MW151 and Whole-brain Radiotherapy in Patients With Intracranial Metastases

Safety and Tolerability of MW151 Administered With Whole-brain Radiotherapy in Patients With Intracranial Metastases

HYPOTHESIS: MW151 intervention during whole-brain radiotherapy for intracranial metastases is safe and will mitigate neurocognitive decline.

RATIONALE: There is non-clinical evidence that MW151 reduces brain inflammation and improves neurocognitive outcomes in animal models of radiation therapy induced cognitive dysfunction, and in animal models of other CNS disorders.

PURPOSE: This feasibility trial will study whether MW151 mitigates neurocognitive decline following whole-brain radiotherapy in adult patients with intracranial metastases from solid tumors.

In Part A, 10 subjects will receive MW151 in an open label evaluation. At least 5 of these subjects will be male. For each subject, safety and tolerability data for the first 24 hours will be reviewed prior to the continuation of dosing. Subjects will also be evaluated for safety during week 1, during week 2, and at week 4. Once the data from Part A have been reviewed by the Safety Monitoring Committee (SMC) for males and females, an additional 30 subjects will be recruited to Part B. These subjects will also receive open label MW-151.

In both parts A and B subjects will take study drug (males), or the first daily dose of study drug (females) before WBRT which will be administered once a day (3Gy), five days a week (Monday to Friday) for two weeks, for total of ten treatments and 30 Gy.

Inclusion Criteria:

A subject will be eligible for inclusion in the study only if all of the following criteria are met:

1. All patients must be willing to and have the capacity to give written informed consent and have signed and dated the informed consent form (ICF) in accordance with ICH and GCP guidelines, as an assurance that all participants understand the risks and benefits of the study

2. All patients must be able to speak and understand English proficiently

3. Histologically or cytologically confirmed diagnosis of a solid tumor malignancy within the past 5 years

   a. If the original histologic proof of malignancy is > 5 years, then pathological (i.e., more recent) confirmation is required (e.g., from a systemic metastasis or brain metastasis)

4. Intracranial metastases (either parenchymal brain metastases orleptomeningeal disease (LMD, also known as neoplastic meningitis, leptomeningeal carcinomatosis, or carcinomatous meningitis)) must be visible on contrast-enhanced MRI

Exclusion Criteria:

A subject will not be eligible for inclusion in the study if any of the following criteria are met:

1. Subject is lactating or is pregnant

2. Severe, active co-morbidity, defined as follows:

   1. Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months
   2. Transmural myocardial infarction within the last 6 months
   3. Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration
   4. Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration
   5. Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects

3. Intractable seizures while on adequate anticonvulsant therapy (i.e., more than one seizure per month for the past 2 months)

4. Clinically significant abnormalities in screening laboratory tests that would affect patient safety as determined by the principal investigator

5. History of psychiatric disorder requiring ongoing medical management

6. History of substance abuse including alcohol within past 5 years Appropriately prescribed medication for the treatment of pain or other symptoms related to the underlying malignancy is acceptable

7. Chronic kidney disease defined as the presence of significant proteinuria on urinalysis and/or eGFR of <60mL/min, as calculated by the clinical site laboratory

8. Inability to follow the instructions or an unwillingness to cooperate with study procedures

9. Known allergy to any component of MW151 as described in investigator's brochure

10. Received treatment with and/or planned treatment with systemic chemotherapy within 3 days prior, during, or for at least 3 days after completion of whole-brain radiotherapy. Concurrent immunotherapy is permitted

11. Prior whole-brain radiotherapy

12. Use of chronic short-acting benzodiazepine

13. Use of chronic NSAID or steroid therapies for chronic inflammatory diseases within 3 days prior to dosing and during the course of the study drug dosing. Use of aspirin for cardiac prophylaxis is acceptable. Use of any other NSAID's or steroids should be reviewed by sponsor, approved and approval documented.

14. Any reason or opinion of the investigator that would prevent the subject from participation in the study

15. Currently receiving treatment with and/or planned treatment with Memantine HCl or combination drugs containing Memantine HCl.