53: Phase 2 trial for sequential treatment after cabozantinib progression in metastatic renal cell carcinoma (Seq-Cabo)

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Background: Cabozantinib has become an established treatment for mRCC in both front-line and refractory settings with favorable response rates. However, the majority of patients develop treatment resistance to cabozantinib.

Methods: We designed a two-cohort phase 2 trial to salvage cabozantinib response, either by escalating the dose of cabozantinib to 80mg PO daily (cohort 1) or by combining cabozantinib 40mg PO daily with nivolumab 480mg IV every 4 weeks (cohort 2) based on investigator choice (Figure 1). Main inclusion criteria include: progressive mRCC after prior cabozantinib monotherapy, radiographically measurable disease, ECOG < 2, adequate end-organ function, minimum of 4 weeks from any other anti-cancer therapies, and age >18 years. Main exclusion criteria include: prior treatment with concurrent cabozantinib/nivolumab, uncontrolled cardiovascular disorders or diabetes mellitus, uncontrolled HIV, concurrent malignancy (excepting completely excised skin cancers and organ-confined Gleason 6 prostate cancer), and pregnancy. Primary endpoint is progression free survival. With the null hypothesis that the median PFS (mPFS) is 3 months tested against an alternative hypothesis that the mPFS is 6 months, and assuming a 2-sided significance level of 10%, 80% power, and 10% drop out, along with 2-year accrual and 1 year follow up, 18 patients per cohort (36 patients total) will be enrolled. Pharmacokinetics, circulating biomarkers, and pre-/post-biopsies are planned for tissue-based analyses. The study is slated to open in early 2023.