Study of Immune Checkpoint Inhibition With Radiation Therapy in Unresectable, Non-metastatic Pancreatic Cancer

A Phase I Study of Immune Checkpoint Inhibition (Anti-CTLA4 and/or Anti-PD-L1) in Combination With Radiation Therapy in Patients With Unresectable and Non-metastatic Pancreatic Cancer

This is an open-label, three-cohort, phase Ib study to determine the safety, recommended phase 2 dose (RP2D), and efficacy of Stereotactic Body Radiation Therapy (SBRT) in combination with either (A) MEDI4736 alone, (B) tremelimumab alone, or (C) the combination of MEDI4736 and tremelimumab for patients with unresectable locally advanced adenocarcinoma of pancreas.

Study Overview

• Status: Withdrawn
• Conditions: Pancreatic Cancer
• Intervention / Treatment: Drug: MEDI4736; Radiation: Stereotactic Body Radiation Therapy (SBRT); Drug: Tremelimumab

Detailed Description

Patients with unresectable, locally advanced adenocarcinoma of pancreas will receive Stereotactic Body Radiation Therapy (SBRT) at a dose of 6 Gy daily, for 5 days. In Cohort A, where MEDI4736 is given, subjects will receive 10 mg/kg of MEDI4736 every 2 weeks, on the same day as, but after the first dose of SBRT is delivered (within 4 hours). In Cohort B, where tremelimumab is given, subjects will receive 10 mg/kg of tremelimumab every 4 weeks, on the same day as, but after the first dose of SBRT is delivered (within 4 hours). In Cohort C, where MEDI4736 and tremelimumab are given in combination, subjects will receive 10 mg/kg of tremelimumab every 4 weeks, on the same day as, but after the first dose of SBRT is delivered (within 4 hours), followed by 10 mg/kg of MEDI4736 every 4 weeks.

Correlative Studies The investigators will evaluate immune changes in peripheral blood samples and in tumor biopsy fine needle aspirate (FNA) specimens pre- and post- treatment from the 3 cohorts that involve the combination of stereotactic body radiation therapy (SBRT) with either (A) MEDI4736 alone, (B) tremelimumab alone, or (C) the combination of MEDI4736 and tremelimumab. FNA biopsies will be done at baseline (within 30 days of treatment initiation) and Day 28 of cycle 2 (between days 22-28 of cycle 2).

• Study Type: Interventional
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Georgetown University Medical Center
  • New York
    • Bronx, New York, United States, 10461
      • Montefiore Medical Center
    • New York, New York, United States, 10016
      • New York University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion:

• Histopathological confirmation of pancreatic adenocarcinoma prior to study entry.
• Unresectable and non-metastatic disease
• At least 1 measurable metastatic lesion by RECIST 1.1, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >20 mm with conventional techniques, or as >10 mm with spiral computed tomography (CT) scan, and that is accessible for biopsy.
• Age >18 years
• ECOG performance status 0-1
• Normal organ and marrow function as defined below:

Absolute Neutrophil Count > 1,000/mcL Platelets ≥ 75,000/mcL Total Bilirubin ≤ 2 x ULN Serum Albumin ≥ 2.5 g/dl ALT or AST up to 3 x ULN if no liver metastases or ALT or AST up to 5 x ULN if liver metastases present Creatinine < 2 x institution upper limit of normal OR Creatinine Clearance > 45 mL/min/1.73 m2, as calculated below, for patients with creatinine levels above institutional normal

• No history of another malignancy in the past 5 years, except for treated non-melanoma skin cancer, superficial bladder cancer, or carcinoma-in-situ of the cervix
• No coexisting medical problems that would limit compliance with the study
• Ability to understand and sign a written informed consent document. Patient must have willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and other study procedures.
• Female subjects of childbearing potential must have a negative serum pregnancy test prior to study entry
• Female subjects of childbearing potential and males must agree to use a highly effective method of contraception for the duration of study treatment, and for six months after discontinuation of the study drug.

Exclusion:

• Resectable, borderline resectable or metastatic disease
• Prior chemotherapy, targeted therapy, immunotherapy, clinical trials or radiotherapy for pancreatic cancer.
• Active or history of concomitant therapy with any of the following: interleukin (IL) 2, interferon, or other non-study immunotherapy regimens, immunosuppressive agents, other investigational therapies, or chronic use of systemic corticosteroids (inhaled and topical steroids are permitted)
• Active or history of chronic autoimmune disease with symptomatic disease within the 3 years before randomization.
• Active or history of inflammatory bowel disease (colitis, Crohn's disease), irritable bowel disease, celiac disease, or other serious, chronic, gastrointestinal conditions associated with diarrhea.
• Diverticulitis within the past 2 years.
• Active HIV infection
• Uncontrolled systemic disease including, but not limited to, ongoing or active systemic infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Brain metastases
• Patients should not be vaccinated with live attenuated vaccines within 1 month of starting tremelimumab and MEDI4736 treatment.
• History of hypersensitivity reaction to human or mouse antibody products
• Evidence of pre-existing idiopathic pulmonary fibrosis on CT scan at baseline
• Unhealed surgical wound at time of treatment, or history of unhealed surgical wound for more than 30 days
• History of an invasive secondary primary malignancy diagnosed within the previous 3 years, except for appropriately treated stage I endometrial or cervical carcinoma, prostate carcinoma treated surgically or non-melanoma skin cancer.
• Non-protocol antineoplastic agents will not be permitted during this study
• Patients may not recieve other investigational agents.
• Pregnant or lactating women
• Subjects with dementia or significantly altered mental status that would prohibit understanding or rendering of information and consent and compliance with the requirements of the protocol.
• Subjects unable or unwilling to abide by the study protocol or cooperate fully.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort A: MEDI4736 + SBRT; MEDI4736 10 mg/kg IV every 2 weeks plus Stereotactic Body Radiation (SBRT) 6 Gy x 5 Days, 10 Subjects	Drug: MEDI4736; anti-PD-L1 human monoclonal antibody; Other Names: Durvalumab; Radiation: Stereotactic Body Radiation Therapy (SBRT); Stereotactic body radiation therapy (SBRT) will be administered at the standard dose of 6 Gy daily for 5 days.
Experimental: Cohort B:Tremelimumab + SBRT; Tremelimumab 10 mg/kg IV every 4 weeks plus Stereotactic Body Radiation (SBRT) 6 Gy x 5 Days, 10 Subjects	Radiation: Stereotactic Body Radiation Therapy (SBRT); Stereotactic body radiation therapy (SBRT) will be administered at the standard dose of 6 Gy daily for 5 days.; Drug: Tremelimumab; anti-CTLA4 human monoclonal antibody; Other Names: CP-675,206
Experimental: Cohort C: MEDI4736 + Tremelimumab + SBRT; MEDI4736 + Tremelimumab (recommended phase 2 IV dose for combination) plus Stereotactic Body Radiation (SBRT) 6 Gy x 5 Days, 16 Subjects	Drug: MEDI4736; anti-PD-L1 human monoclonal antibody; Other Names: Durvalumab; Radiation: Stereotactic Body Radiation Therapy (SBRT); Stereotactic body radiation therapy (SBRT) will be administered at the standard dose of 6 Gy daily for 5 days.; Drug: Tremelimumab; anti-CTLA4 human monoclonal antibody; Other Names: CP-675,206

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Kaplan Meier curves will be used to summarize Overall Survival.	24 Months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival	Kaplan Meier curves will be used to summarize Progression-Free Survival.	24 Months
Response Evaluation Criteria in Solid Tumors (RECIST 1.1)	Response rates will be estimated with exact 95% confidence intervals for each dose level.	24 Months
Immune-related Response Criteria (irRC)	Kaplan Meier curves will be used to summarize Clinical Benefit Rate.	24 Hours

Collaborators and Investigators

• Sponsor: NYU Langone Health
• Collaborators: AstraZeneca
• Investigators: Principal Investigator: Jennifer Wu, MD, NYU Langone Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): August 7, 2016
• Primary Completion (Actual): March 4, 2019
• Study Completion (Actual): March 4, 2019

Study Registration Dates

• First Submitted: August 8, 2016
• First Submitted That Met QC Criteria: August 11, 2016
• First Posted (Estimate): August 16, 2016

Study Record Updates

• Last Update Posted (Actual): April 5, 2019
• Last Update Submitted That Met QC Criteria: April 3, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Keywords: Unresectable; Locally Advanced; Non-Metastatic
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Pancreatic Diseases; Pancreatic Neoplasms; Antineoplastic Agents; Antineoplastic Agents, Immunological; Durvalumab; Tremelimumab
• Other Study ID Numbers: 14-01317

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No