Combination of Spartalizumab, mDCF and Radiotherapy in Patients With Metastatic Squamous Cell Anal Carcinoma (SPARTANA)
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|ClinicalTrials.gov Identifier: NCT04894370|
Recruitment Status : Not yet recruiting
First Posted : May 20, 2021
Last Update Posted : July 30, 2021
|Condition or disease||Intervention/treatment||Phase|
|Squamous Cell Anal Carcinoma Metastatic Squamous Cell Carcinoma||Biological: Sample collection||Phase 2|
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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||47 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Spartalizumab, mDCF (Docetaxel, Cisplatin and 5-fluorouracil) and Radiotherapy in Patients With Metastatic Squamous Cell Anal Carcinoma. A Phase IIA Study|
|Estimated Study Start Date :||November 1, 2021|
|Estimated Primary Completion Date :||November 1, 2023|
|Estimated Study Completion Date :||November 1, 2025|
Phase 1: Radiotherapy (8 Gy on target lesions)
Phase 2: Combination immunotherapy and mDCF regimen mDCF regimen every 2 weeks for 8 cycles
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:
Phase 4: Maintenance treatment with Spartalizumab 400 mg intravenous every 4 weeks for 12 months from enrolment maximum
Biological: Sample collection
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.
- Progression-Free Survival (PFS) rate at 1 year. [ Time Frame: 12 months from enrollment ]
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.
- Objective response rate (ORR) [ Time Frame: 12 months from enrollment ]Addition of complete response (CR) and partial response (PR) rates.
- Overall survival (OS) [ Time Frame: through study completion, an average of 3 years ]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
- Progression-Free Survival (PFS) median. [ Time Frame: through study completion, an average of 3 years ]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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04894370
|Contact: Stefano KIM, Pr||+33 (0)3 81 47 99 firstname.lastname@example.org|
|Contact: Christophe BORG, Pr||+33 (0)3 81 47 99 email@example.com|
|Centre Hospitalier Universitaire de Besançon|
|Besançon, France, 25000|
|Contact: Stefano KIM, Dr|
|Centre Léon Bérard|
|Lyon, France, 69000|
|Contact: Christelle DE LA FOUCHARDIERE, Pr|
|Hôpital Nord Franche Comté|
|Contact: Christophe BORG, Pr|