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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Relapsed/Refractory Lymphoma

Intervention / Treatment
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* Drug: tazemetostat
* Drug: HMPL-689


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention 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<br>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<br>* 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<br>Drug: HMPL-689<br>* 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<br>|

What is the study measuring?
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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 | 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 | 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 | 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 | 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 | 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) | 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) | 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) | 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) | 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) | 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 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 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 |