Immunotherapy Combination Receives Breakthrough Designation for Pancreatic Cancer

Stephen T. Isaacs

The combination of the immunotherapy CRS-207 and the vaccine GVAX Pancreas has received a breakthrough therapy designation from the FDA for its potential as a treatment for patients with metastatic pancreatic cancer.

The new designation is based on results from a phase II study, which showed that treatment with low-dose cyclophosphamide with GVAX followed by CRS-207 extended survival (OS) by 46% compared with cyclophosphamide plus GVAX alone for patients with pancreatic ductal adenocarcinoma. These impressive findings for the immunotherapy combination were presented at the 2014 Gastrointestinal Cancer Symposium earlier this year.

“We are extremely pleased to receive breakthrough therapy designation and the high degree of FDA collaboration toward advancement of our program that it confers,” Stephen T. Isaacs, chairman, president and chief executive officer of Aduro, the company developing the combination, said in a press release. “This designation underscores the potential of our combination immunotherapy approach to make a difference in the lives of patients with pancreatic cancer, which remains a very difficult cancer to treat.”

GVAX is made from irradiated pancreatic cell lines that secrete GM-CSF. Low-dose cyclophosphamide is administered prior to GVAX, to prevent regulatory T cells from inhibiting the antigenic response. CRS-207 is composed of live attenuated Listeria monocytogenes that express meothelin, effectively stimulating an immune response against the protein that is present at high levels on pancreatic cancer cells.

In the phase II study, 90 previously treated patients were randomized in a 2:1 ratio to receive 2 doses of cyclophophamide and GVAX followed by 4 doses of CRS-207 (n = 61) or 6 doses of cyclophophamide and GVAX alone (n = 29). Cyclophosphamide was administered at 200 mg/m² 1 day prior to the GVAX vaccine that was administered at 5 x 10⁸ cells every 3 weeks. CRS-207 was administered at 1 x 10⁹ CFU on weeks 7, 10, 13, and 16.

All patients enrolled in the study had received 1 prior therapy, with 51% having received ≥2 chemotherapy regimens. Patients had adequate organ function and an ECOG performance status of 0-1. The primary endpoint was OS, with secondary endpoints of safety, clinical, and immune responses.

After a median follow-up of 7.8 months, the median OS was 6.1 months with CRS-207 versus 3.9 months with GVAX alone HR=0.54; P = .011). For patients who received ≥3 doses, the median OS was 9.7 versus 4.6 months, for CRS-207 and GVAX, respectively (HR=0.44; P = .0074).

In patients with heavily pretreated metastatic pancreatic cancer (≥2 prior regimens) the median OS was 5.1 months with CRS-207 versus 3.7 months with GVAX alone (HR=0.34; P = .001). CA19-9 stabilization was achieved in 32% of patients treated with CRS-207 compared with 13% for GVAX alone.

The most common grade 3/4 side effects with the combination immunotherapy were lymphopenia (8.2%), pyrexia (4.9%), fatigue (4.9%), and aspartate aminotransferase increase (4.9%). Additional, local reactions were seen following administration of GVAX.

"We are encouraged by our phase II results and look forward to completing enrollment in our phase IIb ECLIPSE trial by end of 2015,” Isaacs said.

The phase IIb ECLIPSE study is currently examining GVAX with cyclophosphamide and CRS-207 versus CRS-207 or chemotherapy (gemcitabine, capecitabine, 5-FU, irinotecan or erlotinib) alone in previously treated patients with metastatic pancreatic adenocarcinoma. This study plans to enroll 240 patients, with a primary endpoint of overall survival.