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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03779113
Recruitment Status : Recruiting
First Posted : December 19, 2018
Last Update Posted : October 10, 2019
Sponsor:
Information provided by (Responsible Party):
Hutchison Medipharma Limited

Tracking Information
First Submitted Date  ICMJE December 10, 2018
First Posted Date  ICMJE December 19, 2018
Last Update Posted Date October 10, 2019
Actual Study Start Date  ICMJE September 26, 2019
Estimated Primary Completion Date December 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 14, 2018)
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 ]
The safety and tolerability of HMPL-523 will be evaluated based on adverse events data.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 14, 2018)
  • 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. ]
    To Characterize the pharmacokinetic properties of HMPL-523 in patients with relapsed or refractory lymphoma
  • 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. ]
    To characterize the pharmacokinetic properties of HMPL-523 in patients with relapsed or refractory lymphoma
  • 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 ]
    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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE An Open-label, Dose Escalation Trial to Evaluate the Safety and Pharmacokinetics of HMPL-523 in Patients With Lymphoma
Official Title  ICMJE 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
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 (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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Non Hodgkin Lymphoma
Intervention  ICMJE Drug: HMPL-523
Oral HMPL-523
Study Arms  ICMJE Experimental: Treatment
All patients to received study drug (HMPL-523)
Intervention: Drug: HMPL-523
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: December 14, 2018)
80
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2022
Estimated Primary Completion Date December 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Tunde Lawrence, MD, PhD 973-786-2789 tundel@hmplglobal.com
Contact: Alisha Khullar 973-287-3081 alishak@hmplglobal.com
Listed Location Countries  ICMJE Italy,   Poland,   Spain,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03779113
Other Study ID Numbers  ICMJE 2018-523-US001
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Hutchison Medipharma Limited
Study Sponsor  ICMJE Hutchison Medipharma Limited
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Tunde Lawrence, MD, PhD Hutchison Medipharma Limited
Principal Investigator: Nathan Fowler, MD MD Anderson
PRS Account Hutchison Medipharma Limited
Verification Date September 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP