Tazemetostat and Palbociclib With CPX-351for R/R AML
Trial statusRecruiting
Trial phasePhase 1
Trial typeInterventional
Biological sexAll
Age18+
SponsorThomas Jefferson University
About this trial
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.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
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
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
Disqualifiers
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
Trial design
Design model
Parallel
Treatments tested in this trial
Tazemetostat
DrugGiven PO
Liposome-encapsulated Daunorubicin-Cytarabine
DrugGiven IV
Bone Marrow Aspiration and Biopsy
Procedure/SurgeryUndergo bone marrow aspiration and biopsy
Biospecimen Collection
Procedure/SurgeryUndergo blood sample collection
Palbociclib
DrugGiven PO
Treatment groups
24 Participants
are divided into 2 treatment groupsGroup A: Part I (tazemetostat, CPX-351)Experimental treatment 4 interventions
Group B: Part II: (Palbociclib Pre-Treatment Followed by CPX-351)Experimental treatment 5 interventions
Trial outcomes
Primary outcomes
1
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.
Time frame
Up to 1 yearSecondary outcomes
1
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.
Time frame
Up to 1 year2
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.
Time frame
Up to 1 year3
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.
Time frame
Up to 1 year4
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.
Time frame
Up to 1 yearOther outcomes
1
Deoxyribonucleic acid (DNA) damage and apoptosis
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 5Sponsors and contacts
Click on the lead sponsor to view all of their trials.
Thomas Jefferson University
Lead sponsor
Pennsylvania Department of Health
Collaborator
Source ClinicalTrials.gov