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Abstract
The irradiated, allogeneic, cellular CSF-470 vaccine plus Bacillus Calmette–Guerin (BCG) and recombinant human granulocyte macrophage-colony stimulating factor (rhGM-CSF) is being tested against medium-dose IFN-α2b in stages IIB–III cutaneous melanoma (CM) patients (pts) after surgery in an open, randomized, Phase II/III study. We present the results of the Phase II part of the ongoing CASVAC-0401 study (ClinicalTrials.gov: NCT01729663). Thirty-one pts were randomized to the CSF-470 vaccine (n = 20) or to the IFN-α2b arm (n = 11). During the 2-year treatment, immunized pts should receive 13 vaccinations. On day 1 of each visit, 1.6 × 107 irradiated CSF-470 cells plus 106 colony-forming units BCG plus 100 µg rhGM-CSF were administered intradermally, followed on days 2–4 by 100 µg rhGM-CSF. IFN-α2b pts should receive 10 million units (MU)/day/5 days a week for 4 weeks; then 5 MU thrice weekly for 23 months. Toxicity and quality of life (QOL) were evaluated at each visit. With a mean and a maximum follow-up of 39.4 and 83 months, respectively, a significant benefit in the distant metastasis-free survival (DMFS) for CSF-470 was observed (p = 0.022). Immune monitoring showed an increase in antitumoral cellular and humoral response in vaccinated pts. CSF-470 was well tolerated; 20/20 pts presented grades 1–2 dermic reactions at the vaccination site; 3/20 pts presented grade 3 allergic reactions. Other adverse events (AEs) were grade 1. Pts in the IFN-α2b arm presented grades 2–3 hematological (7/11), hepatic (2/11), and cardiac (1/11) toxicity; AEs in 9/11 pts forced treatment interruptions. QOL was significantly superior in the vaccine arm (p < 0.0001). Our results suggest that CSF-470 vaccine plus BCG plus GM-CSF can significantly prolong, with lower toxicity, the DMFS of high-risk CM pts with respect to medium-dose IFN-α2b. The continuation of a Phase III part of the CASVAC-0401 study is encouraged.
Highlights
Despite recent advances in its treatment, cutaneous melanoma (CM), an immunogenic and highly mutated tumor [1, 2], continues to be a dreadful disease
The Phase II stage of the CASVAC-0401 study was performed on 31 CM pts who were recruited at the Instituto Alexander Fleming between March 2009 and April 2014
Pt #030 was withdrawn from protocol after receiving four vaccines due to confirmation that millimetric lung lesions detected by CT-scan at screening, and informed as non-specific, later developed as overt metastases; the pt was, at stage IV and understaged at screening
Summary
Despite recent advances in its treatment, cutaneous melanoma (CM), an immunogenic and highly mutated tumor [1, 2], continues to be a dreadful disease. Adjuvant treatment with ipilimumab has yielded similar results to IFN-α2b, increasing DFS at the expense of considerable immune-related toxicities [14], and a Phase III study comparing both treatments is underway (ECOG 1609). Another randomized study (SWOG S1404) is currently comparing high-dose IFN-α2b to pembrolizumab in pts at high risk for recurrence and death after surgery [15]. A Phase III trial (EORTC 18071) of ipilimumab as adjuvant therapy for high-risk stage III melanoma pts, at a dose of 10 mg/kg for 3 years resulted in a significantly higher rate of 5-year recurrence-free survival (40.8%), DMFS (48.3%), and OS (65.4%) than placebo (30.3%, 38.9%, and 54.4% respectively). The rate of immune-related toxicities with ipilimumab was substantial and led to the discontinuation of treatment in ~40% of the pts [16]
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