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Neuro-oncology Apr 2009The 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... (Comparative Study)
Comparative Study
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
PubMed: 18780814
DOI: 10.1215/15228517-2008-072 -
Frontiers in Oncology 2011Sagopilone, a fully synthetic epothilone, is a microtubule-stabilizing agent optimized for high in vitro and in vivo activity against a broad range of tumor models,...
Sagopilone, a fully synthetic epothilone, is a microtubule-stabilizing agent optimized for high in vitro and in vivo activity against a broad range of tumor models, including those resistant to paclitaxel and other systemic treatments. Sagopilone development is accompanied by translational research studies to evaluate the molecular mode of action, to recognize mechanisms leading to resistance, to identify predictive response biomarkers, and to establish a rationale for combination with different therapies. Here, we profiled sagopilone activity in breast cancer cell lines. To analyze the mechanisms of mitotic arrest and apoptosis and to identify additional targets and biomarkers, an siRNA-based RNAi drug modifier screen interrogating 300 genes was performed in four cancer cell lines. Defects of the spindle assembly checkpoint (SAC) were identified to cause resistance against sagopilone-induced mitotic arrest and apoptosis. Potential biomarkers for resistance could therefore be functional defects like polymorphisms or mutations in the SAC, particularly in the central SAC kinase BUB1B. Moreover, chromosomal heterogeneity and polyploidy are also potential biomarkers of sagopilone resistance since they imply an increased tolerance for aberrant mitosis. RNAi screening further demonstrated that the sagopilone-induced mitotic arrest can be enhanced by concomitant inhibition of mitotic kinesins, thus suggesting a potential combination therapy of sagopilone with a KIF2C (MCAK) kinesin inhibitor. However, the combination of sagopilone and inhibition of the prophase kinesin KIF11 (EG5) is antagonistic, indicating that the kinesin inhibitor has to be highly specific to bring about the required therapeutic benefit.
PubMed: 22649765
DOI: 10.3389/fonc.2011.00044 -
The Oncologist 2011The management of castration-resistant prostate cancer (CRPC) presents a clinical challenge because of limitations in efficacy and durability with currently available... (Review)
Review
The management of castration-resistant prostate cancer (CRPC) presents a clinical challenge because of limitations in efficacy and durability with currently available therapeutics. The epothilones represent a novel class of anticancer therapy that stabilizes microtubules, causing cell death and tumor regression in preclinical models. The structure of the tubulin-binding site for epothilones is distinct from that of the taxanes. Moreover, preclinical studies suggest nonoverlapping mechanisms of resistance between epothilones and taxanes. In early-phase studies in patients with CRPC, treatment with ixabepilone, a semisynthetic analog of epothilone B, induced objective responses and prostate-specific antigen declines in men previously progressing on docetaxel-based regimens. Clinical activity has been observed in nonrandomized trials for patients with CRPC using ixabepilone in the first- and second-line settings as a single agent and in combination with estramustine. Patupilone and sagopilone were also shown to have promising efficacy in phase II clinical trials of patients with CRPC. All three epothilones appear to be well tolerated, with modest rates of neutropenia and peripheral neuropathy. The lack of crossresistance between epothilones and taxanes may allow sequencing of these agents. Evaluating epothilones in phase III comparative trials would provide much-needed insight into their potential place in the management of patients with CRPC.
Topics: Epothilones; Humans; Male; Prostatic Neoplasms
PubMed: 21964003
DOI: 10.1634/theoncologist.2010-0014 -
British Journal of Cancer Jan 2012Sagopilone is the first fully synthetic epothilone in clinical development and has demonstrated promising preclinical activity. This phase I/II, prospective, open-label...
BACKGROUND
Sagopilone is the first fully synthetic epothilone in clinical development and has demonstrated promising preclinical activity. This phase I/II, prospective, open-label trial investigated the efficacy and safety of sagopilone plus carboplatin in patients with recurrent platinum-sensitive ovarian cancer (OC).
METHODS
In phase I (dose-escalation stage), patients with OC recurring at least 6 months after platinum-containing chemotherapy received 3-h infusions of sagopilone (initial dose of 12 mg m(-2)) followed by carboplatin every 3 weeks, for 2-6 treatment courses. Patients enrolled in phase II received 3-h infusions of 16 mg m(-2) sagopilone. Efficacy was assessed using modified Response Evaluation Criteria in Solid Tumors (modRECIST) and Gynecologic Cancer InterGroup CA125 criteria. The safety and tolerability of sagopilone were also evaluated.
RESULTS
In all, 45 patients received sagopilone at 12 mg m(-2) or 16 mg m(-2). There were 29 confirmed tumour responses (21 modRECIST and 8 CA125) across both treatment groups, indicating that the primary objective of the study was reached. The main adverse events (AEs) reported were peripheral neuropathy (75.6%), fatigue (71.1%) and nausea (64.4%). Grade ≥3 AEs occurred in 35 patients (77.8%). No deaths related to the study drug were reported.
CONCLUSION
Sagopilone in combination with carboplatin was effective and toxicities were manageable in patients with recurrent platinum-sensitive OC.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Benzothiazoles; Carboplatin; Epothilones; Female; Humans; Middle Aged; Ovarian Neoplasms; Recurrence
PubMed: 22108514
DOI: 10.1038/bjc.2011.499 -
Biologics : Targets & Therapy Dec 2008Epothilones are a new class of antimicrotubule agents currently in clinical trials. Their chemical structures are distinct from taxanes and are more amenable to...
Epothilones are a new class of antimicrotubule agents currently in clinical trials. Their chemical structures are distinct from taxanes and are more amenable to synthetic modification. Six epothilones have been studied in preclinical and clinical trials: patupilone (epothilone B), ixabepilone (BMS247550), BMS 310705, sagopilone (ZK-EPO), KOS-862 (epothilone D), and KOS-1584. In vitro data have shown increased potency in taxane-sensitive and taxane-resistant cancer cell lines. This enhanced cytotoxic effect has been attributed to epothilone being a poor substrate for p-glycoprotein drug resistance protein and having high affinity to the various beta tubulin isoforms. Phase I clinical data have shown different dose-limiting toxicities for each of the epothilones. These effects are drug specific, dose specific, and schedule of administration specific. While diarrhea and myelosuppression are the dose-limiting toxicities for patupilone and BMS 310705, respectively, neurologic toxicity, as seen with taxanes, is the dose-limiting toxicity of ixabepilone, sagopilone, and KOS-862. In an effort to decrease neurologic toxicity, investigators have modified dosing schedules with limited success. Ixabepilone has the most mature clinical results with published phase II and III data, and regulatory approval for clinical use in the treatment of breast cancer. Ixabepilone has also been combined with other anticancer agents and has regulatory approval in combination with capecitabine for heavily treated breast cancer.
PubMed: 19707459
DOI: 10.2147/btt.s3487 -
Annals of Oncology : Official Journal... Sep 2011Sagopilone (ZK 219477), a lipophylic and synthetic analog of epothilone B, that crosses the blood-brain barrier has demonstrated preclinical activity in glioma models.
Sagopilone (ZK-EPO, ZK 219477) for recurrent glioblastoma. A phase II multicenter trial by the European Organisation for Research and Treatment of Cancer (EORTC) Brain Tumor Group.
BACKGROUND
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 AND METHODS
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.
RESULTS
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.
CONCLUSIONS
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
PubMed: 21321091
DOI: 10.1093/annonc/mdq729 -
PloS One Apr 2011Sagopilone, an optimized fully synthetic epothilone, is a microtubule-stabilizing compound that has shown high in vitro and in vivo activity against a broad range of...
Sagopilone, an optimized fully synthetic epothilone, is a microtubule-stabilizing compound that has shown high in vitro and in vivo activity against a broad range of human tumor models. We analyzed the differential mechanism of action of sagopilone in non-small cell lung cancer cell lines in vitro. Sagopilone inhibited proliferation of non-small cell lung cancer cell lines at lower nanomolar concentration. The treatment with sagopilone caused strong disturbances of cellular cytoskeletal organization. Two concentration-dependent phenotypes were observed. At 2.5 nM sagopilone or 4 nM paclitaxel an aneuploid phenotype occur whereas a mitotic arrest phenotype was induced by 40 nM sagopilone or paclitaxel. Interestingly, treatment with 2.5 nM of sagopilone effectively inhibited cell proliferation, but--compared to high concentrations (40 nM)--only marginally induced apoptosis. Treatment with a high versus a low concentration of sagopilone or paclitaxel regulates a non-overlapping set of genes, indicating that both phenotypes substantially differ from each other. Genes involved in G2/M phase transition and the spindle assembly checkpoint, like Cyclin B1 and BUBR1 were upregulated by treatment with 40 nM sagopilone. Unexpectedly, also genes involved in DNA damage response were upregulated under that treatment. In contrast, treatment of A549 cells with a low concentration of sagopilone revealed an upregulation of direct transcriptional target genes of TP53, like CDKN1A, MDM2, GADD45A, FAS. Knockdown of TP53, which inhibited the transcriptional induction of TP53 target genes, led to a significant increase in apoptosis induction in A549 cells when treated with a low concentration of sagopilone. The results indicate that activation of TP53 and its downstream effectors like CDKN1A by low concentrations of sagopilone is responsible for the relative apoptosis resistance of A549 cells and might represent a mechanism of resistance to sagopilone.
Topics: Antineoplastic Agents; Apoptosis; Benzothiazoles; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p21; Cytoskeleton; DNA Damage; Epothilones; Humans; In Vitro Techniques; Lung Neoplasms; Oligonucleotide Array Sequence Analysis; Paclitaxel; Phenotype; Tumor Suppressor Protein p53; Up-Regulation
PubMed: 21559393
DOI: 10.1371/journal.pone.0019273 -
British Journal of Cancer Oct 2009Epothilones are a novel class of microtubule-stabilising agents, and sagopilone is a fully synthetic epothilone that has shown marked in vivo and in vitro preclinical...
BACKGROUND
Epothilones are a novel class of microtubule-stabilising agents, and sagopilone is a fully synthetic epothilone that has shown marked in vivo and in vitro preclinical activity.
METHODS
This phase I, open-label study investigated the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of weekly sagopilone. Twenty-three patients with malignancy resistant or refractory to standard treatment were enrolled into this study evaluating sagopilone doses from 0.6 to 7.0 mg m(-2).
RESULTS
The incidence of drug-related haematological adverse events (AEs) was low, with two grade 3 events observed. Nonhaematological AEs were generally mild and reversible; increased gamma-GT was the only grade 4 event and grade 3 events comprised peripheral neuropathy (n=2), diarrhoea (n=1) and fatigue (n=1). Two grade 3 events were DLTs (diarrhoea and peripheral neuropathy at 7.0 mg m(-2)). The MTD of weekly sagopilone was therefore established as 5.3 mg m(-2). Stable disease was the best overall response (n=3). Microtubule bundle formation in peripheral blood mononuclear cells increased post-treatment, peaking after 1 h. Sagopilone disposition was similar across treatment courses and showed rapidly decreasing serum concentrations after infusion end and a long terminal disposition phase with no obvious accumulation in the serum, probably reflecting a fast uptake into tissues followed by a slow release.
CONCLUSION
Weekly administration of sagopilone could represent an alternative to the 3-weekly administration currently evaluated in phase II trials.
Topics: Adult; Aged; Antineoplastic Agents; Benzothiazoles; Drug Administration Schedule; Epothilones; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms
PubMed: 19773753
DOI: 10.1038/sj.bjc.6605327 -
British Journal of Cancer Aug 2012Preclinical studies in prostate cancer (PC) models demonstrated the anti-tumour activity of the first fully synthetic epothilone, sagopilone. This is the first study to...
Phase II study of first-line sagopilone plus prednisone in patients with castration-resistant prostate cancer: a phase II study of the Department of Defense Prostate Cancer Clinical Trials Consortium.
BACKGROUND
Preclinical studies in prostate cancer (PC) models demonstrated the anti-tumour activity of the first fully synthetic epothilone, sagopilone. This is the first study to investigate the activity and safety of sagopilone in patients with metastatic castration-resistant PC (CRPC).
METHODS
Chemotherapy-naïve patients with metastatic CRPC received sagopilone (one cycle: 16 mg m(-2) intravenously over 3 h q3w) plus prednisone (5 mg twice daily). The primary efficacy evaluation was prostate-specific antigen (PSA) response rate (≥50% PSA reduction confirmed ≥28 days apart). According to the Simon two-stage design, ≥3 PSA responders were necessary within the first 13 evaluable patients for recruitment to continue until 46 evaluable patients were available.
RESULTS
In all, 53 patients received ≥2 study medication cycles, with high compliance. Mean individual dose was 15.1±1.4 mg m(-2) during initial six cycles, mean dose intensity 94±9%. The confirmed PSA response rate was 37%. Median overall progression-free survival was 6.4 months. The most commonly reported adverse events (>10% of patients) were peripheral neuropathy (94.3%), fatigue (54.7%) and pain in the extremities (47.2%). Sagopilone was associated with very little haematological toxicity.
CONCLUSION
This study shows that first-line sagopilone has noteworthy anti-tumour activity and a clinically significant level of neuropathy for patients with metastatic chemotherapy-naïve CRPC.
Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzothiazoles; Epothilones; Humans; Male; Middle Aged; Orchiectomy; Prednisone; Prognosis; Prospective Studies; Prostatic Neoplasms
PubMed: 22850553
DOI: 10.1038/bjc.2012.339 -
Clinical Breast Cancer Dec 2011Treatments 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...
UNLABELLED
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.
BACKGROUND
Patients with progressive metastatic breast cancer to the central nervous system (CNS) have limited treatment options.
PATIENTS AND METHODS
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.
RESULTS
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.
CONCLUSIONS
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
PubMed: 21697017
DOI: 10.1016/j.clbc.2011.03.024