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Epizyme Inc. has revised the Tazemetostat development strategy and made the decision to terminate the hematological malignancies basket trial.
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This trial will study how safely the tazemetostat works with other therapies in various hematological malignancies. Hematologic malignancies are cancers that most often begin in the bone marrow or lymph nodes where blood precursors are produced.
They are often called blood cancers and fall into three categories: leukemia, lymphoma and myeloma.
Tazemetostat has been found to be a safe and effective drug that works in patients with follicular lymphoma where the disease has come back after treatment (known as relapsed) and when other treatment no longer works (known as refractory).
Combining tazemetostat with other treatments may work better in treating patients with hematological malignancies and may improve disease response and durability of response.
This phase 1b/2 trial studies how safely the EZH2 inhibitor tazemetostat works with other therapies in various hematological malignancies. Tazemetostat has been found to be a safe and effective drug that works in patients with relapsed refractory (R/R) follicular lymphoma. Giving tazemetostat in combination with other treatments may work better in treating patients with hematological malignancies and may improve disease response and durability of response.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Arm 1-Tazemetostat plus tafasitamab-cxix (CD19 Ab)/lenalidomide | Active Comparator | Participants with R/R, diffuse large B-cell lymphoma (DLBCL) will receive tazemetostat, tafasitamab, and lenalidomide for approximately 1 year. After approximately 1 year, participants will receive tazemetostat and tafasitamab. |
|
| Arm 2-Tazemetostat plus lenalidomide | Active Comparator | Participants with R/R DLBCL will receive tazemetostat and lenalidomide for approximately 1 year. After approximately 1 year, participants will receive tazemetostat alone. |
|
| Arm 3- Tazemetostat plus BTKi (acalabrutinib) | Active Comparator | Participants with R/R mantle cell lymphomawill (MCL) will receive tazemetostat and acalabrutinib for the entire study. |
|
| Arm 4-Tazemetostat plus CD38 mAbPD (daratumumab/pomalidomide/dexamethasone) | Active Comparator | Participants with R/R multiple myelomawill (MM) will receive tazemetostat, daratumumab, pomalidomide, and dexamethasone for the entire study. Daratumumab may be given intravenously or subcutaneously during this study. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Tazemetostat | Drug | Orally, twice daily in continuous 28-day cycles. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Phase 1b: Recommended Phase 2 Dose (RP2D) of tazemetostat in combination with each partner drug | The safety and tolerability of tazemetostat in combination with each partner drug in participants with R/R malignancies will be evaluated. RP2D of tazemetostat for further evaluation in phase 2 will be selected as assessed by the occurrence of treatment-emergent dose-limiting toxicities (DLTs) and adverse events (AEs). | Evaluated for DLTs during the first 28-day cycle. The RP2D for Phase 2 for each arm will be selected at the end of that arm's experience in Phase 1b |
| Phase 2: Objective Response Rate (ORR) | Overall response rate is defined as proportion of participants with a best response of at least partial remission (including partial remission and complete remission for participants with non-Hodgkin lymphoma in Arms 1, 2, 3, or 5 or partial remission, complete remission, stringent complete response, or very good partial response). | Time from the date of first dose of study drug to the time of response, assessed up to 24 months. |
| Measure | Description | Time Frame |
|---|---|---|
| Phase 2: Progression Free Survival (PFS) | Progression free survival is defined as the time from randomization into the study to the first observation of documented disease progression or death due to any cause. | Up to 24 months. |
| Time to response (TTR) |
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Inclusion Criteria:
Exclusion Criteria:
Presence or history of central nervous system involvement by lymphoma
Less than minimum washout period of prior anticancer therapy as specified by the protocol
Prior allogeneic haematopoietic stem cell transplantation
History of solid organ transplant
Major surgery within 4 weeks of the start of study drug.
Significant cardiac or cardiovascular impairment as specified by protocol
Venous thrombosis or pulmonary embolism within the last 3 months before starting tazemetostat
History of any bleeding disorder, peptic ulcer disease, or significant bleeding within the last 1 month prior to enrollment
Are unable to take oral medication OR have malabsorption syndrome or any other uncontrolled gastrointestinal condition
Patients with known active infection, or reactivation of a latent infection, as specified by the protocol
Known sensitivity or allergy to the study medications
Unwilling to refrain from eating or drinking grapefruit juice, Seville oranges, and grapefruits while on study
Prior exposure to tazemetostat
Any condition that places the subject at unacceptable risk if he/she were to participate in the study or that confounds the ability to interpret data from the study.
Prior history of myeloid malignancies or T-cell lymphoblastic lymphoma (T-LBL)/T-cell acute lymphoblastic leukemia (T-ALL)
For patients with DLBCL in Arm 1 (tazemetostat plus tafasitamab plus lenalidomide) or Arm 2 (tazemetostat plus lenalidomide):
- Prior exposure to lenalidomide
For patients with MCL in Arm 3 (tazemetostat plus acalabrutinib):
For patients with MM in Arm 4:
For patients with FL in Arm 5:
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| Name | Affiliation | Role |
|---|---|---|
| Ipsen Medical Director | Ipsen | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| California Cancer Associates For Research And Excellence, cCARE | Santa Fe | California | 92024 | United States | ||
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| Arm 5- Tazemetostat plus CD20/CD3 BsAb (mosunetuzumab) | Active Comparator | Participants with R/R follicular lymphoma will receive tazemetostat and mosunetuzumab for approximately 1 year. After approximately 1 year, participants will receive tazemetostat alone. |
|
|
| Tafasitamab | Drug | Intravenously, 12 mg/kg, once daily on Cycle 1: Days 1, 4, 8, 15 and 22 of the 28-day cycle. Cycles 2 and 3: Days 1, 8, 15 and 22 of each 28-day cycle. Cycle 4 and beyond: Days 1 and 15 of each 28-day cycle. |
|
| Lenalidomide | Drug | Orally, 10 mg or 20 mg based on kidney function, once daily from Days 1 to 21 of continuous 28-day cycles for up to 12 cycles. |
|
| Acalabrutinib | Drug | Orally, 100 mg, twice daily. |
|
|
| Daratumumab (Intravenously) | Drug | Intravenously, 16 mg/kg actual body weight, once daily on Cycles 1 and 2: Days 1, 8, 15 and 22 of the 28-day cycle. Cycles 3 through 6: Days 1 and 15 each 28-day cycle. Cycle 7 and beyond: Day 1 of each 28-day cycle. |
|
| Mosunetuzumab | Drug | Subcutaneously, step-up doses on Cycle 1 Days 1 (5 mg), 8 (45 mg) and 15 (45 mg) and then 45 mg from Cycle 2 through 12 on Day 1 of the 28-day cycle. |
|
| Daratumumab (Subcutaneously) | Drug | Subcutaneously, 1800 mg, once daily on Cycles 1 and 2: Days 1, 8, 15 and 22 of the 28-day cycle. Cycles 3 through 6: Days 1 and 15 each 28-day cycle. Cycle 7 and beyond: Day 1 of each 28-day cycle. |
|
| Hyaluronidase-Fihj | Drug | Subcutaneously, 30,000 units, once daily on Cycles 1 and 2: Days 1, 8, 15 and 22 of the 28-day cycle. Cycles 3 through 6: Days 1 and 15 each 28-day cycle. Cycle 7 and beyond: Day 1 of each 28-day cycle. |
|
| Pomalidomide | Drug | Orally, 4 mg, once daily on Days 1 to 21 of continuous 28-day cycles. |
|
| Dexamethasone 20mg | Drug | Orally, 20 mg or 40 mg, once daily on Days 1, 8, 15, and 22 of continuous 28-day cycles. |
|
Defined as the time from the first dose of study drug to the earliest date of CR or PR per Lugano Classification (Arms 1, 2, 3, and 5) or sCR, CR, VGPR, or PR per IMWG 2016 criteria (Arm 4) as assessed by Investigator review. |
| Up to 24 months |
| Phase 2: Duration of Response (DOR) | Duration of response is defined as the time from the initial response (at least partial remission) to documented disease progression. | Up to 24 months |
| Phase 2: Disease control rate (DCR) | Defined as the percentage of participants who achieve complete response (CR), partial response (PR), or stable disease per Lugano Classification (Arms 1, 2, 3, or 5) or stringent complete response (sCR), CR, very good partial response (VGPR), PR, or stable disease per IMWG 2016 criteria (Arm 4) at 6 months on study treatment, as assessed by Investigator review. | Up to 24 months |
| Phase 2: Overall Survival (OS) | Overall survival is defined as the time from the first dose of study drug to date of death due to any cause. | Up to 24 months |
| Time to next treatment (TTNT) | Defined as the time from the first dose of study drug to the start of subsequent anticancer therapy | Up to 24 months |
| Percentage of participants with Treatment Emergent Adverse Event (TEAEs) | An Adverse Event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. | Up to 24 months |
| Percentage of participants with clinically significant changes in laboratory parameters | Percentage of participants with clinically significant changes in laboratory parameters including, hematology, serum chemistry, coagulation and urinalysis will be reported. The clinical significance will be evaluated by the investigator. | Up to 24 months |
| Central Care Cancer Center |
| Bolivar |
| Missouri |
| 65613 |
| United States |
| Astera Cancer Center | East Brunswick | New Jersey | 08816 | United States |
| ID | Term |
|---|---|
| D019337 | Hematologic Neoplasms |
| ID | Term |
|---|---|
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
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| ID | Term |
|---|---|
| C000593333 | tazemetostat |
| C000613469 | tafasitamab |
| D000077269 | Lenalidomide |
| C000604908 | acalabrutinib |
| C556306 | daratumumab |
| C467566 | pomalidomide |
| D003907 | Dexamethasone |
| ID | Term |
|---|---|
| D010797 | Phthalimides |
| D010795 | Phthalic Acids |
| D000146 | Acids, Carbocyclic |
| D002264 | Carboxylic Acids |
| D009930 | Organic Chemicals |
| D010881 | Piperidones |
| D010880 | Piperidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D054833 | Isoindoles |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D011246 | Pregnadienetriols |
| D011245 | Pregnadienes |
| D011278 | Pregnanes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D013259 | Steroids, Fluorinated |
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