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

(2019) BMC CANCER. 19.
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Abstract
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 2weeks before the first pembrolizumab dose. Pembrolizumab is administered 3-weekly for a total of 6cycles. Radiation (3x8Gy) 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.
Keywords
PD-1 blockade, Radiation, Immune modulation, Tumor microenvironment, Cervical carcinoma, Endometrial carcinoma, Uterine sarcoma, Drug repurposing, Metronomic chemotherapy, Financial toxicity, D-3 TREATMENT, RADIOTHERAPY, THERAPY, IMMUNOTHERAPY, RESISTANCE, RESPONSES, CELLS, HEAD, MICROENVIRONMENT, PEMBROLIZUMAB

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Citation

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Chicago
Tuyaerts, Sandra, An MT Van Nuffel, Eline Naert, Peter A Van Dam, Peter Vuylsteke, Alex De Caluwé, Sandrine Aspeslagh, et al. 2019. “PRIMMO Study Protocol : a Phase II Study Combining PD-1 Blockade, Radiation and Immunomodulation to Tackle Cervical and Uterine Cancer.” Bmc Cancer 19.
APA
Tuyaerts, S., Van Nuffel, A. M., Naert, E., Van Dam, P. A., Vuylsteke, P., De Caluwé, A., Aspeslagh, S., et al. (2019). PRIMMO study protocol : a phase II study combining PD-1 blockade, radiation and immunomodulation to tackle cervical and uterine cancer. BMC CANCER, 19.
Vancouver
1.
Tuyaerts S, Van Nuffel AM, Naert E, Van Dam PA, Vuylsteke P, De Caluwé A, et al. PRIMMO study protocol : a phase II study combining PD-1 blockade, radiation and immunomodulation to tackle cervical and uterine cancer. BMC CANCER. 2019;19.
MLA
Tuyaerts, Sandra et al. “PRIMMO Study Protocol : a Phase II Study Combining PD-1 Blockade, Radiation and Immunomodulation to Tackle Cervical and Uterine Cancer.” BMC CANCER 19 (2019): n. pag. Print.
@article{8617386,
  abstract     = {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 2weeks before the first pembrolizumab dose. Pembrolizumab is administered 3-weekly for a total of 6cycles. Radiation (3x8Gy) 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.},
  articleno    = {506},
  author       = {Tuyaerts, Sandra and Van Nuffel, An MT and Naert, Eline and Van Dam, Peter A and Vuylsteke, Peter and De Caluwé, Alex and Aspeslagh, Sandrine and Dirix, Piet and Lippens, Lien and De Jaeghere, Emiel and Amant, Frédéric and Vandecasteele, Katrien and Denys, Hannelore},
  issn         = {1471-2407},
  journal      = {BMC CANCER},
  keywords     = {PD-1 blockade,Radiation,Immune modulation,Tumor microenvironment,Cervical carcinoma,Endometrial carcinoma,Uterine sarcoma,Drug repurposing,Metronomic chemotherapy,Financial toxicity,D-3 TREATMENT,RADIOTHERAPY,THERAPY,IMMUNOTHERAPY,RESISTANCE,RESPONSES,CELLS,HEAD,MICROENVIRONMENT,PEMBROLIZUMAB},
  language     = {eng},
  pages        = {10},
  title        = {PRIMMO study protocol : a phase II study combining PD-1 blockade, radiation and immunomodulation to tackle cervical and uterine cancer},
  url          = {http://dx.doi.org/10.1186/s12885-019-5676-3},
  volume       = {19},
  year         = {2019},
}

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