© 2007 European Society for Medical Oncology
Phase I clinical study of the novel epothilone B analogue BMS-310705 given on a weekly schedule
1 IOSI, Bellinzona, Switzerland
2 Istituto Nazionale Tumori, Milano
3 Bristol-Myers Squibb, Wallingford CT, USA
4 SENDO, Milano, Italy
* Correspondence to: Dr L. Gianni, MD, Istituto Nazionale Tumori, Via Venezian, 1, 20133 Milano, Italy. Tel: +39-02-2390-2789; Fax: +30-02-2390-2012; E-mail: luca.gianni{at}istitutotumori.mi.it
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Abstract |
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Background: BMS-310705, a water-soluble semi-synthetic analogue of epothilone B, was selected for clinical development because of its in vivo anti-tumour activity and toxicity profile similar to that of ixabepilone, currently the most extensively evaluated and promising epothilone B analogue. The improved solubility of BMS-310705 allowed a cremophore-free formulation that avoided the need for pre-medication.
Patients and methods: Two schedules were tested, one with drug administrations on days (D) 1, 8 and 15 followed by 1-week's rest, the other with administrations on D1 and 8 (D1&8 schedule) followed by 1-week's rest. Treatment was given as a 15-min infusion without pre-medication against hypersensitivity. The plasma pharmacokinetics of BMS-310705 was studied in 30 patients. An accelerated titration design 2B was applied for dose escalations. Twenty-seven patients were accrued in the D1, 8, 15 and 32 in the D1&8 schedule.
Results: The dose was escalated from 5–30 mg/m2/week with diarrhoea as dose-limiting toxicity; 15 and 20 mg/m2 were the recommended doses in the D1, 8, 15 and D1&8 schedule, respectively. Other frequent non-haematological toxicities were neurotoxicity, mainly paraesthesia, asthenia and myalgia. Preliminary results showed linear pharmacokinetics along the range of doses tested with a short half-life. Five objective responses were reported.
Conclusions: Further clinical development of BMS-310705 might be worthwhile in solid tumours where ixabepilone or other epothilones are not indicated.
Key words: accelerated titration design, epothilone b analogue, phase I, tubulin binder
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Epothilones and their analogues are a new class of microtubule-stabilizing cytotoxics, with a similar mechanism of action to taxanes but a different structure and distinct binding mode to tubulin [1]. Epothilones and analogues were brought into clinical development because of a potency higher than that of taxanes and good anti-tumour activity in cell lines and tumour models resistant to paclitaxel [1]. Structure–activity studies indicated that modifications near the C12–13 epoxide can affect microtubule-stabilizing activity and at least in part cytotoxicity, while substitution at C21 could affect solubility [2] (Fig. 1). Epothilone modifications affecting cellular pharmacology and human drug disposition that are relevant for the selection of the most convenient schedule of treatment are as yet poorly defined [3].
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The epothilone B analogue furthest along in development is ixabepilone (BMS-247550), which has demonstrated anti-tumour activity in multiple tumour types including taxane-resistant breast and prostate cancer [4–10]. The safety profile of the two schedules tested, i.e. daily for 5 consecutive days [11] and once every 3 weeks [12, 13] was similar and associated with dose-limiting neutropenia, fatigue and peripheral neuropathy.
BMS-310705 is an aqueous soluble semi-synthetic analogue of epothilone B that was selected for clinical development because of in vivo anti-tumour activity similar to that of optimally dosed ixabepilone in a series of human tumour xenografts resistant to paclitaxel through different mechanisms, such as the ovarian Pat-7, the pancreatic Pat-26 and the ovarian A2780 carcinoma. Importantly, the in vivo activity was reported at doses below the maximum tolerated dose (MTD), suggesting that an acceptable therapeutic window might be achieved in humans. The toxicity profile was comparable to that of ixabepilone, while the improved solubility allowed a cremophore-free formulation thus possibly avoiding pre-medication.
Here we report the results of the clinical Phase I study and the pharmacokinetic (PK) evaluation of BMS-310705 given at weekly intervals on two different schedules, for three consecutive weeks every 4 weeks or for two consecutive weeks every 3 weeks. The latter was investigated because of the pattern of toxicity observed along the treatment, with many patients missing the administration planned for D15 due to toxicity.
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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eligibility
Patients from two participating centres were eligible if they met the criteria of: histologically or cytologically confirmed diagnosis of solid tumour refractory or not amenable to conventional therapy; age
18 years; Eastern Cooperative Oncology Group (ECOG) performance status (PS) 
1; neutrophils 2.0 x 109/L; platelets 100 x 109/L; liver transaminases 2.5 x ULN (upper limits of normal); bilirubin 1.5 x ULN; serum creatinine 1.5 x ULN; life expectancy of at least 3 months; signed written informed consent. Patients with more than two prior cytotoxic chemotherapy regimens for metastatic disease, pre-existing peripheral neuropathy > NCI Common Toxicity Criteria (CTC version 2.0) grade (G) 1, documented hypersensitivity reaction (HSR) CTC G2 to a prior taxane or epothilone were excluded along with patients with active infections or with symptomatic or progressing brain disease. The Institutional Ethical Boards approved the study protocol.
treatment and study design
BMS-310705 was provided by Bristol Myers Squibb (Wallingford, CT, USA) as lyophilized product to be reconstituted with sterile water for injection to a 2.0 mg/ml solution, and further diluted with 0.9% normal saline to a final concentration of 0.5 mg/ml. BMS-310705 was administered through a 5 µm in-line filter extension set as an infusion over 15 min with an infusion pump without prophylactic pre-medication against hypersensitivity reactions or anti-emetics at first cycle; the latter were introduced with therapeutic intent at subsequent cycles.
Initially a schedule consisting of three weekly administrations [on days (D)1, 8, 15] followed by 1-week's rest, corresponding to one cycle, was tested (Part I of the study). When it became apparent that many patients could not receive the D15 dose because of toxicity, a schedule with two weekly administrations on days 1 and 8 (D1&8 schedule) followed by 1-week's pause and repeated every 3 weeks was evaluated (Part II of the study). Treatment was given weekly if toxicities (except alopecia) had resolved to baseline or G1 according to common toxicity criteria (CTC), otherwise the weekly dose was omitted. The same criteria were applied for starting a new cycle, which could be delayed for a maximum of 2 weeks.
Since in the Phase I trial [14] exploring the schedule involving a single dose of BMS-310705 every 3 weeks the dose of 20 mg/m2 was shown to be tolerable also after repeated administrations, a starting dose of 20 mg/m2 per cycle was selected for the present study, corresponding to 5 mg/m2/week.
The dose was escalated according to a titrated escalation 2B design, as described by Simon et al. [15], with an initial accelerated phase with 100% dose increments and one new patient per dose level, or three in the case of one instance of CTC G2 toxicity occurring at the first cycle. In the case of two or more instances of CTC G2 toxicity or one instance of dose-limiting toxicity (DLT) in the first cycle, the accelerated phase was terminated and the standard escalation phase was started, with dose increments of 33–40% and at least three patients per dose level. The dose escalation was discontinued if at least two of two to six patients presented a DLT at the first cycle; this dose was the maximum administered dose (MAD). The MTD was defined as the dose at which fewer than two of six patients presented a DLT; accrual at the MTD was expanded up to at least 15 patients to define the recommended dose (RD) for Phase II exploration. Other changes introduced in the part of the study with the D1&8 schedule were the use of 25% dose increments, the evaluation of at least three patients per dose level (six in the case of DLT) and treatment of at least 15 patients at the MTD.
DLT was defined as the occurrence at the first cycle of febrile neutropenia, G4 neutropenia lasting more than 5 days, G4 thrombocytopenia or G3 symptomatic thrombocytopenia requiring platelet transfusions, G3 non-haematological toxicity (excluding alopecia), failure to administer any of the weekly doses or to start cycle 2 on time because of persisting haematological (neutrophils < 1.5 x 109/L, platelets < 100 x 109/L) or non-haematological (>G1) toxicity.
The dose was decreased by one level in the case of DLT or G2 neuropathy, for a maximum of two dose reductions.
treatment assessment
Patients’ assessment included physical examination, evaluation of PS and tolerability to treatment. Complete blood counts and blood chemistry were repeated weekly; ECG was repeated 15 min and 24 h after the first infusion and then immediately before starting the infusion on D8.
Tumour response, evaluated according to the RECIST criteria, was assessed after two cycles, or earlier in case of clinical progressive disease (PD); objective responses needed to be confirmed 4 weeks apart. An independent review of response or stabilization lasting three cycles or longer was performed. Treatment was discontinued in case of PD, unacceptable toxicity, lack of recovery from toxicity after a 2-week delay from planned treatment dose, patients request or lack of clinical benefit as judged by the investigator. Toxicity was graded according to the NCI Common Toxicity Criteria (CTC version 2.0).
sample collection and pharmacokinetic analysis
Blood samples were drawn before and at several time points on D1 of the first dose until 48 h after dosing. Samples were kept on ice and centrifuged at 4°C within 30 min ; plasma samples were kept at –70°C until analysis.
Internal standard (IS, 0,05 ml) and ammonium acetate (0.1 M, 0.5 ml) were added to 0.2 ml of plasma samples or calibration standards, loaded onto Waters Oasis HLB solid phase extraction (SPE) cartridges, washed (0.01 M ammonium acetate, 1 ml; 90:10 water:methanol, 1 ml) and extracted with methanol (1 ml) and dried. Extracts were re-dissolved with 0.1 ml ammonium acetate (0.5 mM) in acetonitrile:water (75:25) and injected (5 µl) into a chromatographic system equipped with a high-performance liquid chromatography (HPLC) column (YMC ODS-AQ, 4.6 x 50 mm, 5 µm, Waters Corporation), a separation module (LC-10ADvp, Shimadzu) and a mass spectrometer (Quattro LC, Waters Corporation). Samples were eluted with 5 mM ammonium acetate in acetonitrile:water (85:15) at 0.3 ml/min and 40°C. The tandem mass spectrometry (MS/MS) transitions for BMS-310705 and its IS were 523 > 335 and 494 > 306, respectively, and corresponding retention times were 2.3 min and 3.4 min.
Plasma levels of BMS-310705 were measured by liquid chromatography (LC)/MS/MS assay with a validated assay with a lower limit of detection of 2 ng/ml. Pharmacokinetic parameters were calculated using non-compartmental methods, including peak concentration (Cmax) on D1, area under the curve to the last quantifiable concentration (AUC0–t) and extrapolated to infinity (AUCinf), terminal half-life (T1/2), total body clearance (CLT) and volume of distribution at steady state (VSS).
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results |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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patient characteristics
Overall, 59 patients received BMS-310705, 27 in the D1, 8, 15 schedule and 32 in the D1&8 schedule. The total number of cycles was 175 (69 in the D1, 8, 15 and 106 in the D1&8 schedule) with a median of 2 (range 1–12). Selected patient characteristics are reported in Table 1. At least one prior chemotherapy had been delivered to all patients. Prior therapy consisted of potentially neurotoxic agents in 92% of patients (platinums 76%, taxanes 46%, vincas 14%).
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dose escalation and dose limiting toxicities
part I
In the D 1, 8, 15 schedule the accelerated phase was uneventful while escalating from 5 to 10 and 20 mg/m2/week (Table 2). At the latter dose the only treated patient reported signs of haematological clinical toxicity and the dose was therefore escalated only by 50% to 30 mg/m2. Both patients receiving this dose developed DLTs after D8 dosing, requiring the omission of the D15 dose; therefore further dose escalation was stopped at this dose level, which was the MAD. The lower dose cohort of 20 mg/m2 was then expanded with 15 additional patients and four DLTs were observed. Overall, the main DLT was diarrhoea, which occurred between D8 and 15, precluding the completion of the cycle. The emergent observation of cumulative late onset (median time to onset >3 months) of paraesthesias in 6/16 (37.5%) patients (three of whom were withdrawn from treatment due to neuropathy) prompted the evaluation of an intermediate dose level of 15 mg/m2 tested in seven patients with the occurrence of one DLT (G3 diarrhoea); this dose was recommended for Phase II studies with the D1, 8, 15 schedule.
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part II
With the D1&8 schedule the starting dose was 20 mg/m2; no DLTs were reported at this dose level or at the subsequent one at 25 mg/m2, both tested in three patients. No further escalation was attempted because of the acute toxicity observed at 30 mg/m2 in Part I and accrual at 25 mg/m2 continued to a total of 17 patients. Due to cumulative neurotoxicity seen at 25 mg/m2, requiring treatment withdrawal in five cases, the 20 mg/m2 dose level was further explored in 12 additional patients and was defined as the RD with one DLT out of a total of 15 treated patients (Table 2). As in Part I, diarrhoea was the acute DLT.
toxicity
Overall, haematological toxicity, mainly neutropenia, was limited; neutropenia was dose dependent and occurred mainly at the MAD or MTD. No significant thrombocytopenia was reported. The main toxicities are summarized in Table 3. The most frequent dose-dependent side-effects were diarrhoea and asthenia/fatigue, both reported in about 50% of patients in the first cycle, followed by neutropenia, nausea/vomiting, myalgia/arthralgia and paraesthesia. The first occurrences of arthralgia/myalgia were reported at 15 mg/m2, and consisted of muscular limb pain starting 24 h after treatment and lasting for 48–72 h. Pain was usually controlled by non-steroidal anti-inflammatory drugs (NSAIDs). Paraesthesia was dose-dependent and cumulative: in Part I at 20 mg/m2, its incidence during the first cycle was 12.5% (Table 4) and severity never exceeded G1, while considering the worst severity grade in all cycles, the incidence of paraesthesia by patient was 37%, of G3 in half of the cases (data not shown); in Part II at 25 mg/m2, paraesthesia of G1 only was reported in 12% of patients at first cycle (Table 4) while its incidence increased to 59% with severity ranging from G1 to G3 when all delivered cycles were taken into account (data not shown). Overall, G3 paraesthesia was experienced by 16% of patients treated at 15–25 mg/m2 with either schedule. Peripheral neurotoxicity was the main reason for treatment discontinuation in 13 of 18 patients (72%) who interrupted therapy for toxicity. Two breast cancer patients in the Part I 20 mg/m2 cohort experienced G3 ataxia. One of them received four cycles of doxorubicin and paclitaxel as first-line treatment, completed >6 months before study entry and presented paraesthesia since the second cycle of BMS-310705. In spite of the subsequent dose reduction to 10 mg/m2, at cycle 5 paraesthesia worsened with ataxia, requiring discontinuation of treatment even in the absence of disease progression. Paraesthesia recovered after about 12 months since last dosing of BMS-310705. The second patient also received four cycles of paclitaxel in combination as adjuvant >4 years before study entry and started presenting paraesthesia after two cycles of BMS-310705. Symptoms progressively worsened up to G3 during the subsequent cycles at 10 mg/m2 and treatment was discontinued at cycle 4 due to ataxia, while tumour evaluation still showed partial response. Neurotoxicity recovered in the subsequent 3 months.
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One patient presented a vasovagal reaction during the first half of the second infusion of 20 mg/m2 BMS-310705, with generalized rash, hypotension, vomiting, diarrhoea and tremor. The infusion was interrupted and subcutaneous atropine and intravenous steroids, antihistamines and ranitidine were given with full recovery of symptoms within 1 h. The reaction occurred – though with lower intensity – at the subsequent cycle administered with pre-medication with anti-histamines, corticosteroids and H2-receptor antagonists, and study treatment was permanently discontinued.
anti-tumour activity
Four partial responses – one in breast and one in gastric cancer in Part I and two in breast cancer in Part II – and one complete response – in ovarian cancer in Part II – were observed. All responses were confirmed by an independent review. Taxanes had been previously given in three of the five responders: as adjuvant therapy in the ovarian cancer patient, and for advanced disease in two breast cancer patients, one with PR and the other with PD as best response to prior treatment. The duration of the confirmed CR was 4 months and overall time to progression was 7.5 months. The duration of partial response in breast cancer patients was 4, 3+ and 2+ months, respectively, while the PR in the gastric cancer patient lasted 2 months.
pharmacokinetic results
The PK profile of BMS-310705 in plasma was assessed in 30 patients treated at 5–30 mg/m2 in Part I of the study (Fig. 2). Table 4 reports the preliminary PK parameters of BMS-310705.
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As it is clear from the figure and Table 5, Cmax and AUC increased linearly over the range of tested doses while CLTB did not change with dose. The geometric mean of CLTB values ranged from 200–383 ml/min/m2 (Table 4). Mean VSS values were in the range of 133–494 L/m2, suggesting an extensive extravascular distribution.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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This study aimed at defining the MTD, RD and safety profile of BMS-310705, a water-soluble analogue of epothilone B with favourable features such as the lack of cremophore and a pre-clinical profile of anti-tumour activity comparable to that of ixabepilone.
In the present study, BMS-310705 was first evaluated on a weekly schedule, given on D1, 8, 15 followed by 1 week's rest (Part I of the study); in a subsequent part of the study (Part II), BMS-310705 was given on a D1&8 schedule followed by 1 week's rest. The latter schedule was selected to overcome the observation that in Part I the dose on D15 could not be given in many patients because of diarrhoea – which was the acute DLT at cycle 1 – and/or haematological toxicity.
The identification of the RD was also based on the incidence of cumulative peripheral neuropathy and was defined as 15 mg/m2 in Part I and as 20 mg/m2 in Part II. One complete response in a patient with ovarian cancer and four partial responses (three in patients with metastatic breast cancer and one in a patient with metastatic gastric cancer) were reported. The PK disposition of BMS-310705, studied in Part I only, was consistent with extensive extravascular distribution and characterized by a linear relationship with the dose in the range of 5–30 mg/m2.
The weekly regimen of BMS-310705 in this study was adopted based on clinical practice with paclitaxel and docetaxel, for which tolerability is schedule dependent [16]. However, in the case of BMS-310705, the RD of 20 mg/m2 given on D1&8 every 3 weeks (40 mg/m2 per cycle) in Part I was the same as the RD when administered once every 3 weeks. In addition, the toxicity profile of BMS-310705 given intermittently every 3 weeks was completely different from that of the weekly schedule, with neutropenia, fatigue and mucositis as DLT [14].
There are reports in the literature suggesting that the formulation in polyoxyethylated castor oil might play a role in the occurrence of neurotoxicity with ixabepilone (BMS-247550) treatment [17]. Because of the promising results achieved with ixabepilone in breast cancer, the amelioration of the neurotoxicity profile is a high priority for its clinical development. Active fields of investigations include the development of neuroprotective agents or other counteractive measures, the design of shorter but intensive neo-adjuvant regimens, or the identification of active analogues endowed with a better neurological tolerability. The latter possibility is supported by the observation that epothilone B compound, e.g. patupilone [3], has better neurological tolerability and justifies additional pre-clinical and early clinical investigations to define whether further phase II development of additional epothilone analogues is still worthwhile. In the case of BMS-310705, the neurological tolerability might be better than that of ixabepilone, but paraesthesia still holds as a limiting factor for increasing doses when other toxicities are far from being limiting.
In summary, we defined the RD of BMS-310705 by two different weekly schedules (weekly for three consecutive weeks every 4 weeks in Part I and weekly for two consecutive weeks every 3 weeks in Part II of the study). Cumulative neurological toxicity was limiting with both regimens and could not be ameliorated by decreasing the number of consecutive weekly administrations. Further development of the new epothilone BMS-310705 would be worthwhile only if favourable promising results could be achieved in patients with cancers not suitable for treatment with ixabepilone or other epothilones at a more advanced stage of clinical development.
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Acknowledgements |
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Study sponsorship and study drug supply: Bristol-Myers Squibb. Other sources of support for the study: support of the Swiss League Against Cancer to the SENDO Foundation; ESMO fellowship grant to Dr Lladò.
Conflict of interest statement. Dr Voi is an employee of Bristol-Myers Squibb and owner of stocks of that Company. Dr Gianni has received honoraria from Bristol-Myers Squibb for participation in Advisory Board meetings. None declared for the other authors.
Received for publication December 29, 2006. Revision received April 5, 2007. Accepted for publication April 11, 2007.
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References |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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1. Nettles JH, Li H, Cornett B, et al. The binding mode of epothilone A on
, ß-tubulin by electron crystallography. Science (2004) 305:866–869.2. Borzilleri RM, Vite GD. Epothilones: new tubulin polymerization agents in preclinical and clinical development. Drugs Future (2002) 27:1149–1163.[CrossRef][Web of Science]
3. Rubin RH, Rothermel J, Tesfaye F, et al. Phase I dose finding study of weekly single-agent patupilone in patients with advanced solid tumors. J Clin Oncol (2005) 23:9120–9129.
4. Low JA, Wedam SB, Lee JJ, et al. Phase II clinical trial of Ixabepilone (BMS-247550), an Epothilone B analog, in metastatic and locally advanced breast cancer. J Clin Oncol (2005) 23:2726–2734.
5. Thomas E, Perez EA, Hukhopadhyay P, et al. Phase II trial of ixabepilone in patients with metastatic breast cancer (MBC) who are resistant to an anthracycline, a taxane and capecitabine. Proc Am Soc Clin Oncol (2006) 24:42. (abstract 660).
6. Thomas E, Tabernero J, Fornier M, et al. A Phase II study of the epothilone B analog BMS247550 in patients (pts) with taxane-resistant metastatic breast cancer (MBC). Proc Am Soc Clin Oncol (2003) 22:8. (abstract 30).
7. Rosenberg JE, Kelly WK, Michaelson MD, et al. A randomized phase II study of ixabepilone (lx) or mitoxantrone and prednisone (MP) in patients with taxane (T)-resistant hormone refractory prostate cancer (HRPC). Proc Am Soc Clin Oncol (2005) 23:394. (abstract 4566).
8. Vansteenkiste JF, Breton JL, Sandler A, et al. A randomized phase II study of epothilone analog BMS-247550 in patients (pts) with non-small cell lung cancer (NSCLC) who have failed first-line platinum based chemotherapy. Proc Am Soc Clin Oncol (2003) 22:626. (abstract 2519).
9. Whitehead RP, McCoy S, Rivkin SE, et al. A Phase II trial of epothilone B analogue BMS/247550 (NSC #710428) ixabepilone in patients with advanced pancreas cancer: A Southwest Oncology Group study. Invest New Drugs (2006) 24:515–520.[CrossRef][Web of Science][Medline]
10. Fojo AT, Menefee ME, Peruchynsky M, et al. A translational study of ixabepilone (BMS-247550) in renal cell cancer (RCC): assessment of its activity and demonstration of target engagement in tumor cells. Proc Am Soc Clin Oncol (2005) 23:388. (abstract 4541).
11. Abraham J, Agrawal M, Bakke S, et al. Phase I trial and pharmacokinetic study of BMS-247550, an Epothilone B analog, administered intravenously on a daily schedule for five days. J Clin Oncol (2003) 21:1866–1873.
12. Mani S, McDaid H, Hamilton A, et al. Phase I clinical and pharmacokinetic study of BMS-247550, a novel derivative of Epothilone B, in solid tumors. Clin Cancer Res (2004) 10:1289–1298.
13. Gadgeel SM, Wozniak A, Boinpally RR, et al. Phase I clinical trial of BMS-247550, a derivative of Epothilone B, using accelerated titration 2B design. Clin Cancer Res (2005) 11:6233–6239.
14. Mekhail T, Chung C, Holden S, et al. Phase I trial of novel epothilone B analog BMS-310705 IV q21 days. Proc Am Soc Clin Oncol (2003) 22:129. abstract 515.
15. Simon R, Freidlin B, Rubinstein RL, et al. Accelerated titration designs for Phase I clinical trials in oncology. J Natl Cancer Inst (1997) 89:1138–1147.
16. Fennelly D, Aghajanian C, Shapiro F, et al. Phase I and pharmacologic study of paclitaxel administered weekly with relapsed ovarian cancer. J Clin Oncol (1997) 11:187–192.
17. de Jonge M, Verweij J. The epothilone dilemma. J Clin Oncol (2005) 23:9048–9050.
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