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| ID | Type | Description | Link |
|---|---|---|---|
| JT 24252 | Other Identifier | JeffTrial Number | |
| 4100095617 | Other Grant/Funding Number | Pennsylvania Department of Health Research Formula CURE |
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| Name | Class |
|---|---|
| Pennsylvania Department of Health | OTHER_GOV |
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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.
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:
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Part I (tazemetostat, CPX-351) | Experimental | 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. |
|
| Part II: (Palbociclib Pre-Treatment Followed by CPX-351) | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Tazemetostat | Drug | Given PO |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Up to 1 year |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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). |
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:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Gina Keiffer, MD | Contact | 215-955-2929 | gina.keiffer@jefferson.edu |
| Name | Affiliation | Role |
|---|---|---|
| Gina Keiffer, MD | Thomas Jefferson University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Thomas Jefferson University Hospital | Recruiting | Philadelphia | Pennsylvania | 19107 | United States |
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| ID | Term |
|---|---|
| D015470 | Leukemia, Myeloid, Acute |
| ID | Term |
|---|---|
| D007951 | Leukemia, Myeloid |
| D007938 | Leukemia |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
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| ID | Term |
|---|---|
| C000593333 | tazemetostat |
| C000629812 | CPX-351 |
| D007267 | Injections |
| D003630 | Daunorubicin |
| D003561 | Cytarabine |
| D008081 | Liposomes |
| D001706 | Biopsy |
| D013048 | Specimen Handling |
| C500026 | palbociclib |
| ID | Term |
|---|---|
| D004333 | Drug Administration Routes |
| D004358 | Drug Therapy |
| D013812 | Therapeutics |
| D018943 | Anthracyclines |
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| Liposome-encapsulated Daunorubicin-Cytarabine | Drug | Given IV |
|
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| Bone Marrow Aspiration and Biopsy | Procedure | Undergo bone marrow aspiration and biopsy |
|
| Biospecimen Collection | Procedure | Undergo blood sample collection |
|
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| Palbociclib | Drug | Given PO |
|
|
| Up to 1 year |
| 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. | Up to 1 year |
| 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. | Up to 1 year |
| 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. | Up to 1 year |
| Induction failure/refractory acute myeloid leukemia (AML) | Induction failure/refractory AML defined as failure to attain CR or CRi. | Up to 1 year |
| Time to blood count recovery | 95% confidence intervals will be calculated using Kaplan-Meier method. | 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 | 95% confidence intervals will be calculated using Kaplan-Meier method. | The time measured in months to relapse from day 1 of treatment, assessed up to 1 year |
| Overall survival | 95% confidence intervals will be calculated using Kaplan-Meier method. | The time measured in months from day 1 of treatment, assessed up to 1 year |
| Rate of allogeneic stem cell transplantation | Defined as the proportion of patients who undergo allogeneic stem cell transplantation during the study period. | Up to 1 year |
| Time to transplant | 95% confidence intervals will be calculated using Kaplan-Meier method. | The time measured in months to allogeneic stem cell transplantation from day 1 of treatment, assessed up to 1 year |
| Up to day 5 |
| D006402 |
| Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D009279 |
| Naphthacenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D011083 | Polycyclic Compounds |
| D000617 | Aminoglycosides |
| D006027 | Glycosides |
| D002241 | Carbohydrates |
| D003562 | Cytidine |
| D011741 | Pyrimidine Nucleosides |
| D011743 | Pyrimidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D001087 | Arabinonucleosides |
| D009705 | Nucleosides |
| D009706 | Nucleic Acids, Nucleotides, and Nucleosides |
| D008567 | Membranes, Artificial |
| D001697 | Biomedical and Dental Materials |
| D004337 | Drug Carriers |
| D004304 | Dosage Forms |
| D004364 | Pharmaceutical Preparations |
| D008420 | Manufactured Materials |
| D013676 | Technology, Industry, and Agriculture |
| D040761 | Biomimetic Materials |
| D003581 | Cytodiagnosis |
| D003584 | Cytological Techniques |
| D019411 | Clinical Laboratory Techniques |
| D019937 | Diagnostic Techniques and Procedures |
| D003933 | Diagnosis |
| D003949 | Diagnostic Techniques, Surgical |
| D013514 | Surgical Procedures, Operative |
| D008919 | Investigative Techniques |