Dynamic ctDNA Assessment in Cervical and Anal Canal Tumors: Optimizing Follow-up and Clinical Outcomes (ANA)

Instituto do Cancer do Estado de São Paulo

Status and phase: Enrolling; Phase 2

Conditions: HPV-Related Carcinoma; Uterine Cervical Cancer; HPV-Related Cervical Carcinoma; HPV-Related Anal Squamous Cell Carcinoma; Anal Canal Cancer

Treatments: Diagnostic Test: ctDNA test; Drug: Pembrolizumab

Study type: Interventional

Funder types: Other

Identifiers

NCT06640283

79795024.8.0000.0068 (Registry Identifier)

444027/2023-8 (Other Grant/Funding Number)

NP5125/2024

Details and patient eligibility

About

After definitive radiotherapy (RT) treatment (with or without chemotherapy), cervical and anal canal neoplasms frequently exhibit disease persistence or recurrence. Due to the local inflammatory process post-treatment, response assessment by imaging (current gold standard) is limited, often necessitating multiple follow-ups and repeated invasive biopsies. Conventional follow-up is complex and costly, requiring equipment from secondary and tertiary services, trained radiologists, and patient exposure to radiation and contrast.

In this context of human papillomavirus(HPV)-related neoplasms, recent studies have demonstrated the role of ctDNA (circulating tumor DNA) in assessing the risk of recurrence or disease progression, providing a rationale for using the tool in two fronts:

• Optimizing follow-up based on serial monitoring of ctDNA;
• Selecting patients with positive ctDNA after RT, who are at high risk of recurrence, for treatment intensification.

Monitoring with ctDNA as a standalone follow-up tool in cases evolving with negative ctDNA after RT has the potential to replace imaging exams, being a minimally invasive test performed on a peripheral blood sample. Currently, ctDNA testing has expensive methodologies not available in the Unified Health System (SUS). This project aims to develop a methodology for ctDNA evaluation focused on HPV ctDNA research that is low-cost and executable in SUS, as well to assess the accuracy of this test in the population with HPV-related tumors.

Additionally, we will evaluate whether the early introduction of immunotherapy in patients with positive ctDNA after definitive treatment can increase cure rates. Immunotherapy already has a well-defined role in the treatment of metastatic HPV-related neoplasms. Recently, the use of anti-programmed death-1 (anti-PD1) has also shown benefits in patients with locally advanced cervical cancer with a high risk of recurrence who are candidates for chemoradiotherapy (CRT). Therefore, its use focused on HPV-related tumors, as well as a better understanding of which patients benefit from this strategy, warrants further investigation.

Full description

The ANA study is a research project aimed at enhancing the treatment and outcomes for patients with cervical and anal canal cancer by using innovative diagnostic and therapeutic methods. The study consists of the following phases:

• Patient identification and selection;
• Recruitment of patients diagnosed with cervical or anal canal cancer who are candidates for treatment with radiotherapy (RT), with or without chemotherapy: patients will be selected based on specific criteria to ensure a representative cohort;
• Development and validation of the ctDNA HPV Test: development of a sensitive and specific test to detect HPV DNA in the blood. This test will undergo rigorous validation to ensure its accuracy and reliability;
• ctDNA monitoring: blood samples collection from patients during treatment and follow-up. ctDNA levels will be monitored in real-time to early detection of residual or recurrent disease. This non-invasive method aims to provide a more accurate assessment of treatment efficacy and disease progression. The results of ctDNA will be compared with traditional imaging methods.
• Complementary immunotherapy treatment: patients with positive ctDNA results after (chemo)radiotherapy will be considered for additional immunotherapy. This phase will evaluate the benefits of combining immunotherapy with standard (chemo)radiotherapy in order to improve patient outcomes;
• Follow-up and outcome evaluation: long-term follow-up of patients to assess clinical outcomes, including survival and quality of life.

The ANA study aims to set new standards in the follow-up and management of HPV-related cervical and anal canal cancer by improving patient care within the Brazilian public health system (SUS).

Enrollment: 150 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. Histological diagnosis of anal canal or cervical cancer.

2. Documented presence of HPV.

3. Locally confined or locally advanced disease, defined as:

   1. Anal canal carcinoma stage I to III, according to American Joint Committee on Cancer (AJCC) 8th edition;
   2. Cervical carcinoma stage I B2 to IV A, according to AJCC 8th edition.

4. Indication for definitive treatment with radiotherapy, with or without concomitant chemotherapy.

5. Eastern Cooperative Oncology Group (ECOG)-Performance Status (PS) 0 - 1.

6. Age ≥ 18 years.

7. Signing of the Informed Consent Form (ICF).

8. HIV-positive patients may be included if Cluster of Differentiation 4(CD4) count is greater than or equal to 200.

9. Patients may participate in other concurrent studies, as long as they do not involve interventions related to the treatment of the underlying cancer.

Exclusion criteria

1. Patients with unequivocal distant metastasis at diagnosis.
2. For participants with positive ctDNA after treatment, those candidates for participation in Phase II will be excluded if there is unequivocal radiological progression in the first imaging exam after the completion of radiotherapy (with or without chemotherapy) or routine indication for salvage surgery immediately after the conclusion of definitive treatment.
3. Need for recurrent blood transfusions, such as weekly frequency.
4. Another uncontrolled disease representing a life risk, as determined by medical judgment.
5. Personal history of another active invasive malignant neoplasm in the last 5 years, except for non-melanoma skin carcinomas and in situ carcinomas.
6. Pregnant individuals.
7. Active opportunistic infection or disease.
8. History of autoimmune diseases.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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150 participants in 2 patient groups

Active laboratory monitoring

Other group

Description:

Phase I Monitoring through collection of laboratory tests

Treatment:

Diagnostic Test: ctDNA test

Intervention with Immunotherapy

Experimental group

Description:

Phase II for participants who are ctDNA positive after standard treatment. Intervention will be with Pembrolizumab

Treatment:

Drug: Pembrolizumab