A Study of Tazemetostat in Combination With HMPL-689 in Patients With Relapsed/Refractory Lymphoma

March 29, 2023 updated by: Hutchmed

A Phase II Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of Tazemetostat in Combination With HMPL-689 in Patients With Relapsed/Refractory Lymphoma

A phase II clinical study of tazemetostat combined with HMPL-689 in patients with R/R lymphoma. The study includes 2 phases: dose escalation phase (phase IIa) and expansion phase (phase IIb).

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Dose Escalation Phase (Phase IIa ):Including 10-20 patients for dose escalation, the enrollment will continue until about 10 patients in the dose group with response, as to determine Recommended Phase II dose (RP2D).

Dose Expansion Phase (Phase IIb):Multiple expansion cohorts will be set up according to different tumor types, and about 15-20 patients will be enrolled in each cohort to further observe the anti-tumor effect of Tazemetostat combined with HMPL-689 in different pathological types of R/R lymphoma.

This study is expected to enroll 85-140 patients total in Phase IIa and phase IIb.

Study Type

Interventional

Enrollment (Anticipated)

140

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • China
      • Shanghai, China
        • Recruiting
        • Ruijin Hospital, Shanghai Jiaotong University School Of Medicine

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Criteria: Inclusion Criteria:

  1. Willing and able to give informed consent, as documented by signed ICF
  2. Age ≥ 18 years

  3. Patients with histologically confirmed R/R lymphoma:

    • Phase IIa （dose escalation study）: patients with relapsed or refractory lymphoma who have failed standard treatment and have no standard treatment options

    • Phase IIb（ expansion Study ）: Cohort 1 (DLBCL, FL 3b) Histologically confirmed DLBCL, FL 3b (including primary mediastinal B-cell lymphoma) with relapsed/refractory disease

    Cohort 2 (FL) patients with histologically confirmed R/R FL (Grade 1, 2, 3a)

    Cohort 3 (MCL): Patients with R/R MCL who had prior therapies

    Cohort 4 (PTCL): Patients with histologically confirmed R/R PTCL who have failed or cannot tolerate standard therapy

  4. Patients must have at least one measurable lesion
  5. Life expectancy ≥ 12 weeks
  6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
  7. Adequate bone marrow function, renal function and hepatic function:
  8. Currently human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), or cytomegalovirus (CMV) is inactive
  9. Female patients of childbearing potential must agree to use a double contraception method and male patients with partners of childbearing potential must also use an effective double contraception method during the study period and for 3 months after the final dose

Exclusion Criteria:

  1. Patients who have previously used EZH2 inhibitors and PI3K inhibitors, or previously could not tolerate EZH2 inhibitors or PI3K inhibitors
  2. Patients with brain metastases or leptomeningeal invasion
  3. Has thrombocytopenia, neutropenia, or anemia of Grade ≥3 (per CTCAE 5.0 criteria) and any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS / AML/MPN)
  4. Has abnormalities known to be associated with MDS (e.g. del 5q, chr 7 abn) and multiple primary neoplasms (MPN) (e.g. JAK2 V617F) observed in cytogenetic testing and DNA sequencing

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: tazemetostat combined with HMP689 open-label treatment arm

Dose Escalation Phase (Phase IIa):

patients with relapsed or refractory lymphoma who have failed standard treatment and have no standard treatment options

Dose Expansion Phase (Phase IIb):

Cohort 1 (DLBCL, FL 3b): Histologically confirmed DLBCL, FL 3b (including primary mediastinal B-cell lymphoma) with relapsed/refractory disease ；

Cohort 2 (FL) patients with histologically confirmed R/R FL (Grade 1, 2, 3a)；

Cohort 3 (MCL): Patients with R/R MCL who had prior therapies ；

Cohort 4 (PTCL): Patients with histologically confirmed R/R PTCL who have failed or cannot tolerate standard therapy
Drug: tazemetostat

Dose Escalation Phase (Phase IIa):

Tazemetostat (800 mg BID orally) in a therapeutic cycle of 28 days;

Dose Expansion Phase (Phase IIb):

Tazemetostat (800 mg BID orally) in a therapeutic cycle of 28 days

Drug: HMPL-689

Dose Escalation Phase (Phase IIa):

HMPL-689:20 mg and 30 mg, QD orally in a therapeutic cycle of 28 days.

Dose Expansion Phase (Phase IIb):

HMPL-689 (RP2D) in a therapeutic cycle of 28 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Dose Escalation Phase (Phase IIa):To evaluate the safety, tolerability, and determine the maximum tolerated dose (MTD) and/or RP2D of Tazemetostat in combination with HMPL-689 in patients with R/R lymphoma
Time Frame: from Cycle 1 Day 1 up to Cycle 1 Day 28 (each cycle is 28 days)
Occurrence of Dose Limiting Toxicities (DLTs) During the DLT Observation Period
from Cycle 1 Day 1 up to Cycle 1 Day 28 (each cycle is 28 days)
Dose Expansion Phase (Phase IIb):To evaluate the ORR of Tazemetostat in combination with HMPL-689 in patients with lymphoma
Time Frame: from Cycle 1 Day 1 to PFS (each cycle is 28 days)
Percentage of patients with Complete Response(CR) or Partial Response(PR) as the best response evaluated in accordance with Lugano2014
from Cycle 1 Day 1 to PFS (each cycle is 28 days)
Dose Expansion Phase (Phase IIb):To evaluate the DCR of Tazemetostat in combination with HMPL-689 in patients with lymphoma
Time Frame: from Cycle 1 Day 1 to PFS (each cycle is 28 days)
the proportion of patients with CR or PR or stable disease (SD) as the best response with Lugano2014
from Cycle 1 Day 1 to PFS (each cycle is 28 days)
Dose Expansion Phase (Phase IIb):To evaluate the DOR of Tazemetostat in combination with HMPL-689 in patients with lymphoma
Time Frame: from Cycle 1 Day 1 to PFS (each cycle is 28 days)
as the time from the first appearance of CR or PR to PD or death for any reason (whichever comes first), in the patients with objective response with Lugano2014)
from Cycle 1 Day 1 to PFS (each cycle is 28 days)
Dose Expansion Phase (Phase IIb):To evaluate the PFS of Tazemetostat in combination with HMPL-689 in patients with lymphoma
Time Frame: from Cycle 1 Day 1 to PFS (each cycle is 28 days)
the proportion of patients with CR or PR or stable disease (SD) as the best response with Lugano2014
from Cycle 1 Day 1 to PFS (each cycle is 28 days)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Dose Escalation Phase (Phase IIa):Objective Response Rate (ORR)
Time Frame: From baseline to final assessment at end of safety follow-up visit(through study completion, an average of 2 years)
Percentage of patients with Complete Response (CR) or Partial Response (PR) as the best response evaluated in accordance with Lugano 2014
From baseline to final assessment at end of safety follow-up visit(through study completion, an average of 2 years)
Dose Escalation Phase (Phase IIa)-Complete Response Rate (CR rate)
Time Frame: From baseline to final assessment at end of safety follow-up visit(through study completion, an average of 2 years)
Percentage of patients with Complete Response (CR) as the best response evaluated in accordance with Lugano 2014
From baseline to final assessment at end of safety follow-up visit(through study completion, an average of 2 years)
Dose Escalation Phase (Phase IIa)-Disease control rate (DCR)
Time Frame: From baseline to final assessment at end of safety follow-up visit(through study completion, an average of 2 years)
the proportion of patients with CR or PR or stable disease (SD) as the best response
From baseline to final assessment at end of safety follow-up visit(through study completion, an average of 2 years)
Dose Escalation Phase (Phase IIa)-Duration of response (DoR)
Time Frame: From baseline to final assessment at end of safety follow-up visit(through study completion, an average of 2 years)
as the time from the first appearance of CR or PR to PD or death for any reason (whichever comes first), in the patients with objective response
From baseline to final assessment at end of safety follow-up visit(through study completion, an average of 2 years)
Dose Escalation Phase (Phase IIa)-Time to response (TTR)
Time Frame: From baseline to final assessment at end of safety follow-up visit(through study completion, an average of 2 years)
the time from the first dose of Tazemetostat in combination with HMPL-689 to the first objective response
From baseline to final assessment at end of safety follow-up visit(through study completion, an average of 2 years)
Dose Escalation Phase (Phase IIa)-Progression-free survival (PFS)
Time Frame: From baseline to final assessment at end of safety follow-up visit(through study completion, an average of 2 years)
time from the first dose of study treatment to PD or death for any reason, whichever comes first
From baseline to final assessment at end of safety follow-up visit(through study completion, an average of 2 years)
Dose Escalation Phase (Phase IIa)-Overall survival (OS)
Time Frame: From baseline to final assessment at end of safety follow-up visit(through study completion, an average of 2 years)

time from the first dose of study treatment to death for any reason

time from the first dose of study treatment to death for any reason
From baseline to final assessment at end of safety follow-up visit(through study completion, an average of 2 years)
Dose Expansion Phase (Phase IIb)-Evaluation of Tazemetostat safety and tolerability in Combination with HMPL-689 in Patients with R/R Lymphoma
Time Frame: From baseline to final assessment at end of safety follow-up visit(through study completion, an average of 2 years)
Incidence, severity, and causality to study drug of treatment-emergent adverse events (TEAEs) as determined by the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI-CTCAE 5.0)
From baseline to final assessment at end of safety follow-up visit(through study completion, an average of 2 years)
Geomean maximum concentration (Cmax) of tazemetostat and its metabolite EPZ-6930 in blood
Time Frame: Cycle (C) 1, Day (D) 1: predose of first administration (PoFA); 0.5, 1, 2, 4, 6, 8, and 12 hours postdose. C1D15: PoFA; 0.5, 1, 2, 4, 6, 8, and 12 hours postdose. C1D2, C1D16, C2D1, C3D1 and C4D1: PoFA
Cmax is defined as the maximum observed concentration that a drug achieves in a test area of the body after the drug has been administered. Plasma concentration-time profiles of tazemetostat and EPZ-6930 will be plotted using non-compartmental analysis and will be analyzed to determine Cmax. Cmax will be summarized as the geomean and geomean CV% for all participants.
Cycle (C) 1, Day (D) 1: predose of first administration (PoFA); 0.5, 1, 2, 4, 6, 8, and 12 hours postdose. C1D15: PoFA; 0.5, 1, 2, 4, 6, 8, and 12 hours postdose. C1D2, C1D16, C2D1, C3D1 and C4D1: PoFA
Median time to reach maximum concentration (Tmax) of tazemetostat and its metabolite EPZ-6930 in blood
Time Frame: Cycle (C) 1, Day (D) 1: predose of first administration (PoFA); 0.5, 1, 2, 4, 6, 8, and 12 hours postdose. C1D15: PoFA; 0.5, 1, 2, 4, 6, 8, and 12 hours postdose. C1D2, C1D16, C2D1, C3D1 and C4D1: PoFA
Tmax is defined as the time from dosing to reach the maximum observed concentration a drug achieves in a specified compartment or test area of the body after the drug has been administered. Plasma concentration-time profiles of tazemetostat and EPZ-6930 will be plotted using non-compartmental analysis and will be analyzed to determine Tmax. Tmax will be summarized as the median (min, max) for all participants.
Cycle (C) 1, Day (D) 1: predose of first administration (PoFA); 0.5, 1, 2, 4, 6, 8, and 12 hours postdose. C1D15: PoFA; 0.5, 1, 2, 4, 6, 8, and 12 hours postdose. C1D2, C1D16, C2D1, C3D1 and C4D1: PoFA
Geomean area under the drug concentration-time curve (AUC) of tazemetostat and its metabolite EPZ-6930 after administration of tazemetostat
Time Frame: Cycle (C) 1, Day (D) 1: PoFA; 0.5, 1, 2, 4, 6, 8, and 12 hours postdose. C1D15: PoFA; 0.5, 1, 2, 4, 6, 8, and 12 hours postdose.
AUC represents the total drug exposure over a defined period of time. AUC will be calculated using the linear trapezoidal rule. Plasma concentrations of tazemetostat and EPZ-6930 will be analyzed using a non-compartmental analysis approach to determine individual participant estimates of AUC. AUC will be summarized as the geomean and geomean CV% for all participants
Cycle (C) 1, Day (D) 1: PoFA; 0.5, 1, 2, 4, 6, 8, and 12 hours postdose. C1D15: PoFA; 0.5, 1, 2, 4, 6, 8, and 12 hours postdose.
Geomean minimum observed concentration at steady-state (Cmin) of tazemetostat and its metabolite EPZ-6930 in blood
Time Frame: C1D15, C1D16, C2D1, C3D1 and C4D1: PoFA
Cmin is defined as the minimum observed concentration at steady-state during one dosing interval. Cmin will be summarized as the geomean and geomean CV% for all participants.
C1D15, C1D16, C2D1, C3D1 and C4D1: PoFA
Geomean maximum concentration (Cmax) of HMPL-689 in blood
Time Frame: Cycle (C) 1, Day (D) 1: predose of first administration (PoFA); 0.5, 1, 2, 4, 6, 8, 12 and 24 (C1D2, PoFA) hours postdose. C1D15: PoFA; 0.5, 1, 2, 4, 6, 8, 12 and 24 (C1D16, PoFA) hours postdose. C2D1, C3D1 and C4D1: PoFA
Cmax is defined as the maximum observed concentration that a drug achieves in a test area of the body after the drug has been administered. Plasma concentration-time profiles of HMPL-689 will be plotted using non-compartmental analysis and will be analyzed to determine Cmax. Cmax will be summarized as the geomean and geomean CV% for all participants.
Cycle (C) 1, Day (D) 1: predose of first administration (PoFA); 0.5, 1, 2, 4, 6, 8, 12 and 24 (C1D2, PoFA) hours postdose. C1D15: PoFA; 0.5, 1, 2, 4, 6, 8, 12 and 24 (C1D16, PoFA) hours postdose. C2D1, C3D1 and C4D1: PoFA
Median time to reach maximum concentration (Tmax) of HMPL-689 in blood
Time Frame: Cycle (C) 1, Day (D) 1: predose of first administration (PoFA); 0.5, 1, 2, 4, 6, 8, 12 and 24 (C1D2, PoFA) hours postdose. C1D15: PoFA; 0.5, 1, 2, 4, 6, 8, 12 and 24 (C1D16, PoFA) hours postdose. C2D1, C3D1 and C4D1: PoFA
Tmax is defined as the time from dosing to reach the maximum observed concentration a drug achieves in a specified compartment or test area of the body after the drug has been administered. Plasma concentration-time profiles of HMPL-689 will be plotted using non-compartmental analysis and will be analyzed to determine Tmax. Tmax will be summarized as the median (min, max) for all participants
Cycle (C) 1, Day (D) 1: predose of first administration (PoFA); 0.5, 1, 2, 4, 6, 8, 12 and 24 (C1D2, PoFA) hours postdose. C1D15: PoFA; 0.5, 1, 2, 4, 6, 8, 12 and 24 (C1D16, PoFA) hours postdose. C2D1, C3D1 and C4D1: PoFA
Geomean area under the drug concentration-time curve (AUC) of HMPL-689 after administration of HMPL-689
Time Frame: Cycle (C) 1, Day (D) 1: predose of first administration (PoFA); 0.5, 1, 2, 4, 6, 8, 12 and 24 (C1D2, PoFA) hours postdose. C1D15: PoFA; 0.5, 1, 2, 4, 6, 8, 12 and 24 (C1D16, PoFA) hours postdose
AUC represents the total drug exposure over a defined period of time. AUC will be calculated using the linear trapezoidal rule. Plasma concentrations of HMPL-689 will be analyzed using a non-compartmental analysis approach to determine individual participant estimates of AUC. AUC will be summarized as the geomean and geomean CV% for all participants.
Cycle (C) 1, Day (D) 1: predose of first administration (PoFA); 0.5, 1, 2, 4, 6, 8, 12 and 24 (C1D2, PoFA) hours postdose. C1D15: PoFA; 0.5, 1, 2, 4, 6, 8, 12 and 24 (C1D16, PoFA) hours postdose
Geomean minimum observed concentration at steady-state (Cmin) of HMPL-689 in blood
Time Frame: C1D15, C1D16, C2D1, C3D1 and C4D1: PoFA
Cmin is defined as the minimum observed concentration at steady-state during one dosing interval. Cmin will be summarized as the geomean and geomean CV% for all participants
C1D15, C1D16, C2D1, C3D1 and C4D1: PoFA
To investigate the preliminary efficacy and PK correlation
Time Frame: through study completion, an average of 2 years
The efficacy of participants as assessed by Lugano2014 from different dose groups, to assess the correlation of efficacy and PK of tazemetostat and HMPL-689
through study completion, an average of 2 years
To investigate the preliminary tolerability and PK relationship
Time Frame: through study completion, an average of 2 years
Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 from different dose groups, to assess the correlation of safety and PK of tazemetostat and HMPL-689
through study completion, an average of 2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Hutchmed

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 13, 2023

Primary Completion (Anticipated)

May 1, 2026

Study Completion (Anticipated)

December 1, 2026

Study Registration Dates

First Submitted

December 13, 2022

First Submitted That Met QC Criteria

February 2, 2023

First Posted (Actual)

February 6, 2023

Study Record Updates

Last Update Posted (Actual)

March 30, 2023

Last Update Submitted That Met QC Criteria

March 29, 2023

Last Verified

March 1, 2023

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2021-TAZ-00CH2

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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