A Study of HMPL-295S1 in Patients With Advanced Malignant Solid Tumors

NCT04908046 | Completed Phase 1 DMC

• 1 other identifier: 2020-295-00CH1
• Study Type: interventional
• Target: 47
• Locations: 1 country
• Sites: 1

Brief Summary

The objective of this study is to evaluate the safety, tolerability and PK profile of HMPL-295S1 and determine MTD and/or RP2D in patients with advanced malignant solid tumor. It will be extended to enroll 10-15 patients at this dose after RP2D is determined, as to further evaluate the safety of RP2D and the preliminary efficacy of HMPL-295S1. In addition, an exploratory study on the pharmacokinetic biomarkers of HMPL-295S1 is planned in this study.

Conditions

Advanced Malignant Solid Tumors

Outcome Measures

Primary Outcomes (3)

• Safety and tolerability of oral HMPL-295S1 monotherapy for patients with advanced solid tumors;

  Occurrence of Dose Limiting Toxicities (DLTs) During the DLT Observation Period.

  from Cycle 0Day1 up to Cycle1Day28 (each cycle is 28 days)

• Maximum tolerated dose (MTD)of oral HMPL-295S1.

  1. Occurrence of Adverse Events (AEs) and Treatment-Related AEs. 2. Number of Participants With Clinical Significant Changes in Vital Signs, Laboratory Parameters and 12-Lead Electrocardiogram (ECG) Findings. 3. Incidence of AEs leading to dose interruption, reduction or permanent discontinuation.

  MTD from 1st patient's Cycle 0Day1 (each cycle is 28 days) up to last patient's Last dose in escalation stage. (up to a maximum of approximately 2 years )

• Recommended phase II clinical study dose (RP2D) of oral HMPL-295S1.

  The investigator and the sponsor will determine RP2D jointly based on the following factors: 1. MTD (if reached) 2. PK/pharmacokinetics and relevant efficacy and safety.

  Baseline up to last patient's last tumor assessment completed in escalation stage. (up to a maximum of approximately 2 years )

Secondary Outcomes (9)

• To investigate the pharmacokinetic (PK) profile of oral HMPL-295S1.

  from pre-dose to day 5 of cycle 0. (cycle 0 contains 5 days)

• AUCinf (Cycle 0 ) of HMPL-295S1.

  from pre-dose to day 5 of cycle 0. (cycle 0 contains 5 days)

• AUC(0-tlast) (Cycle 0 ) of HMPL-295S1.

  from pre-dose to day 5 of cycle 0. (cycle 0 contains 5 days)

• Objective Response Rate (ORR)

  From baseline to final assessment at end of safety follow-up visit (up to a maximum of approximately 3 years)

• Time to response (TTR)

  From baseline to final assessment at end of safety follow-up visit (up to a maximum of approximately 3 years)

Other Outcomes (1)

• Exploratory objective: To investigate the pharmacodynamic biomarkers of HMPL-295S1.

  pre-dose to 4 hour after dose in Cycle1Day22(each cycle is 28 days)

Study Arms (1)

HMPL-295S1 open-label treatment arm

EXPERIMENTAL

During dose escalation, single-dose PK evaluation will be carried out firstly in each dose group. At the first therapeutic dose level, the single-dose treatment period is 5 days; from the 2nd dose level, the sponsor can determine the adjustment of single-dose treatment period to 3-5 days based on the available PK profile. Subsequently, the patients will receive oral HMPL-295S1 QD continuously in a therapeutic cycle of 28 days (Day 1 - 28 of each cycle), until reaching the criteria on the end of treatment. The patients in RP2D extended cohort will enter the consecutive treatment period directly.

Drug: HMPL-295S1 with dose escalation stage of 5mg up to 200mg, then expansion stage with recommended dose of therapeutic cycle of 28 days .

Interventions

HMPL-295S1 with dose escalation stage of 5mg up to 200mg, then expansion stage with recommended dose of therapeutic cycle of 28 days . DRUG

Patient starts the initial dose treatment with 5mg QD of HMPL-295S1, during dose escalation, single-dose PK evaluation will be carried out firstly in each dose group. At the first therapeutic dose level, the single-dose treatment period is 5 days; from the 2nd dose level, the sponsor can determine the adjustment of single-dose treatment period to 3-5 days based on the available PK profile. Subsequently, the patients will receive oral HMPL-295S1 QD continuously in a therapeutic cycle of 28 days (Day 1 - 28 of each cycle), until reaching the criteria on the end of treatment. The patients in RP2D extended cohort will enter the consecutive treatment period directly.

HMPL-295S1 open-label treatment arm

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• All the following conditions must be met for enrollment:
• Having understood this study adequately and being voluntary to sign the informed consent form;
• Aged 18\~75 years (inclusive);
• Patients with histopathologically or cytologically confirmed advanced malignant solid tumors who have failure of standard of care or can not tolerate standard of care, or can not obtain standard of care for various reasons, or have no standard of care (regardless of previous surgery);
• Having at least one measurable lesion (in accordance with the RECIST 1.1 criteria); note: the lesion previously irradiated can not be regarded as target lesion, unless unequivocal progression of disease is shown in radiological evidence after radiotherapy;
• United States Eastern Cooperative Oncology Group (ECOG) Performance Status score ≤ 1;
• Life expectancy ≥12 weeks based on investigator's judgment;
• Having adequate bone marrow, hepatic and renal function (no transfusion of whole blood, blood components, blood products, no use of granulocyte colony-stimulating factor or other hematopoietic stimulator or drug for correction within two weeks prior to blood collection):
• Absolute neutrophil count ≥1.5×109/L;
• HGB≥90 g/L;
• Platelet count ≥ 100×109/L;
• Serum total bilirubin ≤ 1.5 × upper limit of normal (ULN) \[alanine aminotransferase (ALT) and aspartate aminotransferase (AST) need to be normal, serum total bilirubin needs to be ≤3 × ULN in the patients with Gilbert disease\];
• Serum ALT and/or AST ≤2.5 × ULN in the patients without hepatic metastasis (ALT and AST ≤5 ×ULN for those with liver metastasis);
• Creatinine clearance ≥ 60 mL/min (calculated according to Cockcroft-Gault formula, see Appendix 11);
• International normalized ratio (INR) ≤1.5, and activated partial thromboplastin time (aPTT) ≤ 1.5 ULN.

You may not qualify if:

• The patients can not participate in this study if any of the following conditions is met:
• Previous antitumor therapy meeting any of the following:
• Previous treatment with a ERK inhibitor and having PD;
• Receiving approved systematic antitumor therapy within 4 weeks prior to the first dose, including chemotherapy, targeted therapy, immunotherapy, biotherapy, etc. (elution for two weeks for hormone therapy or treatment with traditional Chinese medicine and Chinese patent drug with clear antitumor indication);
• In the treatment period of other interventional clinical study (including small molecular chemical drug and macromolecular antibody) within 4 weeks prior to the first dose. Patients can be enrolled in this study if they are involved in non-interventional clinical study (e.g., epidemiological study); and can also be enrolled if they stay in the survival follow-up period of one interventional clinical study.
• Having received major surgery or radical radiotherapy (except for the palliative radiotherapy for bone metastasis) within 4 weeks prior to the first dose.
• Toxicity associated with previous antitumor therapy (including surgery, chemotherapy, radiotherapy, targeted therapy and immunotherapy) not recovered to ≤ CTCAE grade 1, except for alopecia and peripheral neuropathy. The peripheral neurotoxicity needs to be recovered to ≤ CTCAE grade 2 in the patients who have been previously treated with platinum;
• Patients with central nervous system (CNS) malignant tumor or malignant solid tumor with known CNS metastasis;
• Combined with other malignant tumor or having a history of other malignant tumor within 2 years prior to study screening (not including the basal or squamous cell carcinoma of skin, non-melanoma skin cancer, papillary thyroid carcinoma that have been appropriately treated, or radically resected cervical carcinoma in situ and ductal carcinoma in situ);
• Known history of clinically significant liver disease, including viral or other hepatitis, except the following patients:
• HBsAg positive patients can be enrolled if the polymerase chain reaction (PCR) test of hepatitis B virus (HBV) DNA is negative. The investigator can provide preventive or therapeutic antiviral therapy based on patient's condition and diagnostic routines during study treatment;
• Patients with positive hepatitis C virus (HCV) antibody can be enrolled if the PCR test of HCV RNA is negative.
• Patients infected by human immunodeficiency virus (HIV);
• Presence of active bacterial, fungal or viral infection requiring systematic treatment within one week prior to the first dose;
• Use of CYP3A potent inducer within 2 week or 5 half-lives (whichever is longer, 3 weeks needed for St. John's wort) prior to the first dose, see (Appendix 5);

Sponsors & Collaborators

• Hutchmed: lead

Study Sites (1)

Fudan University Shanghai Cancer Center

Shanghai, Shanghai Municipality, 200032, China

Location

Study Officials

• Bin Yang

  Hutchison Medipharma Limited

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 26, 2021
• First Posted: June 1, 2021
• Study Start: May 27, 2021
• Primary Completion: January 29, 2024
• Study Completion: February 23, 2024
• Last Updated: October 15, 2024

Record last verified: 2024-10

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)