Pinometostat With Standard Chemotherapy in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia and MLL Gene Rearrangement

Study Overview
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Brief Summary
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This phase Ib/II trial studies the side effects and best dose of pinometostat and how well it works with standard chemotherapy in treating patients with newly diagnosed acute myeloid leukemia and a type of genetic mutation called MLL gene rearrangement. Pinometostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in standard chemotherapy, such as daunorubicin hydrochloride and cytarabine, 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. Giving pinometostat with standard chemotherapy may work better at treating acute myeloid leukemia.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine a safe and tolerable schedule of pinometostat continuous intravenous infusion in combination with daunorubicin hydrochloride (daunorubicin) and cytarabine in patients with untreated, newly diagnosed acute myeloid leukemia harboring MLL rearrangement. II. Determine the rate of complete remission (complete remission [CR], CR with incomplete hematologic recovery [CRi]) in patients with newly diagnosed acute myeloid leukemia harboring MLL rearrangement after treatment with pinometostat in combination with daunorubicin and cytarabine. SECONDARY OBJECTIVES: I. To observe and record anti-tumor activity. II. Estimate biologic activity of 7 day window treatment of pinometostat monotherapy. III. Estimate the toxicity profile of pinometostat alone (week 1) and in combination with daunorubicin and cytarabine. IV. Estimate event free and overall survival of patients with MLL rearranged acute myeloid leukemia after combination treatment with pinometostat, daunorubicin, and cytarabine. V. Estimate the early death rate (death =< 30 days) of pinometostat, daunorubicin, and cytarabine. VI. Determine the rate of minimal residual disease (MRD) negativity by clinical flow cytometry on post-treatment recovery bone marrow. OUTLINE: This is a phase I, dose-escalation study of pinometostat followed by a phase II study. Patients receive pinometostat intravenously (IV) continuously on days 1-35, daunorubicin hydrochloride IV over 10-30 minutes on days 8-10 and cytarabine IV continuously on days 8-14 in the absence of disease progression or unacceptable toxicity. Patients who do not achieve CR/CRi after treatment receive pinometostat6 IV continuously on days 1-28, daunorubicin hydrochloride IV over 10-30 minutes on days 1 and 2 and cytarabine IV continuously on days 1-5 in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up monthly for 1 year, then every 3 months for up to 4 years.

Official Title
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A Phase 1b/2 Study of Pinometostat in Combination With Standard Induction Chemotherapy in Newly Diagnosed Acute Myeloid Leukemia With MLL Rearrangement

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Cytarabine
* Drug: Daunorubicin
* Drug: Daunorubicin Hydrochloride
* Drug: Pinometostat


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically confirmed acute myeloid leukemia by World Health Organization (WHO) criteria. Patients with treatment-related acute leukemia are eligible if they do not exceed lifetime anthracycline doses Presence of a cytogenetic rearrangement of KMT2A (MLL) by interphase fluorescent in-situ hybridization (FISH) Patients must have previously untreated (with exception of hydroxyurea for count control or all-trans retinoic acid [ATRA] for acute promyelocytic leukemia [APML] that was initially suspected but later ruled out) AML by World Health Organization (WHO) criteria. Treatment with hydroxyurea for count-control of hyperproliferative disease is permitted before and during treatment with pinometostat and chemotherapy Age >=14 years at time of screening, although individual sites may further restrict age eligibility in accordance with local Institutional Review Board (IRB) and hospital policy. Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) Total bilirubin =< 1.5 x institutional upper limit of normal (ULN), unless elevated due to Gilbert syndrome, hemolysis, or leukemia (at the time of eligibility screening) Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN, unless due to leukemia in which case < 5 x ULN (at the time of eligibility screening) Creatinine =< 1.5 x institutional ULN OR glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal (at the time of eligibility screening) Glomerular filtration rate (GFR) => 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal Prothrombin time (PT) and activated partial thromboplastin time (aPTT) =< 1.5 x ULN (both) (at the time of eligibility screening) Human immunodeficiency virus (HIV)-infected patients on effective antiretroviral therapy with undetectable viral load within 6 months are eligible for this trial (at the time of eligibility screening) If evidence of chronic hepatitis B virus (HBV) infection, HBV viral load must be undetectable on suppressive therapy if indicated (at the time of eligibility screening) If history of hepatitis C virus (HCV) infection, must be treated with undetectable HCV viral load (at the time of eligibility screening) For pediatric patients, a serum creatinine based on age/gender as follows: 10 to < 13 years: male = 1.2; female = 1.2 13 to < 16 years: male = 1.3; female = 1.4 >= 16 years: male = 1.7; female = 1.4 Be medically fit, in the opinion of the investigator, for intensive (7+3) induction chemotherapy Left ventricular ejection fraction (LVEF) >= 45% confirmed by echocardiogram or multi-gated acquisition scan (MUGA), AND no symptoms of congestive heart failure exceeding New York Heart Association (NYHA) class II Willingness to comply with all study procedures, including scheduled visits, investigational and standard of care drug administration plans, imaging studies, laboratory tests (including all biomarkers), procedures, and study- and disease-related restrictions The effects of pinometostat on the developing human fetus are unknown. For this reason and because other small molecule inhibitors as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry for the duration of study participation, and for 4 weeks after the last dose of study treatment. 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 treated or enrolled on this protocol must also agree to use adequate barrier contraception prior to the study, for the duration of study participation, and for 90 days after completion of pinometostat administration Ability to understand and the willingness to sign a written informed consent document or, for patients with impaired decision-making capacity, the consent of a close legal guardian who is readily available Exclusion Criteria: Acute promyelocytic leukemia with t(15;17)(q22;q12) and/or PML-RARA molecular rearrangement, or other atypical RARA translocation partner Patients who have received prior chemotherapy for AML, excluding hydroxyurea for count control, or ATRA for APML that was initially suspected but later ruled out Patients who have received any prior investigational agent for acute myeloid leukemia Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study Patients who have a cumulative lifetime exposure (prior to study entry) of greater than 300 mg/m^2 doxorubicin equivalent anthracycline Patients who have received chest radiation (unless organ-sparing) and who have a cumulative lifetime exposure (prior to study entry) of greater than 240 mg/m^2 doxorubicin equivalent anthracycline Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia, or peripheral neuropathy (up to grade 2 is permitted) Patients who are receiving any other investigational agents History of allergic reactions attributed to compounds of similar chemical or biologic composition to pinometostat or other agents used in study Patients receiving any medications or substances that are strong inhibitors or inducers of CYP3A4 are ineligible unless the offending medication can be safely stopped prior to enrollment. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring antibiotics (with exception), symptomatic congestive heart failure, unstable angina pectoris, unstable cardiac arrhythmia not controllable with medications, electrocardiographic evidence of ischemia, or psychiatric illness/social situations that would limit compliance with study requirements. Patients receiving an anti-microbial agent may be eligible if the patient remains afebrile and hemodynamically stable for 72 hours Patients with an active bleeding diathesis Pregnant women are excluded from this study because pinometostat is a small molecule inhibitor with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with pinometostat, breastfeeding should be discontinued if the mother is treated with pinometostat. These potential risks may also apply to other agents used in this study Subjects with known symptomatic leukemia of the central nervous system including leptomeningeal leukemic involvement History of active other malignancy that limits survival to less than 1 year Ongoing viral or drug induced liver injury, including active chronic hepatitis C virus (HCV), chronic active hepatitis B, clinically known alcoholic liver disease, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, primary biliary cirrhosis, other cirrhosis of the liver, history of hepatic encephalopathy, or portal hypertension Any other prior condition that could, in the opinion of the investigator, compromise patient safety or evaluation of the primary outcome

Ages Eligible for Study
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Minimum Age: 14 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (pinometostat)<br>Patients receive pinometostat IV continuously on days 1-35, daunorubicin hydrochloride IV over 10-30 minutes on days 8-10 and cytarabine IV continuously on days 8-14 in the absence of disease progression or unacceptable toxicity. Patients who do not achieve CR/CRi after treatment receive pinometostat IV continuously on days 1-28, daunorubicin hydrochloride IV over 10-30 minutes on days 1 and 2 and cytarabine IV continuously on days 1-5 in the absence of disease progression or unacceptable toxicity. | Drug: Cytarabine<br>* Given IV<br>* Other names: WR-28453;Drug: Daunorubicin<br>* Given IV<br>* Other names: Rubomycin C;Drug: Daunorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubilem;Drug: Pinometostat<br>* Given IV<br>* Other names: EPZ-5676;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose limiting toxicity (Phase Ib) | Safety and tolerability evaluation and dose escalation for phase 1b will be in the usual 3+3 fashion. | Up to 35 days | 
| Complete response (CR) or complete response with incomplete count recovery (CRi) rate | Will be calculated with the exact binomial 95% confidence intervals. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events | Will be graded and reported according to Common Terminology Criteria for Adverse Events version 5. The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns. | For up to 5 years | 
| Time to hematologic count recovery | Will be analyzed using lab evaluation of complete blood counts and differential. | Up to 5 years | 
| Differential blast counts | Will be analyzed using lab evaluation of complete blood counts and differential. | Baseline up to day 8 | 
| Rate of minimal residual disease (MRD) positivity | Will be evaluated by multiparameter flow cytometry, next-generation sequencing (or both) after induction therapy among those patients who attain morphologic and cytogenetic CR. Will be calculated with the exact binomial 95% confidence intervals. | Up to 5 years | 
| Progression free survival | Estimated using the Kaplan-Meier method. | From the start of study treatment until progression or death, whichever occurs earliest, assessed up to 5 years | 
| Overall survival | Estimated using the Kaplan-Meier method. | Up to 5 years |