A Phase Ia/Ib Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Preliminary Antitumor Activity of GH2616 Tablet in Subjects With Advanced Solid Tumors
Overview
- Phase
- Phase 1
- Intervention
- GH2616 Tablets
- Conditions
- Advanced Solid Tumors
- Sponsor
- Suzhou Genhouse Bio Co., Ltd.
- Enrollment
- 156
- Locations
- 1
- Primary Endpoint
- Dose-limiting Toxicities Incidence Count Among Study Participant
- Status
- Recruiting
- Last Updated
- last year
Overview
Brief Summary
This is a Phase Ia/Ib, dose escalation and dose expansion study to evaluate the safety, tolerability, PK, pharmacodynamics (PD) and preliminary efficacy of GH2616 Tablet in subjects with advanced solid tumors. It includes two parts: the dose escalation study (Phase Ia) and the dose expansion study (Phase Ib).
Detailed Description
Phase Ia: Dose Escalation Study This is a Phase Ia, open-label, multi-center, dose escalation study, aiming to investigate the safety, tolerability, PK, PD and preliminary anti-tumor activity of GH2616 Tablet in subjects with advanced solid tumors. • Dose Escalation Phase This study will consist of 8, sequential, ascending-dose cohorts (A1\~ A8) and utilize a "3+3" dose escalation design. Phase Ib: Dose Expansion Study The Phase Ib part is an open-label, multi-center, dose expansion study, aiming to further evaluate the safety, tolerability, PK, PD, and preliminary anti-tumor activity of GH2616 Tablet in subjects with advanced solid tumors harboring TP53 mutation and WGD+ at the RDEs. Phase Ib study will consist of 2 to 3 dose level cohorts (B1 \~ B3) of RDEs identified by the safety, tolerability, PK/PD characteristics, and preliminary efficacy data obtained from Phase Ia study.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Subjects must meet all of the following inclusion criteria to be eligible for participation in this study:
- •Men or women ≥18 years old.
- •The following two points are evaluated by the Investigator and are deemed suitable to participate in the study: a. The subject fully understands the requirements of the study and voluntarily signs the written informed consent; b. Be able to comply with the medication requirements of the study and all study related procedures and evaluations.
- •Meeting the requirements of tumor types shown below:
- •Phase Ia Study:
- •Subjects with a histological or cytological diagnosis of recurrent or metastatic advanced solid tumors who have failed or are intolerant to standard treatment, or have no standard therapy. The specific tumor types include but not limited to high-grade serous ovarian cancer (HGSOC), uterine carcinosarcoma (UCS), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), triple-negative breast cancer (TNBC), bladder urothelial carcinoma (BLCA), colorectal cancer (CRC), etc.
- •Phase Ib study:
- •Dose expansion study (Phase Ib): Subjects with a histological or cytological diagnosis of recurrent or metastatic advanced solid tumors harboring TP53 mutation and WGD+ who have failed or are intolerant to standard treatment, or have no standard therapy.
- •The specific tumor types include but not limited to high-grade serous ovarian cancer (HGSOC), uterine carcinosarcoma (UCS), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), triple-negative breast cancer (TNBC), bladder urothelial carcinoma (BLCA), colorectal cancer (CRC), etc.. Note: The specific tumor types/basket design with specific gene(s) will be determined by the principal Investigator and the Sponsor based on the Phase Ia study results.
- •Survival expectations are ≥ 12 weeks.
Exclusion Criteria
- •In Phase Ia and Ib studies, subjects will be excluded if they meet any of the following criteria:
- •Has received chemotherapy within 21 days prior to the first administration of GH2616 Tablet or has received radiation therapy, biologic therapy, endocrine therapy, targeted therapy, immunotherapy, or other anti-tumor drug treatments within 28 days prior to the first administration of GH2616 Tablet, or other anti-tumor drugs or treatments within the following interval before the first administration of GH2616 Tablet: Nitrosoureas or mitomycin C within 6 weeks prior to the first administration of the investigational drug. Oral fluoropyrimidines, small molecule targeted therapies, and Chinese herbal medicines with indications for anti-tumor within 14 days prior to the first administration of the investigational drug. Local palliative radiation therapy within 14 days prior to the first administration of the investigational drug.
- •Has received other investigational drugs or treatments not yet approved for marketing within 28 days prior to the first administration.
- •Acute toxic effects of prior anti-tumor therapy have not recovered to clinically significant NCI-CTCAE V5.0 grade ≤ 1 toxicity or baseline specified in the inclusion criteria within 28 days prior to the first administration of GH2616 Tablet (excluding toxicities such as alopecia and fatigue that the Investigator deems to have no safety risk).
- •At rest, the average Corrected QT interval (QTc, Fridericia's correction formula used) obtained by 12-lead Electrocardiograph (ECG) examination is \> 450 ms for males or 470 ms for females (confirmed by repeated examinations). A variety of clinically significant arrhythmia, conduction, and resting ECG abnormalities, such as complete left bundle branch block, degree III, degree II, PR interval \>250 ms. Various factors that may increase the risk of prolonged QTc or arrhythmia events, such as heart failure, hypokalemia, congenital long QT syndrome, a family history of long QT syndrome in a direct family member or sudden unexplained death before age 40, and use of any medications known to prolong QT intervals.
- •Has evidence of infectious diseases:
- •Active hepatitis B (hepatitis B surface antigen (HbsAg) positive and hepatitis B virus deoxyribonucleic acid (HBV-DNA) \> 500 IU/ml or 1000 cps/ml or lower limit of detection at the study site \[only if lower limit of detection at the study site is higher than 500 IU/ml or 1000 cps/ml\]), antiviral therapy other than interferon is allowed; active hepatitis C (subjects with hepatitis C virus (HCV) antibody positive but hepatitis C virus ribonucleic acid (HCVRNA) \< lower limit of detection at the study site are allowed to be enrolled);
- •HIV infected patients (HIV 1/2 antibody positive detected by antigen/antibody test); Considering that HIV infections can be chronically managed, expanding cancer clinical trial eligibility to be more inclusive of patients with HIV infections is justified in many cases, and may accelerate the development of effective therapies in cancer patients with these chronic infections. Therefore, well-controlled HIV patients who have been on established antiretroviral therapy (ART) for at least four weeks and have an HIV viral load less than 400 copies/mL prior to enrollment should be included. Note: patients who are using ART drugs that are prohibited or cautious concomitant medications specified in the protocol (e.g. strong inhibitors or strong inducers of P-gp) could be switched to an alternate effective ART regimen (with minimal drug-drug interaction potential) before study participation or should be excluded from the study if their regimen cannot be altered.
- •Known active syphilis infection.
- •Has symptomatic or active central nervous system (CNS) metastases. Treated or untreated asymptomatic patients with CNS lesions are eligible only if all of the following criteria are met:
Arms & Interventions
GH2616 GROUP
Dose Escalation: Dose Escalation Cohorts Subjects will be enrolled at various doses of GH2616. These Dose Escalation Cohorts will be utilized to To determine the maximum tolerated dose (MTD) and/or recommended dose for expansion(s) (RDEs) for Dose Expansion. Dose Escalation: Backfill Cohorts 2 \~ 3 dose cohorts are allowed to be backfilled.These Backfill Cohorts will be utilized to build additional data to support selection of doses and/or tumor types for further study in Dose Expansion. Dose Expansion: Expansion Cohorts 2 \~ 3 dose cohorts are planned.Subjects with advanced solid tumors harboring TP53 mutation and whole genome duplication (WGD+) will be enrolled.These Cohorts will be utilized to to determine the recommended Phase II dose (RP2D) of GH2616 Tablet.
Intervention: GH2616 Tablets
Outcomes
Primary Outcomes
Dose-limiting Toxicities Incidence Count Among Study Participant
Time Frame: 2 years
DLT refers to Dose-Limiting Toxicity. It is defined as a side effect or adverse reaction of a drug or treatment that is severe enough to prevent an increase in dosage. Identifying DLT is crucial in clinical trials for determining the maximum tolerated dose (MTD) of a new drug.
Number of Participants Reporting Adverse Events (AEs) or Serious Adverse Events (SAEs)
Time Frame: 2 years
Adverse events (AE), serious adverse events (SAE), and severity of AE using the NCI-CTCAE version 5.0.
Secondary Outcomes
- Duration of Response (DOR) based on RECIST 1.1 criteria(2 years)
- Plasma Concentration (Cmax)(2 years)
- Area Under the plasma Concentration-Time Curve (AUC)(2 years)
- Disease Control Rate (DCR) based on RECIST 1.1 criteria(2 years)
- Time to CAchieve Cmax (Tmax)(2 years)
- Objective Response Rate (ORR) based on RECIST 1.1 criteria(2 years)
- Progression-Free Survival (PFS) based on RECIST 1.1 criteria(2 years)