REPROGRAM-02: A phase II-III study evaluating an induction treatment with regorafenib and metronomic chemotherapy before the second line chemotherapy in metastatic colorectal cancer.

TPS3639 Background: Angiogenesis is associated with tumor progression, and antiangiogenic molecules have become a cornerstone in the treatment of metastatic colorectal cancer (mCRC). Regorafenib is a multi-kinase inhibitor and is an effective option in 20-25% of heavily pre-treated patients (Grothey et al, Lancet 2013; Li et al, Lancet Oncol 2015). Other therapies target the tumoral micro-environment, as metronomic chemotherapy (CT), with continuous low dose administration of a cytotoxic agent. This allows an anti-tumor effect, an anti-angiogenic activity, a stimulation of the immune system, and a better tolerance. Our team conducted an early research program REPROGRAM-01 study (NCT04534218). 49 patients with mCRC previously exposed to conventional chemotherapies are enrolled and received regorafenib in combination with a multimodal CT including capecitabine, cyclophosphamide and aspirin. We showed that this combination is safe. A tumor necrosis was observed in most patients displaying liver metastases and lymph nodes. In second-line treatment, maintenance of VEGF inhibition with chemotherapy beyond disease progression has clinical benefits in patients with mCRC. However, the short PFS (<6 months) and the poor tumor response observed (below 6%) deserved further investigations (ML18147 and VELOUR trials). Following these clinico-biological observations, the REPROGRAM-02 study (NCT05462613) investigates the potential clinical interest of a sequential treatment strategy including an induction phase based on regorafenib and a multimodal CT combining capecitabine, cyclophosphamide and low-dose aspirin before initiation of chemotherapy in second-line treatment of mCRC patients. Methods: This is a French multi-center open-label, randomized (2:1) clinical trial. Patients with mCRC in progression after a 1 st of chemotherapy, receive either (i) regorafenib (REDOS schedule: 80 mg for week 1, 120 mg for week 2 and 160 mg for week 3 of the first cycle) in combination with CT (capecitabine 625mg/m 2 twice daily and cyclophosphamide 50 mg daily) and low-dose aspirin (75 mg once daily) during 8 weeks as an induction therapy before chemotherapy initiation in the second-line, or (ii) the second line standard chemotherapy (FOLFOX or FOLFIRI with anti-VEGF until progression or unacceptable toxicity). The primary objective is to assess the best response rate during treatment period for the phase II and the overall survival for the phase III. Secondary endpoints are progression-free survival, disease control rate, health related quality of life, toxicity, and the evaluation of exploratory biomarkers. Assuming a significance level of 5% and a power of 80%, a sample size of 93 patients is needed for the phase II and 446 patients for the phase III. The enrollment is ongoing, 13 patients have already been recruited. Clinical trial information: NCT05462613 .