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Saturday, June 25, 2016

Progression-free and overall survival in ovarian cancer patients treated with CVac.......



Progression-free and overall survival in ovarian cancer patients treated with CVac, a mucin 1 dendritic cell therapy in a randomized phase 2 trial | Journal for ImmunoTherapy of Cancer | Full Text

 Published: 21 June 2016

Abstract

Background

CAN-003 was a randomized, open-label, Phase 2 trial evaluating the safety, efficacy and immune outcomes of CVac, a mucin 1 targeted-dendritic cell (DC) treatment as a maintenance therapy to patients with epithelial ovarian cancer (EOC).

Methods

Patients (n  = 56) in first (CR1) or second clinical remission (CR2) were randomized (1:1) to standard of care (SOC) observation or CVac maintenance treatment. Ten doses were administered over 56 weeks. Both groups were followed for progression-free survival (PFS) and overall survival (OS).

Results

Fifty-six patients were randomized: 27 to SOC and 29 to CVac. Therapy was safe with only seven patients with Grade 3–4 treatment-emergent adverse events. A variable but measurable mucin 1 T cell-specific response was induced in all CVac-treated and some standard of care (SOC) patients. Progression free survival (PFS) was not significantly longer in the treated group compared to SOC group (13 vs. 9 months, p  = 0.36, hazard ratio [HR] = 0.73). Analysis by remission status showed in the CR1 subgroup a median PFS of 18 months (SOC) vs. 13 months (CVac); p = 0.69 (HR = 1.18; CI 0.52–2.71). However CR2 patients showed a longer median PFS in the CVac-treated group (median PFS not yet reached, >13 vs. 5 months; p = 0.04, HR = 0.32 CI). OS for CR2 patients at 42 months of follow-up showed a difference of 26 months for SOC vs. > 42 months for CVac-treated (as median OS had not been reached; HR = 0.17 (CI 0.02–1.4) with a p = 0.07).

Conclusions

CVac, a mucin 1-dendritic cell maintenance treatment was safe and well tolerated in ovarian cancer patients. A variable but observed CVac-derived, mucin 1-specific T cell response was measured. Notably, CR2 patients showed an improved PFS and lengthened OS. Further studies in CR2 ovarian cancer patients are warranted (NCT01068509).

Trial registration

NCT01068509. Study Initiation Date (first patient screened): 20 July 2010. Study Completion Date (last patient observation): 20 August 2013, the last patient observation for progression-free survival; 29 April 2015, the last patient was documented regarding overall survival.

Background

Ovarian cancer is typically managed by surgical cytoreduction followed by platinum and taxane-based chemotherapy. While the majority of patients achieve a clinical remission from this initial therapy, more than 70 % will subsequently develop recurrent disease [1]. Immunotherapeutic approaches to cancer rely on stimulation of the immune system to specifically target and destroy tumors. Mucin proteins are promising targets for immunotherapy; in particular, the epithelial mucin surface antigen 1 is overexpressed in adenocarcinomas in an aberrant form [2, 3, 4, 5]. Prior literature have described high levels of MUC1 expression (100 %) in ovarian adenocarcinomas [6] and in late-stage epithelial ovarian cancer (EOC), tumor cells will significantly overexpress mucin 1 showing a significant association between mucin 1 over-expression, histological grade and clinical stage [7, 8]. Therefore, mucin 1 is a specific and appropriate target as an immunotherapy for EOC, whereby the immune system is stimulated to target and destroy tumor cells.
A dendritic cell vaccine targeting the MUC-1 glycoprotein was developed (termed CVac). Prior to the current trial, two clinical trials were conducted with CVac. In the phase I trial, 17 subjects (three healthy volunteers and 14 advanced solid tumor patients) were enrolled, the purpose of which was to establish safety and to observe host immunologic responses. Two of these patients had ovarian cancer, with one patient surviving beyond 12 months post-therapy despite advanced disease. Regarding safety, no anaphylactic reactions were observed and all patients measured a CVac-specific T cell response as measured by ELISpot. No dose limiting toxicities (DLTs) or serious adverse events (SAEs) attributable to CVac were reported in the Phase I study [9].......

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