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NCT Number: NCT05713110

A Study 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).

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Key information

Conditions

Relapsed/Refractory Lymphoma Hemic and Lymphatic Diseases Immune System Diseases Immunoproliferative Disorders Lymphatic Diseases Lymphoma Lymphoproliferative Disorders Neoplasms Neoplasms by Histologic Type

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

Ruijin Hospital, Shanghai Jiaotong University School of Medicine

Shanghai, China

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Criteria: Inclusion Criteria:

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

  • Patients must have at least one measurable lesion
  • Life expectancy ≥ 12 weeks
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
  • Adequate bone marrow function, renal function and hepatic function:
  • Currently human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), or cytomegalovirus (CMV) is inactive
  • 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

  • Patients who have previously used EZH2 inhibitors and PI3K inhibitors, or previously could not tolerate EZH2 inhibitors or PI3K inhibitors
  • Patients with brain metastases or leptomeningeal invasion
  • 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)
  • 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

Treatment and study plan

Tazemetostat

Drug

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

HMPL-689

Drug

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

Primary outcomes

  1. 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

  2. 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

  3. 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

  4. 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)

  5. 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

Secondary outcomes

  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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)

  9. 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.

  10. 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.

  11. 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

  12. 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.

  13. 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.

  14. 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

  15. 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.

  16. 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

  17. 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

  18. 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

Sponsors and collaborators

Lead sponsor

Hutchmed

Industry

Registry information

Official study title

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

Important dates

Study start
2023
Primary completion
2024
Study completion
2024
First posted
Feb 6, 2023
Registry last updated
Jan 22, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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