Study of Pembrolizumab, Radiation and Immune Modulatory Cocktail in Cervical/Uterine Cancer

Study Overview
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Brief Summary
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This is a Phase II study in patients with advanced and/refractory cervical cancer, endometrial carcinoma or uterine sarcoma. Patients will be treated with an immunomodulatory cocktail (Vitamin D, aspirin, Cyclophosphamide and Lansoprazole), followed by pembrolizumab, combined with radiation. In addition, patients will take Curcumin, a food supplement.

Detailed Description
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This is a Phase II multi-center, open-label, non-randomized, 3-cohort study in patients with advanced and/or refractory cervical cancer, endometrial carcinoma or uterine sarcoma. Patients will be treated by an immunomodulatory cocktail (consisting of a daily intake of 2000 IU Vitamin D, 325 mg aspirin, 50 mg Cyclophosphamide and 180 or 30 mg Lansoprazole alternating weekly), followed by pembrolizumab administered intravenously at 200 mg in 21-day treatment cycles, combined with radiation (3x 8Gy in 48h-intervals). In addition, patients will take Curcumin, a food supplement on a daily basis.

Official Title
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A Phase II Investigation of Pembrolizumab (Keytruda) in Combination With Radiation and an Immune Modulatory Cocktail in Patients With Cervical and Uterine Cancer (PRIMMO Trial)

Conditions
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Cervical Cancer, Endometrial Cancer, Uterine Cancer

Intervention / Treatment
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* Drug: Pembrolizumab
* Radiation: Radiation
* Drug: Vitamin D
* Drug: Aspirin
* Drug: Lansoprazole
* Drug: Cyclophosphamide
* Dietary Supplement: Curcumin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have histologically confirmed endometrial carcinoma, cervical carcinoma or uterine sarcoma, refractory or persistent to chemotherapy or recurrent disease after at least one line of chemotherapy. Presence of an index lesion amenable to hypofractionated stereotactic radiotherapy At least one lesion outside the radiation field that can be followed by imaging for clinical response according to RECIST and irRC Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion before and after radiotherapy if technically feasible. Have a performance status of 0 or 1 or 2 on the ECOG Performance Scale. Demonstrate adequate organ function Exclusion Criteria: Currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment. Prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2 agent Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 2 weeks prior to the first dose of trial treatment, Known history of active TB (Bacillus Tuberculosis), Human Immunodeficiency Virus (HIV), HTLV or syphilis,non-infectious pneumonitis, has active autoimmune disease. Has active central nervous system metastases and/or carcinomatous meningitis

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: experimental arm<br>Pembrolizumab, immune modulatory cocktail composed of Vitamin D, Lansoprazole Teva, Cyclophosphamide and Aspirine, radiation and Curcumin | Drug: Pembrolizumab<br>* Efficacy of the combined treatment<br>Radiation: Radiation<br>* Efficacy of the combined treatment<br>Drug: Vitamin D<br>* Efficacy of the combined treatment<br>Drug: Aspirin<br>* Efficacy of the combined treatment<br>Drug: Lansoprazole<br>* Efficacy of the combined treatment<br>Drug: Cyclophosphamide<br>* Efficacy of the combined treatment<br>Dietary Supplement: Curcumin<br>* Efficacy of the combined treatment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate at week 26 | Efficacy (objective response rate) at week 26 according to immune related response criteria (irRC) | week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-emergent adverse events (Safety according to CTCAE4.0). | The number of unmanageable dose limiting toxicities will be reported for the run-in period and the main trial. This analysis will be performed for both the Full Analysis Set (FAS; evaluable patiënts) and extended FAS (eFAS; all patients included in the trial). | up to 30 days post end of study treatment | 
| Objective response rate | Objective response rate at week 26 according to RECIST criteria | week 26 | 
| Best OR | Best overall response | week 26 | 
| PFS | At weeks 26, 52, 75, 104, 130 and 156 the proportion of progression-free patients will be estimated with a 95% confidence interval. | up to 156 weeks | 
| Median PFS | At weeks 26, 52, 75, 104, 130 and 156 the median PFS will be calculated. | up to 156 weeks | 
| OS | At weeks 26, 52, 75, 104, 130 and 156 the proportion of patients surviving will be estimated with a 95% confidence interval. | up to 156 weeks | 
| Median OS | At weeks 26, 52, 75, 104, 130 and 156 the median survival will be calculated. | up to 156 weeks | 
| Quality of life assessment | Quality of life as measured by FACT-Cx questionnaire for the cervical cancer group and by the FACT-G questionnaire for the endometrial carcinoma and uterine sarcoma group. Descriptive statistics of the total score at each visit and the difference with the baseline visit for all other visits will be reported. | Quality of life questionnaires will be completed by the patients at baseline, after 3 months of therapy, after 6 months of treatment (end of treatment) and finally 3 months after therapy. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immunotherapy, Radiotherapy, Immune-modulatory cocktail