PRIMMO study protocol: a phase II study combining PD-1 blockade, radiation and immunomodulation to tackle cervical and uterine cancer.

BACKGROUND: Immunotherapeutic approaches have revolutionized oncological practice but are less evaluated in gynecological malignancies. PD-1/PD-L1 blockade in gynecological cancers showed objective responses in 13-17% of patients. This could be due to immunosuppressive effects exerted by gynecological tumors on the microenvironment and an altered tumor vasculature. In other malignancies, combining checkpoint blockade with radiation delivers benefit that is believed to be due to the abscopal effect. Addition of immune modulation agents has also shown to enhance immune checkpoint blockade efficacy. Therefore we designed a regimen consisting of PD-1 blockade combined with radiation, and different immune/environmental-targeting compounds: repurposed drugs, metronomic chemotherapy and a food supplement. We hypothesize that these will synergistically modulate the tumor microenvironment and induce and sustain an anti-tumor immune response, resulting in tumor regression. METHODS: PRIMMO is a multi-center, open-label, non-randomized, 3-cohort phase 2 study with safety run-in in patients with recurrent/refractory cervical carcinoma, endometrial carcinoma or uterine sarcoma. Treatment consists of daily intake of vitamin D, lansoprazole, aspirin, cyclophosphamide and curcumin, starting 2 weeks before the first pembrolizumab dose. Pembrolizumab is administered 3-weekly for a total of 6 cycles. Radiation (3 × 8 Gy) is given on days 1, 3 and 5 of the first pembrolizumab dose. The safety run-in consists of 6 patients. In total, 18 and 25 evaluable patients for cervical and endometrial carcinoma respectively are foreseen to enroll. No sample size is determined for uterine sarcoma due to its rarity. The primary objective is objective response rate at week 26 according to immune-related response criteria. Secondary objectives include safety, objective response rate at week 26 according to RECIST v1.1, best overall response, progression-free survival, overall survival and quality of life. Exploratory, translational research aims to evaluate immune biomarkers, extracellular vesicles, cell death biomarkers and the gut microbiome. DISCUSSION: In this study, a combination of PD-1 blockade, radiation and immune/environmental-targeting compounds is tested, aiming to tackle the tumor microenvironment and induce anti-tumor immunity. Translational research is performed to discover biomarkers related to the mode of action of the combination. TRIAL REGISTRATION: EU Clinical Trials Register: EudraCT 2016-001569-97 , registered on 19-6-2017. Clinicaltrials.gov: NCT03192059 , registered on 19-6-2017.

A Phase 2 Study to Assess the Immunomodulatory Capacity of a Lecithin-based Delivery System of Curcumin in Endometrial Cancer.

Curcumin is a botanical with anti-tumor and immunomodulatory properties. We hypothesized that curcumin supplementation might influence inflammatory biomarker levels in endometrial carcinoma (EC). In this open-label, non-randomized phase 2 study (NCT02017353), seven EC patients consumed 2 g/day Curcumin Phytosome (CP) orally for 2 weeks. Blood was taken at baseline, days 1, 7, 14, and 21. The following analytes were measured: curcuminoids and metabolites, 56 inflammatory biomarkers, COX-2, frequencies of myeloid-derived suppressor cells, dendritic cells and NK cells, expression of MHC molecules on leukocytes and monocytes and activation/memory status of T cells. Patients completed quality of life (QoL) questionnaires at baseline and end of treatment. Curcumin metabolites were detectable in plasma upon CP intake. CP downregulated MHC expression levels on leukocytes (P = 0.0313), the frequency of monocytes (P = 0.0114) and ICOS expression by CD8+ T cells (P = 0.0002). However, CP upregulated CD69 levels on CD16- NK cells (P = 0.0313). No differences were observed regarding inflammatory biomarkers, frequencies of other immune cell types, T cell activation and COX-2 expression. A non-significant trend to improved QoL was observed. Overall, CP-induced immunomodulatory effects in EC were modest without significant QoL changes. Given the small population and the observed variability in inter-patient biomarker levels, more research is necessary to explore whether benefits of CP can be obtained in EC by different supplementation regimens. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02017353; www.clinicaltrialsregister.eu, identifier 2013-001737-40.