Phase II Study of Neoadjuvant Durvalumab (MEDI4736) and Tremelimumab in Combination With Gemcitabine and Cisplatin in Patients With Intrahepatic Cholangiocarcinoma That is Borderline Resectable/Resectable But With High Risk for Recurrence.
Overview
- Phase
- Phase 2
- Intervention
- Durvalumab
- Conditions
- Borderline Resectable Carcinoma
- Sponsor
- Georgetown University
- Enrollment
- 28
- Primary Endpoint
- Rate of Conversion from unresectable to resectable
- Status
- Withdrawn
- Last Updated
- last year
Overview
Brief Summary
The goal of this clinical trial is to test feasibility and safety of the combination of tremelimumab and durvalumab plus gemcitabine and cisplatin as a neoadjuvant treatment bridge patients to a curative resection in treatment naïve borderline resectable, or resectable with high risk for recurrence intrahepatic cholangiocarcinoma patients. The main question[s] it aims to answer are:
- What is the rate of conversion of unresectable tumor to resectable cancer?
- What are the side effects of this treatment combination?
Participants will undergo an initial tumor biopsy, imaging and laboratory studies prior to starting treatment with durvalumab, tremelimumab, gemcitabine and cisplatin. Participants will continue for 4 cycles and if the tumor is found to be resectable then they will undergo surgical resection. If the tumor is unresectable (can't be surgically removed) after 4 cycles, then participants will receive 4 more cycles and repeated imaging. If the tumor remains unresectable then the participant will be treated with capecitabine for up to 8 cycles and durvalumab for up to 12 months.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients of age 18 years and older at the time of study entry, both sexes, all ethnicities.
- •Patients with histologically proven intrahepatic cholangiocarcinoma, untreated with systemic therapy.
- •Patients with an absence of extrahepatic metastasis (outside of periportal lymph node enlargement) or peritoneal carcinomatosis as demonstrated by CT-scan.
- •Patients with a performance status ECOG 0,
- •Patients with an estimated life expectancy \> 6 months.
- •Patients with disease that is not readily suitable for resection with curative intent, as validated by a multidisciplinary committee with at least one hepatobiliary surgeon, defined as stage II and stage III disease, surgical resectable if there is tumor shrinkage.
- •Patients with at least one measurable lesion according to RECIST 1.1 criteria. Tumor assessment by computed tomography (CT) scan or magnetic resonance imaging (MRI) must be performed within 28 days prior to start of study.
- •Patients with platelets ≥ 75,000/mm3, polynuclear neutrophils ≥ 1500/mm3, hemoglobin ≥ 9g/dL.
- •Patients with serum creatinine \< 1.5 times institutional upper limit of normal (ULN), measured creatinine clearance \> 40 mL/min or Calculated creatinine clearance \> 40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24 hour urine collection for determination of creatinine clearance.
- •Patients with serum bilirubin ≤ 1.5 times institutional upper limit of normal (ULN) (after biliary drainage if necessary).
Exclusion Criteria
- •Patients with hilar or distal cholangiocarcinoma or those with hepatocholangiocarcinoma.
- •Patients who are eligible for surgical resection or liver transplantation based on tumor characteristics.
- •Patients who would not be surgical candidates due to reasons unrelated to their cholangiocarcinoma, e.g. Cirrhosis with portal hypertension
- •Patients with extrahepatic metastases beyond periportal lymph node enlargement
- •Patients with a contraindication or grade 3-4 allergy to durvalumab, tremelimumab, gemcitabine, cisplatin, or capecitabine.
- •Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria
- •Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.
- •Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included only after consultation with the Study Physician.
- •Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug
- •Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of Investigational Product (IP). Note: Local surgery of isolated lesions for palliative intent is acceptable
Arms & Interventions
Durvalumab and Tremelimumab plus gemcitabine/cisplatin
Durvalumab and tremelimumab plus gemcitabine/cisplatin combination therapy. If the tumor is evaluated to be resectable after Cycle 4 (C4), then the patient may proceed with surgical tumor resection. If the tumor is deemed unresectable after C4, then the patient will proceed with Cycle 5-8 followed by reevaluation for surgical resection.
Intervention: Durvalumab
Durvalumab and Tremelimumab plus gemcitabine/cisplatin
Durvalumab and tremelimumab plus gemcitabine/cisplatin combination therapy. If the tumor is evaluated to be resectable after Cycle 4 (C4), then the patient may proceed with surgical tumor resection. If the tumor is deemed unresectable after C4, then the patient will proceed with Cycle 5-8 followed by reevaluation for surgical resection.
Intervention: Tremelimumab
Durvalumab and Tremelimumab plus gemcitabine/cisplatin
Durvalumab and tremelimumab plus gemcitabine/cisplatin combination therapy. If the tumor is evaluated to be resectable after Cycle 4 (C4), then the patient may proceed with surgical tumor resection. If the tumor is deemed unresectable after C4, then the patient will proceed with Cycle 5-8 followed by reevaluation for surgical resection.
Intervention: Gemcitabine
Durvalumab and Tremelimumab plus gemcitabine/cisplatin
Durvalumab and tremelimumab plus gemcitabine/cisplatin combination therapy. If the tumor is evaluated to be resectable after Cycle 4 (C4), then the patient may proceed with surgical tumor resection. If the tumor is deemed unresectable after C4, then the patient will proceed with Cycle 5-8 followed by reevaluation for surgical resection.
Intervention: Cisplatin
Durvalumab and Tremelimumab plus gemcitabine/cisplatin
Durvalumab and tremelimumab plus gemcitabine/cisplatin combination therapy. If the tumor is evaluated to be resectable after Cycle 4 (C4), then the patient may proceed with surgical tumor resection. If the tumor is deemed unresectable after C4, then the patient will proceed with Cycle 5-8 followed by reevaluation for surgical resection.
Intervention: Surgical Resection
Outcomes
Primary Outcomes
Rate of Conversion from unresectable to resectable
Time Frame: 8 Cycles, 21 day cycles
Rate of conversion of unresectable tumor to resectable cancer after neoadjuvant durvalumab + tremelimumab + gemcitabine + cisplatin after 4 or 8 cycles. Surgical evaluation will be done in joint by institutional radiology and hepatobiliary surgery using clinical data (CT/MRI imaging, patient performance status, labs, etc.) If among the evaluable 24 patients, 9 or more (45%) patients undergo such conversion, the investigational treatment will be considered as promising/feasible. The resectable rate will be estimated with its 95% exact confidence interval.
Incidence of related treatment emergent adverse events
Time Frame: 36 months
Number of participants with related treatment emergent adverse events
Secondary Outcomes
- Pathological complete response (pCR)(36 months)
- Event Free Survival (EFS)(36 months)
- Objective Response Rate (ORR)(36 months)
- Overall survival (OS)(36 months)
- Progression-free survival (PFS)(36 months)
- Rate of R0 resection(8 Cycles, 21 day cycles)
- Relapse free survival (RFS)(36 months)
- Patient Reported outcomes (PRO) decline(8 Cycles, 21 day cycles)