Advanced Solid Tumors With MAPK Signal Pathway Mutations
Conditions
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.
Interventions
DRUGGH55
GH55 capsule is a novel small molecule, highly selective dual-mechanism ERK1/2 inhibitor developed by Suzhou Genhouse Bio. Co., Ltd. This product can be used to treat cancers caused by abnormal activation of the MAPK pathway (mutational activation of RAS/RAF/MEK) by targeted inhibition of ERK1/2.
Sponsors
Shanghai East Hospital
Shandong Tumor Hospital
Suzhou Genhouse Bio Co., Ltd.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Subjects must meet all the following inclusion criteria to be qualified for study enrollment: 1. Male or female subjects aged 18-80 years (inclusive). 2. Patients with histologically or cytologically confirmed MAPK mutant (presence of RAS/RAF/MEK/ERK mutations) locally advanced or metastatic solid tumors. 3. Patients who have failed standard treatment or have no standard treatment regimen or are not suitable for standard treatment currently. 4. 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). 5. Eastern Cooperative Oncology Group (ECOG) performance status score: Phase I dose escalation: 0-1. Phase II dose expansion: 0-2. 6. 3 months or longer expected survival. 7. 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 7. Qualified patients (male and female) with childbearing potential must agree to use reliable contraceptives (hormone or barrier or abstinence) with their partners during the study and until at least 3 months after the last dose; female patients with childbearing potential must be negative for the blood pregnancy test within 1 week before the first dose. 8\. Subjects must give informed consent to the study and voluntarily signed the informed consent form prior to study initiation.
Exclusion criteria
Subjects who meet any one of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose-limiting Toxicities Incidence Count Among Study Participants | 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) |
| Number of Participants Reporting Adverse Events (AEs) or Serious Adverse Events (SAEs)Objective | 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) |
| Response Rate (ORR) Based on RECIST 1.1 Criteria | 2 years | ORR is defined as the proportion of participants with complete response or partial response (CR+PR). (phase II) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma concentration (Cmax) | 2 years | Highest observed plasma concentration of GH55. (phase I/II) |
| Progression-free survival (PFS) Based on RECIST 1.1 Criteria | 2 years | PFS is defined as the interval of time between the date of first treatment to the earliest date of disease progression or death which occurs first. (phase I/II) |
| Area under the plasma concentration-time curve (AUC) | 2 years | Area under the plasma concentration time curve of GH55. (phase I/II) |
| Time to achieve Cmax (Tmax) | 2 years | Time of highest observed plasma concentration of GH55. (phase I/II) |
| Duration of response (DOR) Based on RECIST 1.1 Criteria | 2 years | DCR is defined as proportion of participants with complete response, partial response, stable disease(CR+PR+SD). (phase I/II) |
| Number of participants with adverse events | 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 II) |
Countries
China
Contacts
Primary ContactYIMING ZHOU, bachelor
Outcome results
None listed