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

NCT03724084 | Terminated Phase 1 Results FDA Drug

• 3 other identifiers: NCI-2018-0234910212UM1CA186712
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 3

Brief Summary

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.

Conditions

Acute Myeloid Leukemia

Outcome Measures

Primary Outcomes (2)

• Dose Limiting Toxicity (Phase Ib)

  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

  Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

  Up to 3 years

Secondary Outcomes (6)

• Number of Participants With Incidence of Adverse Events

  For up to 3 years

• Time to Hematologic Count Recovery

  Up to 3 years

• Differential Blast Counts

  Baseline up to day 8

• Rate of Minimal Residual Disease (MRD) Positivity

  Up to 3 years

• Progression Free Survival

  From the start of study treatment until progression or death, whichever occurs earliest, assessed up to 3 years

Study Arms (2)

Cohort I (higher and lowers dose pinometostat)

EXPERIMENTAL

Patients receive higher dose pinometostat IV continuously on days 1-7 and lower dose pinometostrat IV continuously on days 8-35. Patients also receive daunorubicin hydrochloride IV over 10-30 minutes on days 8-10 and cytarabine IV continuously on days 8-14. Cycles repeat every 35 days 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; Drug: Daunorubicin; Drug: Daunorubicin Hydrochloride; Drug: Pinometostat

Cohort II (higher dose pinometostat)

EXPERIMENTAL

Patients receive higher dose pinometostat intravenously (IV) continuously on days 1-35. Patients also receive daunorubicin hydrochloride IV over 10-30 minutes on days 8-10 and cytarabine IV continuously on days 8-14. Cycles repeat every 35 days 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; Drug: Daunorubicin; Drug: Daunorubicin Hydrochloride; Drug: Pinometostat

Interventions

Cytarabine DRUG

Given IV

Also known as: .beta.-Cytosine arabinoside, 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-.beta.-D-Arabinofuranosylcytosine, 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-Beta-D-arabinofuranosylcytosine, 1.beta.-D-Arabinofuranosylcytosine, 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-, 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-, Alexan, Ara-C, ARA-cell, Arabine, Arabinofuranosylcytosine, Arabinosylcytosine, Aracytidine, Aracytin, Aracytine, Beta-Cytosine Arabinoside, CHX-3311, Cytarabinum, Cytarbel, Cytosar, Cytosine Arabinoside, Cytosine-.beta.-arabinoside, Cytosine-beta-arabinoside, Erpalfa, Starasid, Tarabine PFS, U 19920, U-19920, Udicil, WR-28453

Cohort I (higher and lowers dose pinometostat); Cohort II (higher dose pinometostat)

Daunorubicin DRUG

Given IV

Also known as: Daunomycin, Daunorrubicina, DNR, Leukaemomycin C, Rubidomycin, Rubomycin C

Cohort I (higher and lowers dose pinometostat); Cohort II (higher dose pinometostat)

Daunorubicin Hydrochloride DRUG

Given IV

Also known as: Cerubidin, Cerubidine, Cloridrato de Daunorubicina, Daunoblastin, Daunoblastina, Daunoblastine, Daunomycin Hydrochloride, Daunomycin, hydrochloride, Daunorubicin.HCl, Daunorubicini Hydrochloridum, FI-6339, Ondena, RP-13057, Rubidomycin Hydrochloride, Rubilem

Cohort I (higher and lowers dose pinometostat); Cohort II (higher dose pinometostat)

Pinometostat DRUG

Given IV

Also known as: DOT1L Inhibitor EPZ-5676, EPZ-5676

Cohort I (higher and lowers dose pinometostat); Cohort II (higher dose pinometostat)

Eligibility Criteria

• Age: 14 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• to \< 13 years: male = 1.2; female = 1.2

You may not qualify if:

• 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

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (3)

Yale University

New Haven, Connecticut, 06520, United States

Location

Johns Hopkins University/Sidney Kimmel Cancer Center

Baltimore, Maryland, 21287, United States

Location

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, 43210, United States

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

Cytarabine; Daunorubicin; EPZ-5676

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates

Limitations and Caveats

Study terminated early due to investigational product not being available

Results Point of Contact

• Title: Dr. James Blachly
• Organization: The Ohio State University Comprehensive Cancer Center

James.Blachly@osumc.edu

614-293-7484

Study Officials

• James S Blachly

  Ohio State University Comprehensive Cancer Center LAO

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 26, 2018
• First Posted: October 30, 2018
• Study Start: April 10, 2019
• Primary Completion: November 14, 2022
• Study Completion: November 14, 2022
• Last Updated: June 18, 2025
• Results First Posted: June 11, 2024

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will share

Locations

US (3)