Trial to Evaluate the Safety and Pharmacokinetics of HMPL-689 in Patients With Lymphomas

A Phase 1, Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of HMPL-689 in Patients With Relapsed or Refractory Lymphoma

An open-label, dose escalation and expansion clinical trial to evaluate the safety, tolerability and PK of HMPL-689 in patients with relapsed or refractory lymphomas

Study Overview

• Status: Active, not recruiting
• Conditions: Lymphoma
• Intervention / Treatment: Drug: HMPL-689

Detailed Description

This is a Phase 1, open-label, multicenter study of HMPL-689 administered orally to patients with relapsed or refractory lymphoma.

HMPL-689 is a selective and potent small molecule inhibitor targeting the isoform phosphoinositide 3'-kinase delta (PI3Kδ), a key component in the B-cell receptor signaling pathway

This study will consist of a dose escalation stage (Stage 1) and a dose expansion stage (Stage 2).

Dose Escalation Stage (Stage 1):

This stage will end when any of the following criteria is met:

• The dose level 1 demonstrates an excessive toxicity, ie, 3 dose limiting toxicities (DLTs) are observed out of the first 3 patients at dose level 1.
• The maximum sample size is reached.
• The MTD and/or RP2D is confirmed.

Dose Expansion Stage (Stage 2):

To further characterize the safety and explore the preliminary anti-tumor activity of HMPL-689 at RP2D, patients with B cell lymphoma will be enrolled in the dose expansion stage.

• Study Type: Interventional
• Enrollment (Actual): 53
• Phase: Phase 1

Contacts and Locations

Study Locations

• Finland
  • Helsinki, Finland, 00029
    • Helsingin yliopistollinen keskussairaala
  • Tampere, Finland, 33520
    • Tampereen yliopistollinen sairaala
• France
  • Nantes, France, 44000
    • CHU de Nantes - Hotel Dieu
  • Pessac, France, 33604
    • CHU de Bordeaux - Hopital Haut-Leveque
  • Val De Marne
    • Créteil Cedex, Val De Marne, France, 94010
      • Hopital Henri Mondor
• Italy
  • Bologna, Italy
    • Azienda Ospedaliera Universitaria Policlinico Sant'Orsola Malpighi IRCCS
  • Milan, Italy
    • Ospedale San Raffaele
• Poland
  • Biała Podlaska, Poland
    • KO-MED Centra Kliniczne
  • Gdańsk, Poland
    • Uniwersyteckie Centrum Kliniczne
  • Kraków, Poland
    • BioResearch Group Sp. Z. o. o.
  • Toruń, Poland
    • Nasz Lekarz Osrodek Badan Klinicznych
  • Wroclaw, Poland, 50-566
    • Uniwersytecki Szpital Kliniczny im. Jana Mikulicza Radeckiego
• Spain
  • Barcelona, Spain
    • ICO Badalona - Hospital Universitari Germans Trias i Pujol
  • Barcelona, Spain
    • ICO l'Hospitalet - Hospital Duran i Reynals
  • Madrid, Spain
    • Fundacion Jimenez Diaz
  • Seville, Spain
    • Hospital Universitario Virgen Macarena
  • Seville, Spain
    • Hospital Universitario Virgen del Rocío
• United States
  • California
    • Anaheim, California, United States, 92801
      • Pacific Cancer Medical Center
    • Anaheim, California, United States, 92801
      • Innovative Clinical Research Institute
    • Oxnard, California, United States, 93030
      • Ventura County Hematology-Oncology Specialists
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Winship Cancer Institute of Emory University
  • New York
    • Westbury, New York, United States, 11590
      • Clinical Research Alliance, Inc
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Levine Cancer Institute- Atrium Health
  • Texas
    • Dallas, Texas, United States, 75246
      • Baylor Scott and White Research Institute
    • Houston, Texas, United States, 77339
      • Renovatio Clinical
    • San Antonio, Texas, United States, 78229
      • University of Texas Health Science Center at San Antonio
  • Washington
    • Spokane, Washington, United States, 99208
      • Medical Oncology Associates, P.S.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. (ECOG) performance status of 0 or 1;
2. Histologically confirmed lymphoma (tumor types are restricted to CLL/SLL, FL (grade 1-3a), MCL, MZL, LPL/WM, PTCL or CBCL);

3. Patients with relapsed or refractory NHL for whom:

   • Standard of care treatment options no longer exist (Stage 1 only);
   • Standard of care treatment options no longer exist with the exception of PI3K-delta inhibitors (Stage 2 only);
4. Expected survival of more than 24 weeks.

Exclusion Criteria:

Patients who meet any of the following criteria will be excluded from study entry:

1. Primary central nervous system (CNS) lymphoma;
2. Any of the following laboratory abnormalities Absolute neutrophil count; <1.0×10^9/L, Hemoglobin <80 g/L Platelets <50 ×10^9/L

3. Inadequate organ function, defined by the following:

   • Total bilirubin ≥1.5 times the upper limit of normal (× ULN);
   • AST or ALT > 2.5 × ULN;
   • Estimated creatinine clearance (CrCl) per Cockcroft-Gault;
   • Dose Escalation stage of trial (Stage 1) - CrCl < 40 mL/min;
   • Dose Expansion stage of trial (Stage 2) - CrCl <30 mL/min;
4. International normalized ratio (INR) > 1.5 × ULN, activated partial thromboplastin time (aPTT) > 1.5 × ULN;
5. Serum amylase or lipase > ULN at screening or known medical history of serum amylase or lipase > ULN;
6. Patients with presence of second primary malignant tumors within the last 2 years;
7. Clinically significant history of liver disease;
8. Prior treatment with any PI3Kδ inhibitors;
9. Any prior use of the following: cancer therapy within 3 weeks of study treatment, GCSF within 7 days of screening, steroid therapy or targeted anti-neoplastic intent within 7 days of treatment, any use of strong CYP3A4 inducers within 2 weeks prior to initiation of study treatment, prior autologous transplant within 6 months of study treatment, prior allogenic stem cell transplant within 6 months of study treatment;
10. Clinically significant active infection or interstitial lung diseases (including drug induced pneumonitis);
11. Major surgical procedure within 4 weeks prior to initiation of study treatment;
12. Adverse events from prior anti-neoplastic therapy that have not resolved to Grade less than or equal to 1, except for alopecia;
13. New York Heart Association (NYHA) Class II or greater congestive heart failure;
14. Congenital long QT syndrome or QTc >470 msec;
15. Currently use medication known to cause QT prolongation or torsades de pointes;
16. History of myocardial infarction or unstable angina within 6 months prior to initiation of study treatment;
17. History of stroke or transient ischemic attack within 6 months prior to initiation of study treatment;
18. Inability to take oral medication, prior surgical procedures affecting absorption, or active peptic ulcer disease;
19. History of inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis);
20. Patients with ongoing chronic gastrointestinal diseases;
21. Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding that, in the investigator's opinion, gives reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or renders the patient at high risk from treatment complications.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment; All patients take HMPL-689 taken daily	Drug: HMPL-689; HMPL-689 is a PI3Kδ inhibitor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of adverse events as evaluated by the NCI CTCAE v5.0 grade	The safety and tolerability of HMPL-689 dose will be evaluated based on adverse events data	From first dose to within 30 days after last dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
maximum plasma concentration (Cmax)	To characterize the pharmacokinetic (PK) properties of HMPL-689 in patients with relapsed or refractory lymphoma	from cycle 1 day 1 30 min pre-dose until cycle 2 day 1 30 min pre dose (escalation) from cycle 1 day 1 30 min pre-dose to Cycle 5 day 1 pre-dose 30 min (expansion) (cycle is 28 days)
Area under the concentration-time curve in a selected time interval (AUC0-t)	To characterize the pharmacokinetic (PK) properties of HMPL-689 in patients with relapsed or refractory lymphoma	from cycle 1 day 1 30 min pre-dose until cycle 2 day 1 30 min pre dose (escalation) from cycle 1 day 1 30 min pre-dose to Cycle 5 day 1 pre-dose 30 min (expansion) (cycle is 28 days)
Objective response rate (ORR) defined as the proportion of patients who have a CR or PR	To evaluate the anti-tumor activity of HMPL-689 in patients with relapsed or refractory lymphoma according to: (1) Chronic Lymphocytic Leukemia (CLL) - modified International Workshop on CLL guidelines, (2) Waldenstrom's Macroglobulinemia (WM) - consensus of international workshops on WM, (3) Lymphomas other than CLL or WM: Lugano Response Criteria for Hodgkin and Non-Hodgkin's Lymphoma	from first dose to within 30 days of last dose

Collaborators and Investigators

• Sponsor: Hutchmed
• Investigators: Study Director: Vijay Jayaprakash, MD, Hutchison Medipharma Limited; Principal Investigator: Jonathan B Cohen, MD, Emory Winship Cancer Institute; Principal Investigator: Nilanjan Ghosh, MD, Atrium Health Levine Cancer Institute

Study record dates

Study Major Dates

• Study Start (Actual): August 26, 2019
• Primary Completion (Estimated): July 1, 2024
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: December 18, 2018
• First Submitted That Met QC Criteria: December 23, 2018
• First Posted (Actual): December 26, 2018

Study Record Updates

• Last Update Posted (Actual): February 28, 2024
• Last Update Submitted That Met QC Criteria: February 27, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: PTCL; FL; MCL; MZL; CLL; SLL; WM; LPL; CBCL
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma
• Other Study ID Numbers: 2018-689-00US1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No