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出境医 / 临床实验 / Immunomonitoring and Biomarker Research in Patients With Squamous Cell Anal Carcinoma (LAND)

Immunomonitoring and Biomarker Research in Patients With Squamous Cell Anal Carcinoma (LAND)

Study Description
Brief Summary:

Even if squamous cell carcinoma of the anal canal (SCCA) is a rare disease, its incidence increases worldwide. SCCA is mostly induced by Human papillomavirus (HPV) infections and HPV-related oncoproteins (E6 and E7) are expressed in more than 90% of SCCA. T stage and N stage are recognized prognostic factors for local and/or distant recurrence in SCCA patients treated by chemoradiotherapy. In fact, ≥T3 or ≥N1 anal cancers are associated with as high as 50% of disease recurrence rate at 2 years.

The University Hospital of Besançon with the Gercor conducted a prospective clinical trial (Epitopes HPV02 study) including 69 advanced SCCA patients and established a new standard of care based on Docetaxel, Cisplatin and 5-FU (5-FluoroUracil) chemotherapy (DCF). Among 69 patients treated with DCF regimen, 66 patients were evaluable for efficacy end-points. The objective response rate was 86% including 44% of complete response, and 47% of patients were progression-free at 12 months of follow-up from the first cycle of DCF treatment. Thus, the "Epitopes-HPV02" trial has demonstrated a high response rate of the DCF regimen with a higher than expected 12 months progression-free survival rate.These results raised the hypothesis of DCF being an immunogenic chemotherapy and in that demonstrating a possibly new role of taxane-based chemotherapy in SCCA patients. More than 50% of patients in complete remission had a detectable immunological response against peptides derived from HPV oncoproteins (E6 or E7) or from the telomerase antigen (which is transactivated by E6).

LAND study will enroll patients with locally advanced SCCA enrolled in OPTIMANAL clinical trial. OPTIMANAL study will assess the feasibility and efficacy to combine nivolumab to mDCF chemotherapy, followed by the standard chemo-radiotherapy, in high risk locally advanced SCCA patients with T3/T4 N1a or N1b/N1c disease.

LAND study is an exploratory translational study, which will analyze the biological mechanisms of action and our ability to track the immune responses against HPV and telomerase. The investigator group will take advantage of the presence of HPV antigens in most patients to set up a specific immunomonitoring program based on tumor samples and blood-derived lymphocytes to better understand the potential synergisms between immunogenic chemotherapy and anti-PD1 (Programmed Death-1), and to identify valuable biomarkers of treatment efficacy.


Condition or disease Intervention/treatment
Anal Canal Cancer Other: Additional biological samples

Study Design
Layout table for study information
Study Type : Observational
Estimated Enrollment : 59 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Immunomonitoring and Biomarker Research Based on Tumor and Blood Samples in Patients With Squamous Cell Anal Carcinoma
Estimated Study Start Date : April 2020
Estimated Primary Completion Date : September 2023
Estimated Study Completion Date : April 2024
Arms and Interventions
Group/Cohort Intervention/treatment
Cohort LAND
Patients enrolled in OPTIMANAL clinical trial
 Other: Additional biological samples

  • Biomonitoring blood sample will be collected: 6 EDTA tubes (6 mL) for PBMC (peripheral blood mononucleated cell), 1 EDTA tube (6 mL) for plasma freezing and 2 EDTA tubes (4 mL) for ctDNA:

    • at baseline,
    • at first tumor assessment (phase 2 in OPTIMANAL study),
    • at second tumor assessment (phase 4 in OPTIMANAL study),
    • at end-point visit.
  • A tumor biopsy or archived tumor sample will be mandatory at baseline.
Outcome Measures
Primary Outcome Measures :
  1. Peripheral CD4 anti-telomerase immunity and MDSC (Myeloid-Derived Suppressor Cells) analysis [ Time Frame: 24 months ]
    Correlation of both peripheral CD4 anti-telomerase immunity and MDSC with progression-free survival.


Biospecimen Retention:   Samples With DNA
  • A tumor biopsy or archived tumor sample will be mandatory at baseline. Tumor samples will be collected for HPV, p53 testing and translational research.

  • Biomonitoring blood sample will be collected: 6 EDTA (ethylenediaminetetraacetic acid) tubes (6 mL) for PBMC, 1 EDTA tube (6 mL) for plasma freezing and 2 EDTA tubes (4 mL) for circulating tumor DNA (ctDNA):

    • at baseline,
    • at first tumor assessment (phase 2 in OPTIMANAL study),
    • at second tumor assessment (phase 4 in OPTIMANAL study),
    • at end-point visit

Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population
Patients with locally advanced squamous cell anal carcinoma enrolled in OPTIMANAL clinical trial, and given consent for LAND-translational study
Criteria

Inclusion Criteria:

  1. Male or female, age ≥18 years,
  2. Patients enrolled in OPTIMANAL trial
  3. Signed and dated informed consent for LAND-translational study
  4. Histologically proved squamous cell anal carcinoma.

Exclusion Criteria:

  1. Patient with any medical or psychiatric condition or disease, which would make the patient inappropriate for entry into this study,
  2. Patient under guardianship, curators or under the protection of justice.
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Stefano KIM, Dr 0381668166 stefanokim@gmail.com
Contact: Christophe BORG, Pr 0381668166 christophe.borg@efs.sante.fr

Locations
Layout table for location information
France
Centre Hospitalier Universitaire de Besançon
Besançon, France
Contact: Stefano KIM, Dr         
Hôpital Nord Franche-Comté
Montbéliard, France
Contact: Christophe BORG, Pr         
Sponsors and Collaborators
Centre Hospitalier Universitaire de Besancon
Investigators
Layout table for investigator information
Study Director: Christophe BORG, Pr CHU Besançon
Tracking Information
First Submitted Date May 7, 2019
First Posted Date May 8, 2019
Last Update Posted Date January 31, 2020
Estimated Study Start Date April 2020
Estimated Primary Completion Date September 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: July 23, 2019) 		Peripheral CD4 anti-telomerase immunity and MDSC (Myeloid-Derived Suppressor Cells) analysis [ Time Frame: 24 months ]
Correlation of both peripheral CD4 anti-telomerase immunity and MDSC with progression-free survival.
Original Primary Outcome Measures
 (submitted: May 7, 2019) 		Peripheral CD4 anti-telomerase immunity and MDSC analysis [ Time Frame: 24 months ]
Correlation of both peripheral CD4 anti-telomerase immunity and MDSC with progression-free survival.
Change History
Current Secondary Outcome Measures Not Provided
Original Secondary Outcome Measures Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title Immunomonitoring and Biomarker Research in Patients With Squamous Cell Anal Carcinoma
Official Title Immunomonitoring and Biomarker Research Based on Tumor and Blood Samples in Patients With Squamous Cell Anal Carcinoma
Brief Summary

Even if squamous cell carcinoma of the anal canal (SCCA) is a rare disease, its incidence increases worldwide. SCCA is mostly induced by Human papillomavirus (HPV) infections and HPV-related oncoproteins (E6 and E7) are expressed in more than 90% of SCCA. T stage and N stage are recognized prognostic factors for local and/or distant recurrence in SCCA patients treated by chemoradiotherapy. In fact, ≥T3 or ≥N1 anal cancers are associated with as high as 50% of disease recurrence rate at 2 years.

The University Hospital of Besançon with the Gercor conducted a prospective clinical trial (Epitopes HPV02 study) including 69 advanced SCCA patients and established a new standard of care based on Docetaxel, Cisplatin and 5-FU (5-FluoroUracil) chemotherapy (DCF). Among 69 patients treated with DCF regimen, 66 patients were evaluable for efficacy end-points. The objective response rate was 86% including 44% of complete response, and 47% of patients were progression-free at 12 months of follow-up from the first cycle of DCF treatment. Thus, the "Epitopes-HPV02" trial has demonstrated a high response rate of the DCF regimen with a higher than expected 12 months progression-free survival rate.These results raised the hypothesis of DCF being an immunogenic chemotherapy and in that demonstrating a possibly new role of taxane-based chemotherapy in SCCA patients. More than 50% of patients in complete remission had a detectable immunological response against peptides derived from HPV oncoproteins (E6 or E7) or from the telomerase antigen (which is transactivated by E6).

LAND study will enroll patients with locally advanced SCCA enrolled in OPTIMANAL clinical trial. OPTIMANAL study will assess the feasibility and efficacy to combine nivolumab to mDCF chemotherapy, followed by the standard chemo-radiotherapy, in high risk locally advanced SCCA patients with T3/T4 N1a or N1b/N1c disease.

LAND study is an exploratory translational study, which will analyze the biological mechanisms of action and our ability to track the immune responses against HPV and telomerase. The investigator group will take advantage of the presence of HPV antigens in most patients to set up a specific immunomonitoring program based on tumor samples and blood-derived lymphocytes to better understand the potential synergisms between immunogenic chemotherapy and anti-PD1 (Programmed Death-1), and to identify valuable biomarkers of treatment efficacy.
Detailed Description Not Provided
Study Type Observational
Study Design Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration Not Provided
Biospecimen Retention:   Samples With DNA
Description:
  • A tumor biopsy or archived tumor sample will be mandatory at baseline. Tumor samples will be collected for HPV, p53 testing and translational research.

  • Biomonitoring blood sample will be collected: 6 EDTA (ethylenediaminetetraacetic acid) tubes (6 mL) for PBMC, 1 EDTA tube (6 mL) for plasma freezing and 2 EDTA tubes (4 mL) for circulating tumor DNA (ctDNA):

    • at baseline,
    • at first tumor assessment (phase 2 in OPTIMANAL study),
    • at second tumor assessment (phase 4 in OPTIMANAL study),
    • at end-point visit
Sampling Method Probability Sample
Study Population Patients with locally advanced squamous cell anal carcinoma enrolled in OPTIMANAL clinical trial, and given consent for LAND-translational study
Condition Anal Canal Cancer
Intervention Other: Additional biological samples

  • Biomonitoring blood sample will be collected: 6 EDTA tubes (6 mL) for PBMC (peripheral blood mononucleated cell), 1 EDTA tube (6 mL) for plasma freezing and 2 EDTA tubes (4 mL) for ctDNA:

    • at baseline,
    • at first tumor assessment (phase 2 in OPTIMANAL study),
    • at second tumor assessment (phase 4 in OPTIMANAL study),
    • at end-point visit.
  • A tumor biopsy or archived tumor sample will be mandatory at baseline.
Study Groups/Cohorts Cohort LAND
Patients enrolled in OPTIMANAL clinical trial
Intervention: Other: Additional biological samples
Publications *
  • Kim S, Jary M, André T, Vendrely V, Buecher B, François E, Bidard FC, Dumont S, Samalin E, Peiffert D, Pernot S, Baba-Hamed N, El Hajbi F, Bouché O, Desrame J, Parzy A, Zoubir M, Louvet C, Bachet JB, Nguyen T, Abdelghani MB, Smith D, De La Fouchardière C, Aparicio T, Bennouna J, Gornet JM, Jacquin M, Bonnetain F, Borg C. Docetaxel, Cisplatin, and 5-fluorouracil (DCF) chemotherapy in the treatment of metastatic or unresectable locally recurrent anal squamous cell carcinoma: a phase II study of French interdisciplinary GERCOR and FFCD groups (Epitopes-HPV02 study). BMC Cancer. 2017 Aug 25;17(1):574. doi: 10.1186/s12885-017-3566-0.
  • Bernard-Tessier A, Jeannot E, Guenat D, Debernardi A, Michel M, Proudhon C, Vincent-Salomon A, Bièche I, Pierga JY, Buecher B, Meurisse A, François É, 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.
  • Kim S, François E, André T, Samalin E, Jary M, El Hajbi F, Baba-Hamed N, Pernot S, Kaminsky MC, Bouché O, Desrame J, Zoubir M, Ghiringhelli F, Parzy A, De La Fouchardiere C, Smith D, Deberne M, Spehner L, Badet N, Adotevi O, Anota A, Meurisse A, Vernerey D, Taieb J, Vendrely V, Buecher B, Borg C. Docetaxel, cisplatin, and fluorouracil chemotherapy for metastatic or unresectable locally recurrent anal squamous cell carcinoma (Epitopes-HPV02): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2018 Aug;19(8):1094-1106. doi: 10.1016/S1470-2045(18)30321-8. Epub 2018 Jul 2.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Not yet recruiting
Estimated Enrollment
 (submitted: May 7, 2019) 		59
Original Estimated Enrollment Same as current
Estimated Study Completion Date April 2024
Estimated Primary Completion Date September 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria

Inclusion Criteria:

  1. Male or female, age ≥18 years,
  2. Patients enrolled in OPTIMANAL trial
  3. Signed and dated informed consent for LAND-translational study
  4. Histologically proved squamous cell anal carcinoma.

Exclusion Criteria:

  1. Patient with any medical or psychiatric condition or disease, which would make the patient inappropriate for entry into this study,
  2. Patient under guardianship, curators or under the protection of justice.
Sex/Gender
Sexes Eligible for Study: All
Ages 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers No
Contacts
Contact: Stefano KIM, Dr 0381668166 stefanokim@gmail.com
Contact: Christophe BORG, Pr 0381668166 christophe.borg@efs.sante.fr
Listed Location Countries France
Removed Location Countries  
 
Administrative Information
NCT Number NCT03942900
Other Study ID Numbers P/2018/381
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement
Plan to Share IPD: No
Responsible Party Centre Hospitalier Universitaire de Besancon
Study Sponsor Centre Hospitalier Universitaire de Besancon
Collaborators Not Provided
Investigators
Study Director: Christophe BORG, Pr CHU Besançon
PRS Account Centre Hospitalier Universitaire de Besancon
Verification Date May 2019

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