SBIR-STTR Award

Directed Chemotherapy Delivery for Leptomeningeal Metastases PI: Lad, Shivanand and McCabe, Aaron Project Summary Leptomeningeal Metastases (LM) is a condition in which cells from a primary solid or hematological tumor metastasize, invade the subarachnoid space, and spread throughout the cerebrospinal fluid (CSF), resulting in seeding of the leptomeninges along the surface of the brain and spinal cord. It represents a late event of cancer progression and the most frequent symptoms include multiple cranial nerve deficits, motor deficits, altered mental status, headache, and radicular pain. There are now 30,000 US cases annually, secondary to over 1 million annual cases of breast and lung cancer, lymphoma and melanoma. There is currently no cure and the outcome is invariably fatal, with median survival of 4-6 weeks if left untreated and 3-6 months with curren therapies. Reduction in tumor burden is the primary goal to extend survival and quality of life. Minnetronix, a medical device development and manufacturing company, proposes this Phase I STTR in collaboration with experts from the Duke Cancer Institute and Neurosurgery Department at Duke University. Phase I will focus on developing Neurapheresis, a cerebrospinal fluid (CSF) processing platform, that will provide rapid and targeted drug delivery with circulation of chemotherapeutic agents. This proposal will demonstrate feasibility using methotrexate (MTX). The objective of the proposed project is to develop a tailored system to deliver lower doses of chemotherapeutics, with less toxicity and maximum bioavailability throughout the subarachnoid space. Specific Aim 1 will focus on conducting in vitro testing using a design matrix tailored for targeted CSF drug delivery and broad distribution and bioavailability. Longevity and mechanical testing will be performed to ensure safety and reliability. Specific Aim 2 will evaluate the in vivo distribution of chemotherapeutic agents and reduction of CSF tumor cells in a validated rabbit LM model. In summary, Neurapheresis is an innovative, new therapeutic option that provides direct access to the CSF and creates active circulation combined with targeted chemotherapy delivery. This treatment is intended to be complementary and does not replace standard of care (SOC) interventions with systemic chemotherapy regimens. Successful completion of this Phase I STTR will provide Minnetronix with the data to justify broader preclinical studies and development of a GLP-quality system for treatment of LM in Phase II. During Phase II, concurrent regulatory, clinical planning, and reimbursement work will be conducted to prepare for an investigational device exemption (IDE) application at the end of Phase II. The long-term goal of the project is to develop a novel therapeutic approach to improve survival for LM patients worldwide.

Public Health Relevance Statement:


Public Health Relevance:
Directed Chemotherapy Delivery for Leptomeningeal Metastases PI: Lad, Shivanand and McCabe, Aaron Project Narrative In this Phase I STTR, Minnetronix plans to develop an innovative, new therapeutic platform for Leptomeningeal Metastases (LM). The most common cancers to metastasize to the leptomeninges are lung, breast, lymphoma and melanoma. Current treatments rely on single bolus injection and passive diffusion of chemotherapeutic agents. However, because of the short half-life and rapid clearance, creating therapeutic levels without creating toxicity is challenging. The median survival is approximately 3 months and new treatment approaches are needed. This project will provide an innovative, directed chemotherapy delivery throughout the neuraxis.

Project Terms:
Animal Model; Animals; Antineoplastic Agents; Biological Availability; Blood - brain barrier anatomy; Blood Circulation; Bolus Infusion; Brain; Breast Lymphoma; Catheters; Cell Count; Cells; Cephalic; Cerebrospinal Fluid; cerebrospinal fluid flow; chemotherapeutic agent; chemotherapy; Chemotherapy-Oncologic Procedure; Clinical; clinical efficacy; clinical practice; Collaborations; Cranial Nerves; Custom; Cytology; cytotoxic; Cytotoxic agent; Data; design; Development; Device or Instrument Development; Devices; Diagnosis; Diffusion; Disease; Doctor of Philosophy; Dose; Drug Delivery Systems; drug distribution; Drug Kinetics; Ensure; Event; Excision; experience; Exposure to; Filtration; Goals; Half-Life; Headache; Hematologic Neoplasms; Hour; Human; Image; improved; In Vitro; in vitro testing; in vivo; Injection of therapeutic agent; innovation; Institutes; Intensive Care Units; Intervention; Interview; Intrathecal Chemotherapy; Invaded; Left; Leptomeninges; Longevity; Lung; Lymphoma; Maintenance; malignant breast neoplasm; Malignant neoplasm of lung; Malignant Neoplasms; Measurement; Mechanics; Medical Device; melanoma; mental state; Metastatic Neoplasm to the Leptomeninges; Methotrexate; minimally invasive; Modeling; Morbidity - disease rate; motor deficit; Neoplasm Metastasis; neoplastic; neoplastic cell; Neuraxis; Neurologic; Neurosurgeon; neurosurgery; neurotoxic; novel; novel therapeutic intervention; novel therapeutics; Oncologist; Oryctolagus cuniculus; Outcome; Pain; Patients; Pharmaceutical Preparations; Phase; Physicians; preclinical study; prevent; Procedures; Process; programs; prototype; public health relevance; Pump; Quality of life; Radiation; radiologist; Research; Safety; Sampling; Schedule; Secondary to; Site; Small Business Technology Transfer Research; Solid Neoplasm; Spinal; Spinal Cord; Staging; standard of care; Subarachnoid Space; Surface; Symptoms; System; targeted treatment; Testing; Therapeutic; Time; Toxic effect; Tumor Burden; tumor progression; Universities; Work

Leptomeningeal Metastases (LM) is a condition in which tumor cells from a primary tumor metastasize, invade the subarachnoid space (SAS) and spread throughout the cerebrospinal fluid (CSF), resulting in seeding along the meninges, brain and spinal cord. LM represents a devastating event of cancer progression. There are 30,000 cases annually and currently no cure, with average survival of 3-6 months with current therapies. Reduction in tumor burden is the primary goal to extend survival and quality of life. Minnetronix, a medical device development and manufacturing company, proposes this Phase II STTR in collaboration with experts from the Duke Cancer Institute and Neurosurgery Department at Duke University. Phase I demonstrated the dramatic results of Neurapheresis, a CSF processing platform, with the ability for targeted circulation of chemotherapeutics (such as Methotrexate, MTX), along with rapid clearance of tumor cells both in vitro and in vivo, in a rabbit LM model. Phase II will optimize and validate a tailored human system to deliver the first-ever platform for LM patients. It will allow for circulation of chemotherapeutic agents (MTX) intrathecally, control of drug concentration and toxicity, rapid removal of tumor cells from the CSF, sampling of CSF to follow circulating tumor cell reduction and drainage of CSF to normalize ICP. Specific Aim 1 will understand and optimize the dosing regimen of intraventricularly delivered MTX during Neurapheresis in a cranial/spinal model and develop a PK model. Specific Aim 2 will demonstrate the safety and efficacy of Neurapheresis filtration and MTX circulation in a pivotal rabbit LM model, refine the PK model, and develop a PK/PD model. Specific Aim 3 will complete the development of the validated Neurapheresis system for intrathecal MTX circulation and targeted removal of cells from the CSF and prepare the system for human trials. Neurapheresis is an innovative, new therapeutic option that provides direct access to the CSF and allows for active circulation of intraventricularly delivered intrathecal agents, combined with targeted reduction in tumor burden. This treatment is complementary and does not replace standard of care (SOC) interventions with systemic regimens. Successful completion of this Phase II STTR will provide Minnetronix with the ability to complete development of a GLP-quality system for the treatment of LM patients. Concurrent regulatory and clinical study planning will be conducted to prepare for an investigational device exemption (IDE) application at the end of Phase II. The long-term goal of the project is to develop a novel tumoricidal approach to reduce morbidity and mortality for LM patients worldwide.