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2568 Pembrolizumab for patients with leptomeningeal disease from advanced solid tumors
- Jarushka Naidoo, Chen Hu, Karisa Schrek, Roisin Connolly, Cesar Santa-Maria, Evan Lipson, Ranee Mehra, Bettegowda, Kristin Redmond, Arun Venkatesan, Stuart Grossman
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- Journal:
- Journal of Clinical and Translational Science / Volume 2 / Issue S1 / June 2018
- Published online by Cambridge University Press:
- 21 November 2018, pp. 44-45
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- Article
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OBJECTIVES/SPECIFIC AIMS: Pembrolizumab is an anti-PD-1 immune checkpoint antibody that has demonstrated promising anti-tumor activity in patients with solid tumor malignancies, including patients with brain metastases from malignant melanoma and non-small cell lung cancer. Leptomeningeal disease (LMD) is a rare form of malignant spread to the central nervous system (CNS), that occurs in 2%–10% of patients with solid tumors, most commonly in breast cancer and non-small cell lung cancer. We propose an open-label phase II study of pembrolizumab in patients with LMD from advanced solid tumors (NCT03091478). This study aims to determine if pembrolizumab therapy can lead to a radiologic, cytologic or clinical response in the CNS, in patients with LMD. METHODS/STUDY POPULATION: Patients with pathologically confirmed advanced solid tumors, and either radiologic or cytologic evidence of LMD, will be identified at a single institution. Radiologic LMD will be defined as a >4 mm area of measurable LMD on gadolinium-enhanced MRI brain/total-spine; and cytologic LMD will be defined as the presence of malignant cells on CSF cytology. Patients will be excluded if they have: active autoimmune conditions that require immunosuppression, received radiation therapy to the only area of measurable LMD within 3 months of study enrollment, have an ECOG performance status <1. Once enrolled, patients will receive pembrolizumab 200 mg intravenously every 3-weeks, until disease progression or unacceptable toxicity. Patients will have CSF sample sampling, blood draws, radiologic imaging of the body (CT), brain/total-spine (gadolinium-enhanced MRI) pre-treatment, after 2 and after 4 cycles of therapy, for response assessment and correlative studies. The primary endpoint of the study is CNS response assessed at 12 weeks/after 4 cycles of pembrolizumab, defined either as radiologic response (reduction in size of LMD on gadolinium-enhanced MRI) and/or cytologic response (conversion of positive to negative CSF cytology on 2 consecutive samples) and/or clinical response. Secondary endpoints will include progression-free survival, overall survival, and safety. To explore the mechanisms by which pembrolizumab may affect LMD, we will assess dynamic changes in genomic and immunologic markers in the CSF and serum pre and post pembrolizumab using next-generation sequencing and multi-color flow cytometry, respectively. RESULTS/ANTICIPATED RESULTS: We will aim to accrue a total of 20 patients, allowing for a 10% drop-out rate, the final sample size will include 18 patients who have received at least 1 dose of pembrolizumab. CNS-response at 12 weeks will be assessed radiologically +/− cytologically, and the proportion of patients with CNS response and associated 95% confidence interval with be reported. CNS-progression-free survival and overall survival will be assessed using the Kaplan-Meier method. Cause of death will be recorded. Safety will be assessed as detailed above, and monitored as per an institutional Data Safety and Monitoring Plan. Exploratory endpoints will include genomic testing of tumor cells and cell-free DNA in CSF and serum, and immunologic studies of immune cells in CSF and serum at pre-defined timepoints. These data will be presented descriptively. We conservatively estimate that we will accrue 1 patient per month at our institution. Study duration will be approximately 24 months, allowing 18 months for accrual and 6 months for follow-up and data analysis. DISCUSSION/SIGNIFICANCE OF IMPACT: There are no currently FDA-approved therapies for patients with LMD from solid tumors. Anti-PD-1 immunotherapy is a promising class of agents, with known efficacy in patients with CNS metastatic disease, across tumor types. This study seeks to identify whether pembrolizumab may lead to CNS responses in patients with LMD. Additionally, genomic and immunologic analyses in CSF and blood pre and post-pembrolizumab may identify mechanisms by which immunotherapy affects the CNS in patients with LMD.
7 - Neuropharmacology
- from SECTION I - PRINCIPLES OF NEUROCRITICAL CARE
- Edited by Michel T. Torbey
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- Book:
- Neurocritical Care
- Published online:
- 27 April 2010
- Print publication:
- 14 September 2009, pp 81-108
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Summary
This chapter focuses on selected pharmacologic topics that play an important role in patient care in the neurointensive care unit. The role of a clinical pharmacist in maximizing patient care in the ICU is discussed. Medication classes that are reviewed include antiplatelet and antithrombotic agents, and antiepileptics. The pharmacologic properties of these agents, including mechanism of action, dosing, side effects, drug interactions, and pharmacokinetic parameters, are discussed in this chapter. More detailed information and in-depth discussion regarding use of these medication classes in specific neurologic and neurosurgical situations is provided in other chapters within this text.
THE PHARMACIST'S ROLE IN THE ICU
As health care evolves and becomes more varied and complex, so must the roles of its professionals. The focus of a pharmacist's place in health care is shifting from the more reactionary established activities of preparation and dispensing to more proactive and influential participation in total patient care. Although physicians are educated in the fundamentals of medication therapy, the specialized training and education of clinical pharmacists allows them to serve as medication experts who are better equipped to recognize, understand, and prevent medication errors. While assuming an increasing responsibility for pharmacotherapeutic outcomes, pharmacists are well suited to aid physicians in drug therapy selection, monitoring, and decision making. Including pharmacists as proactive members of the multidisciplinary healthcare team can maximize drug selection in many ways, including:
▪ Prevention and monitoring of drug interactions and/or adverse drug events (ADEs)
▪ Medication dose adjustments for renal and/or hepatic dysfunction, age, or obesity
▪ Selection of appropriate medication route of Administration
▪ Determination of intravenous fluid, medication, and IV line compatibility
▪ Identification and recommendation of cost-effective therapeutic options
3 - Vasoactive Therapy
- from SECTION I - PRINCIPLES OF NEUROCRITICAL CARE
- Edited by Michel T. Torbey
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- Book:
- Neurocritical Care
- Published online:
- 27 April 2010
- Print publication:
- 14 September 2009, pp 20-37
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Summary
The brain is highly vulnerable to the effects of hypotension and untreated hypertension, both of which are important risk factors for continued cerebral ischemia, intracranial hemorrhage (ICH), and to a lesser extent, subarachnoid hemorrhage (SAH).
The brain plays an important role in the modulation and control of blood pressure (BP) through the baroreceptor reflex, the brain stem pressor and depressor center, and the interaction between the bulbospinal pressor and depressor center. Further, activation and/or dysfunction of these structures may occur during acute neurologic insults triggered by direct injury or, more commonly, by neurohumoral stimulation as a protective response to further neurologic damage.
BLOOD PRESSURE THERAPEUTICS
After a neurologic emergency, it is often desirable to maintain mean arterial pressure (MAP) or cerebral perfusion pressure (CPP) within a relatively narrow range because a patient's autoregulation at the site of injury may not be intact. Excessive hypertension can compromise the brain's ability to autoregulate cerebral blood flow (CBF) and may aggravate elevated intracranial pressure (ICP) and cerebral edema. In contrast, hypotension may worsen ischemic damage in marginally perfused tissue and can trigger cerebral vasodilation and ICP plateau waves.
Initial interventions for elevated blood pressure should begin with antihypertensive medication injections, such as labetalol, hydralazine, or enalaprilat. However, once these medications have been maximized, a short-acting continuous IV infusion with a predictable dose-response relationship and favorable safety profie should be initiated.