HRS-4642 with nimotuzumab plus gemcitabine and nab-paclitaxel as first-line treatment for advanced pancreatic cancer with KRAS G12D

A Single-arm Phase II Study of HRS-4642 With Nimotuzumab and Chemotherapy for First-line Treatment of Advanced Pancreatic Cancer Patients With KRAS G12D Mutations

This trial will try HRS-4642 together with nimotuzumab and standard gemcitabine/nab‑paclitaxel chemotherapy as first‑line treatment for people with metastatic pancreatic cancer whose tumors carry the KRAS G12D mutation.

Quick facts

• Phase: PHASE2
• Study type: Interventional
• Enrollment: 32 (estimated)
• Ages: 18 Years to 75 Years
• Sex: All
• Sponsor: Zhejiang University (other)
• Drugs / interventions: nytuzumab, nitutuzumab
• Locations: 2 sites (Hangzhou, Zhejiang and 1 other locations)
• Trial ID: NCT06770452 on ClinicalTrials.gov

What this trial studies

This is a single‑arm Phase 2 study using a Simon two‑stage design that plans to enroll 32 patients with metastatic pancreatic ductal carcinoma harboring KRAS G12D. Participants will receive HRS‑4642 combined with nimotuzumab plus gemcitabine and nab‑paclitaxel, with screening, on‑study treatment cycles, and post‑treatment safety and survival follow‑up. An initial cohort of at least 15 subjects includes an early safety review after 6–9 patients complete one treatment cycle; if safety and early response criteria (more than five objective responses) are met, enrollment proceeds to the full cohort. The study focuses on response and tolerability of the combination as first‑line therapy in this molecularly defined population.

Who should consider this trial

Good fit: Adults aged 18–75 with metastatic pancreatic ductal carcinoma, a tumor-confirmed KRAS G12D mutation, no prior systemic therapy for advanced disease (or >6 months since adjuvant therapy), at least one measurable lesion, ECOG 0–1, and adequate organ function are ideal candidates.

Not a fit: Patients without the KRAS G12D mutation, those who have received recent systemic therapy for advanced disease, or those with poor performance status or inadequate organ function are unlikely to qualify or benefit from this regimen.

Why it matters

Potential benefit: If successful, the combination could increase response rates and potentially extend survival for patients with KRAS G12D metastatic pancreatic cancer compared with historical outcomes for chemotherapy alone.

How similar studies have performed: This specific HRS‑4642 plus nimotuzumab combination is novel and clinical data are limited, while prior attempts to add EGFR‑targeting antibodies to chemotherapy in pancreatic cancer have shown mixed results and direct KRAS G12D targeting remains largely early‑stage or preclinical.

Eligibility criteria

Inclusion Criteria:

1.Age: 18-75 (including 18 and 75); 2.Metastatic pancreatic cancer (from pancreatic ductal epithelium); 3.Tumor tissue contains KRAS G12D mutation; 4.No systemic antitumor therapy in advanced stage; if previous neoadjuvant / adjuvant therapy, last treatment should be over 6 months; 5.At least one measurable lesion according to the RECIST v1.1 criteria; 6.The ECOG (Eastern Cooperative Oncology) score was 0-1; 7.Expected survival period of 3 months; 8.The functions of vital organs meets the following requirements (any blood components, cell growth factors are not allowed 2 weeks prior to enrollment):

1. Neutrophil count≥1.5×10\^9 / L;
2. Platelet≥100×10\^9 / L;
3. Hemoglobin≥100 g / L;
4. Serum albumin≥30 g / L;
5. Total bilirubin≤1.5×ULN; ALT, AST≤3×ULN and ALP≤2.5×ULN; if the patient has liver metastasis, ALT, ALT and AST≤5×ULN; if the patient has liver or bone metastasis, ALP≤5×ULN;
6. Creatinine clearance≥50 mL/min or serum creatinine ≤1.5×ULN;
7. Urinary protein \<2+; if urine protein≥2+, an additional 24 hours urine protein quantification should be tested, and if 24 hours urine protein quantification \<1g can be enrolled;
8. ECG: QTcF≤450 ms (male), QTcF≤470 ms (female);
9. Cardiac color ultrasound: LVEF (left ventricular ejection fraction) ≥50%; 9.Women of childbearing age must have a blood pregnancy test within 7 days before enrollment, the result should be negative and must be non-lactating and should be willing to use appropriate contraception during the trial and within 6 months of treatment. For men, surgical sterilization or consent to use appropriate contraception during the study and within 6 months after completion of treatment.

10.Volunteer to participate in the study and sign the informed consent form, good compliance, agreed to cooperate with the follow-up.

Exclusion Criteria:

1.Previous treatment:

1. Previous treatment of targeted therapy against KRAS G12D.
2. Previous targeted therapy against EGFR.
3. Received major surgery or major trauma within 4 weeks before enrollment, or palliative local treatment (including but not limited to palliative radiotherapy, interventional therapy) within 2 weeks prior to enrollment.
4. Have received any other clinical study medication within 4 weeks before enrollment, except for an observational (non-interventional) clinical study or interventional clinical study follow-up.

(5)14 days before enrollment with drugs that strongly inhibit or induce the hepatic drug-metabolizing enzymes CYP3A4 or CYP2C8.

2.The presence of a central nervous system (CNS) metastases. 3.Acute or chronic pancreatitis requiring clinical intervention. 4.Symptoms and signs of gastrointestinal obstruction or obstruction within 6 months before initiation of study treatment but can be screened if surgery is performed and the obstruction is completely resolved.

5.Within 2 weeks prior to enrollment, there is a third space effusion (such as a large amount of pleural fluid, ascites, etc.) that can not reach the stable state (no intervention treatment is needed after the removal of the drainage tube), and only a small amount of effusion on imaging and without clinical symptoms can be enrolled.

6.Severe infection occurred within 4 weeks before enrollment, such as severe pneumonia, bacteremia, infectious complications, requiring hospitalization; fever of unknown cause\> 38.5℃ within 2 weeks before enrollment (fever caused by the tumor according to the investigator); 2 weeks of enrollment (except in cases of prophylactic antibiotics).

7.Severe cardiovascular and cerebrovascular disease. 8.Patients with known or suspected interstitial pneumonia except only interstitial changes on imaging.

9.Prior history of clear neurological or psychiatric disorders, including epilepsy and dementia.

10.Presence of non-healing wounds (severe, non-healing or split), uncured fractures.

11.Adverse events due to prior treatment prior to enrollment did not return to NCI-CTCAE level 1 (except for alopecia and enrollment criteria; except AEs not affecting the study medication).

12.Malignant tumors other than the primary tumor within the 5 years before enrollment, except those with low risk of metastasis and death: adequately treated cervical carcinoma in situ, skin basal cells or squamous cell carcinoma, etc.

13.Combined with active hepatitis B (hepatitis B surface antigen positive and HBV DNA 500 IU / mL), hepatitis C (hepatitis C antibody positive, and HCV-RNA above the lower limit of detection of the analytical method). Those known to have acquired immunodeficiency syndrome or test positive for HIV, and those infected with active syphilis. Subjects with active tuberculosis or a history of active tuberculosis infection within 48 weeks before screening, with or without treatment.

14.Known to be allergic to any component of HRS-4642; allergic to any component of nytuzumab or other monoclonal antibody / fusion proteins, albumin paclitaxel, gemcitabine.

15.By the investigator, the patient had other factors that might affect the study results or lead to the forced termination of the study.

Where this trial is running

Hangzhou, Zhejiang and 1 other locations

• First Affiliated Hospital of Zhejiang University Schlool of Medicine — Hangzhou, Zhejiang, China (NOT_YET_RECRUITING)
• The First Affiliated Hospital of Zhejiang University School of Medicine — Hangzhou, Zhejiang, China (RECRUITING)

Study contacts

• Study coordinator: Tingbo Liang, MD

Conditions: Metastatic Pancreatic Carcinoma