Progression-free and overall survival in ovarian cancer patients treated with CVac, a mucin 1 dendritic cell therapy in a randomized phase 2 trial

H J Gray, B Benigno, J Berek, J Chang, J Mason, L Mileshkin, P Mitchell, M Moradi, F O Recio, C M Michener, A Alvarez Secord, N E Tchabo, J K Chan, J Young, H Kohrt, S E Gargosky, J C Goh, H J Gray, B Benigno, J Berek, J Chang, J Mason, L Mileshkin, P Mitchell, M Moradi, F O Recio, C M Michener, A Alvarez Secord, N E Tchabo, J K Chan, J Young, H Kohrt, S E Gargosky, J C Goh

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.

Keywords: Dendritic cells; Immunotherapy; Maintenance; Mucin 1; Ovarian cancer.

Figures

Fig. 1
Fig. 1
Patient Consort. Patients received 10 doses up till week 56 and were subsequently followed until week 104. Week 104 defined the end of study
Fig. 2
Fig. 2
Intracellular cytokine staining (ICS) of CVac-treated patients. Values are corrected for the background (endogenous unstimulated response) subtracted from the mucin 1 (MUC1) challenge shown as a percentage. Values of zero or less are shown as zero. The samples shown represent those patients that had both a baseline sample and a visit 13 sample (completion of 10 doses of CVac treatment) available for analysis
Fig. 3
Fig. 3
Progression-free survival. Progression-free survival was defined as the time from date of randomization to the earlier of disease progression or death due to any cause. Vertical tick marks represent the progression-free survival time of patients without disease progression. Hazard ratio (CVac/SOC) was estimated using a Cox proportional hazards model. P-value was calculated using the log-rank test. a Progression-free survival for patients in complete remission after first-line therapy; CR1. b Progression-free survival for patients in complete remission after second-line therapy; CR2
Fig. 4
Fig. 4
Overall Survival. Overall survival was defined as the time from date of randomization to the date of death due to any cause. Vertical tick marks represent the overall survival time of patients reported alive or lost to follow-up as of the last contact. Hazard ratio (CVAC/OSC) was estimated using a Cox proportional hazards model. P-value was calculated using the log-rank test. a Overall survival for patients in complete remission after first-line therapy; CR1. b Overall survival for patients in complete remission after second-line therapy; CR2

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