Tazemetostat in Combination With Doxorubicin as Frontline Therapy for Advanced Epithelioid Sarcoma

Advanced Soft-tissue Sarcoma Clinical Trial

Official title:

A Phase 1b/3 Global, Randomized, Double-blind, Placebo-Controlled Trial of Tazemetostat in Combination With Doxorubicin as Frontline Therapy for Advanced Epithelioid Sarcoma

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04204941
• Other study ID #: EZH-301
• Secondary ID: 2019-003648-55
• Status: Recruiting
• Phase: Phase 3
• Start date: December 19, 2019
• Est. completion date: January 1, 2030

Study information

• Verified date: April 2024
• Source: Ipsen
• Contact: Ipsen Recruitment Enquiries
• Phone: See e mail
• Email: clinical.trials[@]ipsen.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The participants of this study will have advanced epithelioid sarcoma. Sarcoma is a cancer of the connective tissues, such as nerves, muscles and bones. Epithelioid sarcoma is an ultra-rare sarcoma of the soft-tissue. Part 1 of this trial will evaluate the safety and the level of the study drug that the study drug combinations can be tolerated (known as tolerability). It is also designed to establish a recommended study drug dosage for the next part of the study. Part 2 will evaluate and compare for each of the study drug combinations how long participants live without their disease getting worse. The study drug is called tazemetostat. The study will test tazemetostat in combination with doxorubicin compared to placebo (dummy treatment) in combination with doxorubicin. Doxorubicin is a current front line treatment for epithelioid sarcoma

Description:

The open-label phase 1b portion is designed to evaluate the safety of the combination of tazemetostat + doxorubicin, as well as to establish the maximum tolerated dose (MTD) and the RP3D. The phase 3 portion of the clinical trial aims to compare tazemetostat + doxorubicin to the current front-line standard treatment, single-agent doxorubicin + placebo, when used as first-line treatment in locally advanced unresectable or metastatic ES.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 164
• Est. completion date: January 1, 2030
• Est. primary completion date: January 28, 2029
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria Participants must meet ALL the following inclusion criteria to be eligible to enroll in

this study:

1. Have voluntarily agreed to provide written informed consent and demonstrated willingness and ability to comply with all aspects of the protocol. Study related activities will not start until written consent is obtained.

2. Life expectancy = 3 months before enrollment

3. Phase 1b: 18-65 years old histologically confirmed Soft Tissue Sarcoma

4. Phase 3: =18 years old with unresectable locally advanced or metastatic Epithelioid Sarcoma and tumor tissue available

5. Have measurable disease

6. ECOG performance status of 0, 1, or 2

7. Have adequate hematologic (bone marrow [BM] and coagulation factors), renal and hepatic function as required per protocol

8. Females must not be lactating or pregnant at Screening or Baseline

9. Females must not be pregnant or breast feeding and agree to use highly effective contraception during the clinical trial and for 6 months following the final dose of study

10. Male participants of child-bearing potential must have had either a successful vasectomy or practice highly effective contraception

11. Participants diagnosed with human immunodeficiency virus (HIV) are eligible to participate in the study if their infection is well controlled on anti-retroviral therapy. Exclusion Criteria Participants meeting ANY of the following exclusion criteria are NOT eligible to enroll in

this study:

1. Prior exposure to tazemetostat or other inhibitor(s) of enhancer of zeste homologue-2 (EZH2).

2. Prior systemic anticancer therapy.

3. Contraindications noted in the doxorubicin label

4. Have any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).

5. Have prior history of T-cell lymphoblastic lymphoma/T-cell acute lymphoblastic leukemia (T- LBL/T-ALL).

6. Have participated in another interventional clinical study and received investigational drug within 30 days or 5 half-lives, whichever is longer, prior to the planned first dose of study treatment.

7. Have known active central nervous system (CNS) or any leptomeningeal metastasis of primary extracranial tumor.

8. Participants taking medications that are known potent cytochrome P450 (CYP)3A4 inducers/inhibitors (including St. John's Wort)

9. Are unwilling to exclude Seville oranges, grapefruit juice, AND grapefruit from the diet and all foods that contain those fruits from time of enrollment to through the duration of study participation.

10. Major surgery within 4 weeks before the first dose of study treatment. Participants must have recovered from surgery prior to enrollment to this study.

11. Are unable to take oral medication OR have malabsorption syndrome or any other uncontrolled gastrointestinal condition (eg, nausea, diarrhea, vomiting) that might impair the bioavailability of study treatment.

12. Have an active infection requiring systemic therapy.

13. Are immunocompromised (ie, has a congenital immunodeficiency).

14. Have known hypersensitivity to any component of tazemetostat or doxorubicin.

15. Cardiovascular impairment as stated in the protocol

16. Have a known active infection with hepatitis B virus (HBV, as measured by positive hepatitis B surface antigen), hepatitis C virus (HCV, as measured by positive hepatitis C antibody).

17. Any other major illness that, in the Investigator's judgment, will substantially increase the risk associated with the participant's participation in this study OR interfere with their ability to receive study treatment or complete the study.

18. Female participants who are pregnant or breastfeeding.

19. Participants who have undergone a solid organ transplant.

20. Participants with malignancies other than STS (phase 1b) or ES (Phase 3 only).

21. Participants housed in an institution by order of the authorities or courts.

Related Conditions & MeSH terms

• Advanced Epithelioid Sarcoma
• Advanced Soft-tissue Sarcoma
• Sarcoma

Intervention

Drug:
• Tazemetostat
400 mg, 600 to 800 mg of Tazemetostat will be administered twice daily.
• Doxorubicin HCl
75mg/m2 intravenous injection day 1 of each cycle for up to 6 cycles
• Tazemetostat
800 mg administered orally twice daily in continuous 21-day cycles during cycles 1-6 and in continuous 28-day cycles during cycle 7 and beyond.
• Placebo
Placebo administered orally twice daily in continuous 21-day cycles during cycles 1-6 and in continuous 28-day cycles during cycles 7 and beyond
• Doxorubicin HCl
75mg/m2 intravenous injection day 1 of each cycle for up to 6 cycles

Locations

Country	Name	City	State
Canada	McGill University Faculty of Medicine - Royal Victoria Hospital	Montréal	Quebec
Taiwan	National Taiwan University Hospital	Taipei
United Kingdom	Royal Marsden Foundation Trust	London
United States	University of Michigan Medical Center	Ann Arbor	Michigan
United States	University of Colorado Hospital - Anschutz Cancer Pavilion	Aurora	Colorado
United States	Dana Farber Cancer Insititute	Boston	Massachusetts
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	The Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	Sarah Cannon Research Institute at HealthONE	Denver	Colorado
United States	City of Hope Comprehensive Cancer Center	Duarte	California
United States	Duke University Medical Center	Durham	North Carolina
United States	Mayo Clinic-Jacksonville	Jacksonville	Florida
United States	Sarah Cannon and HCA Research Institute	Nashville	Tennessee
United States	Columbia University Irving Medical Center	New York	New York
United States	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania
United States	University of Pittsburgh Medical Center - Hillman Cancer Center	Pittsburgh	Pennsylvania
United States	Oregon Health and Science University	Portland	Oregon
United States	Washington University	Saint Louis	Missouri
United States	Sarcoma Oncology Research Center	Santa Monica	California
United States	Fred Hutchinson Research Center	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Epizyme, Inc.

Countries where clinical trial is conducted

United States,  Canada,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Dose Limiting Toxicities (DLTs)	Determined by Adverse Events (AEs) and clinical laboratory tests.	1 Cycle/21 days
Primary	Progression free survival (PFS)	Phase 3: Assessed by Independent Review Committee.	Through study completion, an average of two years.
Secondary	Phase 1b: Pharmacokinetics (PK) of tazemetostat when administered in combination with doxorubicin in participants with soft tissue sarcoma (STS): Area under the Plasma Concentration Time Curve from time 0 to 24 hours (AUC0-24)		Cycles 1, 2, 3, and 5 of the first continuous 21-day cycles of combination therapy
Secondary	Phase 1b: PK of tazemetostat when administered in combination with doxorubicin in participants with STS: Area under the Plasma Concentration Time Curve From time 0 to the last observable concentration (AUC0- last)		Cycles 1, 2, 3, and 5 of the first continuous 21-day cycles of combination therapy
Secondary	Phase 1b: PK of tazemetostat when administered in combination with doxorubicin in Pparticipants with STS: The maximum observed concentration (Cmax).		Cycles 1, 2, 3, and 5 of the first continuous 21-day cycles of combination therapy
Secondary	Phase 3: Overall Survival (OS)		Through study completion, an average of two years.
Secondary	Phase 3: Incidence of Adverse Events (AEs)	All AEs, including clinically significant laboratory parameters will be graded by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE)	Through study completion, an average of two years.
Secondary	Phase 3: PFS	Assessed by the investigator	Through study completion, an average of two years.
Secondary	Disease control rate (DCR)	Defined as the number of participants who achieve response complete response (CR) + partial response (PR) or who have stable disease (SD)	Through study completion, an average of two years
Secondary	Objective response rate (ORR)	ORR is defined as the proportion of participants achieving complete or partial response. Determined based on the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1	Through study completion, an average of two years
Secondary	Duration of treatment (DOR)	Defined as the time from first documented evidence of CR or PR to the time of first documented disease progression or death, whichever occurs first	Through study completion, an average of two years
Secondary	Change from baseline in European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQC-30)	The EORTC QLQC-30 physical function, role function, and global health status domains will be assessed	Through study completion, an average of two years
Secondary	PFS2	Defined as time from randomization to objective tumor progression on next-line treatment or death, whichever occurs first	Through study completion, an average of two years
Secondary	Time to first subsequent anti-cancer therapy ((TFST	Defined as the time from randomization to the time to first subsequent therapy	Through study completion, an average of two years
Secondary	Population PK parameters of tazemetostat when administered in combination with doxorubicin: Oral clearance (CL/F)	CL/F is defined as the apparent oral clearance following administration of tazemetostat when administered in combination with doxorubicin	Cycles 1, 2, 3, and 5 of the first continuous 21-day cycles of combination therapy
Secondary	Population PK parameters of tazemetostat when administered in combination with doxorubicin: oral volume of distribution (Vss).		Cycles 1, 2, 3, and 5 of the first continuous 21-day cycles of combination therapy
Secondary	Population PK parameters of tazemetostat when administered in combination with doxorubicin: Area Under the Curve at steady state (AUCss)		Cycles 1, 2, 3, and 5 of the first continuous 21-day cycles of combination therapy
Secondary	Population PK parameters of tazemetostat when administered in combination with doxorubicin: trough concentration (Ctrough)		Cycles 1, 2, 3, and 5 of the first continuous 21-day cycles of combination therapy
Secondary	Population PK parameters of tazemetostat when administered in combination with doxorubicin: Cmax		Cycles 1, 2, 3, and 5 of the first continuous 21-day cycles of combination therapy