Palbociclib and Tazemetostat in Combination With CPX-351 for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia

Sponsor
Thomas Jefferson University (Other)
Overall Status
Not yet recruiting
CT.gov ID
NCT05627232
Collaborator
(none)
15
1
1
35
0.4

Study Details

Study Description

Brief Summary

This phase I trial tests the safety, side effects, and best dose of palbociclib and tazemetostat in combination with CPX-351 in treating patients with acute myeloid leukemia (AML) that has come back (relapsed) or does not respond to treatment (refractory). CPX-351 is a combination of the chemotherapy drugs, daunorubicin and cytarabine, which is the standard of care for AML. Chemotherapy drugs 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. Palbociclib and tazemetostat are enzyme inhibitor drugs that are approved for treating certain cancers but not AML. These drugs may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving CPX-351 chemotherapy with enzyme inhibitors palbociclib and tazemetostat may kill more cancer cells.

Condition or Disease Intervention/Treatment Phase
Phase 1

Detailed Description

PRIMARY OBJECTIVE:
  1. To determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of tazemetostat in combination with anthracycline-based chemotherapy following pre-treatment with standard-dose palbociclib in patients with relapsed/refractory (R/R)-acute myeloid leukemia (AML).
SECONDARY OBJECTIVES:
  1. To evaluate the safety and tolerability of tazemetostat in combination with anthracycline based chemotherapy following pre-treatment with standard-dose palbociclib in patients with R/R-AML.

  2. To evaluate the preliminary efficacy of tazemetostat in combination with anthracycline based chemotherapy following pre-treatment with standard-dose palbociclib in patients with R/R-AML.

EXPLORATORY OBJECTIVE:
  1. To determine whether cell cycle re-entry of AML cells after palbociclib treatment influences deoxyribonucleic acid (DNA) damage and apoptosis induced by combining EZH2 inhibition with anthracycline-based therapy.

OUTLINE: This is a dose-escalation study of tazemetostat.

Patients receive palbociclib and tazemetostat orally (PO) and liposome-encapsulated daunorubicin-cytarabine (CPX-351) intravenously (IV) on study. Patients undergo bone marrow aspiration and biopsy and blood sample collection during screening and on study.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
15 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
De-Condensing H3K27me3-Marked Chromatin is Essential for Novel AML Therapies: Tazemetostat in Combination With CPX-351 Following Palbociclib Pre-Treatment for Patients With Relapsed or Refractory Acute Myeloid Leukemia
Anticipated Study Start Date :
Feb 1, 2023
Anticipated Primary Completion Date :
Jan 1, 2026
Anticipated Study Completion Date :
Jan 1, 2026

Arms and Interventions

Arm Intervention/Treatment
Experimental: Treatment (palbociclib, tazemetostat, CPX-351)

Patients receive palbociclib and tazemetostat PO and CPX-351 IV on study. Patients undergo bone marrow aspiration and biopsy and blood sample collection during screening and on study.

Drug: Palbociclib
Given PO
Other Names:
  • 571190-30-2
  • 6-Acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-8h-pyrido(2,3-d)pyrimidin-7-one
  • Ibrance
  • PD 0332991
  • PD 332991
  • PD 991
  • PD-0332991
  • Pyrido(2,3-d)pyrimidin-7(8H)-one
  • 6-Acetyl-8-cyclopentyl-5-methyl-2-((5-(1-piperazinyl)-2-pyridinyl)amino)-
  • Drug: Tazemetostat
    Given PO
    Other Names:
  • 1403254-99-8
  • E7438
  • EPZ-6438
  • EPZ6438
  • N-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(oxan-4-yl)amino)-4-methyl-4'-((morpholin-4-yl)methyl)(1,1'-biphenyl)-3-carboxamide
  • N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4'-(morpholinomethyl)-[1,1'-biphenyl]-3-carboxamide
  • Drug: Liposome-encapsulated Daunorubicin-Cytarabine
    Given IV
    Other Names:
  • CPX-351
  • Cytarabine-Daunorubicin Liposome for Injection
  • Daunorubicin and Cytarabine (Liposomal)
  • Liposomal AraC-Daunorubicin CPX-351
  • Liposomal Cytarabine-Daunorubicin
  • Liposome-encapsulated Combination of Daunorubicin and Cytarabine
  • Vyxeos
  • Procedure: Bone Marrow Aspiration and Biopsy
    Undergo bone marrow aspiration and biopsy

    Procedure: Biospecimen Collection
    Undergo blood sample collection
    Other Names:
  • Biological Sample Collection
  • Biospecimen Collected
  • Specimen Collection
  • Outcome Measures

    Primary Outcome Measures

    1. Incidence of grade >= 3 non-hematologic dose limiting toxicities [Up to 1 year]

      The primary outcome measure will be grade >= 3 non-hematologic dose limiting toxicities. Adverse events will be coded by organ system and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version (v.) 5.0. the calculation of adverse events incidences will be passed on number of patients per adverse event category. Standard proportions will be used to report rates of safety endpoints. Summary tables will be presented by dose level, seriousness, severity and relatedness.

    Secondary Outcome Measures

    1. Incidence of adverse events [Up to 1 year]

      Assessment of safety and tolerability: Incidence, nature, and severity of adverse events and incidence, nature and severity of treatment-emergent adverse events. The primary outcome measure will be grade >= 3 non-hematologic dose limiting toxicities. Adverse events will be coded by organ system and graded according to the CTCAE v. 5.0. the calculation of adverse events incidences will be passed on number of patients per adverse event category. Standard proportions will be used to report rates of safety endpoints. Summary tables will be presented by dose level, seriousness, severity and relatedness.

    2. Complete response [Up to 1 year]

      Morphologic leukemia-free state: < 5% blasts in bone marrow, no blasts with Auer rods or persistence of extramedullary disease. Morphologic complete response (CR): < 5% blasts in bone marrow with transfusion independence, absolute neutrophil count (ANC) > 1.0 x 10^9/L, platelets >= 100 x10^9/L. CR without minimal residual disease: morphologic CR with negative molecular markers by real-time quantitative polymerase chain reaction or negative multi-parameter flow cytometry. CR with partial hematologic recovery (CRh): as < 5% blasts in bone marrow with no evidence of disease and partial recovery of peripheral blood counts (ANC > 0.5 x 10^9/L and platelets > 50 x 10^9/L). CR with incomplete hematologic recovery (CRi): all CR criteria and transfusion independence but with persistence of neutropenia (ANC < 1.0 x 10^9/L) or thrombocytopenia (platelets < 100 x 10^9/L). Composite complete response: CR + CRh + CRi.

    3. Partial remission (PR) [Up to 1 year]

      PR is defined as decrease of at least 50% in the percentage of bone marrow blasts to 5% - 25% and normalization of blood counts.

    4. Relapse [Up to 1 year]

      Relapse is defined as reappearance of leukemic blasts in the peripheral blood or > 5% blasts in the bone marrow not attributable to other cause (e.g., bone marrow regeneration after chemotherapy) or extramedullary relapse.

    5. Induction failure/refractory acute myeloid leukemia (AML) [Up to 1 year]

      Induction failure/refractory AML defined as failure to attain CR or CRi.

    6. Time to blood count recovery [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]

      95% confidence intervals will be calculated using Kaplan-Meier method.

    7. Relapse free survival [The time measured in months to relapse from day 1 of treatment, assessed up to 1 year]

      95% confidence intervals will be calculated using Kaplan-Meier method.

    8. Overall survival [The time measured in months from day 1 of treatment, assessed up to 1 year]

      95% confidence intervals will be calculated using Kaplan-Meier method.

    9. Rate of allogeneic stem cell transplantation [Up to 1 year]

      Defined as the proportion of patients who undergo allogeneic stem cell transplantation during the study period.

    10. Time to transplant [The time measured in months to allogeneic stem cell transplantation from day 1 of treatment, assessed up to 1 year]

      95% confidence intervals will be calculated using Kaplan-Meier method.

    Other Outcome Measures

    1. Deoxyribonucleic acid (DNA) damage and apoptosis [Up to day 5]

      DNA damage (analysis of gammaH2AX-positive AML cells by confocal microscopy) and apoptosis (Annexin V and caspase 3 activation) will be assessed in S phase-enriched AML cells (16-24 hours post palbociclib treatment) following treatment with the EZH2 inhibitor tazemetostat to de-condense the H3K27me3-marked chromatin and chemotherapy (CPX-351) to induce DNA damage (double strand breaks).

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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/m2 or greater than 450 mg/m2 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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Thomas Jefferson University Hospital Philadelphia Pennsylvania United States 19107

    Sponsors and Collaborators

    • Thomas Jefferson University

    Investigators

    None specified.

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Thomas Jefferson University
    ClinicalTrials.gov Identifier:
    NCT05627232
    Other Study ID Numbers:
    • 22G.769
    First Posted:
    Nov 25, 2022
    Last Update Posted:
    Jan 17, 2023
    Last Verified:
    Jan 1, 2023
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Jan 17, 2023