HMPL-760 Safety and Tolerability Study in Patients With Previously Treated CLL/SLL or NHL

Phase 1

Withdrawn

• Conditions: Waldenstrom Macroglobulinemia; Follicular Lymphoma; MZL; CLL/SLL; NHL; Lymphoplasmacytic Lymphoma; Richter Syndrome; MCL; DLBCL
• Interventions: Drug: HMPL-760

• Registration Number: NCT05176691
• Lead Sponsor: Hutchmed

Brief Summary

An open label single-arm clinical trial to evaluate the safety, tolerability, PK, PD, and preliminary efficacy of HMPL-760 in patients with previously treated CLL/SLL or NHL

Detailed Description

HMPL-760 is a highly potent, selective, and reversible inhibitor against BTK, which would be studied in B-cell malignancy carrying either BTK(WT) or BTK(C481S).

This is a phase 1, open-label, multicenter, single-arm study to evaluate safety, tolerability, PK, PD, and preliminary efficacy of HMPL-760 in patients with previously treated CLL/SLL or NHL

The study consists of 2 parts:

Part 1- Dose Escalation to determine MTD and/or RP2D of HMPL-760

Part 2- Dose Expansion to characterize the safety and tolerability of HMPL-760

Study Timeline

• Study First Submitted: 2021-11-19
• Study First Submitted QC: 2021-12-14
• Study First Posted: 2022-01-04
• Study Start: 2022-02-15
• Primary Completion: 2022-11-16
• Study Completion: 2022-11-16
• Status Verified: 2023-02
• Last Update Submitted: 2023-02-17
• Last Update Posted: 2023-02-21

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: Not specified

Inclusion Criteria

• ECOG performance status of 0 or 1;
• Histologically confirmed NHL or CLL with disease progression or intolerance to either ≥2 prior regimens. Patients with CLL/SLL and indolent NHL must meet criteria for systemic therapy. Patients with gastric extranodal MZL who are H. pylori positive must have failed H. pylori eradication therapy.
• Availability of tumor sample: This may be an archival tissue sample obtained after most recent therapy or a fresh biopsy; if tumor sample is not available for patients in dose escalation, the Sponsor may waive the requirement after discussion.
• Dose expansion stage only: Patients must have been treated with 1 prior regimen containing a BTK inhibitor in cohorts 1 to 5;
• Expected survival of more than 24 weeks as determined by the Investigator.

Exclusion Criteria

• Patients with primary central nervous system lymphoma.

• Any of the following laboratory abnormalities:

  • Absolute neutrophil count (ANC) <0.75×109/L
  • Hemoglobin <8 mg/L
  • Platelets <50×109/L
  • Note: In the dose expansion stage, patients with cell counts below the thresholds listed above may be considered eligible if there is documented bone marrow infiltration and Sponsor approval

• Inadequate organ function

• International normalized ratio (INR) >1.5×ULN, activated partial thromboplastin time (aPTT) >1.5×ULN

  • Patients requiring anticoagulation therapy (except vitamin K antagonists [ie, warfarin]) but with a stable INR within the recommended range according to the local guideline are eligible.

• Patients with presence of second primary malignant tumors within the last 2 years, with the exception of the following:

  • Basal cell carcinoma of the skin
  • Squamous cell carcinoma of the skin
  • Carcinoma in situ of the cervix
  • Carcinoma in situ of the breast

• Clinically significant history of liver disease, including cirrhosis or current known active infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), or cytomegalovirus (CMV).

• Cancer therapy, including chemotherapy, hormonal therapy, biologic therapy, vaccine, or radiotherapy within 3 weeks prior to initiation of study treatment. For oral targeted therapies, a washout period of 5 half-lives of the agent (minimum 3 days) prior to the initiation of study treatment can be used.

• Any granulocyte colony-stimulating factor treatment/blood transfusion within 7 days before the screening hematology test.

• Prior use of any drug that is a strong inducer or inhibitor of CYP3A4 within 2 weeks prior to initiation of study treatment.

• Prior use of proton pump inhibitors (PPIs) within 5 days of study treatment

• Any transplant within 100 days prior to initiation of study treatment

• Clinically significant active infection or with an unexplained fever.

• Treatment within a clinical study of an investigational agent or using an investigational device within 3 weeks prior to initiation of the current study treatment.

• AEs from prior antineoplastic therapy that have not resolved to grade <1

• Pregnant (positive urine or serum beta human chorionic gonadotropin test) or lactating women.

• New Your Heart Association (NYHA) class II or greater congestive heart failure.

NOTE: Only key inclusion/exclusion criteria are listed. Full details are in the protocol.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment	HMPL-760	All patients to receive HMPL-760 daily.

Primary Outcome Measures

Name	Time	Method
MTD	From 1st dose to within 30 days of last dose	To evaluate maximum tolerated dose of HMPL-760 in subjects, if reached
Incidence of DLTs	Up to 28 days after first dose of study drug	Adverse event (AE) that meets protocol defined DLT criteria during dose escalation
Incidence of AEs/SAEs	From 1st dose to within 30 days of last dose	Any untoward medical occurrence associated with the use of study drug
RP2D	From 1st dose to within 30 days of last dose	To determine recommended phase 2 dose of HMPL-760 in subjects

Secondary Outcome Measures

Name	Time	Method
Objective Response Rate (ORR)	From 1st dose of study drug to the time of progressive disease, assessed up to 36 months	ORR is defined as the proportion of subjects achieving partial response and better response during the study
Duration of Response (DoR)	From first dose of study drug to the time of progressive disease, assessed up to 36 months	DoR is defined as the time between the initial response to therapy and subsequent disease progression or relapse.
Clinical Benefit Rate (CBR)	From 1st dose of study drug to the time of progressive disease, assessed up to 36 months	CBR is defined as the proportion of subjects achieving objective response or stable disease
Progression-free Survival (PFS)	From 1st dose of study drug to the time of progressive disease, assessed up to 36 months	PFS is defined as survival without progression of the disease
Maximum Plasma Concentration [Cmax]	From 1st dose to within 30 days of last dose	To determine the maximum observed plasma concentration of HMPL-760
Chemokines	From 1st dose to within 30 days of last dose	To observe blood plasma concentrations of chemokines such as CCL22 and CCL3
Phospho-BTK	From 1st dose to within 30 days of last dose	To observe the whole blood concentrations of phospho-BTK

Trial Locations

Locations (35)

MICS Centrum Medyczne Torun; 🇵🇱 Toruń, Poland

Rabin Medical Center-Beilinson Campus; 🇮🇱 Petach-Tikva, Israel

Tel Aviv Sourasky Medical Center; 🇮🇱 Tel Aviv, Israel

Chaim Sheba Medical Center; 🇮🇱 Ramat Gan, Israel

Centrum Medyczne Pratia Poznan; 🇵🇱 Skórzewo, Poland

Emory University Hospital; 🇺🇸 Atlanta, Georgia, United States

Royal Adelaide Hospital; 🇦🇺 Adelaide, South Australia, Australia

Innovative Clinical Research; 🇺🇸 Anaheim, California, United States

Oncology Consultants, P.A.; 🇺🇸 Houston, Texas, United States

MD Anderson Cancer Centre; 🇪🇸 Madrid, Spain

AMR Kansas City, Formerly Center for Pharmaceutical Research, an AMR company; 🇺🇸 Kansas City, Missouri, United States

Groupe Hospitalier Pitie-Salpetriere; 🇫🇷 Paris cedex 13, Paris, France

CHU Poitiers - Hôpital la Milétrie; 🇫🇷 Poitiers, Vienne, France

Center For Advanced Medicine; 🇺🇸 Saint Louis, Missouri, United States

Hospital Universitario Ramon y Cajal; 🇪🇸 Madrid, Spain

Hospital Universitario Quironsalud Madrid; 🇪🇸 Pozuelo de Alarcon, Madrid, Spain

Clinical Research Alliance; 🇺🇸 Westbury, New York, United States

Johns Hopkins Clinical Research Center; 🇺🇸 Baltimore, Maryland, United States

Renovatio Clinical; 🇺🇸 The Woodlands, Texas, United States

Centre Antoine Lacassagne; 🇫🇷 Nice, Alpes Maritimes, France

Hôpital Saint-Antoine; 🇫🇷 Paris cedex 12, Paris, France

Fondazione Policlinico Universitario Agostino Gemelli IRCCS; 🇮🇹 Lazio, Roma, Italy

Fondazione del Piemonte per l'Oncologia IRCC Candiolo; 🇮🇹 Candiolo, Torino, Italy

Azienda Ospedaliera Universitaria Policlinico Sant'Orsola Malpighi IRCCS; 🇮🇹 Bologna, Italy

Institut Gustave Roussy; 🇫🇷 Villejuif cedex, Val De Marne, France

Summit Medical Group; 🇺🇸 Florham Park, New Jersey, United States

New York University Langone Med Center. Lab; 🇺🇸 New York, New York, United States

Fondazione IRCCS CA' Granda Ospedale Maggiore Policlinico; 🇮🇹 Milano, Italy

Pratia Onkologia Katowice; 🇵🇱 Katowice, Poland

ICO l'Hospitalet - Hospital Duran i Reynals; 🇪🇸 L'Hospitalet de Llobregat, Barcelona, Spain

Wojewodzki Szpital Specjalistyczny w Legnicy; 🇵🇱 Legnica, Poland

Hospital del Mar; 🇪🇸 Barcelona, Spain

Tulane Cancer Center; 🇺🇸 New Orleans, Louisiana, United States

Hadassah University Hospital - Ein Kerem; 🇮🇱 Jerusalem, Israel

Hospital Universitario Virgen del Rocio; 🇪🇸 Seville, Sevilla, Spain