Journal Article

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

Aspeslagh, Sandrine, Van Dam, Peter A., Tuyaerts, Sandra, Dirix, Piet, De Caluwé, Alex, Vandecasteele, Katrien, Vuylsteke, Peter, De Jaeghere, Emiel, Denys, Hannelore, Van Nuffel, An M. T., Amant, Frédéric, Lippens, Lien, Naert, Eline

2019

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Antibodies, Monoclonal, Humanized - administration & dosage / Antibodies, Monoclonal, Humanized - therapeutic use / Antigens / Antineoplastic agents / Antineoplastic Agents - administration & dosage / Antineoplastic Agents - therapeutic use / Aspirin / Aspirin - administration & dosage / Aspirin - therapeutic use / Biological markers / Biomarkers / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cancer therapies / Cancer treatment / Carcinoma / Care and treatment / Cell death / Cervical cancer / Cervical carcinoma / Cervix / Chemokines / Chemoradiotherapy / Chemotherapy / Clinical trials / Clinical Trials, Phase II as Topic / Curcumin / Curcumin - administration & dosage / Curcumin - therapeutic use / Cyclophosphamide / Cyclophosphamide - administration & dosage / Cyclophosphamide - therapeutic use / Cytokines / Development and progression / Dietary supplements / Drug delivery / Drug dosages / Drug Repositioning / Endometrial cancer / Endometrial carcinoma / Endometrial Neoplasms - therapy / Endometrium / Female / Gynecological cancer / Health aspects / Health Promotion and Disease Prevention / Humans / Immune checkpoint / Immune modulation / Immune response / Immune system / Immunomodulation / Immunosuppressive agents / Immunotherapy / Intestinal microflora / Lansoprazole - administration & dosage / Lansoprazole - therapeutic use / Lymphocytes / Medical and radiation oncology / Medical prognosis / Medicine/Public Health / Monoclonal antibodies / Multicenter Studies as Topic / Neoplasm Recurrence, Local - therapy / Oncology / Patients / PD-1 blockade / PD-1 protein / PD-L1 protein / Pembrolizumab / Prognosis / Quality of life / Radiation / Radiation (Physics) / Radiation therapy / Safety / Sarcoma / Sarcoma - therapy / Study Protocol / Surgical Oncology / Survival Analysis / Targeted cancer therapy / Translation / Treatment Outcome / Tumor blood vessels / Tumor microenvironment / Tumors / Uterine cancer / Uterine Cervical Neoplasms - therapy / Vaccines / Vitamin D / Vitamin D - administration & dosage / Vitamin D - therapeutic use / Womens health