Pilot Surgical PK Study of Bemcentinib in Recurrent Glioblastoma Patients
Johns Hopkins Kimmel Cancer Center in Baltimore
Evaluate the penetration of bemcentinib across the blood brain barrier measured by pharmacokinetics/drug concentration of 1.0 µM in tissue resected from a contrast enhancing region of the tumor in 60% of recurrent glioblastoma patients.
1. Patients must have histologically confirmed glioblastoma (GBM) that is progressive or recurrent following radiation therapy chemotherapy. Patients with previous low grade glioma who progressed after RT/chemotherapy and are biopsied and found to have GBM/GS (Gliosarcoma) are eligible. 2. Patients must have measurable, supratentorial contrast-enhancing progressive or recurrent glioblastoma or gliosarcoma by MRI within 21 days of starting treatment. Patient must be able to tolerate MRIs. 3. Patients may have had treatment for no more than 2 prior relapses. 4. Patients must have a tumor tissue form indicating availability of archived tissue from initial resection at diagnosis of GBM or GS, completed and signed by a pathologist. Sites must agree to provide this form within 14 days after treatment start. Availability of tissue is not a requirement for study participation. 5. The following intervals from previous treatments are required to be eligible: 12 weeks from the completion of radiation; 6 weeks from a nitrosourea chemotherapy or mitomycin C; 3 weeks from a non-nitrosourea chemotherapy, 4 weeks from any investigational (not FDA-approved) agents; 2 weeks from administration of a non-cytotoxic, FDA-approved agent, e.g., erlotinib, hydroxychloroquine, etc.); 4 weeks from prior antiangiogenesis therapy (approved or investigational) (e.g., bevacizumab, aflibercept, ramucirumab, cediranib, cabozantinib, etc.); 4 weeks from any immunotherapy intervention. 6. Patients must be undergoing surgery that is clinically indicated as determined by their care providers. Patients must be eligible for surgical resection according to the following criteria: Expectation that the surgeon is able to resect 0.05-0.10 cm3 (50-100 mg) of tumor from enhancing tumor and at least 0.05-0.10 cm3 (50-100 mg) from non-enhancing tumor with low risk of inducing neurological injury. 7. Patients must be 18 years of age or older. 8. Patients must have a Karnofsky Performance Status ? 60% (i.e. the patient must be able to care for himself/herself with occasional help from others). 9. Patients must have the following organ and marrow function: Absolute neutrophil count equal to 1,500/µL; Platelets equal to 100,000/µL; Hemoglobin equal to 9 g/dL; Total bilirubin less than 1.5 × ULN; AST (SGOT)/ALT (SGPT) less than 2.5 × institutional upper limit of normal; Creatinine equal to 1.5 X institutional upper limit of normal AND Creatinine clearance equal to 60 ml/min/1.73m2 for patients with creatinine levels above institutional normal; APTT/PTT equal to 1.5 x institutional upper limit of normal. 10. Patients must have a 12-lead electrocardiogram with a measurable QTcF equal to 450 msec. 11. Patients must be able to provide written informed consent. 12. Women of childbearing potential must have a negative serum pregnancy test prior to study entry. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation, and through 4 months after the last dose of study drug. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of bemcentinib administration. 13. Patients must have no concurrent malignancy except curatively treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix, breast, or bladder. Patients with prior malignancies must be disease-free for less than five years. 14. Patients must be able to swallow whole capsules.
Group A: Patients will receive a pre-operative course of bemcentinib starting 4-6 days prior to scheduled surgical resection for recurrent glioblastoma. Patients will receive an initial loading dose of 400 mg PO daily for 3 days, then receive bemcentinib at the maintenance dose of 200 mg PO daily for 2-4 days, including the day of surgery. The number of days of maintenance dosing (200 mg daily) depends on the day of scheduled surgery. Patients should take the last dose of bemcentinib ideally 3-6 hours before surgery to resect the tumor. Tissue samples obtained from resected tumor will be snap-frozen for determination of intratumoral drug concentration. Blood samples will be collected at selected time points to determine plasma levels of bemcentinib. Group B: Patients receive no pre-operative treatment. During surgery, tissue samples from resected tumor will be collected for correlative studies of bemcentinib. Groups A and B, post-surgery: Bemcentinib will be administered as an oral dose on an outpatient basis, starting with a loading dose of 400 mg once daily for the first 3 days of Cycle 1, and then 200 mg once daily in 21-day cycles.
08/08/2020 05:02 AM