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Concurrent intrathecal and intravenous nivolumab in leptomeningeal disease: phase 1 trial interim results.

ABSTRACT: There is a critical need for effective treatments for leptomeningeal disease (LMD). Here, we report the interim analysis results of an ongoing single-arm, first-in-human phase 1/1b study of concurrent intrathecal (IT) and intravenous (IV) nivolumab in patients with melanoma and LMD. The primary endpoints are determination of safety and the recommended IT nivolumab dose. The secondary endpoint is overall survival (OS). Patients are treated with IT nivolumab alone in cycle 1 and IV nivolumab is included in subsequent cycles. We treated 25 patients with metastatic melanoma using 5, 10, 20 and 50 mg of IT nivolumab. There were no dose-limiting toxicities at any dose level. The recommended IT dose of nivolumab is 50 mg (with IV nivolumab 240 mg) every 2 weeks. Median OS was 4.9 months, with 44% and 26% OS rates at 26 and 52 weeks, respectively. These initial results suggest that concurrent IT and IV nivolumab is safe and feasible with potential efficacy in patients with melanoma LMD, including in patients who had previously received anti-PD1 therapy. Accrual to the study continues, including in patients with lung cancer. ClinicalTrials.gov registration: NCT03025256 .

SUBMITTER: Glitza Oliva IC

PROVIDER: S-EPMC10115650 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Concurrent intrathecal and intravenous nivolumab in leptomeningeal disease: phase 1 trial interim results.

Glitza Oliva Isabella C IC Ferguson Sherise D SD Bassett Roland R Foster Alexandra P AP John Ida I Hennegan Tarin D TD Rohlfs Michelle M Richard Jessie J Iqbal Masood M Dett Tina T Lacey Carol C Jackson Natalie N Rodgers Theresa T Phillips Suzanne S Duncan Sheila S Haydu Lauren L Lin Ruitao R Amaria Rodabe N RN Wong Michael K MK Diab Adi A Yee Cassian C Patel Sapna P SP McQuade Jennifer L JL Fischer Grant M GM McCutcheon Ian E IE O'Brien Barbara J BJ Tummala Sudhakar S Debnam Matthew M Guha-Thakurta Nandita N Wargo Jennifer A JA Carapeto Fernando C L FCL Hudgens Courtney W CW Huse Jason T JT Tetzlaff Michael T MT Burton Elizabeth M EM Tawbi Hussein A HA Davies Michael A MA

Nature medicine 20230330 4

There is a critical need for effective treatments for leptomeningeal disease (LMD). Here, we report the interim analysis results of an ongoing single-arm, first-in-human phase 1/1b study of concurrent intrathecal (IT) and intravenous (IV) nivolumab in patients with melanoma and LMD. The primary endpoints are determination of safety and the recommended IT nivolumab dose. The secondary endpoint is overall survival (OS). Patients are treated with IT nivolumab alone in cycle 1 and IV nivolumab is in ...[more]

PMID: 36997799

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Project description:Study objectiveThis study's purpose was to determine if ondansetron can prevent pruritus after administration of intrathecal morphine in children, as has been demonstrated in adults.DesignA double-blinded, randomized placebo-controlled trial.SettingOperating room and first 24 h postoperative inpatient stay at an academic children's hospital.PatientsForty-six children aged 3-17 years, who received 4-5 mcg/kg intrathecal morphine for urological or orthopedic procedures were included.InterventionsChildren were randomized to receive intravenous ondansetron (treatment) or saline placebo (placebo), prior to intrathecal morphine administration, and q6H for 24 h thereafter. Intraoperative anti-emetics and postoperative rescue treatments for pruritus and nausea were standardized.MeasurementsPatients were interviewed q6H for scored pruritus, nausea, and pain, using standardized scales.Main resultsThe trial was terminated for futility after interim analysis. Forty-six children were recruited and 45 completed data collection. No significant difference was found between both groups for incidence of pruritus (requiring treatment) [relative risk (RR) 0.9, 95% CI: 0.7, 1.2], during the first postoperative 24 h. Notably, the incidence of pruritus was 84% overall, much higher than rates in previously published studies. Intravenous ondansetron significantly reduced the incidence of nausea, compared with the placebo group [RR 0.5, 95% CI: 0.3, 0.9].ConclusionsThis study found no evidence for intravenous ondansetron as an effective preventative for pruritus following intrathecal morphine in children. However, this RCT did find that the rate of pruritus following intrathecal morphine administration may be significantly higher than previously thought. Nausea and vomiting (a secondary outcome) were reduced significantly in the treatment group. The negative findings of this study reinforce the potential dangers of extrapolating the drug effects seen in adults onto pediatric patients.

Dataset Information

Concurrent intrathecal and intravenous nivolumab in leptomeningeal disease: phase 1 trial interim results.

Publications

Concurrent intrathecal and intravenous nivolumab in leptomeningeal disease: phase 1 trial interim results.

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