- Email: [email protected]
Phase I study of the novel, fully synthetic epothilone sagopilone (ZK-EPO) in patients with solid tumors
original article
Annals of Oncology 21: 633–639, 2010 doi:10.1093/annonc/mdp491 Published online 30 October 2009
Phase I study of the novel, fully synthetic epothilone sagopilone (ZK-EPO) in patients with solid tumors P. Schmid1*, P. Kiewe2, K. Possinger3, A. Korfel2, S. Lindemann4, M. Giurescu5, S. Reif6, H. Wiesinger6, E. Thiel2 & D. Ku¨hnhardt3 1
Hammersmith Early Clinical Trials Unit, Charing Cross Hospital, Imperial College London, London, UK; 2Department of Oncology, Hematology and Transfusion Medicine, Charite´ Campus Benjamin Franklin; 3Department of Oncology and Hematology, Charite´ Campus Mitte, Charite´ Universita¨tsmedizin Berlin, Berlin; 4Clinical Pharmacology; 5Global Medical Development Oncology and 6Clinical Pharmacokinetics, Bayer Schering Pharma AG, Berlin, Germany
Received 7 July 2009; revised 27 August 2009; accepted 9 September 2009
antitumor activity in preclinical models. This first-in-human phase I study aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxic effects (DLTs) of 3-weekly sagopilone treatment. Patients and methods: A total of 52 patients with advanced solid tumors received a 30-min infusion of escalating doses of sagopilone (0.6–29.4 mg/m2) every 3 weeks. Nine additional patients were recruited to a 3-h infusion arm (16.53- or 22.0-mg/m2 dose) to assess the incidence of neuropathy with prolonged infusion. Results: The MTD was established as 22.0 mg/m2. DLTs comprised peripheral sensory neuropathy (PNP), infection, hyponatremia, diarrhea, and central ataxia. PNP was the most common grade 3 event, with a similar incidence in the 30-min and 3-h arms. Hematologic adverse events were rare and of low intensity. One confirmed partial response (PR) and one unconfirmed PR were reported in the 30-min arm, and a further unconfirmed PR was observed in the 3-h arm. Eleven patients achieved disease stabilization. Sagopilone showed high levels of tissue binding and no obvious serum accumulation in both arms. Conclusions: These data demonstrate that sagopilone therapy is feasible and well tolerated. The recommended dose for phase II studies is 16.53 mg/m2, once every 3 weeks. Key words: chemotherapy, epothilones, first-in-human study, microtubule-stabilizing agent, phase I study, solid tumors
introduction Microtubules are critical for the correct maintenance of cell structure, signaling, and the formation and function of the mitotic spindle. As a result, microtubules are an established target for novel antitumor drug development. Tubulintargeting agents disrupt the normal dynamic equilibrium of microtubule polymerization and depolymerization, inducing alterations in spindle formation, cell cycle arrest at the G2/M phase, and, ultimately, apoptosis. Although taxanes are longestablished anticancer drugs that induce microtubule polymerization, many human tumors exhibit intrinsic or acquired resistance which necessitates alternative therapeutic approaches [1]. Additionally, the use of Cremophor EL as a vehicle for taxanes and other antineoplastic agents has previously been associated with acute allergic reactions at infusion, as well as neuropathy, dyspnea, and tachycardia, thus requiring premedication to be administered [2].
*Correspondence to: Dr P. Schmid, Hammersmith Early Clinical Trials Unit, Charing Cross Hospital, Imperial College London, Fulham Palace Road, London W6 8RF, UK. Tel: +44-20-8846-1418; Fax: +44-20-8846-1433; E-mail: [email protected]
The epothilones are a novel class of natural products derived from the myxobacterium Sorangium cellulosum that target microtubules [3]. As 16-membered-ring macrolides, they are structurally distinct from taxanes, yet they also induce microtubule polymerization, leading to aberrant spindle formation, mitotic cell cycle arrest, and cell death [4–6]. Unlike taxanes, epothilones are able to retain activity in multidrugresistant cancer cells that overexpress the P-glycoprotein efflux pump [5]. A further advantage of certain epothilones is their increased water solubility, which eliminates the need for formulation with Cremophor EL. Sagopilone (ZK-EPO) is a fully synthetic novel epothilone that was developed to optimize efficacy and tolerability [7]. In vitro, sagopilone is more potent than taxanes and other antitumor agents, with cytotoxic activity observed at sub- or low-nanomolar concentrations [7]. In vivo studies have demonstrated the broad-spectrum antitumor activity of sagopilone in multiple human tumor models, including tumor types that are intrinsically resistant, or have developed resistance, to the taxanes [7]. These data indicate that sagopilone may offer improved efficacy in a range of human cancers in the clinic.
ª The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
original article
Background: Sagopilone (ZK-EPO) is a fully synthetic microtubule-stabilizing agent that has demonstrated high
original article This first-in-human phase I study was designed to establish the maximum tolerated dose (MTD) of sagopilone, administered as a 30-min infusion every 3 weeks to patients with advanced solid tumors refractory to established therapies.
Annals of Oncology
infusion every 21 days. The purpose of this second schedule was to reduce peak serum drug concentrations, as clinical experience with taxanes and other microtubule-stabilizing drugs has indicated that this may reduce the incidence of neuropathy [8, 9]. The same criteria as outlined above were applied for dose escalation and the starting dose was 22.0 mg/m2 sagopilone.
patients and methods study design The primary objective of this phase I study, conducted at two centers, was to determine the MTD and dose-limiting toxic effects (DLTs) of 3-weekly sagopilone administration. Secondary objectives included an assessment of the safety and tolerability, pharmacokinetics, and efficacy of sagopilone. The study was approved by the appropriate independent ethics committee and was conducted in accordance with local regulations, the Declaration of Helsinki, and International Conference on Harmonisation Good Clinical Practice Guidelines.
patient selection Eligible patients were aged ‡18 years, with histologically or cytologically confirmed solid tumors and progressive metastatic or locally advanced disease resistant or refractory to conventional antineoplastic treatment. Inclusion criteria were adequate hematologic, renal, hepatic, and cardiac function [absolute neutrophil count >1.5 · 109/l; platelets >100 · 109/l; hemoglobin level >9 g/dl; increase in serum bilirubin and creatinine level <1.5 · upper limit of normal (ULN); aspartate aminotransferase and alanine aminotransferase <2.5 · ULN in patients without liver involvement or <5.0 · ULN in patients with liver metastases]; World Health Organization (WHO) performance status zero to two; life expectancy ‡3 months; and written informed consent. Patients were excluded from the trial if they had received radiotherapy or major surgery within 2 weeks before study entry or chemotherapy, immunotherapy, or biologic therapy within 4 weeks of study entry. Patients were not eligible if they had other uncontrolled disease, primary brain tumors, active brain metastases, or peripheral sensory neuropathy (PNP) grade >1 [National Cancer Institute–Common Toxicity Criteria (NCI-CTC)].
treatment Sagopilone (30 mg per vial lyophilized powder) was supplied by Bayer Schering Pharma AG (Berlin, Germany) and was administered as a 30-min i.v. infusion every 21 days. Sagopilone treatment was continued until disease progression, evidence of unacceptable toxicity, or patient request to discontinue therapy. Dose escalation was based on a modified Fibonacci design with a starting dose of 0.6 mg/m2 body surface area. Doses were increased by 100%, 67%, 50%, and, thereafter, 33% for successive treatment groups. Dose escalation and determination of the MTD were based on the occurrence of DLTs during cycle 1. DLTs were defined as (i) any grade 3 or 4 non-hematologic toxicity other than nausea, vomiting, or alopecia; (ii) febrile neutropenia or grade 4 neutropenia lasting >5 days; (iii) grade 4 thrombocytopenia; or (iv) any toxicity grade ‡2 that persisted for >5 weeks from drug administration. Patients experiencing DLTs were withdrawn from the trial. At least three patients assessable for toxicity were treated at each dose level. If none of the first three patients experienced a DLT, the next dose level was started. If a DLT occurred in one patient, three additional patients were treated at the same dose. Dose escalation was continued only if a DLT was observed in one patient or less of the expanded cohort. If a DLT occurred in two patients or more, dose escalation was stopped and subsequent patients were treated at the previous dose level. This dose was defined as the MTD if a DLT occurred in one patient or less of six patients. Following the determination of the MTD, the study design was amended to include a second arm in which patients received sagopilone as a 3-h
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assessments Tumor response was assessed using WHO criteria at baseline and at the end of every second treatment cycle. Adverse events and toxic effects were evaluated weekly and recorded for every cycle. They were graded using the NCI-CTC (version 2.0).
pharmacokinetics The serum pharmacokinetics of sagopilone were studied during cycles 1, 2, 4, and 6. In the 30-min arm, blood samples were collected before the start of treatment; 15 min after the beginning of the application; at the end of infusion (0 min); and at 15, 30, 60, and 90 min and 2, 3, 5, 7, 10, 24, 48, 72, 330, and 504 h after the end of infusion. In the 3-h infusion arm, blood samples were taken at baseline; at 15 and 30 min and 1, 2, and 2.9 h after the start of infusion; and at 5, 15, and 30 min and 1, 2, 3, 5, 7, 10, 24, 72, 96, 168, 336, and 504 h after the end of infusion. Serum concentrations of sagopilone were determined by a validated liquid chromatography–mass spectrometry method with a lower limit of quantification of 0.1 ng/ml. Pharmacokinetic evaluation was based on individual serum concentration–time values of sagopilone, and pharmacokinetic parameters were calculated using a commercially available software tool (Kinetika, version 4.2; InnaPhase Corporation, Philadelphia, PA) without recourse to model assumptions.
results patient characteristics Between May 2003 and August 2005, 52 patients were enrolled to the 30-min infusion arm and nine additional patients received sagopilone as a 3-h infusion. Patient baseline characteristics are shown in Table 1. The most common tumor types were head and neck cancer (23%), breast cancer (15%), and colorectal cancer (8%). All but three patients (95%) had previously received systemic antitumor therapy, with 34% of patients having received prior taxanes (Table 1). dose escalation and DLT The 30-min treatment arm. A total of 166 cycles were administered across 12 dose levels (from 0.6 to 29.4 mg/m2), with a median of 2 (range 1–29) cycles per patient. The number of patients treated at each dose is shown in Table 2. Six patients received six or more cycles and 46 (88%) prematurely discontinued treatment at less than six cycles due to disease progression (n = 36), adverse events (n = 7), consent withdrawal (n = 2), or death (n = 1). Adverse events leading to withdrawal included PNP (four patients), central ataxia with PNP (one patient), and infection (two patients). Six patients at dose levels of 3.0, 4.0, and 5.3 mg/m2 were excluded from the per-protocol population because they received a lower dose of sagopilone than planned due to a preparation error by the pharmacy. As the dose escalation had been continued successfully by the time the error was discovered, it was decided to replace patients on dose level 4.0 and 5.3 mg/m2 only but not on dose level 3.0 mg/m2.
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Table 1. Patient characteristics Characteristic Age, years Mean Range Sex, n Male Female WHO performance status, n 0 1 2 Tumor type, n SCCHN Breast cancer Colorectal cancer NSCLC Cholangiocarcinoma Uveal melanoma Others Previous therapy, n Chemotherapy Taxane Platinum therapy Vinca alkaloid therapy Radiotherapy Number of previous systemic therapy regimens, n 0 1 2 3 4 >4
Table 2. Dose escalation 30 min (n = 52)
3 h (n = 9)
59.3 25–80
60.1 50–69
27 25
4 5
23 23 6
3 5 1
12 7 5 4 4 3 17a
2 2 0 0 0 0 5b
49 17 34 11 30
9 4 7 2 7
3 5 13 12 6 13
0 3 0 2 2 2
a
Esophageal cancer, melanoma, pancreatic cancer, adrenal gland cancer (two patients each), small-cell lung cancer, osteosarcoma, mesothelioma, non-melanoma skin cancer, ovarian cancer, endometrial cancer, renal cell cancer, gastric cancer, cancer of unknown primary origin (one patient each). b Vulval adenocarcinoma (two patients), renal cell cancer, gastric cancer, cervical cancer (one patient each). WHO, World Health Organization; SCCHN, squamous cell carcinoma of the head and neck; NSCLC, non-small-cell lung cancer.
DLTs were observed in six patients, affecting one patient each at the 0.6-, 16.53-, and 22.0-mg/m2 doses, respectively, and three patients at the 29.4-mg/m2 dose (Table 3). DLTs comprised infection (one patient), PNP (two patients), PNP in combination with grade 3 central ataxia or grade 3 diarrhea (one patient each), and grade 4 hyponatremia (one patient). The MTD of sagopilone administered as a 30-min infusion once every 3 weeks was identified as 22.0 mg/m2. The 3-h treatment arm. Of the nine patients enrolled on the 3-h infusion arm, five received 22.0 mg/m2 and four received 16.53 mg/m2 sagopilone. All patients received at least one cycle of treatment, with a median of 2 (range 1–4). Five DLTs were
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Dose level (mg/m2)
Treatment arms (n) 30 min (n = 52)
3 h (n = 9)
0.6 1.2 2.0 3.0 4.0 5.3 7.0 9.3 12.4 16.53 22.0 29.4
6 3 3 3a 6b 5c 3 3 3 7 6 4
0 0 0 0 0 0 0 0 0 4 5 0
a
One patient on this dose level was excluded from the analysis as he erroneously received a lower dose of sagopilone. b Three patients on this dose level had to be replaced as they erroneously received a lower dose of sagopilone. c Two patients on this dose level had to be replaced as they erroneously received a lower dose of sagopilone.
observed, all grade 3 PNP, occurring in two patients receiving 16.53 mg/m2 and three patients receiving 22.0 mg/m2 sagopilone (Table 3).
toxicity All patients were assessable for safety. Overall, only a limited number of hematologic adverse events were observed, with no drug-related grade 4 events and very low levels of grade 3 events (Table 4). PNP was the most frequently reported non-hematologic toxicity, and both the incidence and severity of neuropathy events were dose related, with at most one patient affected (grade 1) per group at doses <9.3 mg/m2, one to two patients affected (grade 1/2) per group at doses 9.3 and 12.4 mg/m2, and three or more patients (grades 1–3) per group at doses 16.53, 22.0, and 29.4 mg/m2. During the study, PNP was reported in 21 patients (eight at grade 3) in the 30-min arm and eight patients (five at grade 3) in the 3-h arm; 10 patients discontinued sagopilone therapy due to PNP events. Eight patients had preexisting grade 1 PNP. PNP symptoms were similar to those reported during taxane chemotherapy, and common symptoms included paresthesia, anesthesia, and pain in a ‘glove-and-stocking’ pattern, with the feet more frequently affected. The reversibility of PNP could not be sufficiently investigated after treatment cessation as there were limited opportunities for follow-up due to the advanced disease status of many patients. No neuromotor toxicity was reported, but two patients in the 30-min arm experienced ataxia of central nervous origin, at sagopilone doses of 22.0 mg/m2 (grade 2) and 29.4 mg/m2 (grade 3). Aside from PNP, non-hematologic adverse events were infrequent and generally mild in intensity in both the infusion arms. Grade 3 events included diarrhea, vomiting (two patients each), and nausea (one patient) in the 30-min infusion arm and
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Table 3. Dose-limiting toxic effects Dose level 30 min (n = 52) (mg/m2) No. of patients DLT with DLT/total no. of patients
3 h (n = 9) No. of patients DLT with DLT/total no. of patients
0.6 16.53 22.0 29.4
0 2/4 3/5 0
1/6 1/7 1/6 3/6
Infection PNP PNP Central ataxia with PNP (1) PNP with diarrhea (1) Hyponatremia (1)
0 PNP PNP 0
All events grade 3 except hyponatremia, which was grade 4. DLT, dose-limiting toxic effect; PNP, peripheral sensory neuropathy.
Table 4. Treatment-related hematologic and non-hematologic toxic effects of sagopilone given as a 30-min or 3-h infusion Adverse event (n)
Hematologic adverse events Leukopenia Anemia Lymphopenia Neutropenia Non-hematologic adverse events Peripheral sensory neuropathy Central ataxia Neuropathic pain Myalgia Nausea Vomiting Constipation Diarrhea Arthralgia Fatigue Alopecia Increased c-glutamyltransferase Subileus Hyponatremia Myoclonus
30 min (n = 52) All Grade events ‡3a
3 h (n = 9) All Grade events ‡3a
6 4 3 1
1 0 0 0
0 3 2 2
0 0 1 2
21
8
8
5
2 5 4 13 7 2 3 5 3 2 1 1 1 1
1 2 0 1 2 0 2 0 0 0 0 1 1 1
0 1 2 2 0 1 2 2 2 2 1 0 0 0
0 0 0 0 0 1 0 1 0 0 1 0 0 0
Adverse events were included if incidence was in more than one patient or if reported at grade ‡3. a All events grade 3 except hyponatremia, which was grade 4.
constipation and increased c-glutamyltransferase (one patient each) in the 3-h infusion arm. Although no antiemetic prophylaxis was administered, treatment-related nausea and vomiting were infrequent and predominantly grade 1/2. Hypersensitivity reactions were not observed in either infusion arm, despite the absence of premedication.
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efficacy A total of 36 patients in the 30-min arm and nine patients in the 3-h arm were assessable for response. In the 30-min arm, a partial response (PR) lasting for 130 days was observed in a patient with taxane-pretreated metastatic breast cancer receiving 12.4 mg/m2 sagopilone, and an unconfirmed PR was reported in a patient with taxane-pretreated metastatic breast cancer receiving 16.53 mg/m2 sagopilone. A further unconfirmed PR was observed in a patient with metastatic renal cell cancer at 16.53 mg/m2 sagopilone in the 3-h infusion arm. Stable disease was observed in 11 patients (median duration 87 days, range 42–161 days, at doses 0.6, 1.2, 2.0, 5.3, 9.3, 12.4, and 22.0 mg/m2), with head and neck cancer (five patients), cholangiocarcinoma (two patients), adrenal gland cancer, nonsmall-cell lung cancer, uveal melanoma, and ovarian cancer (one patient each). pharmacokinetics Pharmacokinetic data for both infusion arms (doses 16 and 22 mg/m2 sagopilone) are presented in Table 5 and Figure 1. Sagopilone plasma concentrations peaked after completion of the infusion (30-min or 3-h). Mean concentrations of equivalent sagopilone doses obtained at the end of infusion (Cmax) were approximately five times lower in the 3-h arm compared with the 30-min arm (Figure 1). The sagopilone disposition can be described by a multi-compartmental model, with rapidly decreasing plasma concentrations after the end of infusion (t½ 3 min) and a long terminal disposition phase with plasma half-life (t½) in the range of 52.8–83.4 h. The pharmacokinetic profile of sagopilone appears to be dose linear and independent of infusion rate or duration. The rapid disposition, high volume of distribution (2309–3765 l), and high clearance (665–1232 ml/min) reflect most likely a fast uptake of sagopilone into tissues and a slow release from these tissues. Comparison of Cmax and area under the serum concentration–time curve (AUC) after cycle 1 uncovered no evidence of sagopilone accumulation within the 3-week dosing interval.
discussion This first-in-human phase I study was primarily intended to determine the DLT and MTD of sagopilone, the first fully synthetic epothilone B analogue in clinical development, when administered every 21 days. Sagopilone was found to be safe and well tolerated, with the MTD established at 22.0 mg/m2 administered as a 30-min infusion once every 3 weeks. An additional cohort with a 3-h infusion was evaluated because previous reports with microtubule-stabilizing drugs, including the epothilone B analogue ixabepilone, have indicated that lower peak drug serum concentrations are associated with a decreased incidence of neurotoxic events [9, 10]. The most common DLT and non-hematologic adverse event associated with sagopilone across both arms was PNP. This observation is not unexpected since neuropathy is commonly associated with microtubule-stabilizing agents [11]. The neuropathy reported was mainly grade 1/2, and no grade 4 events or neuromotor toxic effects were observed. The
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Table 5. Pharmacokinetic parameters of sagopilone (16.53 and 22 mg/m2) given as a 30-min or 3-h infusion Infusion duration (h)
Planned dose (mg/m2)
Cmax (ng/ml)
tmax (h)
AUC (ngh/ml)
t½ (h)
CL (ml/min)
Vss (l)
0.5 0.5 3 3
16.53 22.0 16.53 22.0
713 (43.7%) [4] 501 [1] 101 (100%) [3] 81.5 (38.7%) [4]
0.25 0.55 2.02 1.52
390 831 602 563
52.8 62.8 83.4 71.9
1232 662 861 1121
2760 2309 2450 3765
(0.25–0.25) [4] [1] (0.5–2.03) [3] (1.03–2.01) [4]
(17.7%) [3] [1] [1] (23.3%) [3]
(91.1%) [3] [1] [1] (24.3%) [3]
(15.5%) [3] [1] [1] (27.4%) [3]
(81.4%) [3] [1] [1] (64.6%) [3]
All values shown are geometric mean (geometric coefficients of variation in parentheses) except tmax where the median (range) is shown. [n], number of patients with assessable pharmacokinetic parameters; Cmax, maximal serum concentration; tmax, time to reach maximal serum concentration; AUC, area under the serum concentration–time curve; t½, terminal half-life; CL, total body clearance; Vss, volume of distribution.
Mean ± SD 16.53 mg/m 2, 30 minute Mean ± SD 16.53 mg/m 2, 3 hour
B) 1000 Sagopilone (ng/mL)
Sagopilone (ng/mL)
A) 1000
100
10
Mean ± SD 22.0 mg/m 2, 30 minute Mean ± SD 22.0 mg/m 2, 3 hour
100
10
1
1 0
1
3
5
0
8
1
Mean ± SD 16.53 mg/m 2, 30 minute Mean ± SD 16.53 mg/m 2, 3 hour
D) 1000 Sagopilone (ng/mL)
Sagopilone (ng/mL)
C) 1000
3
5
8
Time (h)
Time (h)
100
10
1
Mean ± SD 22.0 mg/m 2 , 30 minute Mean ± SD 22.0 mg/m 2 , 3 hour
100
10
1
0.1
0.1 0 24 48 72 96
168
336
Time (h)
0 24 48 72 96
168
336
Time (h)
Figure 1. Mean concentration–time profiles of sagopilone given as a 30-min or 3-h infusion; (A) 0–8 h at 16.53 mg/m2, (B) 0–8 h at 22.0 mg/m2, (C) 0–336 h at 16.53 mg/m2, and (D) 0–336 h at 22.0 mg/m2.
incidence and type of drug-related neuropathy and neuropathic pain in both the infusion schedules are similar to those previously reported with ixabepilone, with 49%–64% of patients experiencing neuropathy in other phase I studies, including pain in the extremities and sensory disturbances [12–15]. Similar incidences of PNP were reported in phase II (up to 71%) and III (64%) ixabepilone trials [10, 16, 17]. The reversibility of PNP could not be sufficiently investigated after treatment cessation as there were limited opportunities for follow-up due to the advanced disease status of many patients. Ataxia of central nervous origin was observed in two patients and was considered to be sagopilone related due to the ability of sagopilone to cross the blood–brain barrier. However, the patient experiencing grade 3 central ataxia had previously discontinued treatment twice with mitotane due to ataxia. Ataxia has not been widely reported with epothilone B therapy,
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but grade 3 ataxia has previously been associated with KOS862, an epothilone D analogue [18]. Limited population sizes mean that there is insufficient evidence to discount an association between the development of neuropathy and prior taxane treatment or baseline neuropathy events in this study. Several previous studies have indicated that longer paclitaxel and ixabepilone infusion schedules may reduce the incidence of neurotoxic events [8, 9]. In this study, although mean peak concentrations of sagopilone were approximately five-fold lower in the 3-h infusion arm at comparable dose levels, the 3-h infusion did not appear to reduce the level of PNP compared with the 30-min infusion. Associations between longer infusion times and PNP could not be accurately determined, however, due to the small sample size. Other non-hematologic adverse events experienced by patients receiving sagopilone included mild to moderate nausea
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original article and vomiting, which were manageable with standard antiemetic treatments. It is important to note that no antiemetic prophylaxis was administered. Diarrhea is a common DLT for other epothilones [12, 15, 19–21], and it is notable that few patients experienced diarrhea during the sagopilone study reported here. Hematologic adverse events were rarely reported in either infusion schedule and were predominantly of a low grade when they did occur. Neutropenia occurred in only two patients overall, in contrast to previous reports of the epothilones ixabepilone and BMS-310705 for which neutropenia has been shown to be a DLT [9, 12, 15]. A noteworthy advantage of sagopilone therapy is its superior water solubility, which allows formulation without Cremophor EL. Cremophor EL formulation has been widely associated with hypersensitivity reactions as well as clinically important adverse events, such as PNP [2, 12, 15]. No hypersensitivity reactions were observed in this study and premedication was not necessary, indicating that sagopilone does not appear to have intrinsic hypersensitizing properties. These results are supported by early results obtained from sagopilone phase II trials [22–24]. Pharmacokinetic analyses indicate that sagopilone has rapid tissue distribution and extensive tissue binding. The long t½ reported for sagopilone is probably due to the release of the agent from deep tissue compartments rather than the actual rate of metabolism or excretion. The two infusion durations examined were found to produce comparable AUC values; however, as expected, peak serum concentrations of sagopilone were much lower and were reached later in the 3-h treatment arm compared with the 30-min regimen. Due to limited sample sizes, the pharmacokinetic findings of this study require further confirmation. The assessment of efficacy was a secondary objective of this study. One confirmed and two unconfirmed PRs were reported, and disease stabilization was observed in 11 patients. This observation is encouraging considering the small sample size and the level of pretreatment in the patient population. The data presented here represent the first clinical examination of sagopilone treatment and demonstrate that administration once every 3 weeks is feasible and well tolerated. Based on the cycle 1 toxic effects the MTD of sagopilone administered as a 30-min infusion was established as 22.0 mg/m2. Taking into consideration the incidence of relevant toxic effects after cycle 1 and the potential cumulativedose dependency of PNP, however, the recommended starting dose for phase II studies was set at 16.53 mg/m2. Both infusion schedules reported similar safety profiles, but in light of previous reports with other microtubule-targeting agents [8, 9], the 3-h infusion schedule was considered to be preferable for phase II sagopilone trials; in some of these trials further comparisons between the 30-min and 3-h infusions were implemented. Sagopilone is currently being evaluated in a broad phase II program across a wide number of indications. Proof-of-concept has already been established in patients with platinum-resistant ovarian cancer [23] and androgenindependent prostate cancer [24], and clinical responses have been shown in patients with melanoma [25] and small-cell lung cancer [26]. Results are awaited from other ongoing trials.
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funding Bayer Schering Pharma.
acknowledgements The authors would like acknowledge Julia Duffey for providing medical writing support.
references 1. Horwitz SB, Cohen D, Rao S et al. Taxol: mechanisms of action and resistance. J Natl Cancer Inst Monogr 1993; 15: 55–61. 2. ten Tije AJ, Verweij J, Loos WJ et al. Pharmacological effects of formulation vehicles: implications for cancer chemotherapy. Clin Pharmacokinet 2003; 42: 665–685. 3. Gerth K, Bedorf N, Ho¨fle G et al. Epothilons A and B: antifungal and cytotoxic compounds from Sorangium cellulosum (Myxobacteria). Production, physico-chemical and biological properties. J Antibiot (Tokyo) 1996; 49: 560–563. 4. Kowalski RJ, Giannakakou P, Hamel E. Activities of the microtubule-stabilizing agents epothilones A and B with purified tubulin and in cells resistant to paclitaxel (Taxol). J Biol Chem 1997; 272: 2534–2541. 5. Bollag DM, McQueney PA, Zhu J et al. Epothilones, a new class of microtubulestabilizing agents with a taxol-like mechanism of action. Cancer Res 1995; 55: 2325–2333. 6. Lee FYF, Borzilleri R, Fairchild CR et al. BMS-247550: a novel epothilone analog with a mode of action similar to paclitaxel but possessing superior antitumor efficacy. Clin Cancer Res 2001; 7: 1429–1437. 7. Klar U, Buchmann B, Schwede W et al. Total synthesis and antitumor activity of ZK-EPO: the first fully synthetic epothilone in clinical development. Angew Chem Int Ed Engl 2006; 45: 7942–7948. 8. Mielke S, Mross K, Glocker F-X et al. Neurotoxicity of paclitaxel infused weekly over one versus three hours: preliminary results of a phase III trial. Proc Am Soc Clin Oncol 2001; 20: (Abstr 425). 9. Roche´ HH, Cure H, Bunnell C et al. A phase II study of epothilone analog BMS-247550 in patients (pts) with metastatic breast cancer (MBC) previously treated with an anthracycline. Proc Am Soc Clin Oncol 2003; 22: (Abstr 69). 10. Roche´ H, Yelle L, Cognetti F et al. Phase II clinical trial of ixabepilone (BMS247550), an epothilone B analog, as first-line therapy in patients with metastatic breast cancer previously treated with anthracycline chemotherapy. J Clin Oncol 2007; 25: 3415–3420. 11. Marupudi NI, Han JE, Li KW et al. Paclitaxel: a review of adverse toxicities and novel delivery strategies. Expert Opin Drug Saf 2007; 6: 609–621. 12. 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. 13. Aghajanian C, Burris HA III, Jones S et al. Phase I study of the novel epothilone analog ixabepilone (BMS-247550) in patients with advanced solid tumors and lymphomas. J Clin Oncol 2007; 25: 1082–1088. 14. Faivre S, Delbaldo C, Boige V et al. Safety of repeated administrations of ixabepilone given as a 3-hour infusion every other week in combination with irinotecan in patients with advanced malignancies. Eur J Cancer 2008; 44: 674–682. 15. 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. 16. Thomas ES, Gomez HL, Li RK et al. Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol 2007; 25: 5210–5217. 17. Vansteenkiste J, Lara PN Jr., Le Chevalier T et al. Phase II clinical trial of the epothilone B analog, ixabepilone, in patients with non-small-cell lung cancer whose tumors have failed first-line platinum-based chemotherapy. J Clin Oncol 2007; 25: 3448–3455.
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18. Beer TM, Higano CS, Saleh M et al. Phase II study of KOS-862 in patients with metastatic androgen independent prostate cancer previously treated with docetaxel. Invest New Drugs 2007; 25: 565–570. 19. Okuno S, Maples WJ, Mahoney MR et al. Evaluation of epothilone B analog in advanced soft tissue sarcoma: a phase II study of the phase II consortium. J Clin Oncol 2005; 23: 3069–3073. 20. Rubin EH, 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. 21. Zhuang SH, Agrawal M, Edgerly M et al. A phase I clinical trial of ixabepilone (BMS-247550), an epothilone B analog, administered intravenously on a daily schedule for 3 days. Cancer 2005; 103: 1932–1938. 22. Gatzemeier U, von Pawel J, Eschbach C et al. Phase II trial of the novel epothilone sagopilone (ZK-EPO) as second-line therapy in patients with stage IIIB or stage IV non-small-cell lung cancer. In Presented at the ECCO 14. Barcelona, Spain, 23–27 September 2007.
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original article 23. Rustin G, Reed N, Jayson G et al. Phase II trial of sagopilone (ZK-EPO), a novel epothilone, in patients with platinum-resistant ovarian cancer. In Presented at the 15th International Meeting of the European Society for Gynaecological Oncology. Berlin, Germany, 28 October to 1 November 2007. 24. Graff J, Smith DC, Neerukonda L et al. Phase II study of sagopilone (ZK-EPO) plus prednisone as first-line chemotherapy in patients with metastatic androgenindependent prostate cancer. In Presented at the 44th ASCO Annual Meeting. Chicago, IL, 30 May to 3 June 2008. 25. Wenk D, DeConti RC, Urbas P et al. Phase II trial of sagopilone (ZK-EPO), a novel epothilone, in patients with metastatic melanoma. J Clin Oncol 2008; 26: (Abstr 9046). 26. Gauler TC, Christoph D, Gamarra F et al. Phase I study of sagopilone (ZK-EPO) in combination with cisplatin in patients with chemotherapy-naı¨ve extensivedisease small-cell lung cancer (ED-SCLC). Ann Oncol 2008; 19 (Suppl 8): (Abstr 331P).
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Annals of Oncology 21: 633–639, 2010 doi:10.1093/annonc/mdp491 Published online 30 October 2009
Phase I study of the novel, fully synthetic epothilone sagopilone (ZK-EPO) in patients with solid tumors P. Schmid1*, P. Kiewe2, K. Possinger3, A. Korfel2, S. Lindemann4, M. Giurescu5, S. Reif6, H. Wiesinger6, E. Thiel2 & D. Ku¨hnhardt3 1
Hammersmith Early Clinical Trials Unit, Charing Cross Hospital, Imperial College London, London, UK; 2Department of Oncology, Hematology and Transfusion Medicine, Charite´ Campus Benjamin Franklin; 3Department of Oncology and Hematology, Charite´ Campus Mitte, Charite´ Universita¨tsmedizin Berlin, Berlin; 4Clinical Pharmacology; 5Global Medical Development Oncology and 6Clinical Pharmacokinetics, Bayer Schering Pharma AG, Berlin, Germany
Received 7 July 2009; revised 27 August 2009; accepted 9 September 2009
antitumor activity in preclinical models. This first-in-human phase I study aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxic effects (DLTs) of 3-weekly sagopilone treatment. Patients and methods: A total of 52 patients with advanced solid tumors received a 30-min infusion of escalating doses of sagopilone (0.6–29.4 mg/m2) every 3 weeks. Nine additional patients were recruited to a 3-h infusion arm (16.53- or 22.0-mg/m2 dose) to assess the incidence of neuropathy with prolonged infusion. Results: The MTD was established as 22.0 mg/m2. DLTs comprised peripheral sensory neuropathy (PNP), infection, hyponatremia, diarrhea, and central ataxia. PNP was the most common grade 3 event, with a similar incidence in the 30-min and 3-h arms. Hematologic adverse events were rare and of low intensity. One confirmed partial response (PR) and one unconfirmed PR were reported in the 30-min arm, and a further unconfirmed PR was observed in the 3-h arm. Eleven patients achieved disease stabilization. Sagopilone showed high levels of tissue binding and no obvious serum accumulation in both arms. Conclusions: These data demonstrate that sagopilone therapy is feasible and well tolerated. The recommended dose for phase II studies is 16.53 mg/m2, once every 3 weeks. Key words: chemotherapy, epothilones, first-in-human study, microtubule-stabilizing agent, phase I study, solid tumors
introduction Microtubules are critical for the correct maintenance of cell structure, signaling, and the formation and function of the mitotic spindle. As a result, microtubules are an established target for novel antitumor drug development. Tubulintargeting agents disrupt the normal dynamic equilibrium of microtubule polymerization and depolymerization, inducing alterations in spindle formation, cell cycle arrest at the G2/M phase, and, ultimately, apoptosis. Although taxanes are longestablished anticancer drugs that induce microtubule polymerization, many human tumors exhibit intrinsic or acquired resistance which necessitates alternative therapeutic approaches [1]. Additionally, the use of Cremophor EL as a vehicle for taxanes and other antineoplastic agents has previously been associated with acute allergic reactions at infusion, as well as neuropathy, dyspnea, and tachycardia, thus requiring premedication to be administered [2].
*Correspondence to: Dr P. Schmid, Hammersmith Early Clinical Trials Unit, Charing Cross Hospital, Imperial College London, Fulham Palace Road, London W6 8RF, UK. Tel: +44-20-8846-1418; Fax: +44-20-8846-1433; E-mail: [email protected]
The epothilones are a novel class of natural products derived from the myxobacterium Sorangium cellulosum that target microtubules [3]. As 16-membered-ring macrolides, they are structurally distinct from taxanes, yet they also induce microtubule polymerization, leading to aberrant spindle formation, mitotic cell cycle arrest, and cell death [4–6]. Unlike taxanes, epothilones are able to retain activity in multidrugresistant cancer cells that overexpress the P-glycoprotein efflux pump [5]. A further advantage of certain epothilones is their increased water solubility, which eliminates the need for formulation with Cremophor EL. Sagopilone (ZK-EPO) is a fully synthetic novel epothilone that was developed to optimize efficacy and tolerability [7]. In vitro, sagopilone is more potent than taxanes and other antitumor agents, with cytotoxic activity observed at sub- or low-nanomolar concentrations [7]. In vivo studies have demonstrated the broad-spectrum antitumor activity of sagopilone in multiple human tumor models, including tumor types that are intrinsically resistant, or have developed resistance, to the taxanes [7]. These data indicate that sagopilone may offer improved efficacy in a range of human cancers in the clinic.
ª The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
original article
Background: Sagopilone (ZK-EPO) is a fully synthetic microtubule-stabilizing agent that has demonstrated high
original article This first-in-human phase I study was designed to establish the maximum tolerated dose (MTD) of sagopilone, administered as a 30-min infusion every 3 weeks to patients with advanced solid tumors refractory to established therapies.
Annals of Oncology
infusion every 21 days. The purpose of this second schedule was to reduce peak serum drug concentrations, as clinical experience with taxanes and other microtubule-stabilizing drugs has indicated that this may reduce the incidence of neuropathy [8, 9]. The same criteria as outlined above were applied for dose escalation and the starting dose was 22.0 mg/m2 sagopilone.
patients and methods study design The primary objective of this phase I study, conducted at two centers, was to determine the MTD and dose-limiting toxic effects (DLTs) of 3-weekly sagopilone administration. Secondary objectives included an assessment of the safety and tolerability, pharmacokinetics, and efficacy of sagopilone. The study was approved by the appropriate independent ethics committee and was conducted in accordance with local regulations, the Declaration of Helsinki, and International Conference on Harmonisation Good Clinical Practice Guidelines.
patient selection Eligible patients were aged ‡18 years, with histologically or cytologically confirmed solid tumors and progressive metastatic or locally advanced disease resistant or refractory to conventional antineoplastic treatment. Inclusion criteria were adequate hematologic, renal, hepatic, and cardiac function [absolute neutrophil count >1.5 · 109/l; platelets >100 · 109/l; hemoglobin level >9 g/dl; increase in serum bilirubin and creatinine level <1.5 · upper limit of normal (ULN); aspartate aminotransferase and alanine aminotransferase <2.5 · ULN in patients without liver involvement or <5.0 · ULN in patients with liver metastases]; World Health Organization (WHO) performance status zero to two; life expectancy ‡3 months; and written informed consent. Patients were excluded from the trial if they had received radiotherapy or major surgery within 2 weeks before study entry or chemotherapy, immunotherapy, or biologic therapy within 4 weeks of study entry. Patients were not eligible if they had other uncontrolled disease, primary brain tumors, active brain metastases, or peripheral sensory neuropathy (PNP) grade >1 [National Cancer Institute–Common Toxicity Criteria (NCI-CTC)].
treatment Sagopilone (30 mg per vial lyophilized powder) was supplied by Bayer Schering Pharma AG (Berlin, Germany) and was administered as a 30-min i.v. infusion every 21 days. Sagopilone treatment was continued until disease progression, evidence of unacceptable toxicity, or patient request to discontinue therapy. Dose escalation was based on a modified Fibonacci design with a starting dose of 0.6 mg/m2 body surface area. Doses were increased by 100%, 67%, 50%, and, thereafter, 33% for successive treatment groups. Dose escalation and determination of the MTD were based on the occurrence of DLTs during cycle 1. DLTs were defined as (i) any grade 3 or 4 non-hematologic toxicity other than nausea, vomiting, or alopecia; (ii) febrile neutropenia or grade 4 neutropenia lasting >5 days; (iii) grade 4 thrombocytopenia; or (iv) any toxicity grade ‡2 that persisted for >5 weeks from drug administration. Patients experiencing DLTs were withdrawn from the trial. At least three patients assessable for toxicity were treated at each dose level. If none of the first three patients experienced a DLT, the next dose level was started. If a DLT occurred in one patient, three additional patients were treated at the same dose. Dose escalation was continued only if a DLT was observed in one patient or less of the expanded cohort. If a DLT occurred in two patients or more, dose escalation was stopped and subsequent patients were treated at the previous dose level. This dose was defined as the MTD if a DLT occurred in one patient or less of six patients. Following the determination of the MTD, the study design was amended to include a second arm in which patients received sagopilone as a 3-h
634 | Schmid et al.
assessments Tumor response was assessed using WHO criteria at baseline and at the end of every second treatment cycle. Adverse events and toxic effects were evaluated weekly and recorded for every cycle. They were graded using the NCI-CTC (version 2.0).
pharmacokinetics The serum pharmacokinetics of sagopilone were studied during cycles 1, 2, 4, and 6. In the 30-min arm, blood samples were collected before the start of treatment; 15 min after the beginning of the application; at the end of infusion (0 min); and at 15, 30, 60, and 90 min and 2, 3, 5, 7, 10, 24, 48, 72, 330, and 504 h after the end of infusion. In the 3-h infusion arm, blood samples were taken at baseline; at 15 and 30 min and 1, 2, and 2.9 h after the start of infusion; and at 5, 15, and 30 min and 1, 2, 3, 5, 7, 10, 24, 72, 96, 168, 336, and 504 h after the end of infusion. Serum concentrations of sagopilone were determined by a validated liquid chromatography–mass spectrometry method with a lower limit of quantification of 0.1 ng/ml. Pharmacokinetic evaluation was based on individual serum concentration–time values of sagopilone, and pharmacokinetic parameters were calculated using a commercially available software tool (Kinetika, version 4.2; InnaPhase Corporation, Philadelphia, PA) without recourse to model assumptions.
results patient characteristics Between May 2003 and August 2005, 52 patients were enrolled to the 30-min infusion arm and nine additional patients received sagopilone as a 3-h infusion. Patient baseline characteristics are shown in Table 1. The most common tumor types were head and neck cancer (23%), breast cancer (15%), and colorectal cancer (8%). All but three patients (95%) had previously received systemic antitumor therapy, with 34% of patients having received prior taxanes (Table 1). dose escalation and DLT The 30-min treatment arm. A total of 166 cycles were administered across 12 dose levels (from 0.6 to 29.4 mg/m2), with a median of 2 (range 1–29) cycles per patient. The number of patients treated at each dose is shown in Table 2. Six patients received six or more cycles and 46 (88%) prematurely discontinued treatment at less than six cycles due to disease progression (n = 36), adverse events (n = 7), consent withdrawal (n = 2), or death (n = 1). Adverse events leading to withdrawal included PNP (four patients), central ataxia with PNP (one patient), and infection (two patients). Six patients at dose levels of 3.0, 4.0, and 5.3 mg/m2 were excluded from the per-protocol population because they received a lower dose of sagopilone than planned due to a preparation error by the pharmacy. As the dose escalation had been continued successfully by the time the error was discovered, it was decided to replace patients on dose level 4.0 and 5.3 mg/m2 only but not on dose level 3.0 mg/m2.
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Table 1. Patient characteristics Characteristic Age, years Mean Range Sex, n Male Female WHO performance status, n 0 1 2 Tumor type, n SCCHN Breast cancer Colorectal cancer NSCLC Cholangiocarcinoma Uveal melanoma Others Previous therapy, n Chemotherapy Taxane Platinum therapy Vinca alkaloid therapy Radiotherapy Number of previous systemic therapy regimens, n 0 1 2 3 4 >4
Table 2. Dose escalation 30 min (n = 52)
3 h (n = 9)
59.3 25–80
60.1 50–69
27 25
4 5
23 23 6
3 5 1
12 7 5 4 4 3 17a
2 2 0 0 0 0 5b
49 17 34 11 30
9 4 7 2 7
3 5 13 12 6 13
0 3 0 2 2 2
a
Esophageal cancer, melanoma, pancreatic cancer, adrenal gland cancer (two patients each), small-cell lung cancer, osteosarcoma, mesothelioma, non-melanoma skin cancer, ovarian cancer, endometrial cancer, renal cell cancer, gastric cancer, cancer of unknown primary origin (one patient each). b Vulval adenocarcinoma (two patients), renal cell cancer, gastric cancer, cervical cancer (one patient each). WHO, World Health Organization; SCCHN, squamous cell carcinoma of the head and neck; NSCLC, non-small-cell lung cancer.
DLTs were observed in six patients, affecting one patient each at the 0.6-, 16.53-, and 22.0-mg/m2 doses, respectively, and three patients at the 29.4-mg/m2 dose (Table 3). DLTs comprised infection (one patient), PNP (two patients), PNP in combination with grade 3 central ataxia or grade 3 diarrhea (one patient each), and grade 4 hyponatremia (one patient). The MTD of sagopilone administered as a 30-min infusion once every 3 weeks was identified as 22.0 mg/m2. The 3-h treatment arm. Of the nine patients enrolled on the 3-h infusion arm, five received 22.0 mg/m2 and four received 16.53 mg/m2 sagopilone. All patients received at least one cycle of treatment, with a median of 2 (range 1–4). Five DLTs were
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Dose level (mg/m2)
Treatment arms (n) 30 min (n = 52)
3 h (n = 9)
0.6 1.2 2.0 3.0 4.0 5.3 7.0 9.3 12.4 16.53 22.0 29.4
6 3 3 3a 6b 5c 3 3 3 7 6 4
0 0 0 0 0 0 0 0 0 4 5 0
a
One patient on this dose level was excluded from the analysis as he erroneously received a lower dose of sagopilone. b Three patients on this dose level had to be replaced as they erroneously received a lower dose of sagopilone. c Two patients on this dose level had to be replaced as they erroneously received a lower dose of sagopilone.
observed, all grade 3 PNP, occurring in two patients receiving 16.53 mg/m2 and three patients receiving 22.0 mg/m2 sagopilone (Table 3).
toxicity All patients were assessable for safety. Overall, only a limited number of hematologic adverse events were observed, with no drug-related grade 4 events and very low levels of grade 3 events (Table 4). PNP was the most frequently reported non-hematologic toxicity, and both the incidence and severity of neuropathy events were dose related, with at most one patient affected (grade 1) per group at doses <9.3 mg/m2, one to two patients affected (grade 1/2) per group at doses 9.3 and 12.4 mg/m2, and three or more patients (grades 1–3) per group at doses 16.53, 22.0, and 29.4 mg/m2. During the study, PNP was reported in 21 patients (eight at grade 3) in the 30-min arm and eight patients (five at grade 3) in the 3-h arm; 10 patients discontinued sagopilone therapy due to PNP events. Eight patients had preexisting grade 1 PNP. PNP symptoms were similar to those reported during taxane chemotherapy, and common symptoms included paresthesia, anesthesia, and pain in a ‘glove-and-stocking’ pattern, with the feet more frequently affected. The reversibility of PNP could not be sufficiently investigated after treatment cessation as there were limited opportunities for follow-up due to the advanced disease status of many patients. No neuromotor toxicity was reported, but two patients in the 30-min arm experienced ataxia of central nervous origin, at sagopilone doses of 22.0 mg/m2 (grade 2) and 29.4 mg/m2 (grade 3). Aside from PNP, non-hematologic adverse events were infrequent and generally mild in intensity in both the infusion arms. Grade 3 events included diarrhea, vomiting (two patients each), and nausea (one patient) in the 30-min infusion arm and
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Table 3. Dose-limiting toxic effects Dose level 30 min (n = 52) (mg/m2) No. of patients DLT with DLT/total no. of patients
3 h (n = 9) No. of patients DLT with DLT/total no. of patients
0.6 16.53 22.0 29.4
0 2/4 3/5 0
1/6 1/7 1/6 3/6
Infection PNP PNP Central ataxia with PNP (1) PNP with diarrhea (1) Hyponatremia (1)
0 PNP PNP 0
All events grade 3 except hyponatremia, which was grade 4. DLT, dose-limiting toxic effect; PNP, peripheral sensory neuropathy.
Table 4. Treatment-related hematologic and non-hematologic toxic effects of sagopilone given as a 30-min or 3-h infusion Adverse event (n)
Hematologic adverse events Leukopenia Anemia Lymphopenia Neutropenia Non-hematologic adverse events Peripheral sensory neuropathy Central ataxia Neuropathic pain Myalgia Nausea Vomiting Constipation Diarrhea Arthralgia Fatigue Alopecia Increased c-glutamyltransferase Subileus Hyponatremia Myoclonus
30 min (n = 52) All Grade events ‡3a
3 h (n = 9) All Grade events ‡3a
6 4 3 1
1 0 0 0
0 3 2 2
0 0 1 2
21
8
8
5
2 5 4 13 7 2 3 5 3 2 1 1 1 1
1 2 0 1 2 0 2 0 0 0 0 1 1 1
0 1 2 2 0 1 2 2 2 2 1 0 0 0
0 0 0 0 0 1 0 1 0 0 1 0 0 0
Adverse events were included if incidence was in more than one patient or if reported at grade ‡3. a All events grade 3 except hyponatremia, which was grade 4.
constipation and increased c-glutamyltransferase (one patient each) in the 3-h infusion arm. Although no antiemetic prophylaxis was administered, treatment-related nausea and vomiting were infrequent and predominantly grade 1/2. Hypersensitivity reactions were not observed in either infusion arm, despite the absence of premedication.
636 | Schmid et al.
efficacy A total of 36 patients in the 30-min arm and nine patients in the 3-h arm were assessable for response. In the 30-min arm, a partial response (PR) lasting for 130 days was observed in a patient with taxane-pretreated metastatic breast cancer receiving 12.4 mg/m2 sagopilone, and an unconfirmed PR was reported in a patient with taxane-pretreated metastatic breast cancer receiving 16.53 mg/m2 sagopilone. A further unconfirmed PR was observed in a patient with metastatic renal cell cancer at 16.53 mg/m2 sagopilone in the 3-h infusion arm. Stable disease was observed in 11 patients (median duration 87 days, range 42–161 days, at doses 0.6, 1.2, 2.0, 5.3, 9.3, 12.4, and 22.0 mg/m2), with head and neck cancer (five patients), cholangiocarcinoma (two patients), adrenal gland cancer, nonsmall-cell lung cancer, uveal melanoma, and ovarian cancer (one patient each). pharmacokinetics Pharmacokinetic data for both infusion arms (doses 16 and 22 mg/m2 sagopilone) are presented in Table 5 and Figure 1. Sagopilone plasma concentrations peaked after completion of the infusion (30-min or 3-h). Mean concentrations of equivalent sagopilone doses obtained at the end of infusion (Cmax) were approximately five times lower in the 3-h arm compared with the 30-min arm (Figure 1). The sagopilone disposition can be described by a multi-compartmental model, with rapidly decreasing plasma concentrations after the end of infusion (t½ 3 min) and a long terminal disposition phase with plasma half-life (t½) in the range of 52.8–83.4 h. The pharmacokinetic profile of sagopilone appears to be dose linear and independent of infusion rate or duration. The rapid disposition, high volume of distribution (2309–3765 l), and high clearance (665–1232 ml/min) reflect most likely a fast uptake of sagopilone into tissues and a slow release from these tissues. Comparison of Cmax and area under the serum concentration–time curve (AUC) after cycle 1 uncovered no evidence of sagopilone accumulation within the 3-week dosing interval.
discussion This first-in-human phase I study was primarily intended to determine the DLT and MTD of sagopilone, the first fully synthetic epothilone B analogue in clinical development, when administered every 21 days. Sagopilone was found to be safe and well tolerated, with the MTD established at 22.0 mg/m2 administered as a 30-min infusion once every 3 weeks. An additional cohort with a 3-h infusion was evaluated because previous reports with microtubule-stabilizing drugs, including the epothilone B analogue ixabepilone, have indicated that lower peak drug serum concentrations are associated with a decreased incidence of neurotoxic events [9, 10]. The most common DLT and non-hematologic adverse event associated with sagopilone across both arms was PNP. This observation is not unexpected since neuropathy is commonly associated with microtubule-stabilizing agents [11]. The neuropathy reported was mainly grade 1/2, and no grade 4 events or neuromotor toxic effects were observed. The
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Table 5. Pharmacokinetic parameters of sagopilone (16.53 and 22 mg/m2) given as a 30-min or 3-h infusion Infusion duration (h)
Planned dose (mg/m2)
Cmax (ng/ml)
tmax (h)
AUC (ngh/ml)
t½ (h)
CL (ml/min)
Vss (l)
0.5 0.5 3 3
16.53 22.0 16.53 22.0
713 (43.7%) [4] 501 [1] 101 (100%) [3] 81.5 (38.7%) [4]
0.25 0.55 2.02 1.52
390 831 602 563
52.8 62.8 83.4 71.9
1232 662 861 1121
2760 2309 2450 3765
(0.25–0.25) [4] [1] (0.5–2.03) [3] (1.03–2.01) [4]
(17.7%) [3] [1] [1] (23.3%) [3]
(91.1%) [3] [1] [1] (24.3%) [3]
(15.5%) [3] [1] [1] (27.4%) [3]
(81.4%) [3] [1] [1] (64.6%) [3]
All values shown are geometric mean (geometric coefficients of variation in parentheses) except tmax where the median (range) is shown. [n], number of patients with assessable pharmacokinetic parameters; Cmax, maximal serum concentration; tmax, time to reach maximal serum concentration; AUC, area under the serum concentration–time curve; t½, terminal half-life; CL, total body clearance; Vss, volume of distribution.
Mean ± SD 16.53 mg/m 2, 30 minute Mean ± SD 16.53 mg/m 2, 3 hour
B) 1000 Sagopilone (ng/mL)
Sagopilone (ng/mL)
A) 1000
100
10
Mean ± SD 22.0 mg/m 2, 30 minute Mean ± SD 22.0 mg/m 2, 3 hour
100
10
1
1 0
1
3
5
0
8
1
Mean ± SD 16.53 mg/m 2, 30 minute Mean ± SD 16.53 mg/m 2, 3 hour
D) 1000 Sagopilone (ng/mL)
Sagopilone (ng/mL)
C) 1000
3
5
8
Time (h)
Time (h)
100
10
1
Mean ± SD 22.0 mg/m 2 , 30 minute Mean ± SD 22.0 mg/m 2 , 3 hour
100
10
1
0.1
0.1 0 24 48 72 96
168
336
Time (h)
0 24 48 72 96
168
336
Time (h)
Figure 1. Mean concentration–time profiles of sagopilone given as a 30-min or 3-h infusion; (A) 0–8 h at 16.53 mg/m2, (B) 0–8 h at 22.0 mg/m2, (C) 0–336 h at 16.53 mg/m2, and (D) 0–336 h at 22.0 mg/m2.
incidence and type of drug-related neuropathy and neuropathic pain in both the infusion schedules are similar to those previously reported with ixabepilone, with 49%–64% of patients experiencing neuropathy in other phase I studies, including pain in the extremities and sensory disturbances [12–15]. Similar incidences of PNP were reported in phase II (up to 71%) and III (64%) ixabepilone trials [10, 16, 17]. The reversibility of PNP could not be sufficiently investigated after treatment cessation as there were limited opportunities for follow-up due to the advanced disease status of many patients. Ataxia of central nervous origin was observed in two patients and was considered to be sagopilone related due to the ability of sagopilone to cross the blood–brain barrier. However, the patient experiencing grade 3 central ataxia had previously discontinued treatment twice with mitotane due to ataxia. Ataxia has not been widely reported with epothilone B therapy,
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but grade 3 ataxia has previously been associated with KOS862, an epothilone D analogue [18]. Limited population sizes mean that there is insufficient evidence to discount an association between the development of neuropathy and prior taxane treatment or baseline neuropathy events in this study. Several previous studies have indicated that longer paclitaxel and ixabepilone infusion schedules may reduce the incidence of neurotoxic events [8, 9]. In this study, although mean peak concentrations of sagopilone were approximately five-fold lower in the 3-h infusion arm at comparable dose levels, the 3-h infusion did not appear to reduce the level of PNP compared with the 30-min infusion. Associations between longer infusion times and PNP could not be accurately determined, however, due to the small sample size. Other non-hematologic adverse events experienced by patients receiving sagopilone included mild to moderate nausea
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original article and vomiting, which were manageable with standard antiemetic treatments. It is important to note that no antiemetic prophylaxis was administered. Diarrhea is a common DLT for other epothilones [12, 15, 19–21], and it is notable that few patients experienced diarrhea during the sagopilone study reported here. Hematologic adverse events were rarely reported in either infusion schedule and were predominantly of a low grade when they did occur. Neutropenia occurred in only two patients overall, in contrast to previous reports of the epothilones ixabepilone and BMS-310705 for which neutropenia has been shown to be a DLT [9, 12, 15]. A noteworthy advantage of sagopilone therapy is its superior water solubility, which allows formulation without Cremophor EL. Cremophor EL formulation has been widely associated with hypersensitivity reactions as well as clinically important adverse events, such as PNP [2, 12, 15]. No hypersensitivity reactions were observed in this study and premedication was not necessary, indicating that sagopilone does not appear to have intrinsic hypersensitizing properties. These results are supported by early results obtained from sagopilone phase II trials [22–24]. Pharmacokinetic analyses indicate that sagopilone has rapid tissue distribution and extensive tissue binding. The long t½ reported for sagopilone is probably due to the release of the agent from deep tissue compartments rather than the actual rate of metabolism or excretion. The two infusion durations examined were found to produce comparable AUC values; however, as expected, peak serum concentrations of sagopilone were much lower and were reached later in the 3-h treatment arm compared with the 30-min regimen. Due to limited sample sizes, the pharmacokinetic findings of this study require further confirmation. The assessment of efficacy was a secondary objective of this study. One confirmed and two unconfirmed PRs were reported, and disease stabilization was observed in 11 patients. This observation is encouraging considering the small sample size and the level of pretreatment in the patient population. The data presented here represent the first clinical examination of sagopilone treatment and demonstrate that administration once every 3 weeks is feasible and well tolerated. Based on the cycle 1 toxic effects the MTD of sagopilone administered as a 30-min infusion was established as 22.0 mg/m2. Taking into consideration the incidence of relevant toxic effects after cycle 1 and the potential cumulativedose dependency of PNP, however, the recommended starting dose for phase II studies was set at 16.53 mg/m2. Both infusion schedules reported similar safety profiles, but in light of previous reports with other microtubule-targeting agents [8, 9], the 3-h infusion schedule was considered to be preferable for phase II sagopilone trials; in some of these trials further comparisons between the 30-min and 3-h infusions were implemented. Sagopilone is currently being evaluated in a broad phase II program across a wide number of indications. Proof-of-concept has already been established in patients with platinum-resistant ovarian cancer [23] and androgenindependent prostate cancer [24], and clinical responses have been shown in patients with melanoma [25] and small-cell lung cancer [26]. Results are awaited from other ongoing trials.
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funding Bayer Schering Pharma.
acknowledgements The authors would like acknowledge Julia Duffey for providing medical writing support.
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original article 23. Rustin G, Reed N, Jayson G et al. Phase II trial of sagopilone (ZK-EPO), a novel epothilone, in patients with platinum-resistant ovarian cancer. In Presented at the 15th International Meeting of the European Society for Gynaecological Oncology. Berlin, Germany, 28 October to 1 November 2007. 24. Graff J, Smith DC, Neerukonda L et al. Phase II study of sagopilone (ZK-EPO) plus prednisone as first-line chemotherapy in patients with metastatic androgenindependent prostate cancer. In Presented at the 44th ASCO Annual Meeting. Chicago, IL, 30 May to 3 June 2008. 25. Wenk D, DeConti RC, Urbas P et al. Phase II trial of sagopilone (ZK-EPO), a novel epothilone, in patients with metastatic melanoma. J Clin Oncol 2008; 26: (Abstr 9046). 26. Gauler TC, Christoph D, Gamarra F et al. Phase I study of sagopilone (ZK-EPO) in combination with cisplatin in patients with chemotherapy-naı¨ve extensivedisease small-cell lung cancer (ED-SCLC). Ann Oncol 2008; 19 (Suppl 8): (Abstr 331P).
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