Study design, treatment and endpoints
SECONDARY, DISEASE, STAGGERED
This study is an open-label, single-center, phase 1/1b first-in-human dose escalation and expansion clinical trial using concurrent IT and IV nivolumab. The study consisted of two parts: a phase 1 dose escalation portion and a phase 1b dose expansion cohort at the recommended dose. Each cycle was 14 d. Cycle 1 included treatment with IT nivolumab only, subsequent cycles included IT and IV nivolumab treatments. All IT doses were administered via an Ommaya reservoir. Initial IT nivolumab dose levels were flat doses of 5, 10 and 20 mg administered over 5 min. No prophylactic medication was given, but patients were monitored in the hospital for 24 h after each IT nivolumab dose.The initial version of this protocol allowed for patients to be dose escalated up to 20 mg of IT nivolumab. Because this was a first-in-human IT administration of this treatment, safety was routinely evaluated in accordance with our data safety plan. Because no concerning safety signals were noted, the decision to escalate to 50 mg of IT nivolumab (dose level 4, administered over 5 min) in pursuit of a MTD was discussed with the MD Anderson IND office as well as Bristol Myers Squibb and reviewed and approved by the FDA. Importantly, during the initial murine experiments, IT murine anti-PD1 doses equivalent to this human dose were tested and found to be safe.Once the maximum delivered dose was deemed safe, according to the operating rules of the statistical design, the study proceeded with the expansion cohort at the recommended phase 1b dose (Fig. Intrapatient dose escalation was not permitted. IV nivolumab was administered at a flat dose of 240 mg over 30 min every two weeks 24 h after the IT nivolumab dose, regardless of the IT dose level. Patients were enrolled in cohorts of two; to ensure maximum safety for subsequent patients, IT nivolumab start dates were staggered between each subsequent patient with a minimum of 48 h at each dose level.The primary endpoint was to determine the safety and recommended dose of IT nivolumab in combination with IV nivolumab treatment in patients with LMD. OS was a secondary objective, and exploratory objectives included clinical, molecular and immune predictors of safety and efficacy of the regimen, and evaluation of the levels of nivolumab in the CSF and peripheral blood after IT administration.Disease response assessment consisted of cytopathological analysis of CSF every 2 weeks for the initial 8 weeks, and every 8 weeks thereafter. CNS imaging was performed at baseline; at 4 and at 8 weeks; and every 8 weeks thereafter. All CNS imaging was reviewed by two board-certified neuroradiologists.