Clinical trial NCT05713110: A Study of Tazemetostat in Combination With HMPL-689 in Patients With Relapsed/Refractory Lymphoma
Official 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Relapsed/Refractory Lymphoma
Lead sponsor: Hutchmed
Sponsor class: INDUSTRY
First posted: 2023-02-06
Enrollment: 61
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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).

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.

Eligibility criteria: 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

Primary outcomes:
measure: 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
timeFrame: from Cycle 1 Day 1 up to Cycle 1 Day 28 (each cycle is 28 days)
measure: Dose Expansion Phase (Phase IIb):To evaluate the ORR of Tazemetostat in combination with HMPL-689 in patients with lymphoma
timeFrame: from Cycle 1 Day 1 to PFS (each cycle is 28 days)
measure: Dose Expansion Phase (Phase IIb):To evaluate the DCR of Tazemetostat in combination with HMPL-689 in patients with lymphoma
timeFrame: from Cycle 1 Day 1 to PFS (each cycle is 28 days)
measure: Dose Expansion Phase (Phase IIb):To evaluate the DOR of Tazemetostat in combination with HMPL-689 in patients with lymphoma
timeFrame: from Cycle 1 Day 1 to PFS (each cycle is 28 days)
measure: Dose Expansion Phase (Phase IIb):To evaluate the PFS of Tazemetostat in combination with HMPL-689 in patients with lymphoma
timeFrame: from Cycle 1 Day 1 to PFS (each cycle is 28 days)
Secondary outcomes:
measure: Dose Escalation Phase (Phase IIa):Objective Response Rate (ORR)
timeFrame: From baseline to final assessment at end of safety follow-up visit(through study completion, an average of 2 years)
measure: Dose Escalation Phase (Phase IIa)-Complete Response Rate (CR rate)
timeFrame: From baseline to final assessment at end of safety follow-up visit(through study completion, an average of 2 years)
measure: Dose Escalation Phase (Phase IIa)-Disease control rate (DCR)
timeFrame: From baseline to final assessment at end of safety follow-up visit(through study completion, an average of 2 years)
measure: Dose Escalation Phase (Phase IIa)-Duration of response (DoR)
timeFrame: From baseline to final assessment at end of safety follow-up visit(through study completion, an average of 2 years)
measure: Dose Escalation Phase (Phase IIa)-Time to response (TTR)
timeFrame: From baseline to final assessment at end of safety follow-up visit(through study completion, an average of 2 years)
measure: Dose Escalation Phase (Phase IIa)-Progression-free survival (PFS)
timeFrame: From baseline to final assessment at end of safety follow-up visit(through study completion, an average of 2 years)
measure: Dose Escalation Phase (Phase IIa)-Overall survival (OS)
timeFrame: From baseline to final assessment at end of safety follow-up visit(through study completion, an average of 2 years)
measure: Dose Expansion Phase (Phase IIb)-Evaluation of Tazemetostat safety and tolerability in Combination with HMPL-689 in Patients with R/R Lymphoma
timeFrame: From baseline to final assessment at end of safety follow-up visit(through study completion, an average of 2 years)
measure: Geomean maximum concentration (Cmax) of tazemetostat and its metabolite EPZ-6930 in blood
timeFrame: 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
measure: Median time to reach maximum concentration (Tmax) of tazemetostat and its metabolite EPZ-6930 in blood
timeFrame: 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
measure: Geomean area under the drug concentration-time curve (AUC) of tazemetostat and its metabolite EPZ-6930 after administration of tazemetostat
timeFrame: 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.
measure: Geomean minimum observed concentration at steady-state (Cmin) of tazemetostat and its metabolite EPZ-6930 in blood
timeFrame: C1D15, C1D16, C2D1, C3D1 and C4D1: PoFA
measure: Geomean maximum concentration (Cmax) of HMPL-689 in blood
timeFrame: 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
measure: Median time to reach maximum concentration (Tmax) of HMPL-689 in blood
timeFrame: 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
measure: Geomean area under the drug concentration-time curve (AUC) of HMPL-689 after administration of HMPL-689
timeFrame: 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
measure: Geomean minimum observed concentration at steady-state (Cmin) of HMPL-689 in blood
timeFrame: C1D15, C1D16, C2D1, C3D1 and C4D1: PoFA
measure: To investigate the preliminary efficacy and PK correlation
timeFrame: through study completion, an average of 2 years
measure: To investigate the preliminary tolerability and PK relationship
timeFrame: through study completion, an average of 2 years
Other outcomes:
Locations:
city: Shanghai
country: China
facility: Ruijin Hospital, Shanghai Jiaotong University School of Medicine
Study officials:
affiliation: Hutchison Medipharma Limited
name: Bin Yang
role: STUDY_DIRECTOR
References: