VOTRAGE study pazopanib in a population of “frail” elderly patients after geriatric assessment: A phase I study with geriatric criteria

Background: Efficacy and toxicity of targeted therapies don't seem to vary with age, but the impact of side effects in frail elderly patients (≥ 75 years-old) (EP) is a major concern for clinicians. Our study aims to explore an original method to find the maximum tolerated dose of Pazopanib (P), in a population of EP, classified as "frail" after comprehensive geriatric assessment (CGA), using a phase I methodology, integrating a geriatric criterion for DLT (2 points drop in Activity of Daily Living Score (ADL)). Pharmacokinetic and pharmacogenomic studies were planned. Methods: Open-label, multicenter (2), non-randomized, phase 1 dose escalation clinical trial (standard 3 + 3 design) to determine MTD and DLT of P in a population of frail EP, selected after CGA. Tested dose levels of P were 400, 600 and 800 mg /day. Toxicity was assessed during the first cycle (28days). Patients received P until progression. The MTD was defined as the highest dose level for which 6 patients are treated with a maximum of one patient (∼20%) presenting a DLT. Main inclusion criteria • Age ≥ 75 • Metastatic solid cancers (kidney, lung, pancreatic-neuroendocrine, sarcoma, ovary, thyroid, bladder or breast) • "Frail" by CGA. Results: From 11/2012 to 09/2017, 18 pts were included. Median age was of 82.5 (range 75-91). No DLT was reported at 400mg/day. There was 1 DLT (asthenia Grade 3) at 600 mg/day. At 800 mg/day, 3/6 patients experienced a DLT. Two patients had treatment interruption longer than two weeks due to side effects and one experienced a grade 3 hypertension. Diarrhea, fatigue and hypertension were the most frequently treatment related toxicity. Conclusions: Our study used an original way to assess feasibility of an approved treatment in population of frail EP (≥ 75 years-old). The results demonstrate that it is probably deleterious to initiate a treatment with P in this vulnerable population at the approved dose level of 800mg/day. The treatment should be initiated at a lower dose (600mg/day). Our results reinforce the need to proceed to geriatric assessment in EP before initiation of cancer treatment to individualize their management. Clinical trial identification: EudraCT: 2011-005012-29. Legal entity responsible for the study: Institut Claudius Regaud. Funding: Novartis. Disclosure: L. Mourey: Honoraria, travel expenses and research funding: Novartis. All other authors have declared no conflicts of interest.