A Phase I/II Clinical Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Preliminary Antitumor Activity of GH55 in Patients Harboring MAPK Pathway Mutations in Advanced Solid Tumors
Overview
- Phase
- Phase 1
- Intervention
- GH55
- Conditions
- Advanced Solid Tumors With MAPK Signal Pathway Mutations
- Sponsor
- Suzhou Genhouse Bio Co., Ltd.
- Enrollment
- 110
- Locations
- 1
- Primary Endpoint
- Number of Participants Reporting Adverse Events (AEs) or Serious Adverse Events (SAEs)Objective
- Status
- Recruiting
- Last Updated
- last year
Overview
Brief Summary
This is a multi-center, open-label, dose escalation phase I and dose expansion phase II study aimed to evaluate the safety, tolerability, PK and PD profiles as well as to observe the efficacy of GH55 in patients with MAPK mutant advanced solid tumors.
This study is divided into two parts, namely the dose escalation phase I study and the dose expansion phase II study.
Detailed Description
This study is divided into two parts, namely the dose escalation phase I study and the dose expansion phase II study. This study plans to include 5 dose groups, namely 40 mg, 80 mg, 150 mg, 200 mg, and 250 mg, and adopts a "3+3" dose escalation design. All of the 40 mg, 80 mg, 150 mg, 200 mg and 250 mg groups will adopt the "3+3" design, and 3-6 subjects will be enrolled in each group. The enrollment of the first subject and subsequent subject in each dose group should be at least 7 days apart. Subjects will receive a single dose of GH55 on day 1 (Cycle 0 Day 1, C0D1). The investigator will assess the safety data on day 3 (C0D3) to determine whether subjects can be initiated on multiple doses of GH55 \[quaque die (QD) continuously, and 3 weeks per cycle\] on day 4 (C1D1). The dose limiting toxicity (DLT) observation period is from the initiation of single dosing to the end of the first cycle of multiple dosing \[Cycle 0 (3 days) and Cycle 1 (3 weeks)\]. The sponsor and investigator will jointly assess the safety data to determine whether to ascend to the next higher dose. These steps will be repeated until MTD is reached, and the safety, tolerability, and PK profile of single dose and multiple doses of oral administration of GH55 will be assessed. If MTD cannot be determined when the dose escalation study is complete, the sponsor and investigator will jointly determine whether to increase the ascending dose based on the existing safety, tolerability, PK, PD and preliminary efficacy data. All subjects can continue the treatment until disease progression, initiation of new antitumor treatment, withdrawal of informed consent, or death (whichever occurs first). The dose expansion phase II study will begin once the last subject in the dose escalation phase I study has completed the DLT observation. Two dose expansion groups will be designed, with a dose level in each group that is expected to become the RP2D based on the safety, tolerability, PK/PD profile, and preliminary efficacy data of GH55 in the dose escalation phase I study. Two dose expansion groups will enroll 60-80 subjects to further evaluate the efficacy, safety, and PK/PD profile of GH55 in patients with advanced solid tumors.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Subjects must meet all the following inclusion criteria to be qualified for study enrollment:
- •Male or female subjects aged 18-80 years (inclusive).
- •Patients with histologically or cytologically confirmed MAPK mutant (presence of RAS/RAF/MEK/ERK mutations) locally advanced or metastatic solid tumors.
- •Patients who have failed standard treatment or have no standard treatment regimen or are not suitable for standard treatment currently.
- •Dose escalation: At least one assessable tumor lesion according to RECIST version 1.1; Dose expansion: At least one measurable tumor lesion according to RECIST version 1.1 (tumor lesion located in the region of previous radiotherapy or other locoregional treatment sites is usually not considered a measurable lesion, unless this lesion shows clear progression or persists for 3 months after radiotherapy).
- •Eastern Cooperative Oncology Group (ECOG) performance status score: Phase I dose escalation: 0-
- •Phase II dose expansion: 0-
- •3 months or longer expected survival.
- •Major organs are functioning normally, and laboratory tests meet the following criteria during the screening period.
- •Hematological system (has not received any blood transfusion or hematopoietic stimulating factor therapy within the past 14 days) Absolute neutrophil count (ANC) ≥ 1.5 × 109/L Platelet Count (PLT) ≥ 75 × 109/L Hemoglobin (Hb) ≥ 90 g/L Liver function Albumin (ALB) ≥ 3.0 g/dL Total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN) Liver metastasis or liver cancer patients: ≤ 2.5 × ULN Alanine Aminotransferase (ALT) ≤ 2.5 × ULN; Liver metastasis or liver cancer patients: ≤ 5 × ULN Aspartate aminotransferase (AST) ≤ 2.5 × ULN; Liver metastasis or liver cancer patients: ≤ 5 × ULN Renal function Creatinine clearance rate (Ccr) ≥ 60 mL/min (calculated based on the Cockcroft-Gault formula) Coagulation function Activated partial thromboplastin time (APTT) ≤ 1.5 × ULN International normalized ratio (INR) ≤ 1.5 × ULN Cardiac function Left ventricular ejection fraction (LVEF) ≥ 50% QT interval corrected by the Fridericia formula (QTcF) Males \< 450 ms, Females \< 470 ms
Exclusion Criteria
- •Subjects who meet any one of the following exclusion criteria are not eligible for study enrollment:
- •Received antitumor therapy such as chemotherapy within 3 weeks before the first dose, radiotherapy, biotherapy, endocrine therapy, targeted therapy, and immunotherapy within 4 weeks before the first dose, except for the following:
- •Use of nitrosoureas or mitomycin C within 6 weeks prior to the first dose of the investigational drug;
- •Use of oral fluorouracil(s), small molecule targeted drugs, and antitumor traditional Chinese medicine within 2 weeks prior to the first dose of the investigational drug;
- •Local palliative radiotherapy within 2 weeks prior to the first dose of the investigational drug.
- •Received other unmarketed clinical investigational drug or therapy within 4 weeks prior to the first dose.
- •Underwent major organ surgery (excluding needle biopsy) or had significant trauma within 4 weeks prior to the first dose or requires selective surgery during the study period.
- •Use of strong CYP3A4 inhibitors or inducers within 1 week prior to the first dose of the investigational drug.
- •Previously received other selective ERK inhibitors.
- •Previously received allogeneic HSCT or organ transplantation.
Arms & Interventions
GH55 GROUP
Intervention: GH55
Outcomes
Primary Outcomes
Number of Participants Reporting Adverse Events (AEs) or Serious Adverse Events (SAEs)Objective
Time Frame: 2 years
All patients participating in this study will be assessed for incidence and severity of adverse events (AEs) and serious AEs, including changes in laboratory values, vital signs, electrocardiograms, cardiac imaging and ophthalmological assessments (phase I)
Dose-limiting Toxicities Incidence Count Among Study Participants
Time Frame: 2 years
Incidence of dose limiting toxicities (DLTs) in the dose escalation phase. A DLT is defined as an adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurs within the first treatment cycle. (phase I)
Response Rate (ORR) Based on RECIST 1.1 Criteria
Time Frame: 2 years
ORR is defined as the proportion of participants with complete response or partial response (CR+PR). (phase II)
Secondary Outcomes
- Progression-free survival (PFS) Based on RECIST 1.1 Criteria(2 years)
- Duration of response (DOR) Based on RECIST 1.1 Criteria(2 years)
- Plasma concentration (Cmax)(2 years)
- Time to achieve Cmax (Tmax)(2 years)
- Area under the plasma concentration-time curve (AUC)(2 years)
- Number of participants with adverse events(2 years)