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A Dose Escalation Study to Assess the Safety and Tolerability of HMPL-453 in Patients With Advanced Solid Malignancies

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ClinicalTrials.gov Identifier: NCT02966171
Recruitment Status : Terminated (The study was terminated on 23AUG2018 for safety reasons.)
First Posted : November 17, 2016
Last Update Posted : November 21, 2018
Sponsor:
Information provided by (Responsible Party):
Hutchison Medipharma Limited

Brief Summary:
This is a first-time-in-human, phase I, open-label, dose-escalation study of HMPL-453 in patients with advanced or metastatic solid malignancies who have failed or are intolerable to standard therapies or for whom no standard therapies exist. There are preliminary two stages in this study: a dose-escalation stage (stage 1) and a dose-expansion stage (stage 2). We will decide whether to conduct stage 2 or not one month after the last patient included in stage 1.

Condition or disease Intervention/treatment Phase
Solid Tumor Drug: HMPL-453 Phase 1

Detailed Description:

Dose-escalation stage (stage 1): Patients participating in the dose-escalation stage will take a single dose of HMPL-453 on Day 1 and will be followed for one week for safety observations. After one week of observation, if no safety issues occur, patients can continue multiple dosing of HMPL-453 QD and start on the DLT assessment cycles. Each cycle consists of 28-days. Patients are required to draw blood samples for PK and safety analysis at specific time points during the treatment.

The 3+3 design will be employed for the dose escalation and MTD determination. To limit the number of patients being exposed to potentially ineffective doses, one patient will be enrolled and dosed in the initial dose cohort. If there are no DLT or < 2 CTCAE grade 2 toxicities occur in the first treatment cycle, then the study will be escalated to the next dose cohort. Otherwise, the trial will revert to a standard 3+3 design.

Dose-Expansion Stage (Stage 2): This stage is to further evaluate the safety, tolerability, PD profile, and preliminary anti-tumor activity of HMPL-453 at the RP2D in approximately 10 patients with advanced solid tumor. Patients with FGFR dysregulated advanced solid tumors, including but not limited to, advanced gastric cancer, advanced urothelial bladder cancer, or advanced cholangiocarcinoma (patients with cancers of the gallbladder or ampulla of Vater are not eligible) are preferred to be enrolled.

Expansion stage will begin after dose-escalation stage is completed and the MTD/RP2D has been determined. Patients will receive HMPL-453 with 28-day treatment cycles until disease progression, death, intolerable toxicity, no longer benefiting from the study treatment per investigator's discretion, or withdrawal of consent, whichever comes first.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 14 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I, Open-label, Multi-center, Dose Escalation Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-tumor Activity of HMPL-453 in Patients With Advanced Solid Malignancies
Actual Study Start Date : January 2017
Actual Primary Completion Date : August 23, 2018
Actual Study Completion Date : August 23, 2018

Arm Intervention/treatment
Experimental: HMPL-453
Two strengths of HMPL-453 tablets (25 mg and 100 mg based on the free base) will be used for clinical studies. The drug products are coated tablets, which are packaged in white induction sealed HDPE bottles. HMPL-453 will be administered to patients as oral tablet(s) on a daily basis, untill disease progression, intolerable toxicity, or death. Dose levels are to be potentially tested in this study include 25, 50, 100, 200, 300, 400, and 500 mg/day.
Drug: HMPL-453
oral administration




Primary Outcome Measures :
  1. Incidence of DLTs by the NCI CTCAE v4.03 [ Time Frame: Cycle 1 (DLT assessment window, 28 days) of multiple dosing peroid ]

Secondary Outcome Measures :
  1. Incidence of AEs, clinically significant laboratory abnormalities, and electrocardiographic (ECG) changes and vital signs [ Time Frame: from first dose to 30 days after last dose of study treatment ]
  2. maximum plasma concentration (Cmax) [ Time Frame: from first dose to day 56 of multiple dosing peroid ]
  3. time to reach maximum concentration (Tmax) [ Time Frame: from first dose to day 56 of multiple dosing peroid ]
  4. terminal half-life (t1/2) [ Time Frame: from first dose to day 56 of multiple dosing peroid ]
  5. area under the concentration-time curve (AUC0-t) [ Time Frame: from first dose to day 56 of multiple dosing peroid ]
  6. apparent clearance (CL/F) [ Time Frame: from first dose to day 56 of multiple dosing peroid ]
  7. Serum phosphate level increases [ Time Frame: from first dose to Day 21 of the last treatment cycle ]
  8. Objective response rate (ORR) [ Time Frame: Every 8 weeks while being treated with HMPL-453 (expected average of 16 weeks) ]
  9. Duration of response (DoR) [ Time Frame: Every 8 weeks while being treated with HMPL-453 (expected average of 16 weeks) ]
  10. Disease Control Rate (DCR) [ Time Frame: Every 8 weeks while being treated with HMPL-453 (expected average of 16 weeks) ]
  11. Change in tumor size [ Time Frame: Every 8 weeks while being treated with HMPL-453 (expected average of 16 weeks) ]
    Tumor size is defined as the sum of the lengths of the longest diameters of the RECIST 1.1 target lesions (TLs). Percentage change in tumor size will be determined for patients with measurable disease at baseline and is derived at each visit by the percentage change in the sum of the diameters of TLs compared to baseline.

  12. Progression free survival (PFS) [ Time Frame: Every 8 weeks while being treated with HMPL-453 (expected average of 16 weeks) ]

Other Outcome Measures:
  1. FGFR genetic alterations status [ Time Frame: expected average of 16 weeks ]
    Dose Escalation stage (optional): to retrospectively determine the FGFR genetic alterations in tumor sections for the patients who have either a complete or partial response as per RECIST 1.1.

  2. FGFR pathway inhibition by pERK [ Time Frame: from first dose to Day 15 of the first treatment cycle ]
    Dose expansion stage (optional): explores the FGFR pathway inhibition in the fresh tumor samples pre- and after the treatment of HMPL-453.



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Ages Eligible for Study:   25 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • In the dose escalation stage, patients with locally advanced, or metastatic solid tumor who have failed, or intolerable to, standard therapies or for whom no standard therapies exist will be enrolled.
  • In the dose expansion stage, patients with locally advanced, or metastatic solid tumor and FGFR dysregulation who have failed or intolerable to standard therapies or no standard therapies exist are to be enrolled.
  • In the dose escalation stage: evaluable or measurable disease according to RECIST Version 1.1. In the dose expansion stage: measurable disease according to RECIST Version 1.1.
  • Life expectancy of at least 12 weeks.
  • ECOG performance status of 0 or 1

Exclusion Criteria:

  • Prior or current treatment with any selective FGFR inhibitor.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02966171


Locations
Australia, New South Wales
St Vincent's Cancer Services
Sydney, New South Wales, Australia, 2010
Chris O'Brien Lifehouse
Sydney, New South Wales, Australia, 2050
Australia, Victoria
Peninsula and Southeast Oncology
Frankston, Victoria, Australia, 3199
Monash Medical Centre
Melbourne, Victoria, Australia, 3168
Sponsors and Collaborators
Hutchison Medipharma Limited
Investigators
Study Director: Weiss Yang Hutchison Medipharma Limited

Responsible Party: Hutchison Medipharma Limited
ClinicalTrials.gov Identifier: NCT02966171     History of Changes
Other Study ID Numbers: 2015-453-00AU1
First Posted: November 17, 2016    Key Record Dates
Last Update Posted: November 21, 2018
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by Hutchison Medipharma Limited:
Advanced Solid Malignancies

Additional relevant MeSH terms:
Neoplasms