Tazemetostat and Palbociclib With CPX-351for R/R AML

Thomas Jefferson University

Status and phase: Suspended; Phase 1

Conditions: Refractory Acute Myeloid Leukemia; Recurrent Acute Myeloid Leukemia

Treatments: Drug: Palbociclib; Drug: Liposome-encapsulated Daunorubicin-Cytarabine; Drug: Tazemetostat; Procedure: Bone Marrow Aspiration and Biopsy; Procedure: Biospecimen Collection

Study type: Interventional

Funder types: Other

Identifiers

NCT05627232

22G.769

4100095617 (Other Grant/Funding Number)

JT 24252 (Other Identifier)

Details and patient eligibility

About

This is a two-part phase Ib dose escalation study to evaluate the safety and preliminary efficacy of the combination of tazemetostat and CPX-351 following pre-treatment with palbociclib for patients with relapsed or refractory (R/R) acute myeloid leukemia (AML). Part 1 of the study will seek to establish the safety, tolerability, biological activity and recommended Part 2 dose of tazemetostat in combination with standard-dose CPX-351. Once the recommended Part 2 dose is established, the study will proceed to Part 2 where pre-treatment with palbociclib will be administered prior to the tazemetostat/CPX-351 dose combination. The objective of Part 2 is to establish the optimal dose of palbociclib.).

Full description

PRIMARY OBJECTIVE:

Part 1: To determine the optimal dose of tazemetostat in combination with CPX-351 in patients with R/R-AML.

Part 2: To determine the optimal dose of palbociclib pre-treatment prior to combination of tazemetostat/CPX-351 in patients with R/R-AML.

SECONDARY OBJECTIVE:

I. To evaluate the preliminary efficacy of tazemetostat in combination with CPX-351 (Part 1) and of palbociclib Tazemetostat and Palbociclib with CPX-351for R/R AML pre-treatment prior to tazemetostat/CPX-351 combination (Part 2).

EXPLORATORY OBJECTIVES:

1. To determine whether treatment with the EZH2 inhibitor tazemetostat de-condenses the H3K27me3-marked chromatin of AML blasts.
2. To determine whether cell cycle re-entry of AML cells after palbociclib treatment influences DNA damage and apoptosis induced by combining EZH2 inhibition with anthracycline-based therapy

This is a phase 1, single-institution, two-part, dose-escalation study utilizing tazemetostat in combination with CPX-351 (Part 1) and palbociclib pre-treatment followed by tazemetostat/CPX-351 combination (Part 2) for patients with relapsed or refractory AML who are fit to receive intensive chemotherapy. The study will take place in two parts:

Part 1: Dose escalation via traditional 3+3 design of tazemetostat in combination with CPX-351 .

Part 2: Dose escalation via traditional 3+3 design of palbociclib pre-treatment followed by tazemetostat/CPX-351combination.

After completion of study treatment, patients are followed up at 3 months, 6 months, and 1 year for clinical outcomes including survival.

Enrollment: 24 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Provide signed and dated informed consent form

• Willing to comply with all study procedures and be available for the duration of the study

• Male or female >= 18 years of age

• Histologically confirmed acute myeloid leukemia (non-M3) relapsed from or refractory to at least 1 prior line of therapy. Bone marrow aspirate and biopsy within 28 days of screening is acceptable. If no prior bone marrow biopsy is available, bone marrow biopsy must be performed during screening unless:

  * If the subject has >= 20% myeloblasts present in the peripheral blood, a bone marrow biopsy is not necessary to meet this criterion

• Treatment with a prior investigational agent is acceptable so long as it has not been administered within 2 weeks of enrollment and any prior adverse effects have resolved to grade 1 or less with the exception of alopecia

• Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less

• Life expectancy of at least 4 weeks

• Must be able to consume oral medication

• Subjects must have recovered from the toxic effect of any prior therapy to =< grade 1 (except alopecia)

• Creatine clearance (CrCL) >= 45

• Total bilirubin < 2 x upper limit of normal (ULN)

• Female subjects of childbearing age must have a negative pregnancy test

Exclusion criteria

• Subjects with acute promyelocytic leukemia
• Subjects receiving any active chemotherapy agents (except hydroxyurea). Intrathecal methotrexate and cytarabine are permissible
• Subjects whose participation would result in a total cumulative dose of daunorubicin greater than 550 mg/m^2 or greater than 450 mg/m^2 if they previously received mediastinal radiation
• Subjects with evidence of active central nervous system (CNS) leukemia involvement. Lumbar puncture is not required for enrollment in the absence of neurologic symptoms
• Subjects must not be receiving growth factors (except erythropoietin)
• Subjects with currently active second malignancy with the exception of nonmelanoma skin cancer, carcinoma in situ of the cervix, resected prostate cancer with Gleason score =< 6
• Subjects with unstable cardiac disease or uncontrolled arrhythmia
• Subjects with other severe concurrent disease which, in the judgement of the investigator, would make the patient inappropriate to receive high-intensity therapy
• Subjects who are pregnant or breastfeeding
• Subjects with known allergic reactions to components of the study product(s)
• Anything that would place the individual at increased risk or preclude the individual's full compliance with or completion of the study

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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24 participants in 2 patient groups

Part I (tazemetostat, CPX-351)

Experimental group

Description:

Patients receive tazemetostat PO BID on days -1 to 6, and CPX-351 IV over 90 minutes on days 1, 3, and 5. Patients also undergo bone marrow aspiration and biopsy and blood sample collection during screening and on study.

Treatment:

Procedure: Biospecimen Collection

Procedure: Bone Marrow Aspiration and Biopsy

Drug: Tazemetostat

Drug: Liposome-encapsulated Daunorubicin-Cytarabine

Part II: palbociclib Pre-Treatment Followed by Tazemetostat + CPX-351

Experimental group

Description:

Patients receive palbociclib PO QD on days -3 to -1, then tazemetostat PO twice daily (Days -1 to 6), and CPX-351 IV over 90 minutes on days 1, 3, and 5. Patients also undergo bone marrow aspiration and biopsy and blood sample collection during screening and on study.

Treatment:

Procedure: Biospecimen Collection

Procedure: Bone Marrow Aspiration and Biopsy

Drug: Tazemetostat

Drug: Palbociclib

Drug: Liposome-encapsulated Daunorubicin-Cytarabine