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Anti-Obesity Agents

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Phenylpropanolamine

Guaifenesin

Chlorpheniramine, phenylpropanolamine drug combination

Patients receive enasidenib PO QD on days 1-28. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspiration and/or biopsy and collection of blood on study.

Biospecimen Collection

Bone Marrow Aspiration

Bone Marrow Biopsy

Enasidenib

Enasidenib Mesylate

Site Public Contact

Matthew A. Kutny

David L. Becton

Margaret E. Macy

Jennifer J. Clark

Scott M. Bradfield

AeRang Kim

Ziad A. Khatib

Sara Zarnegar-Lumley

Sandeep Batra

Alan D. Friedman

Rajen Mody

Kevin F. Ginn

Jing Chen

Philip M. Monteleone

Joseph G. Pressey

Rene Y. McNall-Knapp

Richard Aplenc

Andrew Bukowinski

Jeffrey E. Rubnitz

Brianna N. Smith

Kathleen (Wiertel) Ludwig

Timothy C. Griffin

Eric J. Lowe

This trial studies the side effects of enasidenib and to see how well it works in treating patients with acute myeloid leukemia that has come back after treatment (relapsed) or has been difficult to treat with chemotherapy (refractory). Patients must also have a specific genetic change, also called a mutation, in a protein called IDH2. Enasidenib may stop the growth of cancer cells by blocking the mutated IDH2 protein, which is needed for cell growth.

PRIMARY OBJECTIVES:

I. To determine the safety of treatment with enasidenib mesylate (enasidenib) administered at continuous daily oral dosing for a 28-day cycle up to 12 cycles in pediatric patients with IDH2-mutant relapsed/refractory (R/R)-acute myeloid leukemia (AML).

II. To characterize the plasma pharmacokinetic (PK) profile of enasidenib in pediatric patients with IDH2-mutant R/R-AML.

SECONDARY OBJECTIVES:

I. To investigate the pharmacodynamic (PD) relationship of oncogenic metabolite 2-hydroxyglutarate (2-HG) to enasidenib treatment in pediatric patients with IDH2-mutant R/R-AML.

II. To describe the clinical activity of enasidenib in pediatric patients with IDH2-mutant R/R-AML.

OUTLINE:

Patients receive enasidenib orally (PO) once daily (QD) on days 1-28. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspiration and/or biopsy and collection of blood on study.

After completion of study treatment, patients are followed up at 30 days, then periodically up to 1 year.

Enasidenib for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia Patients With an IDH2 Mutation

An Open-Label Feasibility Study to Assess the Safety and Pharmacokinetics of Enasidenib in Pediatric Patients With Relapsed/Refractory Acute Myeloid Leukemia (R/R-AML) With an Isocitrate Dehydrogenase-2 (IDH2) Mutation

Frequencies (%) of patients with a dose limiting toxicity stratified by dose level.

A descriptive analysis of the area under the plasma concentration versus time curve of enasidenib including median, minimum and maximum by dose level.

A descriptive analysis of the total plasma clearance of enasidenib including median, minimum and maximum by dose level.

A descriptive analysis of the elimination half-life of enasidenib including median, minimum and maximum by dose level.

A descriptive analysis of the maximum concentration of enasidenib including median, minimum and maximum by dose level.

A descriptive analysis of the plasma 2-HG levels of enasidenib including median, minimum and maximum by dose level.

Frequency (%) of patients with at least partial response by dose level.

Will be reported in a table as frequency of response (%) for total overall response rate (ORR) by dose level.

Median time to response with 95% confidence interval.

Median time to remission with 95% confidence interval.

Median duration of response with 95% confidence interval.

Median duration of remission with 95% confidence interval.

Median time to event with 95% confidence interval.

Median time to death with 95% confidence interval.

National Cancer Institute (NCI)

Children's Oncology Group

Patients receive enasidenib PO QD on days 1-28. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.

Amandeep Salhotra

This phase I trial studies the side effects of using enasidenib as maintenance therapy in treating patients with acute myeloid leukemia with IDH2 mutation following donor stem cell transplant. Enasidenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES:

I. Evaluate the safety and tolerability of enasidenib mesylate as maintenance therapy in post hematopoietic cell transplantation (HCT) patients.

SECONDARY OBJECTIVES:

I. Assess overall and leukemia free survival in patients post allogeneic HCT. II. Estimate relapse incidence, non-relapse mortality, graft versus host disease (GVHD) and relapse free survival (GRFS) in patients receiving enasidenib mesylate maintenance therapy.

EXPLORATORY OBJECTIVES:

I. Monitor disease status among subset of patients with minimal residual disease (MRD) positive disease when starting to receive enasidenib mesylate by multiparameter flow cytometry post allogeneic HCT on patients bone marrow (BM) on days +100 and +365.

II. Investigate clearance of IDH2 mutation post HCT by next generation sequencing-polymerase chain reaction (NGS-PCR) testing on the bone marrow specimens on days +100 and +365 and in peripheral blood every 3 months till 2 year follow up.

III. Investigate mIDH2 variant allele fraction (VAF) by droplet digital PCR (ddPCR) BEAMing technology on bone marrow specimens on days +100 and +365.

OUTLINE:

Patients receive enasidenib orally (PO) once daily (QD) on days 1-28. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and periodically thereafter up to 2 years.

Enasidenib as Maintenance Therapy in Treating Patients With Acute Myeloid Leukemia With IDH2 Mutation After Donor Stem Cell Transplant

Pilot Trial of Enasidenib (AG-221) Maintenance Post Allogeneic Hematopoietic Cell Transplantation in Patients With IDH2 Mutation

Monitor disease status among subset of patients with MRD positive disease by multiparameter flow cytometry post allogeneic hematopoietic cell transplantation (HCT) on patients BM.

Investigate clearance of IDH2 mutation post HCT by next generation sequencing-polymerase chain reaction (NGS-PCR) testing on the bone marrow specimens.

mIDH2 variant allele fraction (VAF) by droplet digital PCR (ddPCR) BEAMing technology on bone marrow specimens.

Toxicity will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0).

Will be analyzed using the Kaplan-Meier curves.

Time to relapse will be censored at the last disease assessment if patients are known to be alive and leukemia free.

Will be analyzed using the curves of cumulative incidence.

City of Hope Medical Center

Immune System Diseases

Syndrome

Preleukemia

Leukemia, Myelomonocytic, Chronic

Leukemia, Myelomonocytic, Juvenile

Myelodysplastic Syndromes

Leukemia, Biphenotypic, Acute

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Myelodysplastic-Myeloproliferative Diseases

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Leukemia, Lymphoid

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Chronic Myelomonocytic Leukemia

Juvenile Myelomonocytic Leukemia

Chronic Graft Versus Host Disease

Acute Leukemia of Ambiguous Lineage

Chronic Myeloproliferative Disorders

Myelodysplastic/myeloproliferative Disease

Antineoplastic Agents

Azacitidine

Antimetabolites

Enzyme Inhibitors

Patients receive azacitidine SC or IV over 30 minutes on days 1-7 and enasidenib mesylate PO QD beginning on day 1. Cycles repeat every 4-6 weeks in the absence of disease progression or unacceptable toxicity.

Courtney DiNardo

This phase II trial studies how well enasidenib and azacitidine work in treating patients with IDH2 gene mutation and acute myeloid leukemia that has come back (recurrent) or does not respond to treatment (refractory). Enasidenib and azacitidine may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES:

I. To determine the clinical activity of enasidenib mesylate (AG221, IDHIFA) in combination with azacitidine (AZA) for patients with relapsed/refractory acute myeloid leukemia is measured by overall response rate (ORR).

SECONDARY OBJECTIVES:

I. To determine duration of response, event-free survival (EFS), and overall survival (OS).

II. To determine the safety of enasidenib in combination with azacitidine in patients with relapsed/refractory acute myeloid leukemia (AML).

EXPLORATORY OBJECTIVES:

I. To evaluate occurrence of minimal residual disease (MRD) negative status by IDH2 mutation analysis and flow cytometry.

II. To investigate possible relationships between baseline protein and gene expression signatures and mutation profile and clinical response to the combination.

III. To evaluate the incidence and characteristics of IDH-inhibitor related differentiation syndrome (IDH-DS) with combination therapy.

OUTLINE:

Patients receive azacitidine subcutaneously (SC) or intravenously (IV) over 30 minutes on days 1-7 and enasidenib mesylate orally (PO) once daily (QD) beginning on day 1. Cycles repeat every 4-6 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 3-6 months for up to 5 years.

Enasidenib and Azacitidine in Treating Patients With Recurrent or Refractory Acute Myeloid Leukemia and IDH2 Gene Mutation

Phase II Study of the Targeted Mutant IDH2 Inhibitor Enasidenib in Combination With Azacitidine for Relapsed/Refractory AML

MRD negative status and exploratory biomarkers will be summarized graphically and with descriptive statistics.

Association between molecular and cellular markers and overall response and/or resistance assessed through logistic regression analyses.

Paired t-test or Wilcoxon signed rank test will be used to assess the marker change over time.

The study will estimate the ORR for the combination treatment, along with the Bayesian 95% credible interval. ORR will be defined as the proportion of patients who had CR (complete remission), CRh (complete remission with incomplete hematologic recovery), CRi (complete remission with incomplete count recovery), PR (partial response), and/or marrow clearance of blasts (MLFS).

Kaplan-Meier method will be used to estimate the probabilities of event-free survival.

Kaplan-Meier method will be used to estimate the probabilities of overall survival.

Log-rank tests will be used to compare among subgroups of patients in terms of DFS or OS.

M.D. Anderson Cancer Center

Anti-Inflammatory Agents

Amino Acids

Venetoclax

Triamcinolone

Triamcinolone Acetonide

Triamcinolone hexacetonide

Triamcinolone diacetate

Decitabine

Bosutinib

Gilteritinib

Ivosidenib

Maleic acid

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Tyrosine

MOLECULAR DIAGNOSIS SEGMENT: Patients receive glasdegib PO QD for at least 14 days until their AML TAC recommendation is made and they are either consented to a treatment arm in the Treatment Segment or go off study.

TREATMENT SEGMENT: Patients receive glasdegib PO QD on days 1-28,decitabine IV over 1 hour on days 1-5, and venetoclax PO QD on days 1-14. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

MOLECULAR DIAGNOSIS SEGMENT: Patients receive glasdegib PO QD for at least 14 days until their AML TAC recommendation is made and they are either consented to a treatment arm in the Treatment Segment or go off study.

TREATMENT SEGMENT: Patients receive glasdegib PO QD and gilteritinib PO QD on days 1-28. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

MOLECULAR DIAGNOSIS SEGMENT: Patients receive glasdegib PO QD for at least 14 days until their AML TAC recommendation is made and they are either consented to a treatment arm in the Treatment Segment or go off study.

TREATMENT SEGMENT: Patients receive glasdegib PO QD and bosutinib PO QD on days 1-28. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

MOLECULAR DIAGNOSIS SEGMENT: Patients receive glasdegib PO QD for at least 14 days until their AML TAC recommendation is made and they are either consented to a treatment arm in the Treatment Segment or go off study.

TREATMENT SEGMENT: Patients receive glasdegib PO QD and ivosidenib PO QD on days 1-28. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

MOLECULAR DIAGNOSIS SEGMENT: Patients receive glasdegib PO QD for at least 14 days until their AML TAC recommendation is made and they are either consented to a treatment arm in the Treatment Segment or go off study.

TREATMENT SEGMENT: Patients receive glasdegib PO QD and enasidenib PO QD on days 1-28 .Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

Bosutinib Monohydrate

Gilteritinib Fumarate

Glasdegib Maleate

Guido Marcucci

This phase Ib trial evaluates the best dose and effect of glasdegib in combination with venetoclax and decitabine, or gilteritinib, bosutinib, ivosidenib, or enasidenib in treating patients with acute myeloid leukemia that has come back (relapsed) after stem cell transplantation. Chemotherapy drugs, such as venetoclax and decitabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Glasdegib, bosutinib, ivosidenib, and enasidenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Glasdegib inhibits the Sonic the Hedgehog gene. Venetoclax inhibits BCL-2 gene. Bosutinib is a tyrosine kinase inhibitor that inhibits BCR-ABL gene fusion. Ivosidenib inhibits isocitrate dehydrogenase-1 gene or IDH-1. Enasidenib inhibits isocitrate dehydrogenase-2 gene or IDH-2. This study involves an individualized approach that may allow doctors and researchers to more accurately predict which treatment plan works best for patients with relapsed acute myeloid leukemia.

PRIMARY OBJECTIVES:

I. Evaluate study feasibility through:

Ia. The ability to obtain a molecular diagnosis within 10 calendar days from study enrollment in at least 90% of participants. (Molecular Diagnosis Segment) Ib. The ability to make a treatment arm assignment within 14 calendar days from study enrollment in at least 90% of participants. (Molecular Diagnosis Segment) II. Assess the safety and tolerability of the drug combination by evaluation of toxicities including: type, frequency, severity, attribution, and duration of the toxicity. (Treatment Segment)

SECONDARY OBJECTIVES:

I. Determine the proportion of participants with successful sequencing by City of Hope (COH) Pathology among those with less than 10% blasts in the marrow aspirate. (Molecular Diagnosis Segment) II. Determine the proportion of participants with successful treatment arm registration based on Treatment Assignment Committee (TAC) assignment. (Molecular Diagnosis Segment) III. Assess the safety of monotherapy glasdegib by evaluation of toxicities including, type, frequency, severity and attribution. (Molecular Diagnosis Segment) IV. Obtain preliminary estimates of remission (complete response \[CR\] + CR with incomplete blood count recovery \[CRi\]) rate and duration of remission. (Treatment Segment)

EXPLORATORY OBJECTIVE:

I. Measure and characterize the leukemia stem cell (LSC) burden. (Treatment Segment)

OUTLINE: This is a dose escalation study of glasdegib maleate (glasdegib) followed by a dose-expansion study.

MOLECULAR DIAGNOSIS SEGMENT: Patients receive glasdegib orally (PO) once daily (QD) for at least 14 days until their acute myeloid leukemia (AML) TAC recommendation is made and they are either consented to a treatment arm in the Treatment Segment or go off study.

TREATMENT SEGMENT: Patients are assigned to 1 of 5 arms.

CHAPTER 1: Patients receive glasdegib PO QD on days 1-28, decitabine intravenously (IV) over 1 hour on days 1-5, and venetoclax PO QD on days 1-14. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

CHAPTER 2: Patients receive glasdegib PO QD and gilteritinib fumarate (gilteritinib) PO QD on days 1-28. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

CHAPTER 3: Patients receive glasdegib PO QD and bosutinib monohydrate (bosutinib) PO QD on days 1-28. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

CHAPTER 4: Patients receive glasdegib PO QD and ivosidenib PO QD on days 1-28. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

CHAPTER 5: Patients receive glasdegib PO QD and enasidenib mesylate (enasidenib) PO QD on days 1-28. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Glasdegib-Based Treatment Combinations for the Treatment of Patients With Relapsed Acute Myeloid Leukemia Who Have Undergone Hematopoietic Cell Transplantation

A Pilot/Phase 1b Study of Glasdegib-Based Treatment Combinations in Adult Patients With Relapsed AML Post Allogeneic Hematopoietic Cell Transplantation

Measured by limiting dilution and engraftment into non-obese diabetic severe combined immunodeficiency gamma severely immunocompromised mice. Graphical statistics will be used. To assess the association between the LSC reduction and the response to the treatment, the median change from baseline to post-treatment (2 cycles) in engraftment levels of secondary mice recipients (n=12 mice/patient, 6 females and 6 males) will be compared by two-sample t test between response and non-response patient groups as LSC donors, across all treatment arms. The effect of treatment on the target genes will be assessed for each arm by linear mixed models (pre- versus multiple post-treatment time points) as well.

Outcome will be dichotomized based on return in =\< 10 calendar days (Yes/No). Assessed by the proportion of successful participants.

Outcome will be dichotomized based on return in =\< 14 calendar days (Yes/No). Assessed by the proportion of participants who receive treatment assignment from TAC.

Toxicity will be graded according to the National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Safety will be based on the assessment of dose limiting toxicity during cycle 1 and cycle 2. Observed toxicities will be summarized in terms of type (organ affected or laboratory determination), severity, time of onset, duration, probable association with the study treatment and reversibility or outcome.

Successful sequencing is defined as passing quality control, and will be determined by City of Hope pathology among those with less than 20% blasts in the marrow aspirate.

Successful placement defined as the enrollment of a participant into one of the treatment arms.

Toxicity will be graded according to the NCI-CTCAE version 5.0. Safety will be based on the assessment of unacceptable toxicity during glasdegib monotherapy. Observed toxicities will be summarized in terms of type (organ affected or laboratory determination), severity, time of onset, duration, probable association with the study treatment and reversibility or outcome.

Response will be based on Dohner et al., 2017 criteria. Response dates recorded will be the date of the first of 2 successive bone marrows showing said response. For this trial, will assess the complete remission rate calculated as the percent of evaluable patients that have confirmed complete response (CR) or incomplete blood count recovery (CRi). 95% Clopper Pearson binomial confidence interval will be calculated. Response rates will also be explored based on number/type of prior therapy(ies).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Enasidenib for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia Patients With an IDH2 Mutation	NCT04203316	Recurrent Acute... Refractory Acut...	Biospecimen Col... Bone Marrow Asp... Bone Marrow Bio... Enasidenib Enasidenib Mesy...	24 Months - 21 Years	Children's Oncology Group
Enasidenib as Maintenance Therapy in Treating Patients With Acute Myeloid Leukemia With IDH2 Mutation After Donor Stem Cell Transplant	NCT03728335	Acute Myeloid L...	Enasidenib Mesy...	18 Years -	City of Hope Medical Center
Enasidenib and Azacitidine in Treating Patients With Recurrent or Refractory Acute Myeloid Leukemia and IDH2 Gene Mutation	NCT03683433	Acute Bilineal ... Acute Biphenoty... Chronic Myelomo... IDH2 Gene Mutat... Myelodysplastic... Recurrent Acute... Refractory Acut...	Azacitidine Enasidenib Mesy...	18 Years -	M.D. Anderson Cancer Center
Enasidenib for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia Patients With an IDH2 Mutation	NCT04203316	Recurrent Acute... Refractory Acut...	Biospecimen Col... Bone Marrow Asp... Bone Marrow Bio... Enasidenib Enasidenib Mesy...	24 Months - 21 Years	Children's Oncology Group
Enasidenib and Azacitidine in Treating Patients With Recurrent or Refractory Acute Myeloid Leukemia and IDH2 Gene Mutation	NCT03683433	Acute Bilineal ... Acute Biphenoty... Chronic Myelomo... IDH2 Gene Mutat... Myelodysplastic... Recurrent Acute... Refractory Acut...	Azacitidine Enasidenib Mesy...	18 Years -	M.D. Anderson Cancer Center
Enasidenib as Maintenance Therapy in Treating Patients With Acute Myeloid Leukemia With IDH2 Mutation After Donor Stem Cell Transplant	NCT03728335	Acute Myeloid L...	Enasidenib Mesy...	18 Years -	City of Hope Medical Center
Glasdegib-Based Treatment Combinations for the Treatment of Patients With Relapsed Acute Myeloid Leukemia Who Have Undergone Hematopoietic Cell Transplantation	NCT04655391	Recurrent Acute...	Bosutinib Monoh... Decitabine Enasidenib Mesy... Gilteritinib Fu... Glasdegib Malea... Ivosidenib Venetoclax	18 Years -	City of Hope Medical Center
Enasidenib as Maintenance Therapy in Treating Patients With Acute Myeloid Leukemia With IDH2 Mutation After Donor Stem Cell Transplant	NCT03728335	Acute Myeloid L...	Enasidenib Mesy...	18 Years -	City of Hope Medical Center

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