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

Primary Purpose

Recurrent Acute Myeloid Leukemia, Refractory Acute Myeloid Leukemia

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Tazemetostat
Liposome-encapsulated Daunorubicin-Cytarabine
Bone Marrow Aspiration and Biopsy
Biospecimen Collection
Palbociclib
Sponsored by
Thomas Jefferson University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Recurrent Acute Myeloid Leukemia

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

  • Thomas Jefferson University HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Part I (tazemetostat, CPX-351)

Part II (palbociclib, CPX-351)

Arm 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.

Patients receive palbociclib PO QD on days -3 to -1, 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.

Outcomes

Primary Outcome Measures

Incidence of grade >= 3 non-hematologic dose limiting toxicities
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

Incidence of adverse events
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.
Complete response
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.
Partial remission (PR)
PR is defined as decrease of at least 50% in the percentage of bone marrow blasts to 5% - 25% and normalization of blood counts.
Relapse
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.
Induction failure/refractory acute myeloid leukemia (AML)
Induction failure/refractory AML defined as failure to attain CR or CRi.
Time to blood count recovery
95% confidence intervals will be calculated using Kaplan-Meier method.
Relapse free survival
95% confidence intervals will be calculated using Kaplan-Meier method.
Overall survival
95% confidence intervals will be calculated using Kaplan-Meier method.
Rate of allogeneic stem cell transplantation
Defined as the proportion of patients who undergo allogeneic stem cell transplantation during the study period.
Time to transplant
95% confidence intervals will be calculated using Kaplan-Meier method.

Full Information

First Posted
November 16, 2022
Last Updated
August 29, 2023
Sponsor
Thomas Jefferson University
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1. Study Identification

Unique Protocol Identification Number
NCT05627232
Brief Title
Palbociclib or Tazemetostat in Combination With CPX-351 for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia
Official Title
A Two-Part Study Evaluating the Combination of Tazemetostat and CPX-351 (Part 1) and Palbociclib With CPX-351 (Part 2) for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
August 28, 2023 (Actual)
Primary Completion Date
January 2026 (Anticipated)
Study Completion Date
January 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Thomas Jefferson University

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This phase I trial tests the safety, side effects, and best dose of palbociclib or 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 or tazemetostat may kill more cancer cells.
Detailed Description
PRIMARY OBJECTIVE: Part 1: To determine the maximum tolerated dose (MTD) of tazemetostat in combination with CPX-351 in patients with relapsed/refractory (R/R)-acute myeloid leukemia (AML). Part 2: To determine the maximum tolerated dose (MTD) of palbociclib in combination with 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 CPX-351 following pre-treatment with palbociclib (part 2). EXPLORATORY OBJECTIVES: I. To determine whether treatment with the EZH2 inhibitor tazemetostat de-condenses the H3K27me3-marked chromatin of AML blasts. Il. 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. OUTLINE: This is a dose-escalation study of tazemetostat or palbociclib in combination with fixed dose CPX-351. Patients are assigned to 1 of 2 parts. PART I: Patients receive tazemetostat orally (PO) twice a day (BID) on days -1 to 6, and CPX-351 intravenously (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. PART II: Patients receive palbociclib PO daily (QD) on days -3 to -1, 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. After completion of study treatment, patients are followed up at 3 months, 6 months, and 1 year for clinical outcomes including survival.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Recurrent Acute Myeloid Leukemia, Refractory Acute Myeloid Leukemia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
24 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Part I (tazemetostat, CPX-351)
Arm Type
Experimental
Arm 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.
Arm Title
Part II (palbociclib, CPX-351)
Arm Type
Experimental
Arm Description
Patients receive palbociclib PO QD on days -3 to -1, 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.
Intervention Type
Drug
Intervention Name(s)
Tazemetostat
Other Intervention Name(s)
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
Intervention Description
Given PO
Intervention Type
Drug
Intervention Name(s)
Liposome-encapsulated Daunorubicin-Cytarabine
Other Intervention Name(s)
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
Intervention Description
Given IV
Intervention Type
Procedure
Intervention Name(s)
Bone Marrow Aspiration and Biopsy
Intervention Description
Undergo bone marrow aspiration and biopsy
Intervention Type
Procedure
Intervention Name(s)
Biospecimen Collection
Other Intervention Name(s)
Biological Sample Collection, Biospecimen Collected, Specimen Collection
Intervention Description
Undergo blood sample collection
Intervention Type
Drug
Intervention Name(s)
Palbociclib
Other Intervention Name(s)
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)-
Intervention Description
Given PO
Primary Outcome Measure Information:
Title
Incidence of grade >= 3 non-hematologic dose limiting toxicities
Description
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.
Time Frame
Up to 1 year
Secondary Outcome Measure Information:
Title
Incidence of adverse events
Description
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.
Time Frame
Up to 1 year
Title
Complete response
Description
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.
Time Frame
Up to 1 year
Title
Partial remission (PR)
Description
PR is defined as decrease of at least 50% in the percentage of bone marrow blasts to 5% - 25% and normalization of blood counts.
Time Frame
Up to 1 year
Title
Relapse
Description
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.
Time Frame
Up to 1 year
Title
Induction failure/refractory acute myeloid leukemia (AML)
Description
Induction failure/refractory AML defined as failure to attain CR or CRi.
Time Frame
Up to 1 year
Title
Time to blood count recovery
Description
95% confidence intervals will be calculated using Kaplan-Meier method.
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
Title
Relapse free survival
Description
95% confidence intervals will be calculated using Kaplan-Meier method.
Time Frame
The time measured in months to relapse from day 1 of treatment, assessed up to 1 year
Title
Overall survival
Description
95% confidence intervals will be calculated using Kaplan-Meier method.
Time Frame
The time measured in months from day 1 of treatment, assessed up to 1 year
Title
Rate of allogeneic stem cell transplantation
Description
Defined as the proportion of patients who undergo allogeneic stem cell transplantation during the study period.
Time Frame
Up to 1 year
Title
Time to transplant
Description
95% confidence intervals will be calculated using Kaplan-Meier method.
Time Frame
The time measured in months to allogeneic stem cell transplantation from day 1 of treatment, assessed up to 1 year
Other Pre-specified Outcome Measures:
Title
Deoxyribonucleic acid (DNA) damage and apoptosis
Description
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).
Time Frame
Up to day 5

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Gina Keiffer, MD
Phone
215-955-2929
Email
gina.keiffer@jefferson.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Gina Keiffer, MD
Organizational Affiliation
Thomas Jefferson University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Thomas Jefferson University Hospital
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19107
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Gina Keiffer, MD
Phone
215-955-2929
Email
gina.keiffer@jefferson.edu

12. IPD Sharing Statement

Learn more about this trial

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

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