An Open-label, Dose Escalation Trial to Evaluate the Safety and Pharmacokinetics of HMPL-523 in Patients With Lymphoma

NCT03779113 | Terminated Phase 1 Results FDA Drug

• 1 other identifier: 2018-523-00US1
• Study Type: interventional
• Target: 69
• Locations: 7 countries
• Sites: 32

Brief Summary

This is a Phase I, open-label, multicenter study of HMPL-523 administered orally to patients with relapsed or refractory lymphoma who have exhausted approved therapy options. This study consists of a dose escalation stage (Stage1) and a dose expansion stage (Stage 2).

Conditions

Non Hodgkin Lymphoma

Keywords

lymphoma; chronic lymphocytic leukemia; Hodgkin lymphoma

Outcome Measures

Primary Outcomes (9)

• Dose Escalation Stage: Number of Patients With Dose-Limiting Toxicities (DLTs)

  A DLT was defined as the occurrence of any of the following treatment-emergent adverse events (TEAEs) during the DLT assessment window, unless clearly unrelated to the study treatment. AEs were graded using National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0: non-hematologic toxicity: all non-hematologic TEAEs of Grade 3 or greater with the exception of Grade 3 nausea or vomiting controlled by supportive therapy; hematologic toxicity: Grade 4 neutropenia \>5 days, Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding or which required platelets transfusion, Grade \>=3 febrile neutropenia (defined as absolute neutrophil count \<1000/cubic millimeter with a single temperature \>38.3 degree Celsius \[°C\] or a sustained temperature of \>=38°C for more than 1 hour), Grade 4 anemia not explained by underlying disease; any TEAE that required a dose delay of \>=15 days; any case of Hy's Law.

  From the first dose of study treatment (Day 1) up to Day 28 of Cycle 1 (each cycle was 28 days)

• Dose Escalation Stage: Number of Patients With Treatment-Emergent Adverse Events, Treatment Related Treatment-Emergent Adverse Events, Treatment-Emergent Adverse Events Leading to Treatment Interruption, Treatment Reduction and Treatment Discontinuation

  An AE was any untoward medical occurrence in a clinical study patient temporally associated with the use of a study treatment, whether or not considered related to the treatment. TEAEs were defined as AEs with an onset date on or after the first dose of study treatment and no later than 30 days after the date of last study treatment administration or start of a new treatment of anti-neoplasm therapy, whichever was earlier. Treatment related AEs were the TEAEs that were reported as related to study treatment by the Investigator.

  From the first dose of study treatment (Day 1) up to 30 days after the last dose of study treatment, approximately 29 months

• Dose Escalation Stage: Recommended Phase 2 Dose of HMPL-523

  RP2D was based on the pharmacokinetics (PK), safety, and tolerability assessments in dose escalation stage patients.

  From the first dose of study treatment (Day 1) up to Day 28 of Cycle 1 (each cycle was 28 days)

• Dose Expansion Stage: Objective Response Rate (ORR)

  ORR:percentage of patients who had best overall response (BOR) with complete response (CR),CR with incomplete marrow recovery (CRi),nodular partial response (nPR) or PR for CLL patients; CR, very good PR(VGPR), PR or minor response(MR) for WM patients; CR or PR for patients with disease type other than CLL and WM. BOR:best response from start of treatment until progression or any further anticancer therapy.CR:absence of serum(S) monoclonal immunoglobulin (Ig)M, normal S IgM, complete resolution of extramedullary disease,morphologically normal bone marrow aspirate and trephine biopsy. CRi:criteria fulfilled for CR but persistent cytopenia, anemia, thrombocytopenia or neutropenia. nPR:patients with residual CLL cells. PR, VGPR, MR:detectable monoclonal IgM,no new signs/symptoms of active disease and PR:\>=50% but \<90% reduction in S IgM,reduction in extramedullary disease,VGPR: \>=90% reduction in S IgM, complete resolution of extramedullary disease, MR: \>=25% but \<50% reduction in S IgM.

  Tumor assessments performed every 8 weeks (+/-7 days) for the first 24 weeks and every 12 weeks (+/-7 days) thereafter until first progression, initiation of new anticancer therapy or death. Approximately 42 months

• Dose Expansion Stage: Complete Response Rate

  CR rate was defined as the percentage of patients who had BOR with CR or CRi for CLL patients, and CR only for other patients. BOR was defined as the best response from start of treatment until progression or any further anticancer therapy. CR was defined as the absence of serum monoclonal IgM, normal serum IgM, complete resolution of extramedullary disease, morphologically normal bone marrow aspirate and trephine biopsy. CRi was defined as the criteria fulfilled for CR but persistent cytopenia, anemia, thrombocytopenia or neutropenia.

  Tumor assessments performed every 8 weeks (+/-7 days) for the first 24 weeks and every 12 weeks (+/-7 days) thereafter until first progression, initiation of new anticancer therapy or death. Approximately 42 months

• Dose Expansion Stage: Clinical Benefit Rate (CBR)

  CBR was defined as the percentage of patients who had BOR of stable disease (SD) or better. BOR was defined as the best response from start of treatment until progression or any further anticancer therapy. SD was defined as detectable monoclonal IgM, \<25% reduction and \<25% increase in serum IgM level, no progression in extramedullary disease, no new signs/symptoms of active disease.

  Tumor assessments performed every 8 weeks (+/-7 days) for the first 24 weeks and every 12 weeks (+/-7 days) thereafter until first progression, initiation of new anticancer therapy or death. Approximately 42 months

• Dose Expansion Stage: Duration of Response (DOR)

  DOR: time from when first response (CR, CRi, PR, nPR, VGPR, PR-L, and MR) was achieved until earlier of first documentation of definitive PD or death from any cause. CR: absence of S monoclonal IgM, normal S IgM, complete resolution of extramedullary disease, morphologically normal bone marrow aspirate and trephine biopsy. CRi: criteria fulfilled for CR but persistent cytopenia, anemia, thrombocytopenia or neutropenia. nPR: patients with residual CLL cells. PR-L: patients achieved PR with CLL-related signs/symptoms other than lymphocytosis and continued on therapy. PR, VGPR,MR:detectable monoclonal IgM,no new signs/symptoms of active disease and PR: \>=50% but \<90% reduction in S IgM,reduction in extramedullary disease,VGPR: \>=90% reduction in S IgM,complete resolution of extramedullary disease,MR: \>=25% but \<50% reduction in S IgM. PD: \>=25% increase in S IgM level from lowest nadir and/or progression in clinical features attributable to disease.

  Tumor assessments performed every 8 weeks (+/-7 days) for the first 24 weeks and every 12 weeks (+/-7 days) thereafter until first progression, initiation of new anticancer therapy or death. Approximately 42 months

• Dose Expansion Stage: Time to Response (TTR)

  TTR was defined as the time from the first dose of study treatment to the first occurrence of CR, CRi, PR, nPR, VGPR, PR-L, or MR. CR: absence of serum monoclonal IgM, normal serum IgM, complete resolution of extramedullary disease, morphologically normal bone marrow aspirate and trephine biopsy. CRi: criteria fulfilled for CR but persistent cytopenia, anemia, thrombocytopenia or neutropenia. nPR: patients with residual CLL cells. PR-L: patients achieved PR with CLL-related signs/symptoms other than lymphocytosis and continued on therapy. PR, VGPR, MR: detectable monoclonal IgM, no new signs/symptoms of active disease and PR: \>=50% but \<90% reduction in serum IgM, reduction in extramedullary disease, VGPR: \>=90% reduction in serum IgM, complete resolution of extramedullary disease, MR: \>=25% but \<50% reduction in serum IgM. Kaplan Meier analysis included only the responders.

  Tumor assessments performed every 8 weeks (+/-7 days) for the first 24 weeks and every 12 weeks (+/-7 days) thereafter until first progression, initiation of new anticancer therapy or death. Approximately 42 months

• Dose Expansion Stage: Progression-Free Survival (PFS)

  PFS was defined as the time from the date of first study treatment to the earliest date of PD or death due to any reason whichever occurred first. PD was defined as \>=25% increase in serum IgM level from lowest nadir and/or progression in clinical features attributable to disease.

  Tumor assessments performed every 8 weeks (+/-7 days) for the first 24 weeks and every 12 weeks (+/-7 days) thereafter until first progression, initiation of new anticancer therapy or death. Approximately 42 months

Secondary Outcomes (17)

• Dose Escalation Stage and Dose Expansion Stage: Maximum Plasma Concentration (Cmax) of HMPL-523

  Dose escalation: Pre-dose and 0.5, 1, 2, 4, 6, 8 hours post-dose on Days 1, 15 and 28 of Cycle 1; Dose expansion: Pre-dose and 0.5, 1, 2, 4, 6, 8 hours post-dose on Days 1 and 28 of Cycle 1

• Dose Escalation Stage and Dose Expansion Stage: Time to Reach Maximum Plasma Concentration (Tmax) of HMPL-523

  Dose escalation: Pre-dose and 0.5, 1, 2, 4, 6, 8 hours post-dose on Days 1, 15 and 28 of Cycle 1; Dose expansion: Pre-dose and 0.5, 1, 2, 4, 6, 8 hours post-dose on Days 1 and 28 of Cycle 1

• Dose Escalation Stage and Dose Expansion Stage: Area Under the Concentration-Time Curve From Time Zero (Pre-Dose) to Time of Last Quantifiable Concentration (AUC0-t) of HMPL-523

  Dose escalation and dose expansion: Pre-dose and 0.5, 1, 2, 4, 6, 8 hours post-dose on Day 1 of Cycle 1

• Dose Escalation Stage and Dose Expansion Stage: Area Under the Concentration-Time Curve During a Dosing Interval (AUCtau) of HMPL-523

  Dose escalation: Pre-dose and 0.5, 1, 2, 4, 6, 8 hours post-dose on Days 1, 15 and 28 of Cycle 1; Dose expansion: Pre-dose and 0.5, 1, 2, 4, 6, 8 hours post-dose on Days 1 and 28 of Cycle 1

• Dose Escalation Stage and Dose Expansion Stage: Apparent Systemic Clearance (CL/F) of HMPL-523

  Dose escalation: Pre-dose and 0.5, 1, 2, 4, 6, 8 hours post-dose on Days 15 and 28 of Cycle 1; Dose expansion: Pre-dose and 0.5, 1, 2, 4, 6, 8 hours post-dose on Day 28 of Cycle 1

Study Arms (1)

Treatment

EXPERIMENTAL

All patients to received study drug (HMPL-523)

Drug: HMPL-523

Interventions

HMPL-523 DRUG

Oral HMPL-523

Treatment

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must meet the following criteria to be eligible for study entry:
• Signed informed consent form (ICF).
• Age ≥18 years.
• ECOG performance status of 0 or 1.
• Histologically confirmed lymphoma, including Hodgkin's lymphoma and non-Hodgkin's lymphoma. In the dose expansion stage, the tumor types may be restricted to any or all of the following tumor types. There may be approximately 10 patients in each cohort depending on response signals suggesting efficacy, except for 2 identified cohorts with approximately 20 patients per cohort: relapsed or refractory CLL/SLL, CLL/SLL post-BTK exposure (n=20), MCL, FL (Grade 1-3a) (n=20), MZL, WM/LPL, PTCL,CBCL, and/or HL
• Patients with relapsed or refractory lymphoma who have exhausted all approved therapy options.
• In the dose expansion stage, patients must have measurable disease for an objective response assessment, except for patients with CLL and WM/LPL
• Availability of tumor sample for patients in dose expansion cohorts: This may be an archival tissue sample obtained after most recent therapy or a fresh biopsy; if tumor sample is not available, the Sponsor may waive the requirement after discussion
• Expected survival of more than 24 weeks as determined by the investigator.
• Male patients must agree to use a condom and female patients of childbearing potential must agree to use highly effective contraceptive measures for 30 days after the last dose of study drug. These include as combined hormonal contraception associated with inhibition of ovulation (oral, intravaginal, and transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, and implantable), intrauterine contraceptive device, intrauterine hormone release system, bilateral tubal occlusion, or a vasectomized partner, provided that male partner is the sole sexual partner of the female patient. Postmenopausal females (women who have not had menses for at least 1 year without an alternative medical cause) are exempt from this criterion.

You may not qualify if:

• Patients with primary central nervous system (CNS) lymphoma.
• Any of the following laboratory abnormalities: Absolute neutrophil count\<1.0×10\^9/L, Hemoglobin \<80 g/L, Platelets \<50×10\^9/L
• Inadequate organ function, defined by the following: Total bilirubin \>1.5 times the upper limit of normal (× ULN), aspartate aminotransferase and/or alanine aminotransferase \>2.5 × ULN, Estimated Creatinine Clearance (CrCl) per Cockcroft-Gault \[Dose Escalation portion of trial (Stage 1) CrCl \< 40 mL/min, Dose Expansion portion of trial (Stage 2) CrCl \< 30 mL/min\], Serum amylase or lipase \>ULN, International normalized ratio \>1.5 × ULN, or activated partial thromboplastin time \>1.5 × ULN
• Patients with clinically detectable second primary malignant tumors at enrollment or other malignant tumors within the last 2 years (with the exception of radically treated basal cell or squamous cell carcinoma of the skin, in situ cervix, or in situ breast cancer).
• Any anticancer therapy, including chemotherapy, hormonal therapy, biologic therapy, vaccine, or radiotherapy within 3 weeks prior to the initiation of study treatment.
• Herbal therapy within 1 week prior to the initiation of study treatment.
• Prior use of any anti-cancer vaccine
• Prior treatment with any spleen tyrosine kinase (SYK) inhibitors (eg, fostamatinib)
• Prior administration of radioimmunotherapy within 3 months before initiation of study treatment.
• Use of strong cytochrome P450 isoform 3A inhibitors and inducers and drugs metabolized by cytochrome P450 isoform 3A, cytochrome P450 isoform 2B6, and cytochrome P450 isoform 1A2, and are identified as narrow therapeutic drugs within 7 days or 3 half-lives, whichever is longer, prior to initiation of study treatment
• Adverse events from prior anticancer therapy that have not resolved to Grade ≤1, except for alopecia.
• Prior autologous stem cell transplant within 6 months prior to the initiation of study treatment.
• Prior allogeneic stem cell transplant within 6 months prior to the initiation of study treatment or with any evidence of active graft versus host disease or requirement for immunosuppressants within 28 days prior to the initiation of study treatment.
• Clinically significant active infection (eg, pneumonia).
• Major surgical procedure within 4 weeks prior to the initiation of study treatment.

Sponsors & Collaborators

• Hutchmed: lead

Study Sites (32)

Pacific Cancer Medical Center, Inc.

Anaheim, California, 92801, United States

Location

Innovative Clinical Research Institute

Downey, California, 90241, United States

Location

Ventura County Hematology-Oncology Specialists

Oxnard, California, 93030, United States

Location

Summit Medical Group

Florham Park, New Jersey, 07932, United States

Location

Clinical Research Alliance

New Hyde Park, New York, 11042, United States

Location

Leo Jenkins Cancer Center/ECU School of Medicine

Greenville, North Carolina, 27834, United States

Location

The University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Renovatio Clinical

The Woodlands, Texas, 77380, United States

Location

Aarhus University Hospital

Aarhus, Denmark

Location

Helsingin yliopistollinen keskussairaala

Helsinki, 00029, Finland

Location

Tampereen yliopistollinen sairaala

Tampere, 33520, Finland

Location

CHU Clermont Ferrand - Hôpital d'Estaing

Clermont-Ferrand, France

Location

Hôpital Henri Mondor

Créteil, France

Location

Groupe Hospitalier Pitie-Salpetriere

Paris, France

Location

CHU Poitiers - Hôpital la Milétrie

Poitiers, France

Location

Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII (Presidio Papa Giovanni XXIII)

Bergamo, Bergamo, 24127, Italy

Location

Ospedale San Raffaele

Milan, Milano, 20132, Italy

Location

Azienda Socio Sanitaria Territoriale di Monza (Presidio San Gerardo)

Monza, Italy

Location

KO-MED Centra Kliniczne

Biała Podlaska, Poland

Location

Uniwersyteckie Centrum Kliniczne

Gdansk, Poland

Location

Nasz Lekarz Przychodnie Medyczne

Torun, Poland

Location

Uniwersytecki Szpital Kliniczny im. Jana Mikulicza Radeckiego

Wroclaw, 50566, Poland

Location

Hospital Universitari Vall d'Hebron

Barcelona, Spain

Location

ICO Badalona - Hospital Universitari Germans Trias i Pujol

Barcelona, Spain

Location

Institut Català d'Oncologia

Barcelona, Spain

Location

Hospital Universitario Ramon y Cajal

Madrid, 28034, Spain

Location

Fundacion Jimenez Diaz

Madrid, Spain

Location

Hospital Universitario Infanta Leonor

Madrid, Spain

Location

Hospital Universitario Quironsalud Madrid

Madrid, Spain

Location

MD Anderson Cancer Centre

Madrid, Spain

Location

Hospital Universitario Virgen del Rocio

Seville, Spain

Location

Hospital Universitario Virgen Macarena

Seville, Spain

Location

MeSH Terms

Conditions

Lymphoma, Non-Hodgkin; Lymphoma; Leukemia, Lymphocytic, Chronic, B-Cell; Hodgkin Disease

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Hematologic Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Limitations and Caveats

The study was terminated based on strategic decision made by the Sponsor to discontinue development of HMPL-523 for lymphoma in the United States, Europe, and Australia with no safety concerns.

Results Point of Contact

• Title: Kuan Sheng, MD
• Organization: HUTCHMED Limited

kuans@hutch-med.com

001-201-704-3352

Study Officials

• Michael Shi, MD

  Hutchmed

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 10, 2018
• First Posted: December 19, 2018
• Study Start: September 26, 2019
• Primary Completion: February 26, 2025
• Study Completion: February 26, 2025
• Last Updated: February 18, 2026
• Results First Posted: February 18, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

IT (3); PL (4); ES (10); US (8); DK (1); FI (2); FR (4)