120 or AG-221) <14 days prior to their first day of study drug administration. In addition, the first dose of AG-881 should not occur before a period ≥5 half-lives of the investigational agent (other than AG-120 or AG-221) has elapsed.
Patients with gliomas who have had prior treatment with bevacizumab (Avastin) are excluded
Patients who are pregnant or breast feeding
Patients 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, patients with tumor fever may be enrolled)
Patients 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 obtained within approximately 28 days of C1D1
Patients with a history of myocardial infarction within the 6 months prior to screening
Patients with known unstable or uncontrolled angina pectoris
Patients with a known history of severe and/or uncontrolled ventricular arrhythmias
Patients with QTc interval ≥450 msec or with other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome)
Patients taking medications that are known to prolong the QT interval unless they can be transferred to other medications within ≥5 half-lives prior to dosing, or unless the medications can be properly monitored during the study.
Patients with known infection with human immunodeficiency virus (HIV) or active hepatitis B or C
Patients with known dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally
Patients with brain metastases that are untreated, symptomatic, or require therapy to control symptoms; or any radiation, surgery, or other therapy, including those used to control symptoms, within 1 month of first dose
Glioma patients with evidence of intracranial or intratumoral hemorrhage either by MRI or CT scan

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCLA Oncology Center	Los Angeles	California	United States	90024
2	University of California San Francisco	San Francisco	California	United States	94143
3	University of Miami	Miami	Florida	United States	33136
4	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
5	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
6	Duke University Medical Center	Durham	North Carolina	United States	27710
7	Sarah Cannon Research Institute	Nashville	Tennessee	United States	37203
8	MD Anderson Cancer Center	Dallas	Texas	United States	75390
9	UT Southwestern Medical Center	Houston	Texas	United States	77030