zk-219477 and Brain-Neoplasms

Sagopilone (ZK 219477), a lipophylic and synthetic analog of epothilone B, that crosses the blood-brain barrier has demonstrated preclinical activity in glioma models.. Patients with first recurrence/progression of glioblastoma were eligible for this early phase II and pharmacokinetic study exploring single-agent sagopilone (16 mg/m(2) over 3 h every 21 days). Primary end point was a composite of either tumor response or being alive and progression free at 6 months. Overall survival, toxicity and safety and pharmacokinetics were secondary end points.. Thirty-eight (evaluable 37) patients were included. Treatment was well tolerated, and neuropathy occurred in 46% patients [mild (grade 1) : 32%]. No objective responses were seen. The progression-free survival (PFS) rate at 6 months was 6.7% [95% confidence interval (CI) 1.3-18.7], the median PFS was just over 6 weeks, and the median overall survival was 7.6 months (95% CI 5.3-12.3), with a 1-year survival rate of 31.6% (95% CI 17.7-46.4). Maximum plasma concentrations were reached at the end of the 3-h infusion, with rapid declines within 30 min after termination.. No evidence of relevant clinical antitumor activity against recurrent glioblastoma could be detected. Sagopilone was well tolerated, and moderate-to-severe peripheral neuropathy was observed in despite prolonged administration.

Topics: Adult; Aged; Antineoplastic Agents; Astrocytoma; Benzothiazoles; Brain Neoplasms; Disease Progression; Disease-Free Survival; Epothilones; Female; Glioblastoma; Humans; Infusions, Intravenous; Male; Middle Aged; Neoplasm Recurrence, Local; Young Adult

Treatments for women with recurrent brain metastases from breast cancer are limited. In this phase II study,we administered sagopilone to patients with breast cancer and brain metastases. We observed modest activity with a central nervous system objective response rate of 13.3%; however, median PFS was disappointing. Further studies should focus on other agents to treat this challenging clinical problem.. Patients with progressive metastatic breast cancer to the central nervous system (CNS) have limited treatment options.. We conducted a phase II study of sagopilone, an epothilone B analogue that crosses the blood-brain barrier, in patients with breast cancer brain metastases. Women were treated with 16 mg/m(2) or 22 mg/m(2) intravenously every 21 days. The primary endpoint was CNS objective response rate (ORR). Secondary endpoints included toxicity, progression-free survival (PFS), and overall survival (OS). Using modified, high-resolution magnetic resonance angiography (MRA), we also evaluated changes in vessel tortuosity with treatment.. Fifteen women were enrolled; all had progressive CNS disease despite whole-brain radiotherapy. Two patients achieved a partial response (ORR, 13.3%) and remained in the study for 6 cycles. Responses were not associated with normalization of tumor-associated vessels on correlative imaging studies. Median PFS and OS were 1.4 months and 5.3 months, respectively. The most common grade 3 toxicities were lymphopenia and fatigue. Enrollment was stopped prematurely because of limited observed activity and slow accrual.. Sagopilone was associated with modest CNS activity in patients with breast cancer; however median PFS was disappointing. Further studies should examine other potentially active agents and/or combinations for this challenging clinical problem.

Topics: Adult; Aged; Antineoplastic Agents; Benzothiazoles; Blood-Brain Barrier; Brain Neoplasms; Breast Neoplasms; Disease-Free Survival; Epothilones; Female; Humans; Infusions, Intravenous; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Treatment Outcome

It has been demonstrated that sagopilone (ZK-EPO) has antitumor activity in human orthotopic glioma models in vitro and in vivo. The objective of this study was to evaluate the safety and efficacy of ZK-EPO in patients with pretreated, recurrent malignant gliomas. Fifteen patients with recurrent malignant gliomas who had received prior surgery, radiotherapy, and >or=2 lines of alkylating chemotherapy were recruited. ZK-EPO (16 mg/m(2)) was administered iv for 3 h every 21 days. The primary end point was six months progression-free survival (PFS-6); secondary end points were safety, toxicity, response rate, and median time to progression (TTP). Magnetic resonance imaging (MRI) evaluations were performed every two cycles and toxicity was evaluated at each cycle using common terminology criteria for adverse events (CTCAE 3.0). A median of four cycles was administered. The median TTP was 13 weeks. PFS-6 was achieved in five patients (33%), three with glioblastoma multiforme and two with anaplastic astrocytoma. The most common treatment-related adverse event was neuropathy, which occurred in 6/15 patients. ZK-EPO had an acceptable safety profile and clinically relevant activity in patients with pretreated, recurrent malignant gliomas.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Benzothiazoles; Brain Neoplasms; Drug Administration Schedule; Epothilones; Female; Glioma; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Severity of Illness Index; Survival Analysis; Young Adult

The aim of this study was to determine the efficacy of sagopilone (ZK-EPO), a novel epothilone, compared with other anticancer agents in orthotopic models of human primary and secondary brain tumors. Autoradiography and pharmacokinetic analyses were performed on rats and mice to determine passage across the blood-brain barrier and organ distribution of sagopilone. Mice bearing intracerebral human tumors (U373 or U87 glioblastoma, MDA-MB-435 melanoma, or patient-derived non-small-cell lung cancer [NSCLC]) were treated with sagopilone 5-10 mg/kg, paclitaxel 8-12.5 mg/kg (or temozolomide, 100 mg/kg) or control (vehicle only). Tumor volume was measured to assess antitumor activity. Sagopilone crossed the blood-brain barrier in both rat and mouse models, leading to therapeutically relevant concentrations in the brain with a long half-life. Sagopilone exhibited significant antitumor activity in both the U373 and U87 models of human glioblastoma, while paclitaxel showed a limited effect in the U373 model. Sagopilone significantly inhibited the growth of tumors from CNS metastasis models (MDA-MB-435 melanoma and patient-derived Lu7187 and Lu7466 NSCLC) implanted in the brains of nude mice, in contrast to paclitaxel or temozolomide. Sagopilone has free access to the brain. Sagopilone demonstrated significant antitumor activity in orthotopic models of both glioblastoma and CNS metastases compared with paclitaxel or temozolomide, underlining the value of further research evaluating sagopilone in the treatment of brain tumors. Sagopilone is currently being investigated in a broad phase II clinical trial program, including patients with glioblastoma, NSCLC, breast cancer, and melanoma.

Topics: Animals; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Phytogenic; Benzothiazoles; Blood-Brain Barrier; Brain; Brain Neoplasms; Cell Line, Tumor; Dacarbazine; Epothilones; Female; Half-Life; Humans; Male; Mice; Mice, Nude; Paclitaxel; Rats; Rats, Wistar; Survival Rate; Temozolomide; Xenograft Model Antitumor Assays