क्लिनिकल गैस्ट्रोएंटरोलॉजी जर्नल

A Phase I Study of Immune Checkpoint Inhibition (anti- CTLA4 and anti-PD-L1) in Combination with Radiation Therapy in Patients with Locally Advanced Unresectable Pancreatic Cancer

Abstract

Jennifer Wu*, Emily C Atkinson, Kevin Du, Susanna Nguy, Anna C Pavlick, Judith D Goldberg, Daniel Becker, Elaine Shum, Steve Y Lee, George Miller, Jennifer Chuy and Lawrence Leichman

Background: No clear consensus exists on the best treatment for unresectable locally advanced pancreatic cancer. Programmed death ligand-1 (PD-L1) inhibitors and cytotoxic T lymphocyte antigen-4 (CTLA-4) inhibitors, especially in combination, have been shown to increase survival in a variety of cancers. Preclinical data indicates potential synergy between immunotherapy, such as PD-L1 and CTLA-4 inhibitors, with radiation therapy. Specifically, in combination with Stereotactic Body Radiation Therapy (SBRT), immunotherapy may provide an effective treatment modality for this difficult-to-treat patient population.

Aim: To determine the safety and recommended phase 2 dose (RP2D) of SBRT in combination with either (A) Durvalumab (MEDI4736) alone, (B) Tremelimumab alone or (C) the combination of Durvalumab (MEDI4736) and Tremelimumab for patients with unresectable locally advanced adenocarcinoma.

Methods: A multi-institutional phase Ib trial of radiation therapy in combination with immune checkpoint inhibition (anti-CTLA4 alone, anti-PD-L1 alone, or anti-CTLA4 with anti-PDL1) in patients with unresectable locally advanced pancreatic cancer.

Cohort A: SBRT plus Durvalumab (MEDI4736): 1 dose escalation

Cohort B: SBRT plus Tremelimumab: 1 dose escalation

Cohort C: SBRT plus Durvalumab (MEDI4736) in combination with Tremelimumab: For Durvalumab (MEDI4736), there will be either 1 dose escalation (if RP2D of Cohort A is >750mg) or no dose escalation (if RP2D of Cohort A is 750mg). For Tremelimumab, there will be flat dosing of 75 mg, no dose escalation. Each cohort will have a standard 3 + 3 dose escalation design. SBRT will be administered at the standard dose of 6.6 Gy daily for 5 days in each cohort.

Results: Due to slow accrual, the study was terminated after 4 subjects were enrolled. Treatment was well-tolerated; no patients discontinued treatment due to adverse events. Adverse events were those commonly seen with immunotherapy, including LFT abnormalities, maculopapular rash, and diarrhea. Pulmonary embolism and duodenal ulcer leading to hemorrhage developed in two different patients, neither of which was related to treatment.

Conclusion: The combination of SBRT with either Durvalumab (MEDI4736) or Tremelimumab appears to be safe and tolerable in four patients with unresectable locally advanced pancreatic adenocarcinoma. Further studies are required to further explore the safety and clinical benefit of this treatment regimen.