Durvalumab and Tremelimumab With Platinum-based Chemotherapy in Intrahepatic Cholangiocarcinoma (ICC)

NCT04989218 | Terminated Phase 1 Results DMC FDA Drug

• 2 other identifiers: IRB-300005453000538122
• Study Type: interventional
• Target: 1
• Locations: 1 country
• Sites: 1

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.

Conditions

Cholangiocarcinoma

Keywords

Durvalumab; Tremelimumab; Platinum-based chemotherapy; Gemcitabine; Cisplatin

Outcome Measures

Primary Outcomes (1)

• Objective Response Rate

  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.

  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.

Secondary Outcomes (3)

• 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

Study Arms (1)

Novel combination of chemotherapy and immunotherapy

EXPERIMENTAL

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.

Drug: Novel combination of chemotherapy and immunotherapy

Interventions

Novel combination of chemotherapy and immunotherapy DRUG

This is a study of the combination of platinum based chemotherapy (gemcitabine and cisplatin) and doublet immunotherapy (durvalumab and tremelimumab) in the preoperative setting for intrahepatic cholangiocarcinoma with high risk features. Gemcitabine and cisplatin are chemotherapy agents used in the management of locally advanced and metastatic cholangiocarcinoma. Durvalumab is a programmed cell death ligand 1 (PDL1) blocking antibody, that improves the immune response against cancer. Tremelimumab is an antibody that targets cytotoxic T cell lymphocyte-associated protein 4 (CTLA4) on regulatory T cells. It also improves the immune response against cancer cells

Also known as: Cisplatin (Platinol), Gemcitabine (Gemzar), Durvalumab (Imfimzi), Tremelimumab

Novel combination of chemotherapy and immunotherapy

Eligibility Criteria

• Age: 18 Years - 89 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Adult male or female age \>18 years at time of study entry
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Life expectancy of \> 6 months
• Body weight \>30 kg
• Adequate normal organ and marrow function as defined below:
• Hemoglobin ≥ 10.0 g/dL

You may not qualify if:

• 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.
• 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.
• History of allogenic organ transplantation.
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[e.g., colitis or Crohn's disease\], diverticulitis \[with the exception of diverticulosis\], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome \[granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.\]). The following are exceptions to this criterion:
• Patients with vitiligo or alopecia
• Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
• Any chronic skin condition that does not require systemic therapy
• Patients without active disease in the last 5 years may be included but only after consultation with the study physician

Sponsors & Collaborators

• University of Alabama at Birmingham: lead

Study Sites (1)

University of Alabama at Birmingham

Birmingham, Alabama, 35294, United States

Location

MeSH Terms

Conditions

Cholangiocarcinoma

Interventions

Immunotherapy; Cisplatin; Gemcitabine; durvalumab; tremelimumab

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms

Intervention Hierarchy (Ancestors)

Immunomodulation; Biological Therapy; Therapeutics; Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring

Limitations and Caveats

Study sponsor discontinued this study due to low accruals and change in sponsor strategy.

Results Point of Contact

• Title: Dr. Mehmet Akce, Associate Professor
• Organization: The University of Alabama at Birmingham

makce@uabmc.edu

2059342992

Study Officials

• Moh'd Khushman, MD

  University of Alabama at Birmingham

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: July 9, 2021
• First Posted: August 4, 2021
• Study Start: January 30, 2023
• Primary Completion: March 20, 2024
• Study Completion: May 1, 2024
• Last Updated: November 5, 2024
• Results First Posted: November 5, 2024

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)