A Study of Tazemetostat in Combination With Various Treatments in Participants With Blood Cancer.

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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.

Official Title
-----------------
ARIA: A Phase 1b/2, Open-label, Multi Cohort Trial of Tazemetostat in Combination With Various Treatments in Subjects With Relapsed or Refractory Hematologic Malignancies

Conditions
-----------------
Relapsed Hematologic Malignancy, Refractory Hematologic Malignancy

Intervention / Treatment
-----------------
* Drug: Tazemetostat
* Drug: Tafasitamab
* Drug: Lenalidomide
* Drug: Acalabrutinib
* Drug: Daratumumab (Intravenously)
* Drug: Mosunetuzumab
* Drug: Daratumumab (Subcutaneously)
* Drug: Hyaluronidase-Fihj
* Drug: Pomalidomide
* Drug: Dexamethasone 20mg


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 for Phase 1b and status 0 to 2 for Phase 2 Must have documented relapsed, refractory, or progressive disease after 2 lines of treatment with systemic therapy Measurable disease Demonstrate adequate organ function Negative test results for acute or chronic hepatitis B virus (HBV) infection, hepatitis C virus (HCV) and human immunodeficiency virus No ongoing clinically significant reactions to prior anticancer treatments Willingness to follow pregnancy precautions and register into the mandatory REMS program in lenalidomide and pomalizdomide arms 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): Prior exposure to a BTKi Medical condition that would make treatment with a BTKi not reasonable (e.g. allergy to BTKi or mutations known not to respond to BTKi treatment or subjects unable to be transitioned off of proton pump inhibitors) For patients with MM in Arm 4: Prior exposure to pomalidomide Untreated or impending spinal cord compression in subjects For patients with FL in Arm 5: Grade 3b, mixed histology, or FL that has histologically transformed to DLBCL. History of significant neurological disorders, hemophagocytic lymphohistiocytosis (HLH), chronic active Epstein-Barr virus (EBV) infection, progressive multifocal leukoencephalopathy (PML), lung disease (ILD), drug-induced pneumonitis, autoimmune pneumonitis, and/or history of severe autoimmune disease

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm 1-Tazemetostat plus tafasitamab-cxix (CD19 Ab)/lenalidomide<br>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. | Drug: Tazemetostat<br>* Orally, twice daily in continuous 28-day cycles.<br>* Other names: IPN60200;Drug: Tafasitamab<br>* 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.<br>Drug: Lenalidomide<br>* 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.<br>|
| Active Comparator: Arm 2-Tazemetostat plus lenalidomide<br>Participants with R/R DLBCL will receive tazemetostat and lenalidomide for approximately 1 year. After approximately 1 year, participants will receive tazemetostat alone. | Drug: Tazemetostat<br>* Orally, twice daily in continuous 28-day cycles.<br>* Other names: IPN60200;Drug: Lenalidomide<br>* 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.<br>|
| Active Comparator: Arm 3- Tazemetostat plus BTKi (acalabrutinib)<br>Participants with R/R mantle cell lymphomawill (MCL) will receive tazemetostat and acalabrutinib for the entire study. | Drug: Tazemetostat<br>* Orally, twice daily in continuous 28-day cycles.<br>* Other names: IPN60200;Drug: Acalabrutinib<br>* Orally, 100 mg, twice daily.<br>* Other names: Bruton tyrosine kinase inhibitor;Drug: Hyaluronidase-Fihj<br>* 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.<br>|
| Active Comparator: Arm 4-Tazemetostat plus CD38 mAbPD (daratumumab/pomalidomide/dexamethasone)<br>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. | Drug: Tazemetostat<br>* Orally, twice daily in continuous 28-day cycles.<br>* Other names: IPN60200;Drug: Daratumumab (Intravenously)<br>* 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.<br>Drug: Daratumumab (Subcutaneously)<br>* 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.<br>Drug: Pomalidomide<br>* Orally, 4 mg, once daily on Days 1 to 21 of continuous 28-day cycles.<br>Drug: Dexamethasone 20mg<br>* Orally, 20 mg or 40 mg, once daily on Days 1, 8, 15, and 22 of continuous 28-day cycles.<br>|
| Active Comparator: Arm 5- Tazemetostat plus CD20/CD3 BsAb (mosunetuzumab)<br>Participants with R/R follicular lymphoma will receive tazemetostat and mosunetuzumab for approximately 1 year. After approximately 1 year, participants will receive tazemetostat alone. | Drug: Tazemetostat<br>* Orally, twice daily in continuous 28-day cycles.<br>* Other names: IPN60200;Drug: Mosunetuzumab<br>* 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.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | 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. | 

Secondary Outcome Measures

| Outcome Measure | 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) | 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 |