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.
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.
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.
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
Legal entity responsible for the study
Institut Claudius Regaud.
L. Mourey: Honoraria, travel expenses and research funding: Novartis. All other authors have declared no conflicts of interest.