Neoplasms

Blood and Lymph Conditions

All Conditions

Rare Diseases

Leukemia

Hematologic Neoplasms

Myeloproliferative Disorders

Bone Marrow Diseases

Hematologic Diseases

Chronic Myeloproliferative Disorders

All Drugs and Chemicals

Antineoplastic Agents

Tin Fluorides

Ivosidenib

Enzyme Inhibitors

After genetic testing, if participants are found to have IDH1 Mutations (a genetic mutation) then they will be assigned to this group and will receive the following study drugs:

Single agent Phase (Cycles 1-3):

The initial phase of treatment will consist of 3 cycles (lasting 28 days) of ivosidenib 500mg daily x 28 days

Combination Phase (Cycle 4 onwards):

If a participant shows clinical benefit (including their disease stabilizing) following the first 3- cycle phase, he or she may go onto the combination phase. Combination treatment will consist of ivosidenib daily x 28 days along with fedratinib daily x 28 days.

After genetic testing, if participants are found to have IDH2 Mutations (a genetic mutation) then they will be assigned to this group and will receive the following study drugs:

Single agent Phase (Cycles 1-3):

The initial phase of treatment will consist of 3 cycles (lasting 28 days) of enasidenib 100mg daily x 28 days

Combination Phase (Cycle 4 onwards):

If a participant shows clinical benefit (including their disease stabilizing) following the first 3- cycle phase, he or she may go onto the combination phase.Combination treatment will consist of enasidenib 100mg daily x 28 days along with fedratinib daily x 28 days.

A drug used to treat acute myeloid leukemia that has a mutated (changed) form of a gene called isocitrate dehydrogenase-1 (IDH1).

A drug used to treat acute myeloid leukemia (AML) that has recurred (come back) or has not gotten better after treatment with other anticancer therapy.

Enasidenib

This medication is used to treat a certain type of cancer (myelofibrosis). Fedratinib belongs to a class of drugs known as JAK (janus kinase) inhibitors. It works by slowing or stopping the growth of cancer cells.

Fedratinib

Olatoyosi Odenike, MD

Anand Patel, MD

The purpose of this research is to gather information on the safety and effectiveness of fedratinib (a drug called a "jak inhibitor" ) in combination with ivosidenib or enasidenib (two anti-cancer drugs). While all three drugs are FDA-approved for various conditions, the US Food and Drug Administration (FDA) has not approved the combination of these drugs for the treatment of rare blood cancers that present Isocitrate dehydrogenase (IDH) mutations, and therefore these drugs can only be given in a research study.

Doctors leading this study hope to learn about the safety of combining fedratinib (a type of drug called a "JAK inhibitor" whichblocks the activity of janus kinase enzymes in your body) with anti-cancer drugs ivosidenib and enasidenib in participants who have rare blood cancers that show Isocitrate dehydrogenase (IDH) mutations (a type of genetic mutation). Your participation in this research will last about 24 months.

The purpose of this research is to gather information on the safety and effectiveness of fedratinib in combination with ivosidenib or enasidenib. While all three drugs are FDA-approved for various conditions, the US Food and Drug Administration (FDA) has not approved the combination of these drugs for the treatment of IDH-mutated blood cancers (known as myeloproliferative neoplasms), and therefore these drugs can only be given in a research study.

A Study of Fedratinib With IDH Inhibition in Advanced-Phase, IDH-Mutated Ph-Negative Myeloproliferative Neoplasms

A Phase Ib Study of Fedratinib With IDH Inhibition in Advanced-Phase, IDH-Mutated Ph-Negative Myeloproliferative Neoplasms

The maximum tolerated dose of fedratinib in combination with ivosidenib in participants who have IDH1-mutated blood cancer. This will be assessed by the number of reported dose-limiting toxicities and adverse events among participants according to the Common Terminology Criteria for Adverse Events version 5.

The number of patients who are living 1 year after the beginning of treatment on study as assessed by data from clinical records.

Overall response rate as assessed by the number of participants who achieve a complete molecular response (CMR), cytogenetic complete response (CCR), acute leukemia response-complete (ALR-C), or acute leukemia response-partial (ALR-P).

Time to response will be defined as time from treatment administration to first documented complete molecular response (CMR), cytogenetic complete response (CCR), acute leukemia response-complete (ALR-C), or acute leukemia response-partial (ALR-P). DCR will be defined as the portion of subjects achieving a complete molecular response,cytogenetic complete response (CCR), acute leukemia response-complete (ALR-C), or acute leukemia response-partial (ALR-P) or stabilized disease for ≥ 3 months.

University of Chicago

Symptoms and General Pathology

Immune System Diseases

Syndrome

Recurrence

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Preleukemia

Leukemia, Myelomonocytic, Chronic

Leukemia, Myelomonocytic, Juvenile

Myelodysplastic Syndromes

Leukemia, Biphenotypic, Acute

Neoplasms by Histologic Type

Disease Attributes

Myelodysplastic-Myeloproliferative Diseases

Chronic Disease

Leukemia, Lymphoid

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Chronic Myelomonocytic Leukemia

Juvenile Myelomonocytic Leukemia

Chronic Graft Versus Host Disease

Acute Graft Versus Host Disease

Acute Leukemia of Ambiguous Lineage

Myelodysplastic/myeloproliferative Disease

Anti-Obesity Agents

Vasoconstrictor Agents

Respiratory System Agents

Azacitidine

Phenylpropanolamine

Guaifenesin

Chlorpheniramine, phenylpropanolamine drug combination

Antimetabolites

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.

Enasidenib Mesylate

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.

National Cancer Institute (NCI)

M.D. Anderson Cancer Center

Anemia, Refractory, with Excess of Blasts

Anemia

Anemia, Refractory

Precancerous Conditions

Myelodysplastic Syndrome With Excess Blasts

Patients who are HMA-naive receive enasidenib PO QD on days 1-28 and azacitidine IV over 30-60 minutes or SC on days 1-7. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients relapsed and/or refractory to HMA therapy receive enasidenib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Quality-of-Life Assessment

Courtney DiNardo, MD

This phase II trial studies the side effects and how well azacitidine and enasidenib work in treating patients with IDH2-mutant myelodysplastic syndrome. Azacitidine and enasidenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES:

I. To determine the safety and tolerability of enasidenib alone, and enasidenib in combination with azacitidine (AZA), for patients with isocitrate dehydrogenase 2 (IDH2) mutated myelodysplastic syndrome (MDS).

II. To assess the efficacy of the combination of enasidenib + azacitidine in hypomethylating agent (HMA) naive subjects with IDH2-mutated MDS, and to assess the efficacy of enasidenib single-agent in subjects with IDH2-mutated MDS who are relapsed/refractory to HMA therapy.

SECONDARY OBJECTIVES:

I. To evaluate molecular and cellular markers that may be predictive of antitumor activity and/or resistance including evaluation of IDH2 variant allele fraction (VAF) levels during treatment and presence of co-occurring mutations.

II. To assess overall survival, event-free survival and duration of response of enasidenib alone, and enasidenib in combination with azacitidine.

EXPLORATORY OBJECTIVES:

I. To assess changes in cellular differentiation and changes in deoxyribonucleic acid (DNA) methylation profiles in IDH2-mutated MDS treated with enasidenib alone and with enasidenib + azacitidine.

II. To evaluate quality of life (QOL) using an MDS-specific measure.

OUTLINE: Patients are assigned to 1 of 2 arms.

ARM I: Patients who are HMA-naive receive enasidenib orally (PO) once daily (QD) on days 1-28 and azacitidine intravenously (IV) oveer 30-60 minutes or subcutaneously (SC) on days 1-7. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients relapsed and/or refractory to HMA therapy receive enasidenib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for up to 3 years.

Azacitidine and Enasidenib in Treating Patients With IDH2-Mutant Myelodysplastic Syndrome

Targeted Therapy With the IDH2-Inhibitor Enasidenib (AG221) for High-Risk IDH2-Mutant Myelodysplastic Syndrome

The association between molecular and cellular markers and overall response and/or resistance will be assessed through logistic regression analyses. Paired t-test or Wilcoxon signed rank test will be used to assess the marker change over time.

Will use the Bayesian method by Thall, Simon and Estey for toxicity monitoring. For purpose of toxicity monitoring, toxicity is defined as any grade 3 or higher treatment related-toxicities by Common Terminology Criteria for Adverse Events criteria.

Defined as complete response (CR), partial response, and marrow CR assessed by International Working Group criteria. Will be estimated along with the 90% credible interval.

The Kaplan-Meier method will be used to estimate the probabilities of EFS. Log-rank tests will be used to compare among subgroups of patients in terms of EFS.

The Kaplan-Meier method will be used to estimate the probabilities of OS. Log-rank tests will be used to compare among subgroups of patients in terms of OS.

Will be summarized graphically and with descriptive statistics.

PDn markers will be summarized graphically and with descriptive statistics.

Celgene

Venetoclax

Enasidenib and venetoclax will be taken by mouth (orally), once a day, every day, continuously.

Every 28-day period will be called a cycle. Participants will start venetoclax alone on Cycle 1 Day 1 and continue the study drug alone until Day 15. On Day 15, participants will take enasidenib and venetoclax together and will continue to take the combination of study drugs until intolerable side effects or disease worsening.

Enasidenib is a drug that blocks a protein called isocitrate dehydrogenase (IDH) 2 from working. The family of IDH proteins have been indicated in the development of leukemia. By blocking IDH2, enasidenib may help stop cancer cells from growing. It is believed that the drug may be more useful in patients with a change (mutation) in their IDH 2 protein. The IDH2 gene (substances in the body that contain instructions for the proper development and function of cells) makes IDH2 proteins. As such, only patients with IDH 2 mutated gene are eligible for this study. Enasidenib is currently approved for the treatment of IDH2 mutated AML.

Venetoclax is a drug that blocks a protein called B-cell lymphoma (BCL2) protein from working. BCL2 is a protein that helps control whether a cell lives or dies and is thought to help cancer cells to live. Blocking BCL2 is believed to help kill cancer cells. Venetoclax is currently approved for the treatment of type of blood cancer called chronic lymphocytic leukemia (CLL) who have received prior treatment.

Steven Chan, M.D.

The purpose of this research study is to see how safe and tolerable, and to find the highest or best dose, of an investigational combination of drugs called enasidenib and venetoclax, in patients with relapsed (the cancer has come back) or refractory (the cancer does not respond or have stopped responding to treatment) acute myeloid leukemia (AML, a type of blood cancer). This study will also see how useful the combination of enasidenib and venetoclax is in the treatment of patients with relapsed or refractory AML.

This study will have two parts: Phase 1b and Phase 2. The part that patients may participate in will depend on when they join the study.

In the phase 1b portion of the study, small groups participants will receive increasing doses of venetoclax in combination with a flat dose of enadisenib until the highest dose or best dose of venetoclax that is safe and tolerable in combination with enadisenib is found.

In the phase 2 portion of the study, an additional group of participants will receive the highest or best dose of venetoclax found in the Phase 1b portion of the study with a flat dose of enadisenib to see how useful the combination is in treating relapsed or refractory acute myeloid leukemia (AML).

Study of Enasidenib and Venetoclax in IDH2-Mutated Blood Cancers

Phase Ib/II Study of IDH2 Inhibitor Enasidenib in Combination With BCL2 Inhibitor Venetoclax in Patients With IDH2-Mutated Myeloid Malignancies (ENAVEN-AML)

The time from the date of first response until progression, relapse, death, or last follow-up.

The first day of treatment until death or last contact.

The number of days from the first day of treatment to the date of earliest evidence of relapse or progression, subsequent treatment other than stem cell transplant while in response, or death, or date of last disease assessment.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Study of Fedratinib With IDH Inhibition in Advanced-Phase, IDH-Mutated Ph-Negative Myeloproliferative Neoplasms	NCT04955938	IDH Mutation IDH1 Mutation IDH2 Gene Mutat... Blood Cancer Myeloproliferat...	Ivosidenib Enasidenib Fedratinib	18 Years -	University of Chicago
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
Azacitidine and Enasidenib in Treating Patients With IDH2-Mutant Myelodysplastic Syndrome	NCT03383575	Acute Myeloid L... Blasts 20-30 Pe... Chronic Myelomo... IDH2 Gene Mutat... Myelodysplastic... Recurrent High ... Refractory High...	Azacitidine Enasidenib Quality-of-Life...	12 Years -	M.D. Anderson Cancer Center
A Study of Fedratinib With IDH Inhibition in Advanced-Phase, IDH-Mutated Ph-Negative Myeloproliferative Neoplasms	NCT04955938	IDH Mutation IDH1 Mutation IDH2 Gene Mutat... Blood Cancer Myeloproliferat...	Ivosidenib Enasidenib Fedratinib	18 Years -	University of Chicago
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
A Study of Fedratinib With IDH Inhibition in Advanced-Phase, IDH-Mutated Ph-Negative Myeloproliferative Neoplasms	NCT04955938	IDH Mutation IDH1 Mutation IDH2 Gene Mutat... Blood Cancer Myeloproliferat...	Ivosidenib Enasidenib Fedratinib	18 Years -	University of Chicago
Study of Enasidenib and Venetoclax in IDH2-Mutated Blood Cancers	NCT04092179	Acute Myeloid L... Relapsed Cancer Refractory Canc... IDH2 Gene Mutat...	Enasidenib Venetoclax	18 Years -	University Health Network, Toronto

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