Pembrolizumab and Chemoradiation Treatment for Advanced Cervical Cancer

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the safety and effectiveness of immunotherapy in combination with chemotherapy and radiation (chemoradiation) for the treatment of advanced cervical cancer. Pembrolizumab, a type of immunotherapy called a checkpoint inhibitor, will be administered after or during chemoradiation.

Detailed Description
-----------------
Primary: (1) To estimate the immunologic effects, as assessed in the tumor & PBMC, of both sequential and concurrent administration of pembrolizumab to CRT. Change between pre and post measurements of HPV E2, E7 specific CD8+ T cells, regulatory FoxP3+ T cells (Tregs) and the ratio of CD8+ T cells to Tregs are the immune measurements of primary interest. (2) To determine the safety of concurrent chemoradiation in combination with pembrolizumab for the treatment of locally advanced cervical cancer. Secondary: (1) To estimate rates of complete metabolic response on PET/CT imaging obtained 12 weeks after CRT. (2) To estimate rates of distant metastasis as the first site of recurrence for patients. (3) To estimate the influence of concurrent and consolidative MK-3475 on levels of plasminogen activator inhibitor-1 (PAI-1), a marker of immunosuppressive TGF-B. (4) To estimate the influence of concurrent and consolidative MK-3475 on levels of IDO, an enzyme that depletes tryptophan, which is essential for T-cell function. (5) To estimate the influence of concurrent and consolidative MK-3475 on levels of MHC class I (CD8+ T cell ligand) and MICA (NK ligand), as measured by MHC. (6) To estimate the progression free survival (PFS) in subjects with locally advanced cervical cancer treated with sequential and concurrent administration of pembrolizumab in relation to CRT. (7) To estimate the overall survival (OS) in subjects with locally advanced cervical cancer treated with sequential and concurrent administration of pembrolizumab in relation to CRT.

Official Title
-----------------
A Randomized Phase II Study of Chemoradiation and Pembrolizumab for Locally Advanced Cancer

Conditions
-----------------
Cervical Cancer

Intervention / Treatment
-----------------
* Drug: Pembrolizumab
* Radiation: Brachytherapy
* Drug: Cisplatin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Confirmed cervical cancer. Must have adequate organ function. Exclusion Criteria: Subject is pregnant. Recurrent cervical cancer. Distant metastases. Malignancy within the last 5 years; basal cell carcinoma or squamous cell carcinoma of the skin that has undergone potentially curative therapy is permissable. Subject has had prior radiation, chemotherapy, targeted therapy, or investigational therapy for cervical cancer. Subject has a immunodeficiency. Known history of HIV, Hepatitis B, Hepatitis C, TB, or inflammatory bowel disease. Hypersensitivity to pembrolizumab or similar drugs. Subject has an active autoimmune disease in the past 2 years. Known history of non-infectious pneumonitis. Subject has an active infection. Subject has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases are permissible. Talk to Study Contact for specifics.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Following chemoradiation<br>Subjects will receive standard chemotherapy weekly and 4-6 fractions of brachytherapy radiation for 5-6 weeks. After chemoradiation is complete, subjects will receive the study drug, pembrolizumab. | Drug: Pembrolizumab<br>* 200 mg of study drug is given through intravenous (IV) administration once every 21 days for 3 months.<br>* Other names: MK-3475;Radiation: Brachytherapy<br>* Radiation is done for standard clinical care purposes.<br>* Other names: chemoradiation;Drug: Cisplatin<br>* 40 mg of chemotherapy drug will be given weekly for 5-6 weeks.<br>* Other names: chemotherapy;|
| Experimental: Concurrent to chemoradiation<br>Subjects will receive standard chemotherapy weekly and 4-6 fractions of brachytherapy radiation for 5-6 weeks. While subjects are receiving chemotherapy and radiation, they will also receive the study drug, pembrolizumab. | Drug: Pembrolizumab<br>* 200 mg of study drug is given through intravenous (IV) administration once every 21 days for 3 months.<br>* Other names: MK-3475;Radiation: Brachytherapy<br>* Radiation is done for standard clinical care purposes.<br>* Other names: chemoradiation;Drug: Cisplatin<br>* 40 mg of chemotherapy drug will be given weekly for 5-6 weeks.<br>* Other names: chemotherapy;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in immunologic markers following combination of study drug with chemoradiation | Expression of immune markers measured at pre and post administration of study drug with chemoradiation will be compared. | At 6 weeks of chemoradiation and 12 weeks post-chemoradiation | 
| Incidence of dose limiting toxicities |  | From start of treatment until 12 weeks post-chemoradiation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Metabolic Response Rate on PET/CT imaging |  | 12 weeks after chemotherapy | 
| Incidence of distant metastases |  | From start of treatment until up to 5 years following end of treatment | 
| Progression Free Survival |  | From start of treatment until up to 5 years following end of treatment | 
| Overall Survival |  | From start of treatment until up to 5 years following end of treatment | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
advanced, cervical cancer, pembrolizumab, chemoradiation, immunotherapy