Human Papilloma Virus (HPV) Circulating Tumor DNA (ctDNA) in Cervical Cancer

Study Overview
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Brief Summary
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This study collects blood samples to determine if the DNA of HPV that causes cervical cancer can be detected in patients with cervical cancer that is new (primary), has come back (recurrent), or has spread to other places in the body (metastatic) and are undergoing treatment with surgery, radiotherapy, chemotherapy, and/or immunotherapy. Researchers may use this information to predict response (good or bad) of the cervical cancer to treatment and detect recurrent cancer sooner.

Detailed Description
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PRIMARY OBJECTIVES: I. To estimate the ctDNA detection rate in cervix cancer patients undergoing surgery, radiotherapy, chemotherapy, and/or immunotherapy in the setting of primary, recurrent or metastatic disease. II. Association of ctDNA baseline levels and clearance kinetics with clinical and radiographic tumor response. III. To explore the association of detectable ctDNA at each time point with invasive recurrence-free survival and overall survival. IV. To explore the use of ctDNA for surveillance and detection of disease recurrence. V. To create a repository for future exploratory studies including analyzing changes in T cell and other immune cell subpopulations during and following therapy for cervix cancer. OUTLINE: Patients are assigned to 1 of 4 cohorts. COHORT 1: Patients undergo collection of blood samples at baseline prior to surgery, at 6 weeks, 3, 6, and 12 months post-surgery, every 6 months during year 2, and at the time of recurrence (if applicable). COHORT 2: Patients undergo collection of blood samples at baseline prior to the first fraction of radiation, during week 4 of radiotherapy, at 6 weeks, 3, 6, and 12 months post-radiotherapy, every 6 months during year 2, and at the time of recurrence (if applicable). COHORT 3: Patients undergo collection of blood samples at baseline prior to the first fraction of radiation, during week 4 of radiotherapy, on the day of the final fraction of radiotherapy, at 3 months post-radiotherapy, every 3 months during years 1 and 2, and at the time of recurrence (if applicable). COHORT 4: Patients undergo collection of blood samples at baseline prior to initiation of chemotherapy or immunotherapy, at 4 weeks and 8 weeks after initiation of chemotherapy or immunotherapy, every 3 months during years 1 and 2, and at the time of recurrence (if applicable).

Official Title
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Human Papilloma Virus (HPV) Circulating Tumor DNA (ctDNA) in Cervical Cancer

Conditions
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Cervical Adenosquamous Carcinoma, Cervical Squamous Cell Carcinoma, Not Otherwise Specified, Infiltrating Cervical Carcinoma, Metastatic Cervical Carcinoma, Recurrent Cervical Carcinoma, Stage I Cervical Cancer FIGO 2018, Stage IA Cervical Cancer FIGO 2018, Stage IA1 Cervical Cancer FIGO 2018, Stage IA2 Cervical Cancer FIGO 2018, Stage IB Cervical Cancer FIGO 2018, Stage IB1 Cervical Cancer AJCC v8, Stage IB2 Cervical Cancer FIGO 2018, Stage IB3 Cervical Cancer FIGO 2018, Stage II Cervical Cancer FIGO 2018, Stage IIA Cervical Cancer FIGO 2018, Stage IIA1 Cervical Cancer FIGO 2018, Stage IIA2 Cervical Cancer FIGO 2018, Stage IIB Cervical Cancer FIGO 2018, Stage III Cervical Cancer FIGO 2018, Stage IIIA Cervical Cancer FIGO 2018, Stage IIIB Cervical Cancer FIGO 2018, Stage IIIC Cervical Cancer FIGO 2018, Stage IIIC1 Cervical Cancer FIGO 2018, Stage IIIC2 Cervical Cancer FIGO 2018, Stage IV Cervical Cancer FIGO 2018, Stage IVA Cervical Cancer FIGO 2018, Stage IVB Cervical Cancer FIGO 2018

Intervention / Treatment
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* Procedure: Biospecimen Collection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able to provide written consent Patient has given permission to give tumor/blood sample for research testing Histological confirmation of squamous cell carcinoma or adenosquamous carcinoma Known HPV status defined as positive staining for p16 on immunohistochemistry (IHC) or DNA in situ hybridization (ISH) for HPV Willingness to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study) Consent to allow blood specimens to be shared with potential external collaborators Cohort #1: Surgery alone for early stage disease (Federation of Gynecology and Obstetrics [FIGO] stage IA-IB1) FIGO 2019 stage IA1, IA2, IB1 Plan to undergo surgery including but not limited to trachelectomy, radical hysterectomy, and lymph node dissection Cohort #2: Post-operative radiation +/- chemotherapy for intermediate and high risk factors Any FIGO stage Status post any definitive surgical procedure (e.g. radical hysterectomy and lymph node dissection) and on final pathology found to have risk factors: Intermediate risk: Lymphovascular space invasion (LVSI), deep cervical stromal invasion, tumor size > 4 cm High risk: pelvic or para-aortic lymph nodes, parametrial invasion, positive surgical margins Plan to undergo pelvic +/- para-aortic radiotherapy with or without chemotherapy per standard of care Cohort #3: Definitive chemoradiotherapy for locally advanced disease (FIGO stage IB2-IIIC) FIGO 2019 Stage IB2-IIIC or not a surgical candidate Plan to undergo definitive chemoradiotherapy including external beam radiotherapy, brachytherapy, and chemotherapy Cohort #4: Systemic treatment for recurrent or metastatic disease Any recurrence (local, regional, or distant) after prior treatment for cervical cancer Metastases at first diagnosis without prior treatment Exclusion Criteria: Other active malignancy =< 2 years prior to registration. EXCEPTIONS: Non-melanotic skin cancer NOTE: If there is a history or prior malignancy, they must not be receiving other specific treatment for cancer Pregnancy or lactation Inability on the part of the patient to understand the informed consent to be compliant with the protocol

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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Cohort 1 (surgery patients)<br>Patients undergo collection of blood samples at baseline prior to surgery, at 6 weeks, 3, 6, and 12 months post-surgery, every 6 months during year 2, and at the time of recurrence (if applicable). | Procedure: Biospecimen Collection<br>* Undergo collection of blood samples<br>|
| Cohort 2 (post-operative radiation +/- chemotherapy patients)<br>Patients undergo collection of blood samples at baseline prior to the first fraction of radiation, during week 4 of radiotherapy, at 6 weeks, 3, 6, and 12 months post-radiotherapy, every 6 months during year 2, and at the time of recurrence (if applicable). | Procedure: Biospecimen Collection<br>* Undergo collection of blood samples<br>|
| Cohort 3 (definitive chemoradiotherapy patients)<br>Patients undergo collection of blood samples at baseline prior to the first fraction of radiation, during week 4 of radiotherapy, on the day of the final fraction of radiotherapy, at 3 months post-radiotherapy, every 3 months during years 1 and 2, and at the time of recurrence (if applicable). | Procedure: Biospecimen Collection<br>* Undergo collection of blood samples<br>|
| Cohort 4 (systemic treatment patients)<br>Patients undergo collection of blood samples at baseline prior to initiation of chemotherapy or immunotherapy, at 4 weeks and 8 weeks after initiation of chemotherapy or immunotherapy, every 3 months during years 1 and 2, and at the time of recurrence (if applicable). | Procedure: Biospecimen Collection<br>* Undergo collection of blood samples<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with undetectable circulating tumor deoxyribonucleic acid (ctDNA) posttreatment in patients with detectable ctDNA pre-treatment | The proportion will be reported along with the exact 95% binomial confidence interval. Additionally will report the mean standard deviation and median interquartile range ctDNA post-treatment in these patients. | At 6 weeks post-surgery (cohort 1), at 4-6 weeks after completion of chemotherapy and radiation (cohort 2), 4-6 weeks post End of chemotherapy and radiotherapy (cohort 3), at 8 weeks after start of chemotherapy or immunotherapy (cohort 4) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ctDNA levels | Will be associated with Federation of Gynecology and Obstetrics stage and assessed using linear regression, reporting the correlation as well as the model estimates. | Baseline | 
| Clinical tumor response | Will be assessed for association with baseline and post-treatment ctDNA using logistic regression. Depending on the number of tumor response, or non-response patients whichever is fewer, multiple variable models may be considered including additional relevant baseline covariates such as disease stage. | At post-treatment assessment, assessed up to 2 years | 
| Radiographic tumor response | Will be assessed for association with baseline and post-treatment ctDNA using logistic regression. Depending on the number of tumor response, or non-response patients whichever is fewer, multiple variable models may be considered including additional relevant baseline covariates such as disease stage. | At post-treatment assessment, assessed up to 2 years | 
| Recurrence-free survival | Baseline ctDNA and ctDNA at measured time points will be considered in Cox models. | Up to 2 years | 
| Overall survival | Baseline ctDNA and ctDNA at measured time points will be considered in Cox models. ctDNA other than at baseline will be considered in these models as a time dependent covariate. Depending on the number of events, multiple variable models may be considered including additional relevant baseline covariates such as disease stage. | Up to 2 years | 
| ctDNA clearance kinetics | Will be correlated with recurrence-free survival. ctDNA other than at baseline will be considered in these models as a time dependent covariate. Depending on the number of events, multiple variable models may be considered including additional relevant baseline covariates such as disease stage. | Up to 2 years | 
| ctDNA conversion | Will be correlated during the active monitoring phase with recurrence-free survival. | Up to 2 years |