Neoplasms

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Digestive System Diseases

Rare Diseases

Carcinoma

Anus Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Rectal Neoplasms

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Intestinal Diseases

Anus Diseases

Rectal Diseases

Anal Cancer

Antineoplastic Agents

All Drugs and Chemicals

Cetuximab

Avelumab

Antineoplastic Agents, Immunological

avelumab 10 mg/kg iv day 1; To be repeated every 2 weeks (14 days) until progression of disease, refuse or inacceptable toxicity.

cetuximab 500 mg/m2 plus avelumab 10 mg/kg iv day 1. To be repeated every 2 weeks (14 days) until progression of disease, refuse or inacceptable toxicity.

* The standard first line treatment in SCCAC is the association of 5-FU with cisplatin reaching a percentage of survival at 5 years of about 32% (Faivre 1999); in a recent case series of patients affected by SCCAC, the combination of 5-FU and cisplatin as first line treatment produced 34.4% objective response rate (ORR) and a 5 years survival rate of 15% (Sclafani 2017);
* No standard second line treatment exists for SCCAC;
* Cetuximab in association with irinotecan has demonstrated promising results in pretreated patients affected by SCCAC (Lukan 2009). In addition, it was recently tested in stage I-III SCCAC in association with cisplatin plus 5-FU and radiotherapy. Despite not reaching their pre-specified endpoints both studies reported an interesting activity in local control of disease, leading to hypothesize that cetuximab warrant further investigation in new strategies (Garg 2017, Sparano 2017);
* Anti-PD1 treatments such as nivolumab and pembrolizumab showed promising activity in metastatic refractory SCCAC in terms of response rate and disease control with acceptable toxicity profiles (Morris 2017, Ott 2017);
* The induction of immunogenic cell death was recently shown for cetuximab-based regimens (Pozzi 2016) and PD-L1 blockade should lead to NK cells activation enhancing cetuximab ADCC (Concha-Benavente 2015, Concha-Benavente 2016).

On the basis of these considerations, the investigators designed the present randomized phase II trial of avelumab alone or avelumab plus cetuximab for previously treated unresectable locally advanced or metastatic SCCAC.

Cetuximab + Avelumab or Avelumab Alone for Unresectable, Locally Advanced or Metastatic Squamous Cell Anal Carcinoma (SCCAC) Progressed After at Least One Line of Systemic Treatment (CARACAS)

Randomized Phase 2 Trial of Cetuximab and Avelumab or Avelumab Alone for Unresectable, Locally Advanced or Metastatic Squamous Cell Anal Carcinoma (SCCAC) Progressed After at Least One Line of Systemic Treatment

The primary endpoint is Objective Response Rate (ORR). ORR is defined as the percentage of patients, relative to the total of enrolled subjects, achieving a complete (CR) or partial (PR) response, according to Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 criteria. The determination of the radiological response will be based on the investigator's reported evaluation.

Gruppo Oncologico del Nord-Ovest

Carcinoma, Squamous Cell

Docetaxel

Fluorouracil

Cisplatin

Immunomodulating Agents

Spartalizumab

Phase 1: Radiotherapy (8 Gy on target lesions)

Phase 2: Combination immunotherapy and mDCF regimen mDCF regimen every 2 weeks for 8 cycles

* Docetaxel (40 mg/m², day 1),
* Cisplatin (40 mg/m², day 1)
* 5-FU (1200 mg/m²/day for 2 days) Spartalizumab: 400 mg intravenous will be administrated every 4 weeks

Phase 3 : Multimodal treatment of residual disease The multimodal treatment is recommended in oligometastatic anal cancer. The support by ablative treatment (surgery, hypofractionnated radiotherapy or by radiofrequency) improve survival.

In absence of progression disease:

* Ablative treatment: surgery, hypofractionnated radiotherapy or by radiofrequency of residual metastases
* and Chemo-radiotherapy (CRT) for local disease

Phase 4: Maintenance treatment with Spartalizumab 400 mg intravenous every 4 weeks for 12 months from enrolment maximum

PBMC collection at baseline, after radiotherapy 8 Gy (gray), at 6 months and at 12 months from inclusion: 6 EDTA tubes of 6 ml of peripheral blood mononuclear cell \[PBMC\] will be sent to the central laboratory (Biomonitoring Platform of Besançon, CHRU de Besançon located at Etablissement Français du Sang) at room temperature within 24 hours via an approved carrier for their processing, storage and immunomonitoring analysis. A sending sheet of the samples will be attached to each single sample.

Plasma collection at baseline, after radiotherapy 8 Gy, at 6 months and at 12 months from inclusion: One 6 ml EDTA tube should be frozen in each investigation center for plasma collection.

Plasma for circulating tumoral DNA (ctDNA) collection at baseline, at 2, 6 and 12 months from inclusion: two EDTA tube of 4 ml should be frozen in each investigation center for ctDNA collection.

Sample collection

Stefano KIM, Pr

Christophe BORG, Pr

Angélique VIENOT, Dr

François GHIRINGHELLI, Pr

This study evaluates the feasibility of the combination of radiotherapy, chemotherapies (docetaxel, cisplatin and 5-fluorouracil) and spartalizumab (anti-PD-1 therapy) in patients with metastatic squamous cell anal carcinoma

In SCCA (squamous cell carcinoma of anus) about 15% of patients are diagnosed in metastatic stage, and around 25-40% of patients will experience disease progression after curative intent chemoradiotherapy (CRT) for localized disease. In patients with non-resectable local recurrences or with distant metastases, the systemic chemotherapy is the standard approach. Recently, taxane-based combination chemotherapy regimens have demonstrated high efficacy or better tolerance than non-taxane based regimens, and became standards based in prospective trials. First, the modified DCF (docetaxel, cisplatin and 5-fluorouracil) showed a high efficacy in Epitopes-HPV02 trial conducted by investigators including 66 patients and became the first validated chemotherapy regimen in advanced SCCA. Then, the pooled analysis of 115 patients confirmed the mDCF regimen as the standard treatment in all fit patients with advanced SCCA.

The combination of different chemotherapy regimens and an anti-PD1/PD-L1 (Programmed cell Death-1/Programmed cell Death-Ligand1) were feasible with improved survival in first-line advanced small-cell and non-small-cell lung cancers. In anal carcinoma, Epitopes-HPV02 trial showed that mDCF regimen was feasible with 53% of grade 3-4 adverse-event, with no grade 4 non-hematological toxicity and no febrile neutropenia. And also considering its property to enhance the anti-tumor immune response, mDCF was recommended as an interesting candidate to be evaluated as a backbone chemotherapy for immunotherapy combinations in SCCA.

In anal carcinoma, investigators are currently conducting a randomized prospective trial promoted by GERCOR (cooperator group) evaluating the association of mDCF and an anti-PD-L1 in metastatic setting. All patients (100) were already enrolled, and no particular safety alert signal was observed at the Data Safety Monitoring Board (DSMB)..

Among different factors that confers a primary resistance to immunotherapy, the lack of antigenic proteins capable to induce immune response, and the downregulation of major histocompatibility complex class 1 (MHC-1) are probably the most important. In fact, the next-generation sequencing (NGS) techniques has demonstrated the correlation between tumor mutation burden (TMB) and response to CKI (checkpoint Inhibitor). Hence, most of "hot" tumors with high TMB could be treated with CKI alone, while "cold" tumors probably need combination strategies. Besides, primary or secondary resistances to CKI caused by downregulation of MHC-1 are well described.

Radiation causes random point mutations and double-stranded breaks in the DNA and modulates the peptide repertoire, increasing tumour-related antigens and TMB to enhance anti-tumour immunity. Radiotherapy has also demonstrated to enhances MHC class I expression.

Investigators decided to associate radiotherapy, PD-1 (Programmed cell Death-1) inhibitor and mDCF (docetaxel, cisplatin and 5-fluorouracil) chemotherapy regimen to improve the efficacy with higher rate of long-lasting progression-free survivors and complete remissions. In addition, the associated extensive ancillary biomarker studies in tissues and peripheral blood will provide a unique opportunity to find out the potential synergic effect mechanism between mDCF, CKI and radiotherapy, as well as to improve our knowledge about underlying resistances.

Combination of Spartalizumab, mDCF and Radiotherapy in Patients With Metastatic Squamous Cell Anal Carcinoma

Spartalizumab, mDCF (Docetaxel, Cisplatin and 5-fluorouracil) and Radiotherapy in Patients With Metastatic Squamous Cell Anal Carcinoma. A Phase IIA Study

PFS rate at 1 year is defined as the number of patients alive without progression at 1 year divided by the overall number of patients evaluable for PFS status at 1 year.

A patient is evaluable for PFS status at 1 year if he dies during the 1 year of follow up or if he is alive with a RECIST evaluation available at 1 year.

Addition of complete response (CR) and partial response (PR) rates.

Delay from the date of inclusion to death from any cause , or the date of the last follow-up, at which point data will be censored

Delay from the date of inclusion to the disease progression or death from any cause, whichever occurs first , or the date of the last follow-up, at which point data will be censored

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Cetuximab + Avelumab or Avelumab Alone for Unresectable, Locally Advanced or Metastatic Squamous Cell Anal Carcinoma (SCCAC) Progressed After at Least One Line of Systemic Treatment (CARACAS)	NCT03944252	Squamous Cell A...	Avelumab Cetuximab	18 Years -	Gruppo Oncologico del Nord-Ovest
Combination of Spartalizumab, mDCF and Radiotherapy in Patients With Metastatic Squamous Cell Anal Carcinoma	NCT04894370	Squamous Cell A... Metastatic Squa...	Sample collecti...	18 Years -	Centre Hospitalier Universitaire de Besancon
Combination of Spartalizumab, mDCF and Radiotherapy in Patients With Metastatic Squamous Cell Anal Carcinoma	NCT04894370	Squamous Cell A... Metastatic Squa...	Sample collecti...	18 Years -	Centre Hospitalier Universitaire de Besancon

Spots Global Cancer Trial Database for squamous cell anal carcinoma