Treatment in three Phase I studies have been completed and patients are currently followed up for survival, immune response and new anti-cancer treatment. Fifty-two (52) patients have been enrolled in these studies. One Phase I study in malignant melanoma is currently ongoing, and two Phase II studies will commence in 2020.
Phase I study – Malignant melanoma
Phase I study with UV1 in combination with pembrolizumab (PD-1 inhibitor) in first line metastatic malignant melanoma patients. Safety and tolerability of treatment will be investigated with the combination in 30 patients on three sites in the USA. Enrolment of patients started in July 2018 and will be completed within 2020.
Malignant melanoma is a type of cancer that develops from the pigment-containing cells known as melanocytes. Melanomas typically occur in the skin but may also occur in the intestines, mouth or the eyes. Worldwide over 280,000 new cases of malignant melanoma were diagnosed in 2018, and it is estimated that more than 60,000 persons died from the disease.
Phase II study – Malignant melanoma (INITIUM)
Phase II proof of concept study named INITIUM where UV1 will be given as first line treatment in combination with anti-PD-1 plus anti-CTLA-4 in metastatic malignant melanoma. This randomized study will comprise 154 patients, where 77 patients will receive anti-CTLA-4 (ipilimumab), anti-PD-1 (nivolumab) plus UV1, and 77 patients will receive anti-PD-1 plus anti-CTLA-4. The study will be conducted at several hospitals in the USA and Europe, commencing first quarter of 2020 and with PFS read-out in 2022. The primary endpoint of the study is the efficacy endpoint progression free survival (PFS), further safety data of the triple combination as well as mechanistical information on the mode of action of the vaccine induced T cells will be investigated.
Checkpoint inhibitor therapy (CTLA-4 and PD-1) is standard of care for advanced malignant melanoma. However, still many patients do not have long time response to the treatment and only 50% survive 5 years. Ultimovacs hopes UV1 vaccination will increase the response rate further for this patient group. If successful, the combination therapy will be a significant innovation and address a large medical need.
Phase II study – Mesothelioma (NIPU)
UV1 will be investigated in a randomized, multi-center phase II trial in advanced malignant plaural mesothelioma (MPM). The trial, named NIPU, investigates UV1 in combination with the checkpoint inhibitors nivolumab and ipilimumab as second-line treatment in mesothelioma. Oslo University Hospital (‘OUS’) is the sponsor of the study. Bristol-Myers Squibb (‘BMS’) and Ultimovacs have entered into agreements with OUS to support the preparations and execution of the trial. A total of 118 patients will be included in the study. Half of the patients will be treated with the combination of UV1, nivolumab and ipilimumab, whereas the other half will receive nivolumab and ipilimumab only.
The study is planned to be conducted at five hospitals in four countries (Norway, Sweden, Denmark and Australia). The study is about to be initiated and patient inclusion is expected to start in Q1 2020. The primary endpoint of the trial is progression-free survival (PFS) and the PFS read-out is expected mid-2022. The necessary approvals from the Norwegian Medicinal Agency and the ethics committee in Norway are in place to initiate the trial.
MPM is a rare malignant tumor originating from the cells lining the mesothelial surface in the lungs. MPM is the most common type of mesothelioma and is a disease with a high unmet medical need with a median overall survival of approximately one year. Most patients are treated with palliative chemotherapy. Patients with disease progression after first-line therapy have few therapeutic options. Asbestos exposure is heavily linked to the development of the disease. It may take 10 – 50 years for symptoms of mesothelioma to manifest after initial asbestos exposure. Even though the use of asbestos to a large extent is banned today, new incidences of mesothelioma will continue to be a medical challenge for decades.
Prostate patients with advanced disease without lung and/or liver metastases were enrolled. These patients had started CAB treatment (GnRH-agonist combined with anti-androgen) prior to UV1 treatment.
Non-small cell lung cancer (NSCLC)
In the lung study stage 3b/4 NSCLC patients were enrolled, who previous had been treated with palliative radiotherapy and /or at least two courses of chemotherapy. These patients were not to be in progression, confirmed by CT, at least 4 weeks prior to UV1 treatment.
Malignant Melanoma – UV1 in combination with ipilimumab
The malignant melanoma patients had unresectable or metastatic disease when enrolled, and were eligible for ipilimumab.
Safety and tolerability were primary endpoints in all three studies, while immune response towards any of the UV1 peptides and efficacy were secondary endpoints.
Three different dose levels of UV1 were investigated in the prostate cancer and NSCLC studies (100, 300 and 700 µg). In the malignant melanoma study, 300 µg UV1 was given in combination with ipilimumab.
Data from the three studies showed that UV1 is generally well tolerated. There were no dose limiting toxicities. UV1 induced an immune response (hTERT specific T-cells) in 78% (range 67-91%) of patients across the three studies.
When combining UV1 with ipilimumab, a CTLA-4 checkpoint inhibitor, 91% of malignant melanoma patients developed an immune response. The responses appeared earlier, required fewer vaccinations, and were stronger and more long lasting compared to vaccination with UV1 alone. These data are compatible with a mechanism of action where blocking CTLA-4 checkpoints induce additional expansion of UV1 specific T cells induced by UV1 vaccination.