Single-center phase I/Ib study of concurrent intrathecal (IT) and intravenous (IV) nivolumab (N) for metastatic melanoma (MM) patients (pts) with leptomeningeal disease (LMD).
Authors: Glitza Isabella Claudia , Phillips Suzanne , Brown Courtney , Haymaker Cara L. , Bassett Roland L. , Lee J. Jack , Rohlfs Michelle L. , Richard Jessie , Iqbal Masood , John Ida , McCutcheon Ian E. , Ferguson Sherise D. , Heimberger Amy B. , O'Brien Barbara Jane , Tummala Sudhakar , Guha- Thakurta Nandita , Debnam Matthew , Burton Elizabeth M. , Tawbi Hussein Abdul-Hassan , Davies Michael A. 
Published: May 2020

10008 Background: MM pts with LMD have a dismal prognosis, with a median overall survival (OS) < 3 months and no approved therapies. IT administration of interleukin-2 (IL2) achieves survival in ~15% of MM LMD pts, but at cost of severe toxicities. Given the favorable clinical activity and safety of systemic anti-PD1, we hypothesized that IT N administration is safe and can achieve clinical benefit in pts with LMD. Methods: The primary objectives of this first-in-human study (NCT03025256) were to determine the safety and the maximum tolerated dose (MTD) of IT N given with IV N in MM pts with LMD. Eligible pts had MM, ECOG PS < / = 2, and evidence of LMD by MRI and/or CSF cytology. Dexamethasone < / = 4mg/daily was allowed. For cycle 1, IT N is administered via intraventricular reservoir on day (D) 1; Blood and CSF is collected at multiple time points for translational research. For subsequent cycles (every 14 days), pts receive IT N on D1, followed by IV N 240 mg on D2. IT N doses evaluated were 5, 10, and 20 mg. Bayesian mTPI methodology was used to define the MTD. The study was recently amended to allow for concurrent BRAF/MEK inhibitor(i) treatment. Results: To date, 15 pts have been treated: two at 5, three at 10, and 10 at 20 mg IT N. Median age at LMD diagnosis was 41.8 (30.9-73.2) years; 6 pts are male. All pts had radiographic evidence of LMD and neurological symptoms; 8 pts had positive CSF cytology. 12 pts received prior therapies for their MM: anti-PD1 (n = 11), BRAFi/MEKi (n = 9), chemo (n = 2), IT IL2 (n = 4) other (n = 2). 11 pts had prior XRT, including whole brain RT (n = 7). 1 pt was treatment-naïve. The median numbers of IT N doses was 4 (1-42). No grade (Gr) 4-5 AEs were attributed to IT N or IV N; only 4 events (Gr 1, n = 2; Gr2, n = 2) were possibly related to the IT N. With a median follow-up of 18.7 weeks (1-83.3 wks), the median OS is 46.1 weeks (0.1-83.3). Clinical response data, translational research endpoints, including changes in CSF cytokines and cfDNA, will be reported. Conclusions: The trial demonstrates the feasibility of prospective clinical trials in MM patients with LMD. The combination of IT/ IV N was safe and well-tolerated, with no unexpected systemic or neurological toxicity. Final presentation will include results of LMD composite response assessment, comparative analysis of longitudinal CSF/blood samples to assess immunologic effects. Finally, the interim OS of the patients is encouraging, and supports further evaluation of IT administration of immunotherapy agents for pts with MM and LMD. Clinical trial information: NCT03025256.