Pharmacokinetics of BSI-201, a poly (ADP-ribose) polymerase-1 (PARP1) inhibitor, in cerebrospinal fluid (CSF) of a patient with breast cancer with carcinomatous meningitis.

Abstract

e13559 Background: Triple-negative breast cancer (TNBC) carries a high risk for brain metastasis and is associated with poor survival. A key role has emerged for PARP1 in the repair of DNA damage, particularly in cancers associated with BRCA1 dysfunction, including TNBC. BSI-201, a small molecule inhibitor of PARP1, has demonstrated significant antitumor activity when added to gemcitabine and carboplatin in treatment of metastatic TNBC. BSI- 201 was provided through a single patient IND to a patient with metastatic TNBC who developed carcinomatous meningitis as the only site of initial relapse. Methods: The patient had an Omaya reservoir inserted to facilitate intrathecal (IT) chemotherapy. The patient received IT methotrexate, which was switched to liposomal-cytarabine due to arachnoiditis. The patient received BSI-201 (5.6 mg/kg IV, biweekly) throughout IT treatment. CSF was sampled via the Omaya reservoir, and BSI-201 and its metabolites were measured prior to dosing and up to 2 hours post-infusion. Results: BSI-201 exposure in the CSF was ∼120 ng/mL at end-of-infusion. BSI-201 was rapidly eliminated from the CSF (t1/2 ∼ 10 min), with a longer-lived metabolite (t1/2 ∼ 21min). Overall exposure of the CNS was estimated to be ∼8% of the total systemic AUC for BSI-201, and Cmax in CSF was ∼7.5% of plasma Cmax. The patient responded to treatment for 5 months before developing disease progression in the bone and a second primary breast cancer. The burden of tumor cells in the CSF was reduced by > 95% throughout treatment. No evidence of systemic or neurologic toxicity from BSI-201 beyond what is normally observed with chemotherapy occurred. Conclusions: BSI-201 and its key metabolites cross the blood-brain barrier with BSI-201 AUC and Cmax in CSF of ∼10% of plasma values. This observation provides a basis for further examination of the role of BSI-201 in the treatment of this metastatic complication. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration BiPar Sciences