Cholangiocarcinoma Resectable
Conditions
Keywords
CCA, Biliary cancer, Neo-adjuvant and adjuvant therapy
Brief summary
Biliary tract cancer is a highly aggressive and heterogeneous group of gastrointestinal cancers that arise from the intra- or extrahepatic bile ducts (CCA), or the gallbladder (GBC)(1-3). While it accounts for only 0.7% of all malignant tumors and 3% of all gastrointestinal malignancies in adults, both incidence and mortality are increasing. Biliary tract cancers usually present at an advanced stage, with only approximately 20% of patients being diagnosed with an early-stage disease (1, 2, 4). There is a high risk of recurrence post curative radical resection, with 60-70% of patients recurring within 5 years, with 5-year survival of around 25% (1, 2, 5). There is evidence for use of adjuvant chemotherapy with fluoropyrimidine- based regimens as per the BILCAP and ASCOT phase III trials \[(5-7).However, despite advances in adjuvant treatment, recurrence rates after resection of BTC remain high even with adjuvant chemotherapy. For example, in the BILCAP study, 5-year RFS was reported as 33.9% (95% CI: 27.6 to 40.2) (1). Therefore, an unmet need exists to optimize peri-operative treatment to reduce recurrence and improve outcomes in patients with resectable BTC.
Detailed description
The only curative management for iCCA is radical surgical resection. However, less than 35% of patients present with resectable disease at diagnosis, and postoperative recurrence and relapse rates are around 50-70%. Despite advances in diagnostics and therapeutic interventions, prognosis remains poor with an overall 5-year survival of less than 20%.1 The results of the TOPAZ-12 and KEYNOTE-9663 study have established PD-L1 (durvalumab) and PD-1 (pembrolizumab) inhibition in combination with gemcitabine and cisplatin as a new standard of care highlighting the role of immune checkpoint inhibition in advanced biliary tract cancer (BTC). In addition, the combination of Nab-Paclitaxel and gemcitabine, cisplatin has demonstrated efficacy in advanced BTC4. Several clinical trials evaluating the efficacy of neoadjuvant combinational therapy with gemcitabine, cisplatin and PD-L1 inhibition are ongoing (NCT04989218, NCT06050252, NCT04308174). Neoadjuvant treatment in iCCA allows for delivery of treatment pre surgery and can induce pathological responses and thereby improve survival. Rilvegostomig is a novel anti-TIGIT/anti-PD-1 bispecific antibody that is currently investigated in a Phase I/II clinical trial (ARTEMIDE-01, NCT04995523) for advanced or metastatic PD-L1-positive non-small cell lung cancer. The study provided promising preliminary evidence on the safety and efficacy of Rilvegostomig.5,6 Furthermore, a Phase III clinical trial (ARTEMIDE-Biliary01) using Rilvegostomig in combination with Capecitabine or Gemcitabine/Cisplatin or S-1 as adjuvant therapy for BTC after resection is underway. The efficacy of Gemcitabine/Cisplatin/Nab-Paclitaxel and Rilvegostomig as neoadjuvant treatment in resectable iCCA has yet to be established. This is a phase II, open-label multi-centre study to assess efficacy of Gemcitabine/Cisplatin/Nab-Paclitaxel and Rilvegostomig treatment in pre-surgical setting for upfront resectable iCCA, followed by adjuvant Gemcitabine/Cisplatin and Rilvegostomig. 40 patients are expected to enrol with resectable iCCA at three sites. Patients will receive prior to surgery: 2 cycles of combinational therapy with Gemcitabine (800mg) /Cisplatin (25mg) /Nab-Paclitaxel (100mg) and Rilvegostomig (Q3W). Post-surgical resection, adjuvant therapy will consist of 4 cycles of Gemcitabine (1000mg) /Cisplatin (25mg) and Rilvegostomig (Q3W). Rilvegostomig (Q3W) will be continued for a total of 12 months in the adjuvant phase. All participants will be followed for survival until the end of study. Dosing of Gemcitabine/Cisplatin/Nab-Paclitaxel and Rilvegostomig may be delayed per the trial management group's discretion but dose reduction will not be allowed. Toxicity management for Gemcitabine/Cisplatin/Nab-Paclitaxel and Rilvegostomig-related toxicity, including management of immune-mediated reactions, infusion-related reactions, and non-immune-mediated reactions will be provided in the Toxicity Management Guidelines
Interventions
DRUGGemcitabine/Cisplatin/Nab-Paclitaxel and Rilvegostomig
: Patients will receive prior to surgery: 2 cycles of combinational therapy with Gemcitabine (800mg) /Cisplatin (25mg) /Nab-Paclitaxel (100mg) and Rilvegostomig (Q3W). Post-surgical resection, adjuvant therapy will consist of 4 cycles of Gemcitabine (1000mg) /Cisplatin (25mg) and Rilvegostomig (Q3W). Rilvegostomig (Q3W) will be continued for a total of 12 months in the adjuvant phase
Sponsors
Sunnybrook Health Sciences Centre
Hamilton Health Sciences Corporation
University Health Network, Toronto
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patient must be capable of providing written informed consent. 2. Age \>18 years at time of study entry 3. Histologically proven intrahepatic cholangiocarcinoma 4. Complete surgical resection of the tumor must be achievable\*. Resection should include a portal lymphadenectomy as per standard of care. 5. No prior cytotoxic, targeted or immune therapy 6. Have provided archival tumor tissue sample or preferably freshly obtained biopsy of a tumor lesion not previously irradiated for mandatory pre-treatment evaluation (baseline). 7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 8. Estimated life expectancy \>3 months 9. Exclusion of distant metastases by CT or MRI of abdomen, pelvis, and thorax, bone scan or MRI (if bone metastases are suspected due to clinical signs). Exclusion of the infiltration of any adjacent organs or structures by CT or MRI, indicating an unresectable situation 10. If underlying liver cirrhosis, Childs Pugh score of 5 or 6 11. If underlying liver disease, ALBI grade ≤2† 12. Patients with HBV infection, which is characterized by positive hepatitis B surface antigen (HBsAg) and/or hepatitis B core antibodies (anti-HBcAb) with detectable HBV DNA (≥10 IU/ml or above the limit of detection per local lab standard), must be treated with antiviral therapy, as per institutional practice, to ensure adequate viral suppression (HBV DNA ≤2000 IU/mL) prior to study entry. Patients must remain on antiviral therapy for the study duration and for 6 months after the last dose of study medication. Patients who test positive for anti-hepatitis B core (HBc) with undetectable HBV DNA (\<10 IU/ml or under limit of detection per local lab standard) do not require anti-viral therapy prior to study entry. These subjects will be tested at every cycle to monitor HBV DNA levels and initiate antiviral therapy if HBV DNA is detected (≥10 IU/ml or above the limit of detection per local lab standard). HBV DNA detectable subjects must initiate and remain on antiviral therapy for the study duration and for 6 months after the last dose of study medication. 13. Patients with HCV infection must have management of this disease per local institutional practice throughout the study. HCV diagnosis is characterized by the presence of detectable HCV ribonucleic acid (RNA) or anti-HCV antibody upon enrollment. 14. Evidence of post-menopausal status or negative serum pregnancy test for female pre-menopausal patients. 15. Adequate normal organ and marrow function as defined below within screening period: * Haemoglobin ≥9.0 g/dL * Absolute neutrophil count (ANC ≥1.0 × 109 /L) * Platelet count ≥100 × 109/L * Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). \<\<This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician. * AST (SGOT)/ALT (SGPT) ≤5 x institutional upper limit of normal. * Measured creatinine clearance (CL) \>50 mL/min or Calculated creatinine clearance CL\>50 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance: Males: Creatinine CL (mL/min) = Weight (kg) x (140 - Age) 72 x serum creatinine (mg/dL) Females: Creatinine CL (mL/min) = Weight (kg) x (140 - Age) x 0.85 72 x serum creatinine (mg/dL) * Albumin ≥2.8g/dl * International normalized ratio ≤1.5 (for patients receiving Warfarin, please consult with the study physician) 16. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up. * Resectability is at the discretion of the investigators at each site but must be discussed at a multidisciplinary tumour board. * based on albumin and bilirubin; ALBI score = (log10 bilirubin \[umol/L\] x0.66) + (albumin \[g/L\] x -0.0852). ALBI grade 1= score ≤ -2.60.
Exclusion criteria
Patients should not enter the study if any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Major pathological response (MPR), defined as >70% tumor necrosis | 2 years | To determine pathological response rate to neoadjuvant Gemcitabine/Cisplatin/Nab-Paclitaxel and Rilvegostomig in resected tumour |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective response rate (ORR) | 3 years | To determine the radiologic objective response rate (ORR) to neoadjuvant Gemcitabine/Cisplatin/Nab-Paclitaxel and Rilvegostomig. |
| The number of patients who experience a surgical delay and/or drop off due to treatment related adverse events (TRAEs) or progressive disease | 2 years | To assess feasibility of pre-operative treatment of Gemcitabine/Cisplatin/Nab-Paclitaxel and Rilvegostomig |
| The number of ≥ grade 3 adverse events (AEs) or immune related adverse events that occur during treatment | 3 years | To assess safety of pre-operative treatment with Gemcitabine/Cisplatin/Nab-Paclitaxel and Rilvegostomig. |
| Rate of R0 | 2 years | Number of resections with negative margins |
Countries
Canada
Outcome results
None listed