Combining a Universal Telomerase Based Cancer Vaccine With Ipilimumab in Patients With Metastatic Melanoma - Five-Year Follow Up of a Phase I/IIa Trial.

Background: Ipilimumab improves survival for patients with metastatic malignant melanoma. Combining a therapeutic cancer vaccine with ipilimumab may increase efficacy by providing enhanced anti-tumor immune responses. UV1 consists of three synthetic long peptides from human telomerase reverse transcriptase (hTERT). These peptides comprise epitopes recognized by T cells from cancer patients experiencing long-term survival following treatment with a first-generation hTERT vaccine, and generate long-lasting immune responses in cancer patients when used as monotherapy. The objective of this trial was to investigate the safety and efficacy of combining UV1 with ipilimumab in metastatic melanoma. Patients and Methods: In this phase I/IIa, single center trial [NCT02275416], patients with metastatic melanoma received repeated UV1 vaccinations, with GM-CSF as an adjuvant, in combination with ipilimumab. Patients were evaluated for safety, efficacy and immune response. Immune responses against vaccine peptides were monitored in peripheral blood by measuring antigen-specific proliferation and IFN-γ production. Results: Twelve patients were recruited. Adverse events were mainly diarrhea, injection site reaction, pruritus, rash, nausea and fatigue. Ten patients showed a Th1 immune response to UV1 peptides, occurring early and after few vaccinations. Three patients obtained a partial response and one patient a complete response. Overall survival was 50% at 5 years. Conclusion: Treatment was well tolerated. The rapid expansion of UV1-specific Th1 cells in the majority of patients indicates synergy between UV1 vaccine and CTLA-4 blockade. This may have translated into clinical benefit, encouraging the combination of UV1 vaccination with standard of care treatment regimes containing ipilimumab/CTLA-4 blocking antibodies.

Long-Term Outcomes of a Phase I Study With UV1, a Second Generation Telomerase Based Vaccine, in Patients With Advanced Non-Small Cell Lung Cancer.

Human telomerase reverse transcriptase (hTERT) is a target antigen for cancer immunotherapy in patients with non-small cell lung cancer (NSCLC). We have tested a novel hTERT vaccine, UV1, designed to give high population coverage. UV1 is composed of three synthetic long peptides containing multiple epitopes identified by epitope spreading data from long-term survivors from previous hTERT vaccination trials. Eighteen non-HLA-typed patients with stage III/IV NSCLC with no evidence of progression after prior treatments, were enrolled in a phase I dose-escalation study of UV1 vaccination with GM-CSF as adjuvant, evaluating safety, immune response, and long-term clinical outcome. Treatment with UV1 was well tolerated with no serious adverse events observed. Seventeen patients were evaluable for tumor response; 15 patients had stable disease as best response. The median progression free survival (PFS) was 10.7 months, and the median overall survival (OS) was 28.2 months. The OS at 4 years was 39% (7/18). Five patients are alive (median survival 5.6 years), and none of these are known to have received checkpoint therapy after vaccination. UV1 induced specific T-cell responses in the majority (67%) of patients. Immune responses were dynamic and long lasting. Both immune response (IR) and OS were dose related. More patients in the highest UV1 dosage group (700 µg) developed IRs compared to the other groups, and the IRs were stronger and occurred earlier. Patients in this group had a 4-year OS of 83%. The safety and clinical outcome data favor 700 µg as the preferred UV1 dose in this patient population. These results provide a rationale for further clinical studies in NSCLC with UV1 vaccination in combination with immune checkpoint blockade. Clinical Trial Registration: https://www.clinicaltrials.gov, identifier NCT0178909.

Elacytarabine in relapsed/refractory acute myeloid leukaemia: an evaluation of clinical efficacy, pharmacokinetics, cardiac safety and effects on lipid profile.

Elacytarabine is the elaidic acid ester derivative of cytarabine, designed to enter cells independently of nucleoside transporters. Effects of elacytarabine on QT interval, serum lipid profile and clinical activity were investigated in 43 relapsed/refractory AML patients. Mean maximum increase in corrected QT interval of 24( ± 29)ms occurred 48 h after elacytarabine infusion without associated arrhythmias or clinical symptoms. A non-clinically significant, elacytarabine exposure-dependent increase in cholesterol was caused by a cholesterol rich lipoprotein depleted of apolipoprotein B formed by infused phospholipids complexing cholesterol. Elacytarabine is clinically active in relapsed/refractory AML: overall response rate (CR + CRi) was 44% (16/36 with 7 non-evaluable patients) and adverse events were manageable. Clinical Trials.gov Identifier: NCT01258816.

Gemcitabine chemoresistance in pancreatic cancer: molecular mechanisms and potential solutions.

Ductal pancreatic adenocarcinoma is associated with a very poor prognosis and most patients are given palliative care. Chemotherapy in the form of gemcitabine has been found to reduce disease-related pain, and the otherwise frequently occurring weight changes, to increase Karnofsky performance status and quality of life and has also resulted in a modest improvement in survival time. The intracellular uptake of gemcitabine is dependent on nucleoside transporters, predominantly human equilibrative nucleoside transporter-1 (hENT-1), which is over-expressed in human pancreatic adenocarcinoma cells. Cellular resistance to gemcitabine can be intrinsic or acquired during gemcitabine treatment. One of the mechanisms is a decrease in hENT-1 expression. Modifications of gemcitabine not rendering it dependent on the nucleoside transporter may be a successful future mode of chemotherapy treatment, and determination of the nucleoside receptor status at the time of diagnosis could potentially also contribute to a more targeted therapy in the future.

Intravenous administration of CP-4055 (ELACYT) in patients with solid tumours. A Phase I study.

PURPOSE: Cytarabine (ara-C) has limited activity in solid tumours. CP-4055 (ELACYT) is a novel ara-C-5'-elaidic acid ester that may circumvent this limitation. CP-4055 maximum tolerated dose (MTD), pharmacokinetics and antitumor activity have been investigated in patients with solid tumours. MATERIAL AND METHODS: Thirty-four patients (19 malignant melanoma, 8 ovarian cancers and 7 NSCLC) received CP-4055 as a 30 min, or 2 hr intravenous (IV) infusion daily for 5 consecutive days every 3 or 4 weeks (D1-5 q3w or D1-5 q4w) in a dose escalation designed study with doses ranging from 30 to 240 mg/m(2)/day. RESULTS: The most frequent CTC grade 1-2 adverse events (AEs) were nausea, fatigue, vomiting, anorexia and pyrexia. Most of the grade 3-4 AEs were neutropenia. The MTD was 200 mg/m(2)/day and 240 mg/m(2)/day for D1-5 q3w and D1-5 q4w, respectively. The MTD was independent of infusion time in the 4 week schedule. CP-4055 was maintained in plasma for up to 5-10 hr at dose levels >150 mg/m(2)/day. One objective partial response (PR) with time to progression (TTP) of 22 months was reported in an advanced malignant melanoma patient. CONCLUSION: CP-4055 was well tolerated; the majority of the AEs were of CTC grade 1. The 3 week schedule was not recommended due to neutropenic nadir between days 18-26. The recommended dose was 200 mg/m(2)/day in a D1-5 q4w schedule. Efficacy data suggest that CP-4055 might be active in treatment of solid tumours.