A Pan-RAS Inhibitor in Combination With Anti-Tumor Therapy in Participants With Advanced Pancreatic Cancer

Official title

A Phase Ib/II Study of the Safety, Tolerability, and Efficacy of a Pan-RAS Inhibitor in Combination With Anti-Tumor Therapy in Participants With Advanced Pancreatic Cancer

Overview

This study aims to evaluate the safety, tolerability, and efficacy of HRS-2329 in combination with other anti-tumor therapies in participants with advanced pancreatic cancer harboring RAS mutations or amplifications.

Interventions

• Drug HRS-2329 Tablet
  HRS-2329 is a novel, potent, oral pan-RAS inhibitor that demonstrates strong inhibitory activity against a broad range of RAS-related targets, including KRAS G12V, KRAS G12C, KRAS G12D, KRAS wild-type, NRAS, and HRAS. HRS-2329 forms a ternary complex with Cyclophilin A (CypA) and the target, thereby blocking the binding of RAS-GTP to downstream proteins and disrupting downstream signaling pathways. This ultimately inhibits tumor cell proliferation and exerts anti-tumor effects. HRS-2329 240 mg
• Drug Nimotuzumab
  Nimotuzumab is a marketed drug, a recombinant humanized monoclonal antibody targeting the epidermal growth factor receptor (EGFR). Nimotuzumab is administered at 400 mg by intravenous infusion over at least 60 minutes on Days 1 and 8 of each 3-week cycle.
• Drug HS-20093
  HS-20093 is a B7-H3 antibody-drug conjugate (ADC) composed of the HS-20093 naked antibody (HS-20093 Ab) and a small-molecule toxin (HS-9265, also known as SHR169265) conjugated via a cleavable tetrapeptide linker. The anti-B7-H3 antibody is a humanized immunoglobulin G1 (IgG1) monoclonal antibody (mAb), and the small-molecule toxin, an exatecan derivative, is a topoisomerase I inhibitor. HS-20093 injection is administered at 8.0 mg/kg by intravenous infusion on Day 1 of each 3-week cycle.
• Drug Adebrelimab
  Adebrelimab is a recombinant humanized anti-PD-L1 monoclonal antibody injection. It specifically blocks the binding of PD-1 to PD-L1, thereby terminating the immunosuppressive signals transmitted through PD-1 to T cells. This enables T cells to re-recognize tumor cells and exert cytotoxic effects, ultimately inhibiting tumor growth. Adebrelimab injection is administered at 1200 mg by intravenous infusion on Day 1 of each 3-week cycle.

Primary outcome measures

• Objective Response Rate [Time frame: From enrollment to upto 2 years]

Secondary outcome measures (5)

• Disease Control Rate (DCR) [Time frame: From enrollment to upto 2 years]
• Duration of Response [Time frame: From enrollment to upto 2 years]
• Progression-Free Survival [Time frame: From enrollment to upto 2 years]
• Overall Survival [Time frame: From enrollment to upto 2 years]
• Adverse event [Time frame: From enrollment to upto 2 years]

Eligibility criteria

Inclusion criteria

• Age ≥ 18 years.
• Histopathologically confirmed locally advanced or metastatic pancreatic adenocarcinoma (originating from pancreatic ductal epithelium) that is not amenable to curative therapy.
• RAS mutation or amplification detected in tumor tissue or blood (by RAS testing).
• Prior anti-tumor therapy:

• For cohort HRS-2329-A: at least one line of standard systemic therapy in the advanced setting;
• For cohorts HRS-2329-B and HRS-2329-C: at most one line of standard systemic therapy in the advanced setting.
• At least one measurable lesion according to RECIST version 1.1 criteria.
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1.
• Life expectancy ≥ 3 months.
• Adequate function of vital organs.
• Use of appropriate contraceptive methods during the study period, and so forth.
• Voluntary participation in this study with signed informed consent, good compliance, and willingness to cooperate with follow-up assessments.

Exclusion criteria

• Prior treatment with drugs similar to the investigational product.
• Known presence of central nervous system (CNS) metastases.
• Acute or chronic pancreatitis requiring clinical intervention.
• Gastrointestinal disorders that may affect drug administration/absorption, including but not limited to dysphagia, malabsorption syndrome, refractory nausea, vomiting, or diarrhea, Crohn's disease, and ulcerative colitis.
• Gastrointestinal obstruction, or signs/symptoms of gastrointestinal obstruction; however, patients who have undergone surgical intervention with complete resolution of the obstruction may be considered for screening.
• Concurrent biliary obstruction with risk of biliary tract infection (patients with treatable biliary obstruction may be enrolled if adequate biliary drainage is achieved and the risk of biliary infection is resolved after treatment).
• Third-space fluid collections (e.g., massive pleural effusion, ascites) that cannot be stabilised (i.e., no intervention required after drainage removal) within 2 weeks prior to enrolment; patients with only a small amount of fluid detected by imaging and without clinical symptoms may be enrolled.
• Severe infection within 4 weeks prior to enrolment, such as severe pneumonia, bacteraemia, or infectious complications requiring hospitalisation; unexplained fever >38.5°C within 2 weeks prior to enrolment ; signs/symptoms of infection requiring intravenous antibiotic therapy within 2 weeks prior to enrolment.
• Severe cardiovascular or cerebrovascular diseases.
• Known or suspected interstitial lung disease (isolated imaging findings of interstitial changes are not excluded).
• History of definite neurological or psychiatric disorders, including epilepsy and dementia.
• Non-healing wounds (severe, non-healing, or dehiscent), or unhealed fractures.
• Adverse events from prior therapy not recovered to NCI-CTCAE Grade ≤1 at enrolment .
• History of malignancies other than the primary tumour within 5 years prior to enrolment, with the exception of malignancies with low risk of metastasis and death, such as adequately treated carcinoma in situ of the cervix, basal cell carcinoma, or squamous cell carcinoma of the skin.
• Active hepatitis B infection.
• For Cohort C, conditions that are unsuitable for immunotherapy.
• Known allergy to any component of any of the study drugs to be administered.
• Any other condition that, in the investigator's judgement, may affect the study results or result in premature termination of the study.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• the First Affiliated Hospital, School of Medicine — Hangzhou

Identifiers

NCT: NCT07736612 · CAPT08

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗