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Enasidenib in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia With an IDH2 Gene Mutation

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ClinicalTrials.gov Identifier: NCT03881735
Recruitment Status : Not yet recruiting
First Posted : March 19, 2019
Last Update Posted : April 8, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Roswell Park Cancer Institute

Brief Summary:
This phase II trial studies how well enasidenib works in treating in patients with acute myeloid leukemia with an IDH2 gene mutation that has come back or has not responded to treatment. Enasidenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. In this study we are investing if enasidenib can be used as maintenance therapy post salvage induction chemotherapy.

Condition or disease Intervention/treatment Phase
Blasts Under 5 Percent of Peripheral Blood White Cells Bone Marrow Blasts Decreased by 50 Percent or More Compared to Pretreatment Level IDH2 Gene Mutation Recurrent Acute Myeloid Leukemia Refractory Acute Myeloid Leukemia Drug: Enasidenib Procedure: Hematopoietic Cell Transplantation Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. Evaluate the effect of IDH2 inhibition following conventional high dose salvage chemotherapy with detectable IDH2 mutations on event free survival (EFS) in patients with relapsed/refractory acute myeloid leukemia (AML).

SECONDARY OBJECTIVES:

I. Evaluate the effect of IDH2 inhibitor maintenance therapy following intensive salvage therapy: i.e., rate of hematocrit (HCT), duration of maintenance therapy and overall survival in patients with IDH2 mutant relapsed/refractory AML.

EXPLORATORY OBJECTIVES:

I. Evaluate the changes in IDH2 mutational variant allelic frequency and deoxyribonucleic acid (DNA) methylation signature while on enasidenib therapy.

OUTLINE: Patients are assigned to 1 of 2 cohorts.

COHORT I: Patients receive enasidenib orally (PO) once daily (QD). Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo a hematopoietic cell transplantation (HCT) 7-14 days after treatment. Within 30-100 days following the transplant, patients receive enasidenib QD. Treatment repeats every 28 days for 24 cycles in the absence of disease progression or unacceptable toxicity.

COHORT II: Patients receive enasidenib PO QD. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 6 months and then yearly for 5 years.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 86 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of Intensive Salvage Therapy Followed by Enasidenib for Patients With AML Harboring Mutations in IDH2 Who Have Failed or Been Refractory to One Prior Line of Therapy
Estimated Study Start Date : April 15, 2019
Estimated Primary Completion Date : November 19, 2021
Estimated Study Completion Date : November 19, 2022


Arm Intervention/treatment
Experimental: Cohort A (enasidenib, hematopoietic cell transplantation)
Patients receive enasidenib PO QD. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo a HCT 7-14 days after treatment. Within 30-100 days following the transplant, patients receive enasidenib QD. Treatment repeats every 28 days for 24 cycles in the absence of disease progression or unacceptable toxicity.
Drug: Enasidenib
Given PO
Other Names:
  • AG-221
  • CC-90007

Procedure: Hematopoietic Cell Transplantation
Undergo HCT
Other Names:
  • HCT
  • Hematopoietic Stem Cell Transplantation
  • HSCT
  • stem cell transplantation

Active Comparator: Cohort B (enasidenib)
Patients receive enasidenib PO QD. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: Enasidenib
Given PO
Other Names:
  • AG-221
  • CC-90007




Primary Outcome Measures :
  1. Event-free survival (EFS) in each cohort [ Time Frame: At 12 months ]
    Defined as the binomial proportion of evaluable patients who are alive and disease free 12 months after enrollment. Two-sided 95% Jeffreys confidence interval estimates will be used to describe the plausible range for the true EFS rate in each patient group. The EFS rates will be estimated separately for each cohort, on an intent-to-treat basis.


Secondary Outcome Measures :
  1. Success rate of hematopoietic cell transplantation (HCT) [ Time Frame: Up to 5 years ]
  2. Median duration of maintenance therapy in both cohorts [ Time Frame: Up to 5 years ]
  3. Overall survival in each cohort [ Time Frame: At 12 and 24 months ]

Other Outcome Measures:
  1. Evaluation of IDH2 mutant allele burden [ Time Frame: Up to 5 years ]
    Will use droplet digital polymerase chain reaction (PCR) from baseline study entry and at follow up every 3 months to follow changes in variant allele frequency (VAF).

  2. Change in deoxyribonucleic acid (DNA) methylation signature [ Time Frame: Up to 5 years ]
    Will be evaluated by evaluated by bi-sulfite pyrosequencing.



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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:

  • Confirmed diagnosis of AML harboring a mutation in IDH2 relapsed or refractory to first line cytarabine/anthracycline induction chemotherapy, failed to respond to or relapsed following at least 2 cycles of hypomethylating agent (azacitidine, decitabine, sgi-110)

    • First relapse defined as untreated hematologic relapse (according to International Working Group criteria) after one line of intensive regimen for AML including at least one cytarabine containing induction block with a total dose no less than 700 mg/m^2 per cycle and 3 days of an anthracycline that induced a complete remission (CR)/complete remission with incomplete hematologic recovery (CRi)/complete remission with incomplete platelet recovery (CRp). Subjects are allowed to receive induction, consolidation, transplant and/or maintenance therapy prior to achieving their first CR/CRi/CRp
    • Refractory to induction therapy is defined as never achieving CR, CRi or CRp (according to International Working Group criteria) after one line of intensive regimen for AML (reinduction, consolidation and/or transplant allowed) including at least one cytarabine containing induction block with a total dose no less than 700 mg/m^2 per cycle and 3 days of an anthracycline
  • Subjects considered eligible for intensive chemotherapy
  • Subjects had received a first salvage within the last 60 days (day 15 to 60 following most recent cytarabine-based standard salvage number [#] 1 therapy) who achieved either > 50% reduction in blast percentage from the pre-treatment bone marrow OR < 20% cellularity with any blast percentage AND < 5% peripheral blood blasts
  • Have an Eastern Cooperative Oncology Group (ECOG) performance status of =< 2
  • Normal total blood serum bilirubin with the exception of elevation due to Gilbert?s disease (within 72 hours of enrollment)
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.0 x upper limit of normal (ULN) (within 72 hours of enrollment)
  • Adequate renal function within 72 hours of enrollment, defined as blood creatinine =< 1.5 x ULN
  • Women of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to enrollment and either commit to continued abstinence from heterosexual intercourse or begin one acceptable method of birth control pills or barrier contraception. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
  • Men must use a latex condom during any sexual contact with women of childbearing potential
  • Willing to adhere to protocol specific requirements
  • Clinically significant toxic effects of prior therapy (except hydroxyurea) resolved to grade =< 1 before the start of study
  • Participant or legal representative must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure

Exclusion Criteria:

  • Acute promyelocytic leukemia (APL)
  • Subject has or is suspected of having central nervous system (CNS) leukemia. Evaluation of cerebrospinal fluid is only required if CNS involvement by leukemia is suspected during screening
  • Clinically active or unstable graft-versus-host disease (GVHD) requiring treatment that precludes administration of chemotherapy as defined in this protocol
  • Prior anti-leukemia therapy within 5 x the half-life for other investigational agents and consolidation chemotherapy within last 14 days

    • Prior use of hydroxyurea or isolated doses of cytarabine for palliation (i.e., control of white blood count [WBC]) are allowed but should be discontinued at least 24 hours prior to enrollment. Other agents used strictly with palliative intent might be allowed during this period after discussing with principal investigator
  • Pre-existing liver disease (e.g. cirrhosis, chronic hepatitis B or C, nonalcoholic steatohepatitis, sclerosing cholangitis)
  • Subject is known seropositive or active infection with human immunodeficiency virus (HIV), or active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV)
  • Subject has active uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment)
  • Pregnant or nursing female participants
  • Subjects of childbearing potential not willing to use adequate contraception
  • Subject has significant active cardiac disease within 6 months prior to the start of study treatment, including New York Heart Association (NYHA) class III or IV congestive heart failure; acute coronary syndrome (ACS); and/or stroke; or left ventricular ejection fraction (LVEF) < 40% by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan obtained within 28 days prior to the start of study treatment
  • Subject with concurrent severe and/or uncontrolled medical or psychiatric conditions that in the opinion of the investigator may impair the participation in the study or the evaluation of safety and/or efficacy
  • Subject has immediately life-threatening, severe complications of leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation
  • Subject is known to have dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally
  • Subjects has uncontrolled hypertension (systolic blood pressure [BP] > 180 mmHg or diastolic BP > 90 mmHg)
  • Subject has known (or suspected to have) hypersensitivity to any of the components of study treatment
  • Subject has corrected QT (QTc) interval (i.e., Fridericia?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
  • Subject is taking the following sensitive CYP substrate medications that have a narrow therapeutic range are excluded from the study unless the subject can be transferred to other medications at least 5 half-lives prior to the start of study treatment: phenytoin (CYP2C9), S-mephenytoin (CYP2C19), thioridazine (CYP2D6), theophylline, and tizanidine (CYP1A2)
  • Subject who is taking the breast cancer resistance protein (BCRP) transporter-sensitive substrate (i.e., rosuvastatin) should be excluded from the study unless the subject can be transferred to other medications at least 5 half-lives prior to the start of study treatment
  • Subject has prior history of malignancy, other than myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN) or AML. However, subjects with the following history/concurrent conditions are allowed:

    • Basal or squamous cell carcinoma of the skin
    • Carcinoma in situ of the cervix
    • Carcinoma in situ of the breast
    • Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, node, metastasis clinical staging system)
  • Concurrent participation in another therapeutic clinical trial
  • Unwilling or unable to follow protocol requirements
  • Any condition which in the investigator?s opinion deems the participant an unsuitable candidate to receive study drug

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): NCT03881735


Locations
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United States, New York
Roswell Park Cancer Institute Not yet recruiting
Buffalo, New York, United States, 14263
Contact: Swapna Thota    716-845-7610    Swapna.Thota@roswellpark.org   
Principal Investigator: Swapna Thota         
Sponsors and Collaborators
Roswell Park Cancer Institute
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Swapna Thota Roswell Park Cancer Institute

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Responsible Party: Roswell Park Cancer Institute
ClinicalTrials.gov Identifier: NCT03881735     History of Changes
Other Study ID Numbers: I 67118
NCI-2019-00332 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
I 67118 ( Other Identifier: Roswell Park Cancer Institute )
P30CA016056 ( U.S. NIH Grant/Contract )
First Posted: March 19, 2019    Key Record Dates
Last Update Posted: April 8, 2019
Last Verified: April 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms