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

Official title

A Two-Part Phase 1b Study Evaluating the Combination of Tazemetostat and CPX-351 (Part 1) and Palbociclib Pre-Treatment Followed by CPX-351 (Part 2) for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia

Overview

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 (Part 1) and of pre-treatment with palbociclib followed by CPX-351 (Part 2) 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 dose for further evaluation (RDFE) of tazemetostat in combination with standard-dose CPX-351. Part 2 of the study will seek to establish the safety, tolerability, biological activity RDFE of pre-treatment palbociclib prior CPX-351.

Detailed description

PRIMARY OBJECTIVE:

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

Part 2: To determine the RDFE of palbociclib pre-treatment prior to 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 pre-treatment followed by CPX-351 (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 1b, single-institution, two-part, dose-escalation study utilizing tazemetostat in combination with CPX-351 (Part 1) and palbociclib pre-treatment followed by CPX-351 (Part 2) for patients with R/R-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.

Once the RDFE of tazemetostat in combination with CPX-351 and the RDFE of palbociclib pre-treatment followed by CPX-351 have been determined, we hope to pursue further evaluation of the safety and preliminary efficacy of the three-drug combination pending further protocol amendment..

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

Interventions

• Drug Tazemetostat
  Given PO
• Drug Liposome-encapsulated Daunorubicin-Cytarabine
  Given IV
• Procedure Bone Marrow Aspiration and Biopsy
  Undergo bone marrow aspiration and biopsy
• Procedure Biospecimen Collection
  Undergo blood sample collection
• Drug Palbociclib
  Given PO

Primary outcome measures

• Incidence of grade >= 3 non-hematologic dose limiting toxicities [Time frame: Up to 1 year]

Secondary outcome measures (10)

• Incidence of adverse events [Time frame: Up to 1 year]
• Complete response [Time frame: Up to 1 year]
• Partial remission (PR) [Time frame: Up to 1 year]
• Relapse [Time frame: Up to 1 year]
• Induction failure/refractory acute myeloid leukemia (AML) [Time frame: Up to 1 year]
• Time to blood count recovery [Time frame: The number of days until ANC > 1.0 x 10^9/L and platelets >= 100 x 10^9/L from day 1 of treatment, assessed up to 1 year]
• Relapse free survival [Time frame: The time measured in months to relapse from day 1 of treatment, assessed up to 1 year]
• Overall survival [Time frame: The time measured in months from day 1 of treatment, assessed up to 1 year]
• Rate of allogeneic stem cell transplantation [Time frame: Up to 1 year]
• Time to transplant [Time frame: The time measured in months to allogeneic stem cell transplantation from day 1 of treatment, assessed up to 1 year]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• Thomas Jefferson University Hospital — Philadelphia

Identifiers

NCT: NCT05627232 · 22G.769 · JT 24252 · 4100095617

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗