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

NCT03779113

Description:

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 (Stage 1) and a dose expansion stage (Stage 2).

Related Conditions:
  • Chronic Lymphocytic Leukemia
  • Follicular Lymphoma
  • Hodgkin Lymphoma
  • Lymphoma
  • Lymphoplasmacytic Lymphoma
  • Mantle Cell Lymphoma
  • Marginal Zone Lymphoma
  • Non-Hodgkin Lymphoma
  • Small Lymphocytic Lymphoma
  • Waldenstrom Macroglobulinemia
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: An Open-label, Dose Escalation Trial to Evaluate the Safety and Pharmacokinetics of HMPL-523 in Patients With Lymphoma
  • Official Title: A Phase I, Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of HMPL-523 in Patients With Relapsed or Refractory Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: 2018-523-US001
  • NCT ID: NCT03779113

Conditions

  • Non Hodgkin Lymphoma

Interventions

DrugSynonymsArms
HMPL-523Treatment

Purpose

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 (Stage 1) and a dose expansion stage (Stage 2).

Detailed Description

      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 (Stage 1) and a dose expansion stage (Stage 2).

      Dose Escalation Stage (Stage 1) Dosing will begin at 100 mg once daily (QD). A cycle of study
      treatment will be defined as 28 days of continuous dosing. The modified 3+3 design will be
      applied for dose escalation and MTD determination to limit the number of patients exposed to
      potentially ineffective or unsafe doses. The study will enroll 1 patient and the patient will
      be treated for a 28-day cycle in the initial dose cohort. If there is no Dose Limiting
      Toxicity (DLT) and no more than 2 treatment-emergent adverse events (TEAEs) of Common
      Terminology Criteria for Adverse Events (CTCAE) Grade ≤2 in the first treatment cycle, the
      study will be escalated to the next dose cohort and continue with the standard 3+3 design.
      Otherwise, the trial will revert to a standard 3+3 design from the initial dose cohort. A
      minimum of 3 patients will be enrolled and observed for toxicity in each successive dose
      cohort after the initial dose cohort. If the 3 patients initially enrolled in a given dose
      cohort complete the DLT assessment window (Cycle 1, Days 1-28) without experiencing a DLT, 3
      patients will be enrolled at the next higher dose level. If 2 or more of the initial 3
      patients enrolled at any dose level experience a DLT during the DLT assessment window, the
      dose escalation will be halted. If 1 of the initial 3 patients enrolled at any dose level
      experiences a DLT during the DLT assessment window, additional patients will be enrolled at
      that dose level for a minimum of 6 evaluable patients for DLT. If a DLT is observed in 1 of
      the 6 valuable patients at this dose level, dose escalation will proceed to the next
      pre-defined dose level. If DLTs are observed in 2 or more of the 6 evaluable patients at a
      given dose level, the dose escalation will be halted. If the dose escalation is completed due
      to 2 or more DLTs at a dose level and that dose level is ≥50% higher than the previous dose
      level, then an intermediate dose level may be evaluated for toxicity in the same manner as
      described above. If the dose level is <50% higher than the previous dose level, in which only
      3 DLT evaluable patients were enrolled, 3 additional patients will be enrolled at that dose
      level to comprise 6 DLT evaluable patients.

      The proposed dose escalation scheme comprises Cohorts 1 to 5 with dosing levels of 100 mg QD,
      200 mg QD, 400 mg QD, 600 mg QD and 800 mg QD, respectively. The need for dose escalation
      beyond 800 mg QD, the specific dose to be tested and the potential for twice-daily (BID)
      dosing will be evaluated jointly by investigators and the sponsor based on the cumulative
      clinical safety, pharmacokinetic, and preliminary efficacy data. Safety monitoring and
      evaluation of dose escalation will be carried out by the Safety Review Committee, which will
      be comprised of the sponsor's study team members (including medical monitor, safety monitor
      and Pharmacokinetic scientist) and the site principal investigators. The adverse event
      profile and serum concentration of HMPL-523 data will be evaluated to determine whether it is
      safe to continue the assigned HMPL-523 dose for dose escalation or whether the dose should be
      de-escalated to the lower dose level.

      Dose Expansion Stage (Stage 2)

      The adverse event profile, serum concentration, and preliminary anti-tumor activity of
      HMPL-523 at the maximum tolerated dose(MTD)/recommended phase 2 dose(RP2D) will be further
      evaluated in approximately 50 patients with relapsed or refractory indolent B-cell
      non-Hodgkin's lymphomas. The tumor types of the dose expansion stage are restricted to:

        -  10 patients with chronic lymphocytic leukemia/small lymphocytic lymphoma

        -  10 patients with mantle cell lymphoma

        -  10 patients with follicular lymphoma (Grade 1-3a)

        -  10 patients with marginal zone lymphoma

        -  10 patients with Waldenström's macroglobulinemia/lymphoplasmacytic lymphoma.

      Patients will receive HMPL-523 at the MTD/RP2D for continuous 28-day treatment cycles until
      disease progression, death, intolerable toxicity, at investigator's discretion that the
      patient can no longer benefit from the study treatment, patient withdrawal from the study, or
      the end of study, whichever comes first.
    

Trial Arms

NameTypeDescriptionInterventions
TreatmentExperimentalAll patients to received study drug (HMPL-523)
  • HMPL-523

Eligibility Criteria

        Inclusion Criteria:

          1. Signed informed consent form

          2. Age ≥18 years

          3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

          4. Histologically confirmed lymphoma, including Hodgkin's lymphoma and non-Hodgkin's
             lymphoma a. In the dose expansion stage, the tumor types are restricted to relapsed or
             refractory chronic lymphocytic leukemia/small lymphocytic lymphoma, mantel cell
             lymphoma, follicular lymphoma (Grade 1-3a), marginal zone lymphoma, and Waldenstrom's
             macroglobulinemia/lymphoplasmacytic lymphoma.

          5. Patients with relapsed or refractory lymphoma who have exhausted approved therapy
             options

          6. In the dose expansion stage, patients must have measurable disease for objective
             response assessment, except for patients with chronic lymphocytic leukemia and
             Waldenstrom's macroglobulinemia/lymphoplasmacytic lymphoma.

          7. Expected survival of more than 24 weeks as determined by the investigator

          8. Male or female patients of child-bearing potential must agree to use double barrier
             contraception, condoms, sponge, foams, jellies, diaphragm or intrauterine device,
             contraceptives (oral or parenteral), Implanon®, injectables, or other measures to
             avoid pregnancy during the study and for 90 days after the last day of treatment.
             Post-menopausal females (>50 years old and without menses for >1 year) and women who
             are surgically postmenopausal are exempt from this criterion.

        Exclusion Criteria:

          1. Patients with primary central nervous system lymphoma

          2. Any of the following laboratory abnormalities: Absolute neutrophil count <1.5×109/L,
             Hemoglobin <80 g/L, Platelets <75 ×109/L

          3. 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 < 50 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

          4. 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)

          5. Any anti-cancer therapy, including chemotherapy, hormonal therapy, biologic therapy,
             or radiotherapy within 3 weeks prior to initiation of study treatment

          6. Herbal therapy within 1 week prior to initiation of study treatment

          7. Prior use of any anti-cancer vaccine

          8. Prior treatment with any spleen tyrosine kinase (SYK) inhibitors (eg, fostamatinib)

          9. Prior administration of radioimmunotherapy within 3 months before initiation of study
             treatment

         10. 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

         11. Adverse events from prior anti-cancer therapy that have not resolved to Grade ≤ 1,
             except for alopecia

         12. Prior autologous stem cell transplant within 6 months prior to initiation of study
             treatment

         13. Prior allogeneic stem cell transplant within 6 months prior to initiation of study
             treatment or with any evidence of active graft versus host disease or requirement for
             immunosuppressants within 28 days prior to initiation of study treatment

         14. Clinically significant active infection (eg, pneumonia)

         15. Major surgical procedure within 4 weeks prior to initiation of study treatment

         16. Clinically significant history of liver disease, including cirrhosis, current alcohol
             abuse, or current known active infection with human immunodeficiency virus, hepatitis
             B virus, or hepatitis C virus.

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

         18. New York Heart Association Class II or greater congestive heart failure

         19. Congenital long QT syndrome or correct QT interval using Fridericia's formula (QTcF)
             >480 msec

         20. Currently use medication known to cause QT prolongation or Torsades de Pointes

         21. History of myocardial infarction or unstable angina within 6 months prior to
             initiation of study treatment

         22. History of stroke or transient ischemic attack within 6 months prior to initiation of
             study treatment

         23. Inability to take oral medication, prior surgical procedures affecting absorption, or
             active peptic ulcer disease

         24. Treatment in a clinical study within 30 days prior to initiation of study treatment

         25. 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Adverse Events evaluated by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0
Time Frame:From first dose to within 30 days after the last dose
Safety Issue:
Description:The safety and tolerability of HMPL-523 will be evaluated based on adverse events data.

Secondary Outcome Measures

Measure:Maximum plasma concentration (Cmax)
Time Frame:From Cycle 1, Day 1, 5 min pre-dose 1st dose until Cycle 1, Day 28 8 hours post-dose.
Safety Issue:
Description:To Characterize the pharmacokinetic properties of HMPL-523 in patients with relapsed or refractory lymphoma
Measure:Area under the concentration-time curve in a selected time interval (AUC0-t)
Time Frame:From Cycle 1, Day 1, 5 min pre-dose 1st dose until Cycle 1, Day 28 8 hours post-dose.
Safety Issue:
Description:To characterize the pharmacokinetic properties of HMPL-523 in patients with relapsed or refractory lymphoma
Measure:Objective response rate (ORR) defined as the proportion of patients who have a CR or PR
Time Frame:From first dose to within 30 days after the last dose
Safety Issue:
Description:To evaluate the anti-tumor activity of HMPL-523 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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Hutchison Medipharma Limited

Trial Keywords

  • lymphoma
  • mantle cell
  • marginal zone
  • waldenstrom
  • chronic lymphocytic leukemia
  • follicular

Last Updated

October 8, 2019