Atezolizumab plus modified docetaxel-cisplatin-5-fluorouracil (mDCF) regimen versus mDCF in patients with metastatic or unresectable locally advanced recurrent anal squamous cell carcinoma: a randomized, non-comparative phase II SCARCE GERCOR trial

Abstract

Background: Modified docetaxel, cisplatin, and 5-fluorouracil (mDCF) regimen has become a new standard for the treatment of metastatic or unresectable locally advanced recurrent squamous cell carcinoma of the anus (SCCA) after demonstrating improved efficacy (12-month PFS of 47%) in the Epitopes-HPV02 trial. Antibodies targeting the checkpoint inhibitor (CKI) programmed cell death protein-1 (PD1) have demonstrated the efficacy as monotherapies in second-line treatment of SCCA. The aim of this study is to evaluate the combination of atezolizumab and mDCF as first-line chemotherapy in a non-comparative multicentre randomized phase II study of advanced SCCA patients.

Methods: Patients with chemo-naive advanced histologically proven SCCA, metastatic or unresectable locally advanced recurrence, and Eastern Cooperative Oncology Group-performance status (ECOG-PS) < 2 will be eligible. The primary endpoint is a 12-month PFS rate. Using one-arm non-parametric survival with unilateral alpha type I error of 5% and a statistical power of 80%, the upper critical value for the 12-month PFS rate is 47% to reject H0. Assuming 5% lost to follow-up, 99 patients will be randomized on a 2:1 basis, 66 to the experimental arm (arm A, mDCF plus atezolizumab) and 33 to the standard arm (arm B, mDCF). In both arms, 8 cycles of mDCF will be administered. In arm A, patients receive mDCF with a fixed dose of atezolizumab (800 mg every 2 weeks) and are followed up to 1 year. Secondary endpoints are overall survival, PFS, response rate, safety, health-related quality of life, and an extensive biomarker programme and its correlation with the treatment efficacy.

Discussion: Although the Epitopes-HPV02 trial has changed long-lasting prognosis of patients with SCCA in advanced stage disease, more than 50% of patients will progress at 12 months. The purpose of the SCARCE trial to establish the addition of atezolizumab to mDCF as a new standard in this rare disease. Associated biomarker studies and the control arm could contribute to better understanding of the potential synergic and tumour resistance mechanisms in SCCA.

Trial registration: NCT03519295.

Keywords: Advanced; Anal carcinoma; Atezolizumab; Chemotherapy; Docetaxel; Immunotherapy.

Fig. 1

Schedule of enrolment, interventions, and assessments. a Clinical examination: height (at baseline only), weight, and ECOG-PS. b Vital signs: pulse, blood pressure and body temperature. c Blood analysis: complete blood count including red blood cells, haemoglobin, haematocrit, lymphocytes, white blood cells and differentials and platelets, blood electrolytes, bicarbonates, glycemia, proteinemia, albumin, blood urea nitrogen, creatinine, creatinine clearance (MDRD), calcium, magnesium, AST, ALT, gamma-GT, conjugated and total bilirubin, ALP, TSH, LDH, and C-reactive protein. d PET-scan at baseline, at first visit of phase 2 and at the end-point visit (except in case of early progression). CT-scans and PET-scans will be collected for a central review. e The EORTC-QLQC30 questionnaire: every second chemotherapy cycles in phase 1, and every 2 months during phase 2 until the end-point visit. f Blood samples for biomonitoring: 1 EDTA tube of 6 ml (plasma) and 8 EDTA tubes of 6 ml (PBMC). g According to the NCI-CTCAE guidelines version 4.03. h Only in HIV-positive patients. £ Immunotherapy alone: to be continued 1 cycle every to weeks up to a maximum of 12 months from the randomization date. * The end-point visit: to be performed 12 months after randomization or 4 weeks after the last chemotherapy cycle in case of premature end of treatment (for toxicity, progression, or patient or physician decision). $ The follow-up visit: to be performed every 3 months from the end-point visit to a patient death or at least 3 years after randomization