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IDH2 Inhibition Using Enasidenib as Maintenance Therapy for IDH2-mutant Myeloid Neoplasms Following Allogeneic Stem Cell Transplantation

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ClinicalTrials.gov Identifier: NCT03515512
Recruitment Status : Recruiting
First Posted : May 3, 2018
Last Update Posted : June 13, 2019
Sponsor:
Collaborator:
Celgene
Information provided by (Responsible Party):
Amir Fathi, Massachusetts General Hospital

Brief Summary:

This research study is studying a targeted therapy drug as a possible treatment for IDH2 mutant acute myeloid leukemia or chronic myelomonocytic leukemia while undergoing hematopoietic stem cell transplantation.

The drug involved in this study is:

-Enasidenib.


Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Chronic Myelomonocytic Leukemia Drug: Enasidenib Phase 1

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 approved enasidenib as a treatment option for some cancers, but not for the specific indication under study with this protocol.

Enasidenib is currently used to treat AML with an IDH2 mutation that has come back or has not improved after previous AML treatment. This study is examining whether or not enasidenib may be beneficial and well-tolerated as an agent to prevent the relapse of IDH2-mutated AML or other myeloid neoplasms after participants have undergone hematopoietic stem cell transplantation (HSCT). IDH2 is an enzyme that, when mutated, can overproduce metabolites and compounds that contribute to the growth of tumors and cancerous cells. Enasidenib may help block the over production of these substances.

There is an FDA-approved test available to detect IDH2 mutations in patients with AML, but for the purposes of participation in this clinical trial, an investigational test may be used to determine the presence of an IDH2 mutation.

In this research study, the investigators are:

  • Looking for the maximum dose of enasidenib that individuals can take without experiencing severe side effects following HSCT.
  • Looking at how often Graft-Versus-Host-Disease (GVHD) occurs in participants taking enasidenib. GVHD is a complication of transplant.
  • Assessing the rates of relapse for participants taking enasidenib after HSCT.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 22 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Study of IDH2 Inhibition Using Enasidenib as Maintenance Therapy for IDH2-mutant Myeloid Neoplasms Following Allogeneic Stem Cell Transplantation
Actual Study Start Date : July 17, 2018
Estimated Primary Completion Date : May 31, 2021
Estimated Study Completion Date : May 31, 2024


Arm Intervention/treatment
Experimental: Enasidenib
Enasidenib will be administered orally once daily in 28-day cycles
Drug: Enasidenib
Enasidenib may help block the over production of IDH2, which when mutated, can overproduce metabolites and compounds that contribute to the growth of tumors and cancerous cells
Other Name: idhifa




Primary Outcome Measures :
  1. Maximum Tolerated Dose (MTD) [ Time Frame: 28 Days ]
    The maximum tolerated dose of Enasidenib in this patient population. The Maximum Tolerated Dose (MTD) is defined as the highest dose level at which 0 or 1 of six patients experiences a dose-limiting toxicity (DLT). MTD is determined using a standard 3 + 3 dose escalation cohort, where 3 participants will be enrolled on the starting dose of 50 mg daily and if no DLT is experienced after a full 28-day cycle, 3 additional participants will be enrolled at the next dose level of 100mg daily. If during any dose level, 1 patient out of 3 develops a DLT, then 3 additional patients will be added to that dose level. If 2 out of the 3 patients placed on any dose level experience a DLT, the preceding dose is considered MTD. If 1 out of 6 participants has a DLT, the next higher dose level will commence accrual. If ≥ 2 of 6 patients have a DLT, then the preceding dose will be considered MTD.

  2. Number of participants with dose limiting toxicities (DLT) [ Time Frame: 28 days ]
    Dose limiting toxicities are adverse events that occur during the first 28-day cycle that are considered serious enough to prevent an increase in the Enasidenib dose level. Adverse events are graded and documented per Common Terminology Criteria for Adverse Events (CTCAE 4).


Secondary Outcome Measures :
  1. The number of participants with Enasidenib related adverse events [ Time Frame: From the start of treatment until 30 days after the end of treatment, treatment may continue for up to 12 28-day cycles ]
    The number of participants with treatment related adverse events grouped by grade. Adverse events are assessed using Common Terminology Criteria for Adverse Events (CTCAE 4). Adverse events are considered to be related to treatment if they are deemed to be possibly, probably, or definitely related to treatment with Enasidenib by the investigator.

  2. Cumulative incidence of acute GVHD [ Time Frame: Cycle 1 days 1, 8, and 15; day 1 of every subsequent cycle (cycles are 28-days), up to 100 days after the start of treatment ]
    The cumulative incidence of acute graft versus host disease (GVHD). Acute GVHD is graded according to a composite grading of the clinical stages of skin rash, liver function, and intestinal tract function. Skin rash is assessed by the portion of the body covered by rash, liver function is assessed based on blood bilirubin levels, and intestinal track function is assessed based on the volume of diarrhea per day. The acute GVHD grade ranges from 1 to 4 with 1 representing less severe effects and 4 the most severe. The incidence represents the proportion of participants that experienced any grade acute GVHD.

  3. Cumulative incidence of chronic GVHD [ Time Frame: Cycle 1 days 1, 8, and 15; Day 1 of cycles 2-12 (1 cycle is 28-days), up to 1 year of total follow-up ]

    Cumulative incidence of chronic graft versus host disease (GVHD). cGHVD is assessed as per the National Institutes of Health consensus development project on criteria for clinical trials in cGVHD. cGVHD is graded as mild, moderate, or severe. The cGVHD grade is based on an aggregate score of different organ systems. The organ systems are graded from 0 to 3, with 0 being no-symptoms and 3 being the most severe symptoms. The cumulative incidence represents the proportion of participants that have any grade cGVHD.

    cGVHD Grade:

    • Mild: Involves only 1 or 2 organs or sites (except the lung), with no clinically significant functional impairment
    • Moderate: Involves at least 1 organ or site with clinically significant but no major disability or 3 or more organs or sites with no clinically significant functional impairment. A lung score of 1 will also be considered moderate cGVHD
    • Severe: Indicates major disability caused by cGVHD. A lung score of 2 will also be considered severe cGVHD

  4. Plasma and marrow 2-hydroxyglutarate levels [ Time Frame: Screening, cycle 1 days 8 and 15, day 1 of cycles 2 and 3, at the time of relapse, up to one year total follow-up ]
    Summary of the median 2-hydroxyglutarate levels at each time-point.

  5. IDH clonal evolution via whole genome sequencing [ Time Frame: Screening, cycle 1 days 8 and 15, day 1 of cycles 2 and 3, at the time of relapse, up to one year total follow-up ]
    Count summary of the specific Isocitrate dehydrogenase (IDH) mutations experienced by participants as assessed using whole genome sequencing.

  6. IDH Mutational burden via next-generation sequencing [ Time Frame: Screening, cycle 1 days 8 and 15, day 1 of cycles 2 and 3, at the time of relapse, up to one year total follow-up ]
    Summary of the number of mutations in the Isocitrate dehydrogenase (IDH) gene as assessed using next-generation sequencing.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Pathologically confirmed diagnosis of IDH2-mutant acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML).
  • IDH2 mutations will include any IDH2 R140 or R172 alterations
  • Eligibility and enrollment will be based on local IDH2 mutational testing performed at any center. The presence of an IDH2 mutation at the time of initial diagnosis or any other time thereafter is necessary and sufficient. The presence of an IDH2 mutation at time of enrollment is not necessary for the purposes of eligibility.
  • Between the ages of 18 and 75 years
  • Will undergo first allogeneic hematopoietic stem cell transplantation (HSCT) for their malignancy. Conditioning may have been 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 50%, as measured by MUGA scan or echocardiogram
  • Female patients of childbearing potential must have a negative pregnancy test, as measured by serum or urine testing
  • The effects of enasidenib on the developing human fetus are unknown. For this reason women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) during the entire study treatment period and through 6 months 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 < 50%, as measured by MUGA scan or echocardiogram)
  • Current or history of ventricular or life-threatening arrhythmias or diagnosis of long-QT syndrome
  • Systemic infection requiring IV antibiotic or antifungal or antiviral therapy within 7 days preceding the first dose of study drug, or other severe infection
  • Known dysphagia, short-gut syndrome, gastroparesis, or other condition(s) that limits the ingestion or gastrointestinal absorption of drugs administered orally
  • Uncontrolled hypertension (systolic blood pressure [BP] > 180 mmHg or diastolic BP > 100 mmHg)
  • 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
  • Concomitant receipt of the following sensitive CYP substrate medications that have a narrow therapeutic range (unless the participant can be transferred to other medications at least 5 half-lives prior to the start of study treatment): paclitaxel and docetaxel (CYP2C8), phenytoin (CYP2C9), S-mephenytoin (CYP2C19), thioridazine (CYP2D6), theophylline, and tizanidine (CYP1A2)
  • Concomitant receipt of the breast cancer resistance protein (BCRP) transporter-sensitive substrate rosuvastain (unless the participant can be transferred to another medication at least 5 half-lives prior to the start of study treatment)
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03515512


Contacts
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Contact: Amir T Fathi, MD 617-724-1124 afathi@partners.org

Locations
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United States, Maryland
Johns Hopkins Cancer Center Recruiting
Baltimore, Maryland, United States, 21287
Contact: Mark Levis, MD       levisma@jhmi.edu   
Principal Investigator: Mark Levis, MD         
United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02214
Contact: Amir T Fathi, MD    617-724-1124    afathi@partners.org   
Principal Investigator: Amir T Fathi, MD         
Dana Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Robert j Soiffer, MD       RSOIFFER@PARTNERS.ORG   
Principal Investigator: Robert J. Soiffer, MD         
United States, Ohio
Ohio State University Comprehensive Cancer Center Recruiting
Columbus, Ohio, United States, 43210
Contact: Alice Mims, MD       Alice.Mims@osumc.edu   
Principal Investigator: Alice Mims, MD         
Sponsors and Collaborators
Massachusetts General Hospital
Celgene
Investigators
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Principal Investigator: Amir t Fathi, MD Massachusetts General Hospital

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Responsible Party: Amir Fathi, Principal Investigator, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT03515512     History of Changes
Other Study ID Numbers: 18-022
First Posted: May 3, 2018    Key Record Dates
Last Update Posted: June 13, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Amir Fathi, Massachusetts General Hospital:
Acute Myeloid Leukemia
Chronic Myelomonocytic Leukemia
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid, Acute
Leukemia, Myelomonocytic, Chronic
Leukemia, Myelomonocytic, Juvenile
Neoplasms
Neoplasms by Histologic Type
Leukemia, Myeloid
Myelodysplastic-Myeloproliferative Diseases
Bone Marrow Diseases
Hematologic Diseases