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

NCT06640283 | Recruiting Phase 2 DMC

• 3 other identifiers: NP5125/202479795024.8.0000.0068444027/2023-8
• Study Type: interventional
• Target: 150
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

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

Keywords

HPV; ctDNA; Cervical tumors; Anal canal tumors; Molecular diagnosis; Diagnostic test; Biomarkers

Outcome Measures

Primary Outcomes (1)

• General Objective

  The objective of this study is to develop and validate a low-cost ctDNA test focused on detecting HPV-associated ctDNA for use in patients within the Brazilian Unified Health System (SUS). The test will be evaluated for its effectiveness in improving traditional monitoring methods and guiding the intensification of adjuvant treatment for anogenital neoplasms, including anal canal and cervical cancer. The impact of the test will be measured by correlating ctDNA detection with clinical outcomes of patients over time.

  2 years

Other Outcomes (9)

• Number of HPV-focused ctDNA tests developed and validated

  2 years

• Performance of the validated HPV-related ctDNA test

  2 years

• Comparison of accuracy between standard ctDNA and HPV-focused ctDNA

  2 years

Study Arms (2)

Active laboratory monitoring

OTHER

Phase I Monitoring through collection of laboratory tests

Diagnostic Test: ctDNA test

Intervention with Immunotherapy

EXPERIMENTAL

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

Drug: Pembrolizumab

Interventions

ctDNA test DIAGNOSTIC_TEST

ctDNA involves the collection of peripheral blood samples for the analysis of circulating tumor DNA (ctDNA). The samples are processed using next-generation sequencing (NGS) and/or digital polymerase chain reaction (PCR) techniques to detect specific genetic alterations related to the tumor. The objective is to assess the presence and quantity of ctDNA, providing information on tumor burden and treatment response.

Active laboratory monitoring

Pembrolizumab DRUG

Participants will receive the institution's standard treatment during Phase I. If ctDNA remains positive between 8 and 12 weeks after the standard treatment, the participant will be invited to proceed to Phase II, which will consist of intravenous immunotherapy for up to 12 months, or until disease progression or unacceptable toxicity occurs. Continuous monitoring with ctDNA testing will be performed during Phase II.

Intervention with Immunotherapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histological diagnosis of anal canal or cervical cancer.
• Documented presence of HPV.
• Locally confined or locally advanced disease, defined as:
• Anal canal carcinoma stage I to III, according to American Joint Committee on Cancer (AJCC) 8th edition;
• Cervical carcinoma stage I B2 to IV A, according to AJCC 8th edition.
• Indication for definitive treatment with radiotherapy, with or without concomitant chemotherapy.
• Eastern Cooperative Oncology Group (ECOG)-Performance Status (PS) 0 - 1.
• Age ≥ 18 years.
• Signing of the Informed Consent Form (ICF).
• HIV-positive patients may be included if Cluster of Differentiation 4(CD4) count is greater than or equal to 200.
• Patients may participate in other concurrent studies, as long as they do not involve interventions related to the treatment of the underlying cancer.

You may not qualify if:

• Patients with unequivocal distant metastasis at diagnosis.
• 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.
• Need for recurrent blood transfusions, such as weekly frequency.
• Another uncontrolled disease representing a life risk, as determined by medical judgment.
• Personal history of another active invasive malignant neoplasm in the last 5 years, except for non-melanoma skin carcinomas and in situ carcinomas.
• Pregnant individuals.
• Active opportunistic infection or disease.
• History of autoimmune diseases.

Sponsors & Collaborators

• Conselho Nacional de Desenvolvimento Científico e Tecnológico: collaborator
• Instituto do Cancer do Estado de São Paulo: lead

Study Sites (1)

Instituto do Câncer do Estado de São Paulo - ICESP

São Paulo, 01246-000, Brazil

RECRUITING

Related Publications (6)

• Bernard-Tessier A, Jeannot E, Guenat D, Debernardi A, Michel M, Proudhon C, Vincent-Salomon A, Bieche I, Pierga JY, Buecher B, Meurisse A, Francois E, Cohen R, Jary M, Vendrely V, Samalin E, El Hajbi F, Baba-Hamed N, Borg C, Bidard FC, Kim S. Clinical Validity of HPV Circulating Tumor DNA in Advanced Anal Carcinoma: An Ancillary Study to the Epitopes-HPV02 Trial. Clin Cancer Res. 2019 Apr 1;25(7):2109-2115. doi: 10.1158/1078-0432.CCR-18-2984. Epub 2018 Nov 30.

  PMID: 30504426 BACKGROUND

• Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N, Bartlett BR, Wang H, Luber B, Alani RM, Antonarakis ES, Azad NS, Bardelli A, Brem H, Cameron JL, Lee CC, Fecher LA, Gallia GL, Gibbs P, Le D, Giuntoli RL, Goggins M, Hogarty MD, Holdhoff M, Hong SM, Jiao Y, Juhl HH, Kim JJ, Siravegna G, Laheru DA, Lauricella C, Lim M, Lipson EJ, Marie SK, Netto GJ, Oliner KS, Olivi A, Olsson L, Riggins GJ, Sartore-Bianchi A, Schmidt K, Shih lM, Oba-Shinjo SM, Siena S, Theodorescu D, Tie J, Harkins TT, Veronese S, Wang TL, Weingart JD, Wolfgang CL, Wood LD, Xing D, Hruban RH, Wu J, Allen PJ, Schmidt CM, Choti MA, Velculescu VE, Kinzler KW, Vogelstein B, Papadopoulos N, Diaz LA Jr. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014 Feb 19;6(224):224ra24. doi: 10.1126/scitranslmed.3007094.

  PMID: 24553385 BACKGROUND

• Cabel L, Bonneau C, Bernard-Tessier A, Hequet D, Tran-Perennou C, Bataillon G, Rouzier R, Feron JG, Fourchotte V, Le Brun JF, Benoit C, Rodrigues M, Scher N, Minsat M, Legrier ME, Bieche I, Proudhon C, Sastre-Garau X, Bidard FC, Jeannot E. HPV ctDNA detection of high-risk HPV types during chemoradiotherapy for locally advanced cervical cancer. ESMO Open. 2021 Jun;6(3):100154. doi: 10.1016/j.esmoop.2021.100154. Epub 2021 May 19.

  PMID: 34022731 BACKGROUND

• Jeannot E, Becette V, Campitelli M, Calmejane MA, Lappartient E, Ruff E, Saada S, Holmes A, Bellet D, Sastre-Garau X. Circulating human papillomavirus DNA detected using droplet digital PCR in the serum of patients diagnosed with early stage human papillomavirus-associated invasive carcinoma. J Pathol Clin Res. 2016 Jun 28;2(4):201-209. doi: 10.1002/cjp2.47. eCollection 2016 Oct.

  PMID: 27917295 BACKGROUND

• Jeannot E, Latouche A, Bonneau C, Calmejane MA, Beaufort C, Ruigrok-Ritstier K, Bataillon G, Larbi Cherif L, Dupain C, Lecerf C, Popovic M, de la Rochefordiere A, Lecuru F, Fourchotte V, Jordanova ES, von der Leyen H, Tran-Perennou C, Legrier ME, Dureau S, Raizonville L, Bello Roufai D, Le Tourneau C, Bieche I, Rouzier R, Berns EMJJ, Kamal M, Scholl S. Circulating HPV DNA as a Marker for Early Detection of Relapse in Patients with Cervical Cancer. Clin Cancer Res. 2021 Nov 1;27(21):5869-5877. doi: 10.1158/1078-0432.CCR-21-0625. Epub 2021 Jul 1.

  PMID: 34210686 BACKGROUND

• Lefevre AC, Pallisgaard N, Kronborg C, Wind KL, Krag SRP, Spindler KG. The Clinical Value of Measuring Circulating HPV DNA during Chemo-Radiotherapy in Squamous Cell Carcinoma of the Anus. Cancers (Basel). 2021 May 18;13(10):2451. doi: 10.3390/cancers13102451.

  PMID: 34070045 BACKGROUND

MeSH Terms

Conditions

Uterine Cervical Neoplasms; Anal Canal Carcinoma

Interventions

pembrolizumab

Condition Hierarchy (Ancestors)

Uterine Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Uterine Cervical Diseases; Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases

Study Officials

• Maria DP Estevez Diz, Doctor

  Oncologist

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Research Center, Assistant

CONTACT

+55 11 3893-3566; icesp.pesqclinica@hc.fm.usp.br

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Oncologist, Principal Investigator

Model Details: 84 to150 patients will be tested for HPV in their tumor samples 68 patients with negative ctDNA after CRT will be monitored with ctDNA plus routine image 16 patients with positive ctDNA after CRT will receive anti-PD1

Study Record Dates

• First Submitted: October 4, 2024
• First Posted: October 15, 2024
• Study Start: March 14, 2025
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): January 1, 2027
• Last Updated: December 24, 2025

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will not share

Locations

BR (1)