GH55 Capsule is a novel, highly selective small molecule dual mechanism ERK1/2 inhibitor. GH21 Capsule is a potent, orally active human SHP2 allosteric inhibitor. The combination of an ERK1/2 inhibitor and an SHP2 inhibitor achieves a dual effect: synergistic upstream and downstream blockade of the aberrantly activated RTK MAPK signaling pathway, as well as complementation of resistance mechanisms.
This study will evaluate the safety, tolerability and pharmacokinetic (PK) characteristics of GH55 Capsule in combination with GH21 Capsule in patients with advanced solid tumors with aberrantly activated MAPK signaling pathway, and investigate the efficacy of this combination regimen in the same patient population.
1. Aged 18-80 years (inclusive), regardless of gender.
2. Histologically or cytologically confirmed locally advanced or metastatic solid tumor with aberrantly activated MAPK signaling pathway (RAS/RAF/MEK/ERK).
3. Failed standard treatment, has no standard treatment options, refuses standard treatment, or is not eligible for standard treatment at the current stage.
4. Has at least one measurable tumor lesion per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
- Nitrosourea or mitomycin C: within 6 weeks before the first dose;
- Oral fluoropyrimidines, small-molecule targeted drugs, or traditional Chinese medicine with anti-tumor indications: within 2 weeks before the first dose;
- Local palliative radiotherapy: within 2 weeks before the first dose.
2. Received other unmarketed clinical research drugs or treatments within 4 weeks before the first dose.
Single group
Phase I dose escalation
DrugDrug: GH55 Drug: GH21 Treatment Group: Subjects will receive oral GH55 and GH21 following a dose-escalation design until confirmed disease progression, unacceptable toxicity, or fulfillment of any study withdrawal criterion.
Phase I: Dose Expansion
DrugDrug: GH55 Drug: GH21 Treatment Group: Subjects will receive oral GH55 and GH21 at two dose levels established in the Dose Escalation phase until confirmed disease progression, unacceptable toxicity, or fulfillment of any study withdrawal criterion.
phase II
DrugDrug: GH55 Drug: GH21 Treatment Group: Subjects will receive oral GH55 and GH21 at the fixed dose established during the Phase I portion until confirmed disease progression, unacceptable toxicity, or fulfillment of any study withdrawal criterion.
Phase Ia: Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) (according to NCI CTCAE 5.0).
Evaluated at each dose level GH55 and GH21, as graded by National Cancer Institute (NCI) Common Terminology for Adverse Events (CTCAE) version 5.0.
Phase Ia: Dose Limited Toxicity (DLT)
Evaluated at each dose level GH55 and GH21, as graded by National Cancer Institute (NCI) Common Terminology for Adverse Events (CTCAE) version 5.0.
Phase Ib and Phase II: Progression-Free Survival (PFS)
Antitumor activity was evaluated by assessing tumor response using RECIST 1.1 criteria.
Phase Ib and Phase II: Objective response rate (ORR)
The number (%) of patients with a best overall response of complete response (CR) or partial response (PR) per RECIST v1.1 as assessed by investigator.
Phase Ia, Phase Ib and Phase II: Evaluation of pharmacokinetics
Area under the concentration-time curve (AUC) from time 0 to time of last concentration measured and from time 0 extrapolated to infinity and from time 0 to time of the dosing interval at steady state
Phase Ib and Phase II: Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) (according to NCI CTCAE 5.0).
Graded by National Cancer Institute (NCI) Common Terminology for Adverse Events (CTCAE) version 5.0.
Phase Ia, Phase Ib and Phase II: Evaluation of pharmacokinetics
Maximum plasma concentration
Phase Ia, Phase Ib and Phase II: Evaluation of pharmacokinetics
Time to maximum observed concentration
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Suzhou Genhouse Bio Co., Ltd.
Lead sponsor
Shanghai Goboard Cancer Hospital
Collaborator
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