Study of Orally Administered AG-881 in Patients With Advanced Hematologic Malignancies With an IDH1 and/or IDH2 Mutation

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

The purpose of this Phase I, multicenter study is to evaluate the safety, pharmacokinetics, pharmacodynamics and clinical activity of AG-881 in advanced hematologic malignancies that harbor an IDH1 and/or IDH2 mutation

Study Overview

• Status: Completed
• Conditions: Myelodysplastic Syndrome; Hematologic Malignancies; Acute Myeloid Leukemia (AML)
• Intervention / Treatment: Drug: AG881

Detailed Description

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 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. Anticipated time on study treatment is until disease progression or unacceptable toxicity occurs or the patient is removed at the discretion of the investigator.

• Study Type: Interventional
• Enrollment (Actual): 46
• Phase: Phase 1

Contacts and Locations

Study Locations

• France
  • Villejuif, France, 94800
• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
  • Illinois
    • Chicago, Illinois, United States, 60611
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
  • New York
    • New York, New York, United States, 10065
  • Texas
    • Houston, Texas, United States, 77030

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Patients must be ≥18 years of age

Patients must have documented IDH1 and/or IDH2 gene-mutated disease

Patients must have an advanced hematologic malignancy with an IDH1 and/or IDH2 mutation

Patient must be able to understand and willing to sign an informed consent

Patients must have ECOG PS of 0 to 2

Patients 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 leukemic involvement

Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤3.0 × ULN, unless considered due to involvement by the neoplasm under consideration for treatment

Patients must have adequate renal function as evidenced by a serum creatinine ≤2.0 × ULN or Creatinine clearance 40 mL/min based on the Cockroft-Gault glomerular filtration rate (GFR) estimation

Patients 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 the start of therapy. 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 been naturally postmenopausal (i.e., who have not menstruated at all) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)

Exclusion Criteria:

Patients who have undergone HSCT within 60 days

Patients who received systemic anticancer therapy or radiotherapy <14 days prior to their first day of study drug administration

Patients who received an investigational agent <14 days prior

Patients who are pregnant or breast feeding

Patients with an active severe infection who require 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 within approximately 28 days of C1D1

Patients with a history of myocardial infarction within the last 6 months

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

Patients taking medications that are known to prolong the QT interval

Patients with known infection with human immunodeficiency virus (HIV) or active hepatitis B or C

Patients with clinical symptoms suggesting active central nervous system (CNS) leukemia or known CNS leukemia. Evaluation of cerebrospinal fluid is only required if there is a clinical suspicion of CNS involvement by leukemia during Screening

Patients with immediately life-threatening, severe complications of hematologic malignancies such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Safety/tolerability; incidence of adverse events	Up to 26 weeks, on average
Maximum Tolerated Dose and/or the recommended Phase II dose of AG-881 in patients with advanced hematologic malignancies	Up to 26 weeks, on average

Secondary Outcome Measures

Outcome Measure	Time Frame
Pharmacodynamic levels of AG-881	Up to 26 weeks, on average
Pharmacodynamic levels of 2-HG	Up to 26 weeks, on average
Pharmacokinetics of AG-881 in patients with advanced hematologic malignancies	Up to 26 weeks, on average
Clinical Activity according to the 2003 revised IWG criteria for AML, the 2006 modified IWG criteria for MDS, disease-specific response criteria for other hematologic malignancies	Up to 26 weeks, on average

Collaborators and Investigators

• Sponsor: Agios Pharmaceuticals, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): August 7, 2015
• Primary Completion (Actual): March 21, 2018
• Study Completion (Actual): March 21, 2018

Study Registration Dates

• First Submitted: July 6, 2015
• First Submitted That Met QC Criteria: July 8, 2015
• First Posted (Estimate): July 9, 2015

Study Record Updates

• Last Update Posted (Actual): March 8, 2019
• Last Update Submitted That Met QC Criteria: March 6, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Keywords: MPN; AML; MDS; acute myeloid leukemia; hematologic malignancies; AITL; myelodysplastic syndrome; IDH1; IDH2; AG-881; dual mutation
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms by Site; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Leukemia; Neoplasms; Myelodysplastic Syndromes; Hematologic Neoplasms; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia
• Other Study ID Numbers: AG881-C-001