Phase I trial of a pathotropic retroviral vector expressing a cytocidal cyclin G1 construct (Rexin-G) in patients
Evanthia Galanis1, Stephanie K Carlson, Nathan R Foster
1Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota 55905, USA. galanis.evanthia@mayo.edu
Abstract:
Rexin-G is a pathotropic retroviral vector displaying a von Willebrand factor-targeting motif and expressing a dominant negative cyclin G1 gene. We undertook a phase I trial of intravenous (i.v.) administration of Rexin-G in patients with gemcitabine refractory, metastatic pancreatic adenocarcinoma. Twelve patients were treated. Dose escalation was performed from a dose of 1 x 10(11) colony forming units (CFU) per cycle to 6 x 10(11) CFU per cycle. The treatment was well tolerated. One dose-limiting toxicity (DLT) at dose level 2 (1.5 x 10(11) CFU per cycle) was observed, consisting of grade 3 transaminitis. There was no detection of replication-competent virus in patients' peripheral blood mononuclear cells (PBMCs) or viral integration in DNA obtained from PBMCs, and no development of neutralizing antibodies. No evidence of antitumor activity was observed. The best objective response was progressive disease in 11 of the 12 study patients, while 1 patient showed radiographically stable disease with clinical deterioration and increase in the CA19.9 tumor marker. Median time to progression was 32 days. The median duration of survival of the study patients was 3.5 months from treatment initiation. Rexin-G is well tolerated in doses up to 6 x 10(11) CFU in patients with recurrent pancreatic cancer, but there was no evidence of clinical antitumor activity.
Insights
Rexin-G, a novel gene therapy, was evaluated in patients with advanced pancreatic cancer. While well-tolerated, this phase I trial found no significant antitumor activity, indicating limited clinical benefit for recurrent pancreatic adenocarcinoma.
Area of Science:
- Oncology
- Gene Therapy
- Viral Vector Technology
Background:
- Pancreatic cancer is a leading cause of cancer death, often diagnosed at advanced stages.
- Gemcitabine chemotherapy is a standard treatment, but resistance frequently develops in metastatic pancreatic adenocarcinoma.
- Novel therapeutic strategies are needed to improve outcomes for patients with refractory pancreatic cancer.
Purpose of the Study:
- To evaluate the safety and tolerability of Rexin-G, a pathotropic retroviral vector, in patients with gemcitabine-refractory metastatic pancreatic adenocarcinoma.
- To assess the preliminary efficacy and biological activity of Rexin-G.
- To determine the maximum tolerated dose (MTD) or recommended phase II dose of Rexin-G.
Main Methods:
- Phase I clinical trial with dose escalation of intravenous Rexin-G.
- Treatment administered in cycles with doses ranging from 1 x 10(11) to 6 x 10(11) colony forming units (CFU).
- Safety assessments included monitoring for dose-limiting toxicities (DLTs), viral shedding, and immune response.
Main Results:
- Rexin-G was well-tolerated up to 6 x 10(11) CFU per cycle.
- One DLT (grade 3 transaminitis) occurred at 1.5 x 10(11) CFU.
- No replication-competent virus or viral integration was detected; no neutralizing antibodies developed.
- No objective antitumor response was observed; 11/12 patients had progressive disease.
- Median time to progression was 32 days, and median survival was 3.5 months.
Conclusions:
- Intravenous Rexin-G is safe and well-tolerated in patients with recurrent pancreatic cancer at doses up to 6 x 10(11) CFU.
- The study demonstrated no evidence of clinical antitumor activity or significant biological effect.
- Further investigation of Rexin-G in pancreatic cancer is not warranted based on these findings.
