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

2022-RA-638-ESGO Pembrolizumab with multimodal immunomodulation in chemotherapy-pretreated cervical, endometrial, and uterine cancer: the PRIMMO phase II trial

Introduction/Background To decrease immunosuppression and enhance T-cell activation in the tumour microenvironment, we conducted an open-label, investigator-initiated, multicohort, phase II trial (NCT03192059) of pembrolizumab with multimodal immunomodulation. Methodology Chemotherapy-pretreated patients were recruited into two experimental cohorts (cervical carcinoma or endometrial carcinoma) and one exploratory cohort (uterine sarcoma). Patients received an immunomodulatory five-drug cocktail consisting of low-dose cyclophosphamide, aspirin, lansoprazole, vitamin D, and curcumin starting two weeks before radioimmunotherapy (figure 1). Pembrolizumab, 200 mg/dose, was administered on day 1 of each 21-day cycle from day 15 onwards; one of the tumour lesions was irradiated (8Gyx3) on days 15, 17, and 19. The primary endpoint was objective response rate (irORR) per immune-related response criteria (irRC) at week 26; a lower bound of its 90% confidence interval (CI) of >10% in either experimental cohort was considered successful. Results Fifty patients were enrolled and treated across the cohorts (cervical, n=18; endometrial, n=25; sarcoma=7). Pathology review revealed that 3/7 sarcoma patients had carcinosarcoma. At week 26, the irORR was 11.1% (90%CI, 2.0 to 31.0) in cervical cancer, 12.0% (90%CI, 3.4 to 28.2) in endometrial cancer, and 14.3% (90% CI, 0.7 to 52.1) in uterine (carcino)sarcoma. The best overall response rate per RECIST v1.1 was 22.2% (90%CI, 8.0 to 43.9), 12.0% (90%CI, 3.4 to 28.2), and 28.6 (90%CI, 5.3 to 65.9). Median PFS was 13.4 weeks (11.3 to 26.1), 13.1 weeks (13.1 to 19.4), and 34.3 weeks (95%CI, 5.6 to 77.9) (figure 2A-C). Grade≥3 treatment-related adverse events were reported in 10 (55.6%), 9 (36.0%), and 4 (57.1%) patients. Overall, there was one (2.0%) possible treatment-related death. Health-related quality of life was generally stable over time. Multi-parameter immune monitoring characterised the patients and revealed changes throughout study treatment. Conclusion PRIMMO did not show sufficient evidence of a positive risk-to-benefit ratio to recommend a confirmatory phase III trial