Nivolumab, Ipilimumab and Chemoradiation in Pancreatic Cancer.

Conditions

• Borderline Resectable, Locally Advanced or Metastatic Pancreatic Cancer

Eligibility Criteria

Sex

ALL

Age

18 Years - N/A

Healthy Volunteers

Not accepted

Interventions

• Gemcitabine — DRUG
  800 mg/m2 Day 1, 8, 15: Q4W IV Infusion
• Nab-paclitaxel — DRUG
  100 mg/m2 Day 1, 8, 15: Q4W IV Infusion
• Nivolumab — DRUG
  3 mg/kg Day 1, Q4W IV Infusion
• Ipilimumab — DRUG
  1 mg/kg Day 1 Cycle 1 IV Infusion
• SBRT — RADIATION
  Patients will be planned and treated with SBRT on a MRidian MR guided Linac. Prescription dose shall be according to the following specifications: * Prescription dose shall be according to the following specifications: * A total dose of 24 Gy in 3 fractions (3 fractions/week) are prescribed as the mean dose to the PTV. * Pauses are accepted but the treatment should be delivered within 10 calendar days. * PTV should be covered by 95% isodose (PTV D99% \>95%).

Study Details

Pancreatic ductal adenocarcinoma (PDAC) remains a dreadful disease due to its often advanced stage at diagnosis and poor sensitivity to chemotherapy. A locally unresectable tumor (locally advanced pancreatic cancer (LAPC)) is present in 30% of the cases and is defined as a surgically unresectable tumor encasing the adjacent arteries \[celiac axis, superior mesenteric artery (SMA)\]. In these patients, chemotherapy has been the standard treatment for decades, optionally combined with radiotherapy. Patients with borderline resectable pancreatic cancer (BRPC) comprise a group of patients with PDAC who are at a high risk of having positive margins if upfront resection is pursued. In addition, multiple studies have reported these patients have increased probability of early recurrence of local and systemic disease resulting in poorer outcomes. Although some patients are treated with an aggressive surgery-first approach and adjuvant systemic therapies, a preoperative chemotherapy and/or chemoradiation approach is becoming more common for all patients with BRPC, and this strategy is adapted in Danish and international guidelines. Majority of patients present with metastatic pancreatic cancer (mPC). Therapy options are limited by chemotherapy in palliative setting. The superiority of the FOLFIRINOX regimen demonstrated in the phase III mPC setting led many centers to investigate FOLFIRINOX with or without chemoradiotherapy in patients with LAPC tumor. Gemcitabine combined with nab-paclitaxel is the approved first-line treatment for patients with advanced PC. This regimen showed a median progression-free survival (PFS) of 5.5 months and a median overall survival (OS) of 8.5 months and is the predominantly used regimen in metastatic PC. The role of radiation therapy in the management of nonresectable PC remains controversial. The results of small randomized trials comparing chemoradiotherapy with chemotherapy of patients with LAPC are divergent. Immunotherapy has emerged as a therapeutic approach that offers effective and durable treatment options for subsets of patients with various types of cancer. However, these successes have not manifested similar benefits for PDAC patients mostly due to a lack of pre-existing T-cell immunity and/or a highly immunosuppressive tumor microenvironment (TME). Considering the emerging role of the TME, the combination of checkpoint blocking antibodies with agents that target the inhibitory effects of the TME could lead to better responses in tumor historically resistant to checkpoint blocking antibody approaches. For example, in heavily pretreated patients with advanced/metastatic PDAC, preliminary data from the phase 2 study CHECKPAC (NCT02866383) showed that checkpoint inhibition in combination with stereotactic body radiotherapy (SBRT) provided durable clinical benefit in a small proportion of patients, including prolonged, sustained partial responses. Furthermore, the addition of standard-of-care chemotherapy could further potentiate the anti-tumor effects of immunotherapy approaches by reducing the tumor burden, exposing antigens, and directly affecting the immunosuppressive TME compartment. To explore the safety and synergy of the proposed combinatorial approach, participants with borderline resectable, locally advanced or mPC will receive nivolumab and ipilimumab administered in combination with gemcitabine and nab-paclitaxel followed by immune-chemoradiation.

Key Dates

Start date

Jun 2, 2020

Status verified

May 2024

Primary completion

May 24, 2024

Completion

Dec 5, 2024

Study Design

Enrollment

55 participants (actual)

Allocation

NA

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Arms

• Experimental: Experimental
  Nivolumab 3 mg/kg will be given on day 1 (± 2 days) of each 28-day treatment cycle until the progression of disease, discontinuation due to toxicity, withdrawal of consent. Ipilimumab 1 mg/kg will be given once only on day 1 cycle 1. Nivolumab will be administered as an IV infusion over 30 (± 5) minutes and then, after a 30 minutes rest period, ipilimumab will be administered as an IV infusion over 30 (± 5) minutes. Pre-medication for chemotherapy (based on standard-of-care and local institutional standards) and chemotherapy will then be administered after a further 30 minutes rest period. The recommended dose of nab-paclitaxel is 100 mg/m2 administered as an IV infusion over 30 to 40 minutes on Days 1, 8, and 15 of each 28-day cycle. Gemcitabine 800 mg/m2 will be administered over 30 to 40 minutes immediately after nab-paclitaxel on Days 1, 8, and 15 of each 28-day cycle.

Primary Outcome Measure

Incidence of treatment-related AEs, SAEs, AEs leading to discontinuation, death, and laboratory abnormalities [ Time Frame: 12 months ]