An Open-label Window of Opportunity Trial to Evaluate the Activity of Durvalumab (MEDI4736) and Tremelimumab With Platinum-based Chemotherapy (Gemcitabine and Cisplatin) in Intrahepatic Cholangiocarcinoma (ICC)
Overview
- Phase
- Phase 1
- Status
- Terminated
- Enrollment
- 1
- Locations
- 1
- Primary Endpoint
- Objective Response Rate
Overview
Brief Summary
This pilot trial will be used to assess the activity, safety and feasibility of doublet immunotherapy and platinum-based chemotherapy in resectable intrahepatic cholangiocarcinoma with high risk features. The hypothesis is that the combination of durvalumab/MEDI4736 and tremelimumab (doublet immunotherapy) with platinum-based chemotherapy (gemcitabine and cisplatin) will yield an objective of 52% and improve complete resection rates in intrahepatic cholangiocarcinoma. This will facilitate margin negative resection and ultimately reduce recurrence rates and improve survival. Carrying out this trial in the neoadjuvant setting potentially allows improved overall survival and also provides an opportunity for discovery of biomarkers that may predict response to therapy.
Detailed Description
All enrolled participants will receive the study intervention. Patients will receive up to 4 cycles of interventional agents prior to surgical resection. They will undergo imaging scans after the 2nd and 4th cycle (before surgery) of intervention agents. The short interval of scans (6 weeks) allows investigators to identify non responders. These patients may be encouraged to come off study and be treated based on the treating oncologist's choice. Since the investigational agents include 'standard of care' agents, a good argument can be made that these patients would not have benefitted from standard therapy only. Patients with at least stable disease after the 2nd treatment cycle will proceed with study interventions. However, patients with radiologic progression but who remain clinically stable may be allowed to continue treatment if the patient elects to, pending confirmation of progression and after a discussion between the investigator and sponsor-investigator.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 89 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Subject must meet all of the following applicable inclusion criteria to participate in this study:
- •Histologically/cytologically confirmed diagnosed intrahepatic cholangiocarcinoma
- •Measurable disease based on RECIST 1.1 and have 1 or more radiologic features compatible with high risk (for resection and recurrence) but still considered technically resectable per multidisciplinary tumor board (Surgical oncologist, radiologist and medical oncologist minimum) meeting. High risk features would include at least 1 of the following criteria-
- •A large tumor (\> 5cm) that would benefit from preoperative tumor shrinkage with systemic therapy
- •T1b-T4 tumor thought to be technically resectable
- •Multifocal tumors/ a tumor with satellite lesions confined to the same lobe, thought to be technically resectable
- •Suspicious or involved lymph nodes (N1) thought to be technically resectable
- •Tumor with any vascular involvement/invasion considered technically resectable
- •No extrahepatic metastases
- •Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent and any locally required authorization (e.g., Health Insurance Portability and Accountability Act in the US) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations.
Exclusion Criteria
- •Has had previous local (surgery, radiation, embolizing procedure) or systemic therapy for borderline resectable intrahepatic cholangiocarcinoma.
- •Participation in another clinical study with an investigational product during the last 3 months.
- •Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study.
- •Has ampullary cancer, extrahepatic cholangiocarcinoma or gall bladder cancer.
- •Patients with distant extrahepatic metastatic disease including distant (non-regional lymph nodes). NOTE: Regional lymph nodes depend on tumor site; for left sided lesions, regional lymph nodes include inferior phrenic, hilar and gastrohepatic lymph nodes. For right sided lesions, regional lymph nodes include hilar periduodenal and peripancreatic lymph nodes.
- •Has any other histologic subtype except adenocarcinoma or mixed histology with adenocarcinoma/hepatocellular carcinoma.
- •Any unresolved toxicity NCI CTCAE Grade \> 2 from previous anticancer therapy except for 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 sponsor-investigator.
- •Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included only after consultation with the sponsor-investigator. Any medical contraindication to the use of platinum-based doublet chemotherapy as judged by the treating physician.
- •. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of study drugs.
Arms & Interventions
Novel combination of chemotherapy and immunotherapy
This study has one arm. All enrolled patients will receive a combination of a platinum based chemotherapy regimen (gemcitabine and cisplatin) and a combination of two immune check point inhibitors, anti- CTLA4 (Tremelimumab) and anti PDL-1 (durvalumab).
Gemcitabine will be administered (gemzar) intravenously, 1000mg/m2 on Day 1 and Day 8 of a 21 day cycle for up to 4 cycles. Cisplatin (Platinol) will be administered intravenously, 25mg//m2 on Day 1 and Day 8 of a 21 day cycle for up to 4 cycles.
Tremelimumab will be administered intravenously, 300mg flat dose, on Day 1 of cycle 1 only. Durvalumab will be administered intravenously 1500mg on Day 1 of a 21 day cycle for 4 cycles.
Intervention: Novel combination of chemotherapy and immunotherapy (Drug)
Outcomes
Primary Outcomes
Objective Response Rate
Time Frame: Assessments will occur after 2 cycles (6 weeks) of receiving treatment and after 4 cycles (12 weeks) of receiving treatment or before surgical resection, whichever happens first.
We will obtain computerized tomography (CT) and/or magnetic resonance imaging (MRI) scans to assess the response to the intervention agents. We are interested in determining the percentage of patients who achieve a complete response or partial response (complete response plus partial response equals to objective response) when treated with intervention agents.
Secondary Outcomes
- The Percentage of Participants That Complete Preoperative Therapy(Baseline through 16 weeks of treatment)
- Determine the Safety of the Combination of Intervention Agents by Assessing the Percentage of Patients Who Experience Dose Limiting Toxicities or Develop Adverse Reactions(Baseline through 16 weeks of treatment)
- Determine Changes in the Tumor mRNA Gene Expression Pattern, Phenotype of Circulating Cytotoxic T Cells, and Changes in Circulating Markers of Immunogenic Cell Death Following Treatment With Intervention Agents(Baseline through 24 months)
Investigators
Mehmet Akce, MD
Associate Professor
University of Alabama at Birmingham