PRIMMO study protocol: a phase II study combining PD-1 blockade, radiation and immunomodulation to tackle cervical
Sandra Tuyaerts1,2, An M T Van Nuffel3, Eline Naert4,5
1Division of Gynecologic Oncology, Department of Oncology, KU Leuven, Leuven, Belgium. sandra.tuyaerts@kuleuven.be.
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.
Insights
This study investigates a novel combination therapy for gynecological cancers, integrating PD-1 blockade, radiation, and immune-modulating compounds to enhance anti-tumor immunity and overcome the immunosuppressive tumor microenvironment.
Area of Science:
- Oncology
- Immunotherapy
- Gynecological Cancers
Background:
- Immunotherapy, particularly PD-1/PD-L1 blockade, shows limited efficacy in gynecological malignancies (13-17% response).
- This may stem from the immunosuppressive tumor microenvironment and altered vasculature characteristic of these cancers.
- Combining checkpoint inhibitors with radiation and immune modulators has shown promise in other cancers, potentially via abscopal effects.
Purpose of the Study:
- To evaluate a novel combination regimen for recurrent/refractory gynecological cancers.
- To synergistically modulate the tumor microenvironment and induce a sustained anti-tumor immune response.
- To assess the efficacy and safety of PD-1 blockade combined with radiation and immune/environmental-targeting compounds.
Main Methods:
- A multi-center, phase 2 study (PRIMMO) enrolling patients with cervical carcinoma, endometrial carcinoma, or uterine sarcoma.
- Treatment involves daily oral administration of vitamin D, lansoprazole, aspirin, cyclophosphamide, and curcumin, starting 2 weeks before pembrolizumab.
- Pembrolizumab is administered every 3 weeks for 6 cycles, with radiation (3x8 Gy) on days 1, 3, and 5 of the first cycle. Exploratory research includes biomarker analysis.
Main Results:
- The primary objective is to determine the objective response rate at week 26 per immune-related response criteria.
- Secondary objectives include safety, response by RECIST v1.1, best overall response, progression-free survival, overall survival, and quality of life.
- Translational research will explore immune biomarkers, extracellular vesicles, cell death, and the gut microbiome.
Conclusions:
- This study tests a combination of PD-1 blockade, radiation, and immune/environmental-targeting compounds.
- The regimen aims to overcome the immunosuppressive tumor microenvironment and stimulate anti-tumor immunity.
- Translational research will identify biomarkers associated with the combination's mechanism of action.
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