Intraperitoneal irinotecan with concomitant FOLFOX and bevacizumab for patients with unresectable colorectal peritoneal metastases: protocol of the multicentre, open-label, phase II, INTERACT-II trial.

INTRODUCTION: The peritoneum is the second most affected organ for the dissemination of colorectal cancer (CRC). Patients with colorectal peritoneal metastases (CPM) face a poor prognosis, despite the majority of patients being treated with palliative systemic therapy. The efficacy of palliative systemic therapy is limited due to the plasma-peritoneum barrier. The poor prognosis of unresectable CPM patients has resulted in the development of new treatment strategies where systemic therapy is combined with local, intraperitoneal chemotherapy. In the recently published phase I study, the maximum tolerated dose and thus the recommended phase II dose of intraperitoneal irinotecan was investigated and determined to be 75 mg. In the present study, the overall survival after treatment with 75 mg irinotecan with concomitant mFOLFOX4 and bevacizumab will be investigated. MATERIALS AND METHODS: In this single-arm phase II study in two Dutch tertiary referral centres, 85 patients are enrolled. Eligibility criteria are an adequate performance status and organ function, histologically confirmed microsatellite stable and unresectable CPM, no previous palliative therapy for CRC, no systemic therapy<6 months for CRC prior to enrolment and no previous cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS and HIPEC). Patients will undergo a diagnostic laparoscopy as standard work-up for CPM and if the peritoneal disease is considered unresectable (eg, Peritoneal Cancer Index (PCI)>20, too extensive small bowel involvement), a peritoneal access port and a port-a-cath are placed for administration of intraperitoneal and intravenous chemotherapy, respectively. Patients may undergo up to 12 cycles of study treatment. Each cycle consists of intravenous mFOLFOX4 with bevacizumab and concomitant intraperitoneal irinotecan (75 mg), which is repeated every 2 weeks, with a maximum of 12 cycles. Modified FOLFOX-4 regimen consists of 85 mg/m2 oxaliplatin plus 200 mg/m2 LV and 5-FU 400 mg/m2 bolus on day 1 followed by 1600 mg/m2 5-FU as a 46 hours infusion. Study treatment ends after the 12th cycle, or earlier in case of disease progression or unacceptable toxicity. The primary outcome is overall survival and key secondary outcomes are progression-free survival, safety (measured by the amount of grade ≥3 adverse events (Common Terminology Criteria for Adverse Events V.5.0)), patient-reported outcomes and pharmacokinetics of irinotecan. It is hypothesised that the trial treatment will lead to a 4 month increase in overall survival; from a median of 12.2 to 16.2 months. ETHICS AND DISSEMINATION: This study is approved by the Dutch Authority (CCMO, the Hague, the Netherlands), by a central medical ethics committee (MEC-U, Nieuwegein, the Netherlands) and by the institutional research boards of both research centres. Results will be submitted for publication in peer-reviewed medical journals and presented to patients and healthcare professionals. TRIAL REGISTRATION NUMBER: NCT06003998.

A comprehensive analysis of factors related to carmustine/bevacizumab response in recurrent glioblastoma.

PURPOSE: Patients with recurrent glioblastoma (rGBM) have a poor prognosis, with survival ranging from 25 to 40 weeks. Antiangiogenic agents are widely used, showing a variable response. In this study, we explored the efficacy of carmustine plus bevacizumab (BCNU/Bev) for treating rGBM. METHODS/PATIENTS: In this study, we assessed 59 adult patients with histologically confirmed rGBM who were treated with BCNU/Bev as second-line regimen. The response rate (RR), progression-free survival (PFS) and overall survival (OS) were evaluated according to their molecular expression profile, including CD133 mRNA expression, MGMT methylation (pMGMT), PDGFR amplification, YKL40 mRNA expression, IDH1/2 condition, p53 and EGFRvIII mutation status. RESULTS: Median follow-up was 18.6 months, overall RR to the combination was 56.3%, and median PFS was 9.0 months (95% CI 8.0-9.9). OS from time of diagnosis was 21.0 months (95% CI 13.2-28.7) and from starting BCNU/Bev it was 10.7 months (95% CI 9.5-11.8). IDH1/2 mutations were found in 30.5% of the patients, pMGMT in 55.9% and high CD133 mRNA expression in 57.6%. Factors which positively affected PFS included performance status (p = 0.015), IDH+ (p = 0.05), CD133 mRNA expression (p = 0.009) and pMGMT+ (p = 0.007). OS was positively affected by pMGMT+ (p = 0.05). Meanwhile, YKL40 negatively affected PFS (p = 0.01) and OS (p = 0.0001). Grade ≥ 3 toxicities included hypertension (22%) and fatigue (12%). CONCLUSIONS: BCNU/Bev is a safe and tolerable treatment for rGBM. Patients with MGMT+/IDH+ derive the greatest benefit from the treatment combination in the second-line setting. Nonetheless, high YKL40 expression discourages the use of antiangiogenic therapy.