Epothilone Analogues Research Articles

Ixabepilone given weekly in patients with advanced malignancies: Final efficacy and safety results of a phase I trial

2040 Background: Ixabepilone is a potent tubulin-targeting agent. The first epothilone analog, ixabepilone, has been developed to optimize the characteristics of the naturally occurring epothilone B. Methods: This open-label, single-arm Phase I dose escalation study was designed to establish the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety and a recommended dose of ixabepilone when administered as a weekly infusion to patients (pts) with solid tumors who had failed standard therapy. Eligible pts were aged ≥18 years and had histologically/cytologically confirmed solid tumor disease and an ECOG status of 0–2. Ixabepilone was administered weekly as a 30-minute infusion on a 21-day schedule. Due to neurotoxicity, infusion time was increased to 1 hour with a 1-week break allowed. Dosing ranged from 1–30 mg/m2. Tumor evaluations were performed every 6 or 8 weeks (21-day or 28-day schedule, respectively). Toxicity was evaluated continuously. Results: 34 pts were treated on the 21-day schedule (median age 55, range 30–73) and 52 on the 28-day schedule (median age 55, range 33–79). 88% of pts had received prior chemotherapy. Grade 3 fatigue was the DLT in 2 of the 4 pts treated with 30 mg/m2 ixabepilone. No DLTs were seen at doses ≤25 mg/m2 on the 21-day schedule, or at doses of 15, 20 or 25 mg/m2 on the 28-day schedule. The MTD was 25 mg/m2 for the 21-day schedule. Of 12 pts who received this dose and schedule, 7 (58%) experienced Grade 1/2 neuropathy, 1 (8%) developed Grade 3 sensory neuropathy and 3 (25%) experienced Grade 3 fatigue. Of 52 pts who received 20 mg/m2 on the 28-day schedule, 2 (13%) had Grade 3 neutropenia, 1 (7%) had Grade 3/4 sensory neuropathy and 4 (27%) had Grade 3 fatigue. Five pts (two pts [21-day schedule], three pts [28-day schedule]) with breast, colon, ovary, head and neck tumors achieved objective partial responses. Conclusions: The recommended doses of ixabepilone from this study are 25 mg/m2 (30-minute weekly infusion, 21-day schedule) and 20 mg/m2 (1-hour weekly infusion, 28-day schedule). Ixabepilone demonstrated efficacy and an acceptable safety profile in pts with a broad range of tumor types, several of whom had failed a taxane. [Table: see text]

Phase II study of ixabepilone in patients (pts) with taxane-resistant metastatic breast cancer (MBC): Final report

10505 Background: Ixabepilone is the first epothilone analog in a new class of antineoplastic agents, which optimizes the properties of the naturally occurring epothilone B. The epothilones promote tumor cell death by uniquely binding to tubulin and stabilizing microtubules. Methods: This international, multicenter, open-label Phase II trial was designed to assess the activity of ixabepilone in pts with highly resistant MBC who had progressed following taxane treatment. Eligible pts were aged ≥18 years with MBC (progressed on or within 4 months of taxane therapy [or within 6 months if adjuvant taxane only]). Pts must have received a taxane as their last regimen. Pts were excluded if they had received ≥3 prior chemotherapy regimens for MBC or had ≥Grade 2 neuropathy. Ixabepilone was administered intravenously as a 3-hour infusion at a dose of 40 mg/m2 every 3 weeks. Results: Of 49 pts (median age 54 years, range 30–81), 86% of pts had received at least two prior chemotherapy regimens. 98% had received prior anthracycline treatment. 73% of pts had progressed within 1 month of their last taxane dose. 84% had visceral metastases. Pts received a median of three cycles (range 1–5) and median cumulative dose of 120 mg/m2 (range 40–498 mg/m2). The tumor response rate (number of responders [complete and partial response]/number of response-evaluable pts) was 12% (95% CI = 4.7–26.5%). All the responders (n = 6) had partial responses; five of the six had not responded to prior taxane therapy. The responders received a median of 10.5 cycles (range 5–15) and had a median duration of response of 10.4 months (95% CI = 6.3–22.0 months). In 20 pts (41%) stable disease was reported as the best overall outcome. The majority of these pts (16 of 20, 80%) received ≥4 cycles of ixabepilone therapy. The median time to progression was 2.2 months (95% CI = 1.4–3.2 months); the median survival was 7.9 months (95% CI = 6.1–14.5 months). Conclusions: Ixabepilone (40 mg/m2 as a 3-hour infusion every 3 weeks) demonstrates promising antitumor activity, along with an acceptable safety profile in pts with clearly defined taxane-resistant MBC. [Table: see text]

Phase I/II trial in patients with metastatic breast cancer (MBC) previously treated with a taxane and an anthracycline: Final safety data

10528 Background: Ixabepilone, a semi-synthetic analog of the natural product epothilone B, has shown anti-tumor activity in a broad range of tumor types including breast cancer. Preclinical studies suggest synergy between ixabepilone and capecitabine in breast cancer models and has fuelled interest in the clinical setting. Methods: This open-label Phase I/II study was conducted to determine the recommended Phase II (and III) doses of ixabepilone and capecitabine using a 3-hour infusion of ixabepilone given on Day 1 (Schedule A) or a 1-hour infusion of ixabepilone given for 3 days (Schedule B) in combination with capecitabine given orally on Days 1–14 every 21 days in patients (pts) with MBC previously treated with a taxane and an anthracycline. Eligible pts were aged ≥18 years with pathologic diagnosis of breast cancer and evidence of MBC, who had received prior treatment with a taxane and an anthracycline in the adjuvant or metastatic setting. Pts were excluded if they had received >3 prior chemotherapy regimens in the metastatic setting or had ≥Grade 2 neuropathy. Toxicity was continuously monitored using NCI CTC v2. Results from the 62 pts treated with 40 mg/m2 as a 3 hr-infusion ixabepilone and 2000 mg/m2 capecitabine are shown here. Results: 56 of the 62 pts (90%) were aged <65 years. 80% of pts had visceral disease; 44% were ER/PR/HER-2 negative. 44% of pts had received ≥ two prior chemotherapies in the metastatic setting. Grade 3 neuropathy (sensory and motor) was reported in 12 pts and 1 pt (19%, 2%), respectively. Hand-foot syndrome, reported in 39 pts (63%), was primarily Grade 2 (26%) or 3 (34%). Hematologic toxicities included Grade 4 leukopenia (7 pts, 12%) and Grade 4 neutropenia (16 pts, 26%). Dose reductions were used to manage sensory neuropathy and hematologic abnormalities. Conclusions: The recommended Phase II (and III) doses are 40 mg/m2 ixabepilone (3-hour infusion on Day 1 every 21 days) and 2000 mg/m2 capecitabine (divided BID on Days 1–14 every 21 days). This ixabepilone/capecitabine combination demonstrated a manageable safety profile and promising clinical anti-tumor activity in pts with MBC previously treated with a taxane and an anthracycline. [Table: see text]

A phase II trial of the epothilone B analog BMS-247550 in patients (pts) with hepatobiliary cancer (HBC): An updated analysis

14050 Background: BMS-247550 is a semi-synthetic analog of epothilone B that induces mitotic arrest at G2M by microtubule stabilization. We previously reported (Proc ASCO 2003) a RR of 17% in HBC and present our final analysis. Methods: Pts with histologically confirmed hepatocellular cancer (HCC), gallbladder cancer (GB) and cholangiocarcinoma (C) were eligible. Pts had no prior chemotherapy, PS 0–2 and ≤ grade 1 neuropathy. Pts received BMS-247550 40mg/m2 intravenously over 3 hours every 21 days. A Simon, optimal two-stage design was employed. We proceeded to the 2nd stage of accrual after 3 confirmed PRs in the first 21 pts. Primary endpoint: Response rate (RR). Results: From 1/02–4/05, 54 pts (52% male) were enrolled, 53 pts evaluable for toxicity, 48 pts evaluable for response. 1 pt was ineligible due to incorrect diagnosis but evaluated for toxicity. Pt characteristics: median age 65 (range 19–88); ECOG performance status 0(48%), 1(48%), 2(4%); HCC (38%), GB (40%), C (22%); metastatic disease (75%); 129 cycles were administered (median 2; range 1–14). There were 3 Gr 5 toxicities: 1 pt died unexpectedly 48 hours within drug administration; 1 complication of neutropenic fever; 1 found unresponsive after fall. Gr 3–4 toxicities (% pts): neutropenia (39%), neutropenic fever (6%), anemia (6%), thrombocytopenia (2%), nausea (13%), transaminase elevation (9%), fatigue (7%), and hypersensitivity (4%). Neuropathy: Gr 3–4 (5%); Gr 1–2 (39%). 3 pts were removed from study due to persistent neuropathy. Responses: 8% PR (2 HCC, 1 GB, 1C); 56% SD. 4/7 HCC pts received ≥ 10 cycles. Median survival: 7 months [95% CI (5.0, 10.8)]; PFS: 2.6 months [95% CI [1.4, 4.1)]; Conclusions: Despite initial tumor responses and a few pts with prolonged SD in HCC, BMS-247550 does not appear to have clinically significant activity in HBC. Supported by NCI grant N01-CM-17102. [Table: see text]

A phase II study of ixabepilone (BMS 247550) in metastatic renal cell carcinoma

14646 Introduction Ixabepilone (BMS) is a semi-synthetic analog of Epothilone B that functions as a microtubule stabilizer and has anti-cancer effects in several cancers including renal cell carcinoma (RCC) (Zhuang, ASCO 2004). The initial phase II study in RCC utilized a difficult and unconventional dosing schedule (6 mg/m2 IV days 1–5 every 21 days). Hence, this phase II study in RCC was designed to verify previous observations and to test the safety, feasibility, and activity of administering BMS once every 3 weeks- a schedule used in other malignancies. Methods Treatment consists of BMS 40 mg/m2 IV on day 1 every 3 weeks. Eligibility included metastatic RCC with clear or non-clear cell histology, no limits on the number of previous treatments, performance status 0–2, and normal organ function. The primary endpoint is the overall response rate by RECIST criteria on radiologic evaluation conducted every 9 weeks. Accrual to the full planned 41 patients (pts) will proceed provided that 2 or more responses are observed in the first 21 pts. Results Ten pts have enrolled (4 clear cell) with 1 declining participation prior to receiving any treatment. Eight pts have completed at least 3 cycles. Grade 3–4 toxicities include lymphopenia-2, diarrhea-2, alopecia-1, and infection-1. Grade 1–2 toxicities seen in more than 50% of pts include alopecia, neuropathy, nausea, fatigue, anemia, and lymphopenia. We have observed 1 unconfirmed partial response of short duration and 1 pt exhibited stable disease with a minor response but discontinued treatment due to excessive neurotoxicity. Three pts continue on treatment. Conclusions Toxicity at 40 mg/m2 IV on day 1 every 3 weeks is higher than previously reported with the daily x 5 schedule. While lymphopenia, diarrhea, neuropathy, and fatigue are all expected adverse events, the rates of toxicity across all grades is higher than previous reports. VHL mutation analysis is planned and will be correlated with response to therapy. Accrual and pt follow up continue. No significant financial relationships to disclose.

Manageable safety profile in patients with taxane-resistant metastatic breast cancer (MBC) treated with ixabepilone: Final report

10587 Background: The epothilones, a new class of antineoplastic agents, promote tumor cell death by stabilizing microtubules and inducing apoptosis. Ixabepilone was selected from over 300 epothilone analogs due to its high in vivo efficacy, good metabolic stability and low protein binding. Methods: This international, multicenter, open-label Phase II trial was designed to assess the activity of ixabepilone in patients (pts) with highly resistant MBC who had progressed following taxane treatment. Eligible pts were aged ≥18 years with MBC (progressed on or within 4 months of taxane therapy [or within 6 months if adjuvant taxane only]). Pts were excluded if they had had ≥3 prior chemotherapy regimens for MBC or had ≥Grade 2 neuropathy. Ixabepilone (40 mg/m2 q3w) was administered as a 3-hour infusion for a maximum of 18 cycles, unless there was evidence of progressive disease and/or pts met discontinuation criteria. Toxicity was evaluated continuously. Results: Of 49 pts (median age 54 years, range 30–81), 86% of pts had received ≥2 prior chemotherapy regimens. Treatment-related adverse events (TRAEs) were manageable and mostly Grade 1 or 2 (45%). Treatment-related neuropathy was mostly sensory, mild-to-moderate, cumulative and reversible. Sensory neuropathy was managed mainly with dose reductions (12 out of 49 pts had their dose reduced due to neuropathy). Treatment-limiting or severe neuropathy generally resolved or lessened in intensity within 1–2 months after therapy discontinuation. Febrile neutropenia was reported in only 2 pts, in addition, 2 pts (4%) developed treatment-related infection with neutropenia. Only six pts (12%) required growth factor support for neutropenia during their treatment. Progressive disease was the most common reason for discontinuing the study (36%), with 16% discontinuing due to TRAEs. Conclusions: Ixabepilone demonstrates an acceptable safety profile, along with promising antitumor activity, in pts with clearly defined taxane-resistant MBC. [Table: see text] [Table: see text]

Prediction of Antitumor Activity for Epothilone Analogues Based on 3D Molecular Descriptors

Abstract In order to predict the antitumor activities of various epothilone analogues, a set of molecular descriptors, including electronic, topological, and geometrical descriptors and molecular shape indices ( K-order moment shape indices), were calculated to characterize the structural and physicochemical properties for 150 compounds. The 30 descriptors selected with genetic algorithm were employed to establish the classification model of epothilone analogues by using support vector machine (SVM). This SVM system gives a total prediction accuracy of 83.3% by the ‘leave-one-out’ (LOO) method and that of 80.6% by the five-fold cross-validation method. The present study indicates that the K-order moment shape indices defined by us are useful for the description of configuration isomers, and SVM is a facilitating tool in prediction of the antitumor activity of epothilone analogues.

Design, Total Synthesis, and Evaluation of Novel Open-Chain Epothilone Analogues

[structure: see text] The design, total synthesis, and biological evaluation of two open-chain analogues of epothilone incorporating the critical C1-C8 fragment and the aromatic side chain held together by a small molecular scaffold have been achieved. Biological evaluation revealed that further restraint between the flexible C1-C8 region and the molecular scaffold may be necessary for potent inhibition of cell proliferation.

Structure–Activity Relationships in Side‐Chain‐Modified Epothilone Analogues—How Important is the Position of the Nitrogen Atom?

Side-chain-modified epothilone analogues 1 b, 2 b, and 3 b were prepared through stereoselective total synthesis to assess the importance of N-atom positioning in the side chain for tubulin polymerization and antiproliferative activity. Surprisingly, 1 b, 2 b, and 3 b appear to induce tubulin polymerization with activities similar to those of 1 a, 2 a, and 3 a, respectively. Substantial differences in antiproliferative activity were observed between 1 a and 2 a, and 1 b and 2 b, but not between 3 a and 3 b.

Heterologous Production of Epothilone C and D in Escherichia coli

The epothilones are a family of polyketide natural products that show a high potential as anticancer drugs. They are synthesized by the action of a hybrid nonribosomal peptide synthetase/polyketide synthase in the myxobacterium Sorangium cellulosum. In this work, the genes encoding the entire cluster,epoA, epoB, epoC, epoD, epoE, and epoF, were redesigned and synthesized to allow for expression in Escherichia coli. The expression of the largest of the proteins, EpoD, also required the protein be separated into two polypeptides with compatible module linkers. Using a combination of lowered temperature, chaperone coexpression, and alternative promoters, we succeeded in producing a soluble protein from all genes in the epothilone cluster. The entire synthetic epothilone cluster was then expressed in a strain of E. coli modified to enable polyketide biosynthesis, resulting in the production of epothilones C and D. Furthermore, feeding a thioester of the normal substrate for EpoD to cells expressing the epoD, epoE, and epoF genes also led to the production of epothilones C and D. The design of the synthetic epothilone genes together with E. coli expression provides the ideal platform for both the biochemical investigation of the epothilone PKS and the generation of novel biosynthetic epothilone analogues.

Development of Novel Chemotherapeutic Agents to Evade the Mechanisms of Multidrug Resistance (MDR)

A number of novel microtubule-targeting agents are currently under investigation. These agents can potentially evade the mechanisms underlying the development of the multidrug resistance (MDR) phenotype commonly associated with recurrent breast cancer. Epothilones are among the most advanced of the new agents in clinical development. Structurally unrelated to taxanes, epothilones may be poor substrates for MDR, and the expression of MDR proteins is not altered in epothilone-resistant in vitro models. Cross resistance between epothilones and taxanes is not observed in vitro or in vivo. Ixabepilone (BMS-247550) is a semisynthetic analog of epothilone B that has shown antitumor activity both in vitro and in vivo, including taxane-resistant human tumor xenograft models. Ixabepilone is currently being studied in phase III trials in patients with metastatic breast cancer as monotherapy and in combination with capecitabine. Activity has also been observed in other solid tumors. Patupilone (EPO906, epothilone B) and epothilone D (KOS-862) are in early phase I/II clinical studies in patients with a variety of solid tumors. The development of these novel agents may evade MDR and may improve the outcome of patients with breast cancer.

The Epothilone Dilemma

Because of their potent antitumor activity, drugs targeting microtubules are among the most commonly prescribed anticancer agents. These agents fall into the following two broad categories: agents that inhibit tubulin/microtubule polymerization and agents that stabilize preformed microtubules under depolymerizing conditions (the taxanes). The broad clinical antitumor activity of taxanes has stimulated the search for mechanistically similar agents that overcome the difficulties related to formulation and administration and yet subvert the typical mechanism of cellular resistance conferred by the drug efflux by P-glycoprotein and show preserved activity in paclitaxel-resistant cells with mutations in beta-tubulin. The epothilones (a name derived from its molecular features; epoxide, thiazole, and ketone) have emerged as a new class of microtubule-targeting agents and were originally isolated from the broth of a fermenting soil bacteria, Sorangium cellulosum. The epothilones and taxanes have overlapping binding sites to the surface of beta-tubulin, and the microtubule polymerization–inducing mechanism of epothilones seems to be similar to that of taxanes. Preclinical studies indicate a relatively broad spectrum of activity for epothilones. They are generally 5 to 25 times more potent than paclitaxel in inhibiting cell growth in cultures. Epothilones and taxanes seem to differ distinctly in their drug-resistance mechanisms because the cytotoxic effects of the epothilones are preserved in multi-drug resistance– expressing cell lines and in cells harboring tubulin mutations, which demonstrate resistance to paclitaxel. Five epothilone analogs are currently undergoing clinical assessment; these are ixabepilone (aza-epothilone, BMS-247550), BMS-310705 (a water-soluble analog of epothilone B), patupilone (epothilone B, EPO906), epothilone D (KOS-862), and ZK-EPO. Patupilone was one of the earliest epothilones entering clinical development. It has been evaluated in phase I studies using a 5-minute bolus administration weekly, administered 6 of every 9 weeks or 3 of every 4 weeks, once every 3 weeks, or daily times five as a prolonged infusion. In this issue, Rubin et al describe a dose-finding study of the weekly administration of patupilone in patients with advanced solid tumors. A total of 91 patients were treated at dose levels ranging from 0.3 to 3.6 mg/m/wk in a classic, phase I, 3 3 dose-escalation design. Dose-limiting toxicity consisting of grade 3 diarrhea was observed at both of the dose levels of 3.6 and 3.0 mg/m in the 6 weeks on and 3 weeks off dosing schedule. Therefore, the recommended dose for this schedule was set at 2.5 mg/m/wk. Because the drug-related diarrhea often peaked in severity during the fourth week of treatment, an alternative schedule (3 weeks on and 1 week off) was also studied, resulting in the same recommended dose per administration (2.5 mg/m/wk). The most common non–dose-limiting toxicities included nausea, vomiting, and fatigue. Importantly and in contrast to the results with taxanes, only one patient developed alopecia, and there was no neurologic toxicity. As with weekly taxane schedules, hematologic toxicity was limited. The pharmacokinetic data revealed that drug clearance was nonrenal and not related to body-surface area (BSA). Over the dose range studied, systemic drug exposure was dose proportional. There were three partial responses, two of which occurred in patients previously treated with taxanes, and 42% of the patients experienced disease stabilization for a median duration of 16.3 weeks. Given the absence of data on tumor growth rate before study entry, the latter data are obviously difficult to interpret. As stated, the side effects observed with weekly administration of patupilone are strikingly different from those associated with weekly administration of taxanes. Yet, it is important to note there are also major differences in adverse effect profiles between the various epothilones presently in clinical development. Ixabepilone (BMS-247550) is formulated in polyoxyethylated castor oil. Not unexpectedly, during phase I studies, hypersensitivity reactions were seen necessitating prophylactic administration of oral histamine-1 and histamine-2 blockers. Both the once every 21 days schedule and the weekly schedule resulted in doselimiting neutropenia and sensory neuropathy. Early sensory neuropathic changes were already detectable after two cycles of treatment. During the early phase II studies using the schedule of every 3 weeks, grade 3 or 4 neuropathy JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 36 DECEMBER 2

Activation of the Steroid and Xenobiotic Receptor (Human Pregnane X Receptor) by Nontaxane Microtubule-Stabilizing Agents

Because induction of drug efflux transporters is one of the major underlying mechanisms of drug resistance in cancer chemotherapy, and human pregnane X receptor (hPXR) is one of the principal "xenobiotic" receptors whose activation induces transporter and drug-metabolizing enzyme gene transcription, it would be ideal to develop chemotherapy drugs that do not activate hPXR. This report describes studies undertaken to explore the characteristics of hPXR stimulation and mechanisms of drug-receptor interactions in vitro with new anti-tubulin drugs. In vitro transient transcription, glutathione S-transferase pull-down assays, and mammalian one-hybrid and two-hybrid systems were used to explore drug-receptor interactions. Loss of righting reflex was used to assess effects of drugs on PXR activity in vivo. The current study showed that paclitaxel, discodermolide, and an analogue of epothilone B, BMS-247550, induced CYP3A4 protein expression in HepG2 hepatoma cells. Transient transcription assays of a luciferase reporter in the presence and absence of a GAL4-steroid and xenobiotic receptor (SXR) plasmid in HepG2 cells showed that these drugs activate hPXR. This was not true for the inactive analogue of paclitaxel, baccatin III, or for an analogue of epothilone A, analogue 5, none of which stabilizes microtubules. To determine the mechanisms by which paclitaxel, discodermolide, and BMS-247550 activate hPXR, a mammalian two-hybrid assay was done using VP16SRC-1 (coactivator) and GAL4-SXR. SRC-1 preferentially augmented the effects of these drugs on hPXR. Expression of SMRT (corepressor) but not NCoR suppressed the drug-induced activation of SXR by approximately 50%, indicating a selectivity in corepressor interaction with hPXR. These drugs resulted in shortened duration of loss of righting reflex in vivo, indicating drug-induced activation of PXR in mice. These findings suggest that activation of hPXR with selective displacement of corepressors is an important mechanism by which microtubule-stabilizing drugs induce drug-metabolizing enzymes both in vitro and in vivo.

Investigation of antitumor effects of synthetic epothilone analogs in human myeloma models in vitro and in vivo

26-Trifluoro-(E)-9,10-dehydro-12,13-desoxyepothilone B [Fludelone (Flu)] has shown broad antitumor activity in solid tumor models. In the present study, we showed, in vitro, that Flu significantly inhibited multiple myeloma (MM) cell proliferation (with 1-15 nM IC50), whereas normal human bone marrow stromal cells (HS-27A and HS-5 lines) were relatively resistant (10- to 15-fold higher IC50). Cell-cycle analysis demonstrated that Flu caused G2/M phase arrest and induced cell apoptosis. After Flu treatment, caspase-3, -8, and -9 were activated, cytochrome c and second mitochondrial-derived activator of caspase were released to the cytosol, and c-Jun N-terminal kinase was activated, indicating that mitochondria were involved in the apoptosis. Flu toxicity to human hematopoietic stem cells was evaluated by CD34+ cell-apoptosis measurements and hematopoietic-progenitor assays. There was no significant toxicity to noncycling human CD34+ cells. We compared the efficacy of Flu with the epothilone analog 12,13-desoxyepothilone B (dEpoB) in xenograft nonobese diabetic/severe combined immunodeficient mouse models with subcutaneous or disseminated MM. Flu caused tumor disappearance in RPMI 8226 subcutaneous xenografts after only five doses of the drug (20 mg/kg of body weight), with no sign of relapse after 100 d of observation. In a disseminated CAG MM model, mice treated with Flu had a significantly decreased tumor burden, as determined by bioluminescence imaging, and prolonged overall survival vs. mice treated with dEpoB or vehicle control, indicating that Flu may be a promising agent for MM therapy.

A phase I study of the novel, third generation epothilone ZK-EPO in patients with advanced solid tumors

2051 Background: Epothilones are a new class of cytotoxic agents that induce tubulin polymerization. ZK-EPO, the only fully synthetic, third-generation analogue of epothilone B, is a highly potent tubulin stabilizer that has shown substantial preclinical antitumor activity, including against taxane-resistant models. This Phase I study was initiated to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of ZK-EPO in patients with advanced solid tumors. Secondary objectives were to determine the safety, tolerability, pharmacokinetics and antitumor activity of ZK-EPO. Methods: Patients with histologically confirmed advanced solid tumors that were resistant/refractory to conventional antineoplastic treatment (n=44), or for whom no standard therapy was available (n=3), were enrolled on the trial. ZK-EPO was given as a 30-minute intravenous infusion once every 3 weeks; the starting dose was 0.6 mg/m2, and dose levels were escalated using a modified Fibonacci design. Treatment was continued until disease progression or unacceptable toxicity occurred. Results: To date, 47 patients (median age 54 years; range 25–80) have received a total of 151 courses of ZK-EPO (median 3; range 1–23) at 12 dose levels up to 29 mg/m2. The most common adverse events were peripheral sensory neuropathy (mostly grade 1–2; 16 patients) and nausea (8 patients). Hematological toxicity was mild and infrequent (grade 2 leukopenia in 2 patients). Dose-limiting grade 3 (Common Toxicity Criteria) peripheral neuropathy and grade 3 ataxia occurred at 16 mg/m2 (1 patient) and 29 mg/m2 (1 patient), respectively. No other DLTs have been observed, and the MTD has not been reached. Two confirmed partial remissions were observed in patients with taxane-pretreated breast cancer (one with taxane resistant disease) receiving 12 and 16 mg/m2 ZK-EPO, respectively. Stable disease lasting up to 16+ months (median 5.5; range 3–16+) was observed in 13 patients (NSCLC, cholangiocarcinoma, head and neck cancer, uveal melanoma, and adrenal carcinoma). Conclusions: The trial is ongoing and the MTD for ZK-EPO has not been reached. Preliminary data indicate that ZK-EPO is well tolerated, with antitumor activity observed in 15 patients. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Schering AG, Berlin, Germany Schering AG, Berlin, Germany

NABTT 2111: A phase I trial of BMS-247550 for patients with recurrent high-grade gliomas

1563 Background: BMS-247550 is a semi-synthetic analog of epothilone B, a novel non-taxane microtubule-stablizing agent. A phase I trial of this agent in patients with recurrent high-grade glioma is in progress Methods: Patients (pts) receive BMS-247550 on a 1-hour infusion, daily x 5 every 3 weeks. Cohorts of 3 pts are treated at each dose level starting at 5 mg/m2/day. Pts are stratified into groups A and B according to the use or non-use, respectively, of cytochrome P450 enzyme-inducing anticonvulsants. Dose escalation for each group occurs separately using the continual reassessment method (CRM) to calculate each dose level. The MTD is reached when the CRM assigns two consecutive dose levels within 10% of the previous level. Pharmacokinetic sampling (PKs) occurs on days 1–5 of cycle 1. Results: Twenty-nine pts have been enrolled: median age 54 years (range 22–75); 21 (72%) male; 12 in group A. All had received radiation and 25 (data on 3 missing) had received prior chemotherapy. Four dose levels (5, 6, 7, 7.7 mg/m2) have been tested in group A with no dose-limiting toxicities (DLT). Six dose levels (5, 7.5, 6, 6.6, 7, 6.8 mg/m2) have been tested in group B with 1 treatment-related death (sepsis/typhlitis) at 7.5 mg/m2,and 2 DLTs (grade 4 ANC and grade 3 febrile neutropenia) at 7 mg/m2. Data for the 6.8mg/m2 are currently under review, however 1 DLT (grade 3 arthralgia) has been observed. Other grade 3 treatment-related toxicities: anemia, abdominal cramping, arthralgias, neuropathic pain, and fatigue. Of 23 pts evaluable for response, 5 had stable disease and 18 have progressed. PKs are being assessed. Conclusions: To date, BMS-247550 has not shown new toxicities in glioma pts with the possible exception of typhlitis for which BMS-247550 could not be excluded as the cause. The most severe toxicity has been hematological. Dose escalation in group B is near completion, and the MTD will be close to that (6 mg/m2) established in non-CNS pts. Dose escalation continues on group A and the MTD will be ≥ 7.7 mg/m2. Because BMS 247550 is a substrate for the P450 system, pharmacodynamic differences between the groups A and B may emerge. No significant financial relationships to disclose.

Phase II genomics study in patients receiving ixabepilone as neoadjuvant treatment for breast cancer (BC): Preliminary efficacy and safety data

586 Background: Previous studies have confirmed the activity of ixabepilone (BMS-247550, a semi-synthetic analog of epothilone) in metastatic BC. The present study was designed to determine the pathological response obtained with ixabepilone as neoadjuvant therapy for BC and to obtain tumor samples for analysis of gene expression and identification of potential predictors of response to ixabepilone. Methods: Women with invasive stage IIA-IIIB breast cancer with tumors ≥3 cm diameter received 40 mg/m2 ixabepilone as a 3-hour infusion on Day 1 for up to four 21-day cycles, followed by surgery within 3–4 weeks of completion of chemotherapy. Biopsies for analysis of mRNA expression were obtained both pre- and post-therapy. Adjuvant chemotherapy with an anthracycline combination regimen followed by radiotherapy and tamoxifen were administered as indicated. Pathological response was assessed using the Sataloff criteria. Results: A total of 164 patients were enrolled. Data were available for 47 patients for this...

The Epothilones and Related Analogues-A Review of Their Syntheses and Anti-Cancer Activities

The macrocylic polyketide class of compounds known as the epothilones has generated substantial interest over the last few years in the areas of chemistry, biology, and medicine due to their interesting structure and, more importantly, their activity against numerous cancer cell lines, including drug-resistant, especially Taxol-resistant, cancer cell lines. To date, numerous total syntheses have been published, hundreds of epothilone analogues have been synthesized, and detailed structure activity relationship studies have been conducted. The purpose of this review is to give a brief summary of the latest advances made concerning the epothilones. Recent total or partial syntheses will be presented along with the syntheses of new epothilone analogues and their corresponding biological data. In addition, we will look at the current state of research into an economically viable method for the biosynthesis of the epothilones and related analogues.

Evaluation of Epothilone B Analog in Advanced Soft Tissue Sarcoma: A Phase II Study of the Phase II Consortium

Epothilones are a new class of nontaxane tubulin polymerization agents that have activity in taxane-resistant tumors. Epothilone B (BMS-247550) is a semisynthetic analog of the natural product epothilone B. This study was performed to determine the activity of BMS-247550 in patients with soft tissue sarcomas (STSs) who had not received prior chemotherapy for metastatic disease. Patients with measurable, advanced, or metastatic STS with no prior chemotherapy for metastatic disease were treated with BMS-2457550 50 mg/m(2) intravenously during 1 hour every 21 days. All responses were confirmed 4 weeks later. Thirty-one patients (median age, 54 years; range, 19 to 78 years; 48% female) were entered onto the trial and were assessable for response. All but one patient had an Eastern Cooperative Oncology Group performance score of 0% or 1%, and 39% had received prior adjuvant chemotherapy. Mean follow-up was 22 months, with a confirmed response rate of 6% (95% CI, 0% to 17%). Median time to progression was 4.5 months (95% CI, 1.9 to 8.3 months), and 1 year progression-free survival was 17% (95% CI, 8% to 38%). Median survival was 16.4 months, with a 1-year survival of 61% (95% CI, 46% to 81%). Toxicity was mainly hematologic, with eight of 31 (26%) patients experiencing grade 3 to 4 leukopenia; 15 of 31 patients (48%) experienced grade 3 to 4 neutropenia. The grade 3 to 4 nonhematologic toxicities included neuropathies (26%), myalgia (13%), and fatigue (10%). BMS-247550 has limited activity against STSs when given in this dose and schedule. The clinical toxicity is similar to that of taxanes.

Recent Developments in the Chemical Biology of Epothilones

Epothilones A and B are naturally occurring microtubule-stabilizers, which inhibit the growth of human cancer cells in vitro at nM or even sub-nM concentrations. In contrast to paclitaxel (Taxol) epothilones are also active against different types of multidrug-resistant cancer cell lines in vitro and against multidrug-resistant tumors in vivo (epothilone B). Their attractive preclinical profile has made epothilones important lead structures in the search for improved cytotoxic anticancer drugs and epothilone B is currently undergoing phase II clinical trials. Numerous synthetic and semi-synthetic analogs have been prepared since the absolute stereochemistry of epothilone B was first disclosed in mid-1996 and their in vitro biological activity has been determined. Apart from generating a wealth of SAR information, these efforts have led to the identification of at least four compounds (in addition to epothilone B), which are currently at various stages of clinical evaluation in humans. This review is first intended to provide a summary of the basic features of the in vitro biological profile of epothilone B, with particular emphasis on recent developments in this area. A second part will outline the most relevant aspects of the epothilone SAR with regard to effects on tubulin polymerization, in vitro antiproliferative activity, and in vivo antitumor activity. This will include a brief discussion of research directed at the determination of the bioactive conformation of epothilones. In a final section, the preclinical profile of those epothilone analogs currently in clinical development will be discussed in greater detail.