Colorectal Adenocarcinoma Metastatic in the Liver
Conditions
Brief summary
This is a single-center, open-label, exploratory phase II trial to evaluate efficacy and safety of Retlirafusp alfa (PD-L1/TGF-βRII bispecific fusion protein) combined with standard first-line targeted-chemotherapy as conversion therapy in adult patients with initially unresectable microsatellite-stable (MSS/pMMR) colorectal adenocarcinoma liver metastases. Two pre-defined cohorts are enrolled: Cohort 1 for RAS/BRAF wild-type left-sided primary tumor (mFOLFOX6 + cetuximab + Retlirafusp alfa); Cohort 2 for RAS/BRAF-mutant or right-sided primary tumor (CAPEOX + bevacizumab + Retlirafusp alfa).
Interventions
DRUGRetlirafusp alfa Combined with Targeted Therapy and Chemotherapy
Cohort 1 (RAS/BRAF wild-type, left-sided primary colon cancer): * Retlirafusp alfa 1800 mg IV D1 every 3 weeks * Cetuximab 500 mg/m² IV D1 every 2 weeks * mFOLFOX6: Oxaliplatin 85 mg/m² IV D1 q2w; Leucovorin 400 mg/m² IV D1 q2w; 5-FU 400 mg/m² IV bolus D1 q2w plus 2400 mg/m² 48-h continuous infusion q2w. Cohort 2 (RAS/BRAF mutant OR RAS/BRAF wild-type right-sided primary colon cancer): * Retlirafusp alfa 1800 mg IV D1 every 3 weeks * Bevacizumab 7.5 mg/kg IV D1 every 3 weeks * CAPEOX: Oxaliplatin 130 mg/m² IV D1 q3w; Capecitabine 1000 mg/m² orally twice daily D1-14 q3w.
Sponsors
Peking University Cancer Hospital & Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 79 Years
Healthy volunteers
No
Inclusion criteria
1. Signed written informed consent before any trial-related procedure. 2. Age ≥18 and ≤79 years, male or female. 3. Histopathologically confirmed colorectal adenocarcinoma; liver metastasis confirmed by pathology or imaging. 4. No prior first-line systemic therapy (targeted, immunotherapy, systemic chemotherapy) specifically for liver metastases. 5. At least 1 measurable lesion per RECIST 1.1. 6. Multidisciplinary-team-confirmed initially unresectable colorectal liver metastases (cannot achieve R0/R1 resection; or predicted future remnant liver volume \< 30 %; or insufficient hepatic inflow/outflow). Patients with extra-hepatic metastases (excluding brain / bone metastases) amenable to local therapy are eligible. 7. Microsatellite-stable (MSS) / mismatch-repair-proficient (pMMR) confirmed by IHC or PCR. 8. ECOG Performance Status 0-1. 9. Expected survival ≥12 weeks. 10. No urgent-surgery indications (e.g., primary-tumor bleeding, obstruction). 11. Adequate organ function within 14 days prior to first study-drug: * ANC ≥1.5 × 10⁹/L; Platelets ≥75 × 10⁹/L; Hb \> 70 g/L * Total bilirubin ≤1.5 × ULN; Albumin ≥28.0 g/L * AST / ALT ≤5 × ULN * Creatinine ≤1.5 × ULN; Cockcroft-Gault creatinine clearance ≥60 mL/min * INR / PT ≤1.5 × ULN 12. Females of reproductive potential / males with reproductive-potential partners agree to highly-effective contraception starting 7 days prior first dose until 24 weeks after last dose. 13. Serum pregnancy test negative within 7 days before first dose (women of child-bearing potential). 14. Willing and able to comply with all trial visits, treatment and assessments.-
Exclusion criteria
* 1\. Inability to tolerate systemic chemotherapy or subsequent surgery. 2. Liver metastases occurring during or within 6 months after completion of oxaliplatin-based adjuvant chemotherapy for primary colorectal tumor. 3\. Major surgery within 6 weeks before study entry; severe trauma / non-healing wounds / fractures. 4\. Myocardial infarction, unstable angina, coronary-artery-bypass-graft within prior 3 months; NYHA class III-IV heart failure. 5\. Prior treatment with immune-checkpoint-inhibitors (anti-PD-1/PD-L1, anti-CTLA-4 etc.). 6\. Concurrent or prior other malignancy whose expected survival is shorter than colorectal-liver-metastasis prognosis. 7\. History of allogeneic hematopoietic-stem-cell or solid-organ transplant (except corneal transplant). 8\. History of moderate-severe hypersensitivity / anaphylaxis to antibody-based therapeutics. 9\. Clinically-significant bleeding diathesis or major bleeding episode within prior 3 months (e.g., gastrointestinal bleeding, esophageal varices, hematemesis, hemoptysis). 10\. Symptomatic large-volume ascites / pleural effusion / pericardial effusion requiring intervention. 11\. Primary-tumor perforation, abdominal infection occurring within prior 3 months without adequate management. 12\. Known hypersensitivity to active ingredients or excipients of study drugs. 13. Active peptic ulcer, gastrointestinal obstruction, active GI bleeding, perforation, malabsorption, uncontrolled inflammatory bowel disease. 14\. Pregnant or lactating women. 15. Concurrent participation in another interventional clinical trial. 16. Any other condition judged by investigator to make subject unsuitable for trial participation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate | Following 3 or 6 cycles (each cycle is ~21 days) of the treatment, approximately 9 or 18 weeks overall | The proportion of subjects achieving complete response or partial response, assessed by investigators according to RECIST 1.1 criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Major Pathological Response Rate | Following 3 or 6 cycles (each cycle is ~21 days) of the treatment, approximately 9 or 18 weeks overall | — |
| Surgical Conversion Rate | Following 3 or 6 cycles (each cycle is ~21 days) of the treatment, approximately 9 or 18 weeks overall | The proportion of subjects with successful conversion surgery. The criteria for successful conversion are as follows: evaluation of liver metastases achieves partial response after the conversion therapy; liver tumor-free status can be achieved through surgical resection ± ablation or stereotactic radiotherapy, with a residual liver volume exceeding 40%; liver function is classified as Child-Pugh Class A, and other liver function and laboratory parameters meet surgical and anesthesia requirements. |
| Progression-free Survival | assessed up to 18 months | The time from the initiation of treatment until disease progression or death from any cause, whichever occurs first. |
| Overall Survival | assessed up to 18 months | Description: The time from the initiation of treatment until death from any cause. |
| Safety | From first dose through 90 days after last study-drug administration. | Incidence, severity (NCI-CTCAE v5.0) of treatment-emergent adverse events (TEAE), treatment-related adverse events (TRAE), immune-related adverse events (irAE), serious adverse events (SAE), and post-operative complications. |
Countries
China
Contacts
CONTACTKun Wang
Outcome results
None listed