The purpose of this clinical phase I/IIa, open label, single arm, interventional study (EudraCT No 2013-005582-39) is to investigate the safety, clinical and immunological responses of a therapeutic telomerase peptide vaccine, UV1, combined with ipilimumab in patients with metastatic melanoma (MM).
The CTLA-4 antibody ipilimumab produces long term survival benefits in ca.20% of patients with MM. The mechanism of action of ipilimumab suggests that combinations with therapies inducing tumor-specific immune responses, such as vaccines, may lead to additive and even synergistic anti-tumor activity. We hypothesized that a telomerase peptide-based vaccine in combination with ipilimumab would improve therapeutic efficacy in patients with MM. Telomerase promotes elongation of telomeres after each cell division, representing the key enzymatic process in preventing telomere shortening. It is responsible for human cell immortalization and cancer pathogenesis, and is present in 85-90% of cancer tissues. Thus, telomerase-based immunotherapy has been investigated in several tumor types. Available blood samples from long term cancer survivors previously treated with different types of human telomerase reverse transcriptase subunit (hTERT) vaccines identified a new set of peptide epitopes. T cell responses to these peptides form spontaneously after vaccination by epitope spreading and are found only in patients with remarkable clinical courses, suggesting a role in tumor eradication. This led to the development of UV1, a therapeutic cancer vaccine consisting of a mixture of 3 synthetic peptides representing naturally occurring fragments of human hTERT. Ongoing phase I/IIa trials with UV1 in non-small-cell lung cancer and prostate cancer (EudraCT No 2012-001852-20 and 2012-002411-26, respectively) have shown potent, durable T cell responses against UV1 peptides and low toxicity (unpublished data).
In the present protocol, patients with a histologically or cytologically confirmed diagnosis of unresectable AJCC stage III/IV MM, ECOG 0-1 and an adequate renal, hepatic and hematological function are eligible. Any previous treatment is allowed. Patients with active brain metastases, a history of autoimmune disease, splenic surgery or irradiation, allogenic stem cell transplantation, known hypersensitivity to the investigational products, uncontrolled infectious disease, pregnant or breastfeeding, will be excluded. Intradermal UV1 vaccines of 300 mcg and 75 mcg GM-CSF are administered 7, 5, and 3 days before and 11 days after the first dose of ipilimumab, then 3 days before every dose of ipilimumab, and subsequently every 4th week until week 48 or treatment cessation. Ipilimumab 3 mg/kg is given IV every 3rd week for a total of 4 doses. Each patient will be followed up 5 weeks after the completion of the last study treatment. Adverse events are recorded in coherence with CTCAE vs. 4.0. Tumor response is evaluated according to RECIST vs.1.1. Immune responses against UV1 peptides are monitored by standard immunoassays. Potential predictive biomarkers will be explored in an extensive program involving sequential tumor biopsies, DNA sequencing and mRNA expression. The first patient was enrolled 16 January 2015, estimated completed recruitment by one year. 3 out of 20 patients have been recruited so far. Data from the first 3 patients until week 16 will be reported.
Citation Format: Elin Aamdal, Tormod Kyrre Guren, Else Marit Inderberg Suso, Gunnar Kvalheim, Jon Amund Kyte, Øyvind Kongstun Arnesen, Steinar Aamdal, Gustav Gaudernack. Combining the telomerase peptide cancer vaccine UV1 with CTLA-4 blockade in patients with metastatic malignant melanoma: Proof of principle and early clinical reports from a phase I/IIa trial. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B141.
- ©2016 American Association for Cancer Research.