Cervical Cancer
Conditions
Keywords
advanced, cervical cancer, pembrolizumab, chemoradiation, immunotherapy
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.
Interventions
DRUGPembrolizumab
200 mg of study drug is given through intravenous (IV) administration once every 21 days for 3 months.
RADIATIONBrachytherapy
Radiation is done for standard clinical care purposes.
DRUGCisplatin
40 mg of chemotherapy drug will be given weekly for 5-6 weeks.
Sponsors
Merck Sharp & Dohme LLC
Linda R Duska
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Immunologic Markers Following Combination of Study Drug With Chemoradiation | 12 weeks post-chemoradiation | Expression of immune markers measured at pre and post administration of study drug with chemoradiation will be compared, analyzed and enumerated using QuPath software to provide a cell #/mm2 (not per high power field) and the ratio of CD8+ cells:FoxP3+ cells/mm2 was calculated. |
| Number of Participants With Dose Limiting Toxicities | From start of treatment until 12 weeks post-chemoradiation | To determine the safety of concurrent chemoradiation in combination with pembrolizumab for the treatment of locally advanced cervical cancer |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Metabolic Response Rate on PET/CT Imaging | 12 weeks after chemotherapy | To estimate rates of complete metabolic response on PET/CT imaging obtained 12 weeks after CRT |
| Incidence of Distant Metastases | From start of treatment until up to 5 years following end of treatment | To estimate the rates of distant metastasis as the first site of recurrent for patients |
| Progression Free Survival | From start of treatment until up to 5 years following end of treatment | To estimate the progression free survival (PFS) in subjects with locally advanced cervical cancer treatment with sequential and concurrent administration of pembrolizumab in relation to CRT |
| Overall Survival | From start of treatment until up to 5 years following end of treatment | 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Following Chemoradiation 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.
Pembrolizumab: 200 mg of study drug is given through intravenous (IV) administration once every 21 days for 3 months.
Brachytherapy: Radiation is done for standard clinical care purposes.
Cisplatin: 40 mg of chemotherapy drug will be given weekly for 5-6 weeks. | 48 |
| Concurrent to Chemoradiation 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.
Pembrolizumab: 200 mg of study drug is given through intravenous (IV) administration once every 21 days for 3 months.
Brachytherapy: Radiation is done for standard clinical care purposes.
Cisplatin: 40 mg of chemotherapy drug will be given weekly for 5-6 weeks. | 46 |
| Total | 94 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 3 |
| Overall Study | Disease Progression | 0 | 2 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Non-Compliance | 3 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | Following Chemoradiation | Concurrent to Chemoradiation | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5 Participants | 2 Participants | 7 Participants |
| Age, Categorical Between 18 and 65 years | 43 Participants | 44 Participants | 87 Participants |
| Age, Continuous | 49 years | 48 years | 48 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 4 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 42 Participants | 38 Participants | 80 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 4 Participants | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants | 6 Participants | 15 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants | 2 Participants | 8 Participants |
| Race (NIH/OMB) White | 28 Participants | 37 Participants | 65 Participants |
| Region of Enrollment United States | 48 participants | 46 participants | 94 participants |
| Sex: Female, Male Female | 48 Participants | 46 Participants | 94 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 8 / 48 | 5 / 46 |
| other Total, other adverse events | 18 / 48 | 11 / 46 |
| serious Total, serious adverse events | 40 / 48 | 27 / 46 |
Outcome results
Primary
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, analyzed and enumerated using QuPath software to provide a cell #/mm2 (not per high power field) and the ratio of CD8+ cells:FoxP3+ cells/mm2 was calculated.
Time frame: 12 weeks post-chemoradiation
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Following Chemoradiation | Change in Immunologic Markers Following Combination of Study Drug With Chemoradiation | 31.31 ratio of cells per mm^2, CD8+: FoxP3+ | Standard Deviation 124.77 |
| Concurrent to Chemoradiation | Change in Immunologic Markers Following Combination of Study Drug With Chemoradiation | 140.33 ratio of cells per mm^2, CD8+: FoxP3+ | Standard Deviation 812.53 |
Primary
Number of Participants With Dose Limiting Toxicities
To determine the safety of concurrent chemoradiation in combination with pembrolizumab for the treatment of locally advanced cervical cancer
Time frame: From start of treatment until 12 weeks post-chemoradiation
Population: Subjects on Treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Following Chemoradiation | Number of Participants With Dose Limiting Toxicities | 0 Participants |
| Concurrent to Chemoradiation | Number of Participants With Dose Limiting Toxicities | 4 Participants |
Secondary
Incidence of Distant Metastases
To estimate the rates of distant metastasis as the first site of recurrent for patients
Time frame: From start of treatment until up to 5 years following end of treatment
Population: Number of subjects on treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Following Chemoradiation | Incidence of Distant Metastases | 6 Participants |
| Concurrent to Chemoradiation | Incidence of Distant Metastases | 6 Participants |
Secondary
Metabolic Response Rate on PET/CT Imaging
To estimate rates of complete metabolic response on PET/CT imaging obtained 12 weeks after CRT
Time frame: 12 weeks after chemotherapy
Population: Subjects that completed Radiation Therapy within 56 days.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Following Chemoradiation | Metabolic Response Rate on PET/CT Imaging | 2 Participants |
| Concurrent to Chemoradiation | Metabolic Response Rate on PET/CT Imaging | 7 Participants |
Secondary
Overall Survival
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
Time frame: From start of treatment until up to 5 years following end of treatment
Population: Number of subjects on treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Following Chemoradiation | Overall Survival | 42 Participants |
| Concurrent to Chemoradiation | Overall Survival | 41 Participants |
Secondary
Progression Free Survival
To estimate the progression free survival (PFS) in subjects with locally advanced cervical cancer treatment with sequential and concurrent administration of pembrolizumab in relation to CRT
Time frame: From start of treatment until up to 5 years following end of treatment
Population: Number of Subjects on Treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Following Chemoradiation | Progression Free Survival | 41 Participants |
| Concurrent to Chemoradiation | Progression Free Survival | 38 Participants |