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IDH1 Inhibition Using Ivosidenib as Maintenance Therapy for IDH1-mutant Myeloid Neoplasms Following Allogeneic Stem Cell Transplantation

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03564821
Recruitment Status : Recruiting
First Posted : June 21, 2018
Last Update Posted : January 6, 2020
Sponsor:
Collaborator:
Agios Pharmaceuticals, Inc.
Information provided by (Responsible Party):
Amir Fathi, Massachusetts General Hospital

Tracking Information
First Submitted Date  ICMJE June 7, 2018
First Posted Date  ICMJE June 21, 2018
Last Update Posted Date January 6, 2020
Actual Study Start Date  ICMJE January 16, 2019
Estimated Primary Completion Date July 31, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 19, 2018)
Maximum Tolerated Dose [ Time Frame: 28 Days ]
Participants will be enrolled in standard 3 + 3 dose escalation cohorts in order to determine the maximum tolerated dose (MTD). The first 3 participants will be started on 500mg of Ivosidenib, administered daily for 28 consecutive days (1 cycle). If the 500mg/day dose level is tolerated, an additional 10 participants will be treated at this dose level. If the 500mg/day dose is not tolerated, the dose will be decreased to 250mg/day. If 250mg daily is tolerated, then an additional 10 participants will be treated at 250mg daily. The only doses studied will be 500mg daily and 250mg daily (the latter, if necessary). If 250mg daily dosing is not tolerated, then the study will end without expansion. Dose limiting toxicities are assessed and graded using Common Terminology Criteria for Adverse Events (CTCAE 4).
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 19, 2018)
  • Ivosidenib-related Adverse Events, categorized by grade [ Time Frame: From the start of treatment until 30 days after the end of treatment, up to 13 months total ]
    Adverse events will be assessed and graded using Common Terminology Criteria for Adverse Events (CTCAE 4).
  • Cumulative incidence of acute GVHD [ Time Frame: From the start of treatment with Ivosidenib until the onset of Acute GVHD, up to 100 days ]
    Cumulative incidence of acute graft versus host disease (GVHD), measured from start of treatment with Ivosidenib.
  • Cumulative incidence of chronic GVHD [ Time Frame: From the start of treatment with Ivosidenib until the onset of chronic GVHD, up to 24 months ]
    The cumulative incidence of chronic GVHD, measured from start of treatment with Ivosidenib. Chronic GVHD will be assessed using the National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease.
  • Plasma and marrow 2-hydroxyglutarate levels [ Time Frame: Screening, cycle 1 days 8 and 15 (cycles are 28 days), before the start of cycles 2 and 3, and at the time of relapse; up 24 months total time ]
  • IDH clonal evolution and mutational burden [ Time Frame: Screening, cycle 1 days 8 and 15 (cycles are 28 days), before the start of cycles 2 and 3, and at the time of relapse; up 24 months total time ]
    Isocitrate dehydrogenase (IDH) clonal evolution and mutational burden in patients with IDH1-mutant myeloid neoplasms who receive Ivosidenib after hematopoietic stem cell transplantation. Next-generation sequencing will be used to assess mutational burden (i.e. the fraction of AML cells harboring IDH mutations, corrected for copy number) at various time points. SNaPshot genotyping analysis platform will be used to perform these analyses.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE IDH1 Inhibition Using Ivosidenib as Maintenance Therapy for IDH1-mutant Myeloid Neoplasms Following Allogeneic Stem Cell Transplantation
Official Title  ICMJE A Phase 1 Study of IDH1 Inhibition Using Ivosidenib as Maintenance Therapy for IDH1-mutant Myeloid Neoplasms Following Allogeneic Stem Cell Transplantation
Brief Summary

This research study is studying a drug as a possible treatment for IDH1-mutant myeloid neoplasms.

-The drug involved in this study is ivosidenib (AG-120)

Detailed Description

This research study is a Phase I clinical trial, which tests the safety of an investigational drug and also tries to define the appropriate dose of the investigational drug to use for further studies. "Investigational" means that the drug is being studied.

The FDA (the U.S. Food and Drug Administration) has not approved ivosidenib as a treatment for any disease.

Ivosidenib is an inhibitor of the protein IDH1. Ivosidenib is currently being studied as a treatment for myeloid cancers like acute myeloid leukemia or myelodysplastic syndromes with an IDH1 mutation. This study is examining whether or not ivosidenib is beneficial and well-tolerated as an agent to prevent the relapse of IDH1-mutated acute myeloid leukemia or other myeloid neoplasms after hematopoietic stem cell transplantation. IDH1 is an enzyme that, when mutated, can overproduce metabolites (substances that help with metabolism) and compounds that contribute to the growth of tumors and cancerous cells. Ivosidenib may help block the over production of these substances and possibly reduce the chances of relapse.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE IDH1 Mutation Myeloid Neoplasms
Intervention  ICMJE Drug: Ivosidenib
Ivosidenib is an inhibitor of the protein IDH1
Study Arms  ICMJE
  • Experimental: Ivosidenib (500mg/day)
    -Ivosidenib will be administered orally every day
    Intervention: Drug: Ivosidenib
  • Experimental: Ivosidenib (250mg/day)
    -Ivosidenib will be administered orally every day
    Intervention: Drug: Ivosidenib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 19, 2018)
22
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 31, 2024
Estimated Primary Completion Date July 31, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Pathologically confirmed diagnosis of IDH1(R132)-mutant acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML). IDH1 mutations could have been detected by any mutational technique at any prior point including at diagnosis or remission.
  • Between the ages of 18 and 75 years
  • Will undergo allogeneic hematopoietic stem cell transplantation (HSCT) for their malignancy. Conditioning may be either conventional myeloablative (MAC) or reduced intensity conditioning (RIC).
  • HSCT Donor will be one of the following:

    • 5/6 or 6/6 (HLA-A, B, DR) matched related donor
    • 7/8 or 8/8 (HLA-A, B, DR, C) matched unrelated donor. Matching in the unrelated setting must be at the allele level.
    • Haploidentical related donor, defined as ≥ 3/6 (HLA-A, B, DR) matched --≥ 4/6 (HLA-A, B, DR) umbilical cord blood (UCB). Matching in the UCB setting is at the antigen level. Recipients may receive either one or two UCB units. In the case of 2 UCB units, both units must have been at least 4/6 matched with the recipient.
  • ECOG performance status ≤ 2
  • Participants must have normal organ and marrow function as defined below:

    • Absolute neutrophil count ≥ 1000/µL without growth factor support (e.g. GCSF) in the previous 7 days
    • Platelet count ≥ 50,000/µL without transfusional support in the previous 7 days
    • AST (SGOT), ALT (SGPT) and Alkaline phosphatase < 3x institutional upper limit of normal (ULN)
    • Direct bilirubin < 2.0 mg/dL
    • Calculated creatinine clearance ≥ 40 mL/min (Cockcroft-Gault formula)
    • LVEF must be equal to or greater than 40%, as measured by MUGA scan or echocardiogram
  • Female patients of childbearing potential must have a negative pregnancy test
  • The effects of ivosidenib on the developing human fetus are unknown. For this reason female participants of child-bearing potential and male participants must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) during the entire study treatment period and through 90 days after the last dose of treatment
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  • Prior allogeneic hematopoietic stem cell transplants.
  • Evidence of relapsed/recurrent/residual disease as assessed by bone marrow aspirate and biopsy performed within 42 days prior to study entry.
  • History of other malignancy(ies) unless

    • the participant has been disease-free for at least 5 years and is deemed by the investigator to be at low risk of recurrence of that malignancy, or
    • the only prior malignancy was cervical cancer in situ and/or basal cell or squamous cell carcinoma of the skin
  • Known diagnosis of active hepatitis B or hepatitis C
  • Current or history of congestive heart failure New York Heart Association (NHYA) class 3 or 4, or any history of documented diastolic or systolic dysfunction (LVEF < 40%, as measured by MUGA scan or echocardiogram)
  • Current or history of ventricular or life-threatening arrhythmias or diagnosis of long-QT syndrome
  • QTc interval (i.e., Friderica's correction [QTcF]) ≥ 450 ms or other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome) at screening
  • Systemic infection requiring IV antibiotic therapy within 7 days preceding the first dose of study drug, or other severe infection
  • Uncontrolled intercurrent illness that would limit compliance with study requirements.
  • HIV-positive participants on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with study drug. In addition, these participants are at increased risk of lethal infections when treated with marrow-suppressive therapy.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Amir T Fathi, MD 617-724-4000 afathi@partners.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03564821
Other Study ID Numbers  ICMJE 18-123
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Amir Fathi, Massachusetts General Hospital
Study Sponsor  ICMJE Massachusetts General Hospital
Collaborators  ICMJE Agios Pharmaceuticals, Inc.
Investigators  ICMJE
Principal Investigator: Amir T Fathi, MD Massachusetts General Hospital
PRS Account Massachusetts General Hospital
Verification Date January 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP