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

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

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.

Study Overview

• Status: Withdrawn
• Conditions: Refractory Hematologic Malignancy; Relapsed Hematologic Malignancy
• Intervention / Treatment: Drug: Tafasitamab; Drug: Lenalidomide; Drug: Tazemetostat; Drug: Acalabrutinib; Drug: Daratumumab (Intravenously); Drug: Daratumumab (Subcutaneously); Drug: Hyaluronidase-Fihj; Drug: Pomalidomide; Drug: Dexamethasone 20mg; Drug: Mosunetuzumab

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.

• Study Type: Interventional
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Ipsen Recruitment Enquiries; Phone Number: see e mail; Email: clinical.trials@ipsen.com

Study Locations

• United States
  • California
    • Santa Fe, California, United States, 92024
      • California Cancer Associates for Research and Excellence, cCARE
  • Missouri
    • Bolivar, Missouri, United States, 65613
      • Central Care Cancer Center
  • New Jersey
    • East Brunswick, New Jersey, United States, 08816
      • Astera Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 for Phase 1b and status 0 to 2 for Phase 2
2. Must have documented relapsed, refractory, or progressive disease after 2 lines of treatment with systemic therapy
3. Measurable disease
4. Demonstrate adequate organ function
5. Negative test results for acute or chronic hepatitis B virus (HBV) infection, hepatitis C virus (HCV) and human immunodeficiency virus
6. No ongoing clinically significant reactions to prior anticancer treatments
7. Willingness to follow pregnancy precautions and register into the mandatory REMS program in lenalidomide and pomalizdomide arms

Exclusion Criteria:

1. Presence or history of central nervous system involvement by lymphoma
2. Less than minimum washout period of prior anticancer therapy as specified by the protocol
3. Prior allogeneic haematopoietic stem cell transplantation
4. History of solid organ transplant
5. Major surgery within 4 weeks of the start of study drug.
6. Significant cardiac or cardiovascular impairment as specified by protocol
7. Venous thrombosis or pulmonary embolism within the last 3 months before starting tazemetostat
8. History of any bleeding disorder, peptic ulcer disease, or significant bleeding within the last 1 month prior to enrollment
9. Are unable to take oral medication OR have malabsorption syndrome or any other uncontrolled gastrointestinal condition
10. Patients with known active infection, or reactivation of a latent infection, as specified by the protocol
11. Known sensitivity or allergy to the study medications
12. Unwilling to refrain from eating or drinking grapefruit juice, Seville oranges, and grapefruits while on study
13. Prior exposure to tazemetostat
14. 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.
15. Prior history of myeloid malignancies or T-cell lymphoblastic lymphoma (T-LBL)/T-cell acute lymphoblastic leukemia (T-ALL)

16. For patients with DLBCL in Arm 1 (tazemetostat plus tafasitamab plus lenalidomide) or Arm 2 (tazemetostat plus lenalidomide):

    - Prior exposure to lenalidomide

17. 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)

18. For patients with MM in Arm 4:

    • Prior exposure to pomalidomide
    • Untreated or impending spinal cord compression in subjects

19. 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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

5

Arms and Interventions

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

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

Collaborators and Investigators

• Sponsor: Epizyme, Inc.
• Investigators: Study Director: Ipsen Medical Director, Ipsen

Study record dates

Study Major Dates

• Study Start (Actual): December 22, 2021
• Primary Completion (Actual): July 5, 2023
• Study Completion (Actual): July 5, 2023

Study Registration Dates

• First Submitted: December 29, 2021
• First Submitted That Met QC Criteria: January 14, 2022
• First Posted (Actual): January 25, 2022

Study Record Updates

• Last Update Posted (Actual): August 15, 2023
• Last Update Submitted That Met QC Criteria: August 11, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Hematologic Diseases; Neoplasms; Hematologic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antineoplastic Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Protein Kinase Inhibitors; Dexamethasone; Pomalidomide; Lenalidomide; Daratumumab; Antibodies, Monoclonal; Acalabrutinib; Tyrosine Protein Kinase Inhibitors
• Other Study ID Numbers: EZH-1501

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No