A phase II study of ispinesib (SB-715992) in patients with metastatic or recurrent malignant melanoma:a National Cancer Institute of Canada Clinical Trials Group trial
Christopher W. Lee • Karl Bélanger • Sanjay C. Rao • Teresa M. Petrella • Richard G. Tozer • Lori Wood • Kerry J. Savage • Elizabeth A. Eisenhauer •
Timothy W. Synold • Nancy Wainman • Lesley Seymour
Received: 1 August 2007 / Accepted: 10 October 2007 / Published online: 26 October 2007
Ⓒ Springer Science + Business Media, LLC 2007
Summary To assess the response rate and toxicity of the kinesin spindle protein (KSP) inhibitor, ispinesib, in malig- nant melanoma. Seventeen patients were enrolled from April to November 2005. Ispinesib was administered as a 1-hour infusion at a dose of 18 mg/m2 once every 3 weeks until disease progression. No objective responses were seen. Six patients (35%) had a best response of stable disease for a median duration of 2.8 months. Disease progression was documented in 9 (53%) after 1 or 2 cycles. Eighty-eight
percent of patients received ≥90% of planned dose intensity. Grade 3 non-hematologic toxicities included dizziness (1) and blurred vision (1). There was one episode of febrile neutropenia, but no grade 3 or 4 biochemical adverse events. Pharmacokinetics was consistent with prior studies. KSP immunoreactivity was seen in 14 of 16 available archival tissue samples (88%). Ispinesib can be safely administered using the dose and schedule employed, with mild hemato- logic and non-hematologic toxicity. No objective responses
C. W. Lee (*)
BC Cancer Agency – Fraser Valley Centre, 13750 96th Avenue,
Surrey, BC, Canada V3V 1Z2 e-mail: [email protected]
K. Bélanger
Centre Hospitalier de l’Université de Montréal, Hôpital Notre-Dame,
1560 Sherbrooke Street East, Montreal, QC, Canada H2L 4M1
S. C. Rao
BC Cancer Agency – Centre for the Southern Interior, 399 Royal Avenue,
Kelowna, BC, Canada V1Y 5L3
T. M. Petrella
Odette Cancer Centre, 2075 Bayview Avenue,
Toronto, ON, Canada M4N 3M5
R. G. Tozer
Juravinski Cancer Centre, 699 Concession Street,
Hamilton, ON, Canada L8V 5C2
L. Wood
Queen Elizabeth II Health Sciences Centre, 1278 Tower Road, 4th Floor Bethune Building, Halifax, NS, Canada B3H 2Y9
K. J. Savage
BC Cancer Agency – Vancouver Centre, 600 West 10th Avenue,
Vancouver, BC, Canada V5Z 4E6
E. A. Eisenhauer : N. Wainman : L. Seymour
National Cancer Institute of Canada Clinical Trials Group, Queen’s University,
10 Stuart Street,
Kingston, ON, Canada K7L 3N6
T. W. Synold
City of Hope National Medical Center, 1500 East Duarte Road,
Duarte, CA 91010, USA
were observed, and further development of single-agent ispinesib in malignant melanoma is not recommended. Although KSP expression appears to be common in melanoma, KSP may not be a suitable target for its treatment.
Keywords Ispinesib . Kinesin spindle protein . Melanoma . Phase II trial
Introduction
The incidence of malignant melanoma has increased in the last decade [1, 2]. A significant proportion of individuals has advanced disease at presentation or suffers a relapse not amenable to curative resection, with 5-year survival rates less than 10% [3]. Standard treatment with single-agent dacarbazine results in tumor response rates of 20% at best, and the duration of response is typically a few months [4]. Biologic agents such as interleukin-2 may produce durable responses, but only in a minority of highly selected patients [5]. Combination chemotherapy and biochemotherapy are more likely to achieve tumor response, but are not associated with a survival benefit when compared to dacarbazine alone [6]. Overall, the impact of current therapeutic strategies for advanced malignant melanoma is limited.
Chemotherapy agents that affect microtubule formation, such as the vinca alkaloids and taxanes, have demonstrated single-agent activity in treatment of metastatic melanoma, with reported objective response rates comparable to those seen with dacarbazine [7–11]. There is particular interest in the combination of paclitaxel and carboplatin in first- and second-line therapy based on recent studies [12, 13].
Ispinesib (SB-715992) is a novel agent that is a potent and selective inhibitor of the kinesin spindle protein (KSP). KSP is required for assembly of microtubules into the mitotic spindle, necessary for cells to progress through mitosis, and is only active during mitosis. Prolonged inhibition of KSP leads to activation of the spindle assembly checkpoint and apoptosis [14]. Inhibitors of KSP have demonstrated antitumor activity in vitro, includ- ing in paclitaxel-resistant cell lines [15, 16].
Ispinesib is administered intravenously and appears to be reasonably well tolerated. The most significant side effects encountered in phase I trials have been myelosuppression, diarrhea and mild fatigue [17–19]. Unlike with vinca alkaloids and taxanes, side effects related to interference with tubulin function in non-dividing cells, such as neu- rotoxicity, have not been problematic.
A drug targeting KSP warranted assessment in malignant melanoma. Accordingly, the National Cancer Institute of Canada Clinical Trials Group conducted a phase II trial
evaluating the efficacy of ispinesib in patients with meta- static or recurrent disease.
Patients and methods
Study design
This was an open-label phase II trial. The primary objective was to evaluate the efficacy of ispinesib in metastatic melanoma by determining the tumor response rate (com- plete and partial responses). Secondary objectives were to assess the toxicity of ispinesib, characterize its population pharmacokinetics, and describe the relationship between KSP immunoreactivity and clinical outcomes.
Patient eligibility
Patients were required to have histologically proven melanoma with documented evidence of metastatic or recurrent disease deemed to be incurable by standard therapies, such as metastatectomy. Individuals with meta- static ocular or mucosal melanoma were permitted to enroll. Other eligibility criteria included: age ≥18 years; an Eastern Cooperative Oncology Group (ECOG) perfor- mance status of 0, 1 or 2; life expectancy of at least 12 weeks; and adequate hematologic, renal and biochem- ical parameters. Specifically, absolute granulocyte count
≥1.5×109/L and platelet count ≥100×109/L; serum creati- nine ≤1.5 times the upper limit of normal; serum bilirubin normal; and aspartate and alanine aminotransferases ≤2.5 times the upper limit of normal. Prior treatment with adjuvant immunotherapy was permitted, but patients pre- viously treated with chemotherapy were excluded. Patients had to have measurable disease according to the RECIST criteria. Individuals with brain metastases were not eligible, except those with a solitary lesion that had been resected. All patients gave informed consent. The protocol was approved by the research ethics boards for the participating centres.
Treatment
Ispinesib was administered as a 1-hour infusion at a dose of
18 mg/m2 once every 3 weeks. Dose adjustments were required for prolonged neutropenia or thrombocytopenia, or any grade 3 or greater non-hematologic major organ toxicity except alopecia.
Treatment was continued until disease progression, unless any of the following occurred: unacceptable toxicity was encountered; an intercurrent illness developed that in the judgment of the investigator warranted discontinuation; or the patient requested treatment be discontinued.
Response and toxicity evaluation
Patients were examined and underwent laboratory studies prior to each cycle. Diagnostic imaging was repeated every second cycle, to assess for response. Response was evaluated using the RECIST criteria. Toxicity was mea- sured using the Common Terminology Criteria for Adverse Events version 3.0 at each cycle.
Pharmacokinetics
Serial blood samples were obtained prior to the first dose of ispinesib, immediately after completion of the infusion, then at the following time intervals after the infusion: 30–60 minutes, 1.5–2.5 hours, 4–6 hours, 20–29 hours, and 36– 48 hours. If a dose modification was required after the first cycle, serial blood sampling was repeated the second cycle. The method for the determination of ispinesib in human plasma has been validated over the range 0.1 to 100 ng/mL using high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS). Ispinesib was ex- tracted from 50 μL of human plasma by protein precip- itation using 75/25 acetonitrile/10 mM ammonium formate (pH 3) containing an isotopically labeled internal standard ([2H4]-ispinesib). Extracts were analyzed by HPLC-MS/MS using a TurboIonSpray™ interface and multiple reaction
monitoring.
A population pharmacokinetic analysis was conducted using NONMEM (Globomax LLC; Hanover, MD) on phase I ispinesib data following an 18 mg/m2 dose, the maximum tolerated dose from a once (1-hour intravenous infusion) every 21 day schedule [18]. Once a final model was selected, it was validated using the posterior predictive check method. Upon validation of the final population model, it was used to simulate plasma ispinesib concentra- tion-time profiles resulting from a dose of 18 mg/m2. A post-hoc median profile with 95% confidence intervals was simulated using the population pharmacokinetic model developed using phase I data. Observed data were overlaid on the simulated profile to determine if the observed data exhibit the central tendency and variability of the phase I data obtained at the same dose level.
Correlative studies
Archival tissue samples were retrieved. Formalin-fixed, paraffin-embedded tissue were cut in 4-μm sections and placed onto positively charged slides. Slides were deparaffi- nized in xylene, and rehydrated in decreasing concentra- tions of ethanol:water. Following antigen retrieval and blocking, sections were incubated for 30 minutes with an anti-KSP monoclonal antibody (provided by Dr. Yun-Fu Hu, GlaxoSmithKline) at a dilution of 1:5,000.
Immunohistochemical staining was performed using an Envision+ polymer (rabbit) and the Dako Autostainer Universal Staining System. Slides were counterstained with 50% Mayer’s hematoxylin. Human tonsillar tissue was used as the positive control for KSP staining.
The KSP stained slides were read as positive or negative by an investigator blinded to clinical outcomes (TWS). Staining intensity was scored in a semi-quantitative manner from no staining (0) to strong staining (3+). The highest score was recorded if there were more than one section stained and varying levels of staining intensity seen.
Statistical analysis
Objective tumor response was the primary endpoint. A two-stage design was employed, with 15 evaluable patients to be enrolled in the first stage [20]. In the event of at least one response among these first 15, the second stage would enroll an additional 10 patients. With a significance level of 0.12, this design would have a power of 0.89 to detect a response rate of 20%, which was considered clinically relevant.
Other analyses
The pharmacokinetic data was used to determine total systemic clearance, peak concentration, area under the curve, and half-lives, and the distribution of these parameter estimates was summarized with histograms, medians, quartiles and ranges.
The percentage of tissue samples staining positive for KSP was determined. The best response to treatment was compared to the intensity of staining.
Results
Patient characteristics
Between April and November 2005, 17 patients were enrolled at seven centres across Canada; two more than originally planned as several patients were consented at the time the first stage of enrollment was nearing completion. Patient demographics and disease character- istics are presented in Table 1. The median age was 61 years (range, 30 to 87), and twelve were male. All patients had an ECOG performance status of 0 or 1. The primary site of melanoma was limb (5 patients), head and neck (4), trunk/retroperitoneal/abdomen (4), ocular (2) and unknown (2). The most common sites of metastases were nodal (13 patients), lung (10), soft tissue (8), liver (7) and adrenals (4). The median number of sites involved was three (range, 1 to 12).
Table 1 Patient demographics and disease characteristics Characteristic No. of patients
Patients entered 17
Age, years
Median
61
Range 30–87
ECOG performance status
0 6
1 11
Gender
Male 12
Female 5
Prior therapy
None 7
Adjuvant systemic therapya 4
Radiotherapy 7
Site of primary
Limb 5
Trunk/retroperitoneal/abdomen 4
Head and neck 4
Ocular 2
Unknown 2
Metastatic sites
Lymph nodes 13
Lung 10
Soft tissue 8
Liver 7
Adrenal 4
Bone 2
Other 24
Number of metastatic sites
1 2
2 6
3 1
4 or more 8
a Adjuvant interferon (n=3) and levamisole (n=1)
Table 3 Hematologic toxicities
Variable Nadir Day to nadir Median Range Median Range
No objective tumor responses were seen, leading to closure of the study. Six patients (35%) had a best response of stable disease, for a median duration of 2.8 months (range,
2.5 to 13.6). Eleven (65%) had a best response of disease progression, which was documented in 9 (53%) after only 1 or 2 cycles.
Toxicity
The most frequent grade 3 or 4 hematologic adverse events were neutropenia and lymphopenia (Table 3). There was one episode of febrile neutropenia in 66 cycles of therapy administered.
Other adverse events are listed in Table 4. The most common non-hematologic adverse events were injection site reactions (10, 59%), fatigue (7, 41%), nausea (6, 35%), anorexia and vomiting (5, 29%), and sensory neuropathy (4, 24%), although these were grade 2 in severity at worst. Grade 3 or 4 non-hematologic adverse events considered to be related to therapy were dizziness and blurred vision; each occurring in a single patient. The episode of blurred vision was due to bilateral keratitis, which occurred during
Patients completed a median of two cycles (range, 1 to 20), with 8 patients (47.1%) receiving three or more cycles of therapy (Table 2). Fifteen patients (88.2%) received
Table 4 Other toxicities by grade
Total patients (n=17) Grade
≥90% of the planned dose intensity. Two required dose
reductions at cycle 2, and one patient had dose interruptions Toxicity No. % 1 2 3 4
due to injection site reactions. Fatigue 7 41 2 5 – –
Injection site reaction 10 59 6 4 – –
Anorexia 5 29 3 2 – –
Table 2 Cycles administered
Constipation 2 12 – 2 – –
the first cycle and resolved with conservative management. One patient had a grade 2 myalgia during the first cycle, which could not be attributed to a cause other than study treatment and that required narcotic analgesia while on therapy. No grade 3 or 4 biochemical adverse effect was encountered.
Pharmacokinetics
Serial blood samples were available on 12 of the 17 patients enrolled.
Using a population pharmacokinetic model derived from phase I data of the maximum tolerated dose of 18 mg/m2, a comparison of the sampled observed data in this study was made. Ispinesib plasma concentrations following an 18 mg/m2 dose were comparable to those observed in phase I studies, as shown in Fig. 1. The fixed and random effects of the population pharmacokinetic model adequately des- cribe the central tendency and variability of the observed data.
Immunohistochemistry
Archival tissue specimens were available for 16 patients. Only two specimens (13%) exhibited no staining for the anti- KSP monoclonal antibody used. Seven demonstrated 1+ staining, two specimens were scored as 2+, and five scored as 3+. There was no correlation between tumor response and staining intensity (Table 5).
Discussion
The KSP inhibitor ispinesib is well tolerated and can be safely administered at the dose and schedule employed in this study. It has mild hematologic and non-hematologic toxicity and although some sensory neuropathy is encoun-
Fig. 1 Ispinesib observed concentrations at 18 mg/m2
Table 5 KSP immunostaining and best response to treatment (n=16)
Staining intensity No. Best response
Stable disease Progressive disease
0 2 0 2
1+ 7 4 3
2+ 2 1 1
3+ 5 1 4
tered, its side effect profile is distinct from other agents that affect microtubule formation. However, unlike the vinca alkaloids and taxanes, ispinesib does not appear to have any meaningful activity in metastatic melanoma.
Melanoma is inherently resistant to a wide spectrum of chemotherapy agents with different mechanisms of action. Resistance to the vinca alkaloids and taxanes is likely on the basis of mutations or alterations in expression of tubulin, drug efflux via the multidrug resistance proteins (MRPs) and dysregulation of apoptosis [21].
Plasma concentrations of ispinesib achieved in this study were comparable to those observed in the phase I study that determined the maximum tolerated dose to be 18 mg/m2 [18]. At this dose level, ispinesib is expected to inhibit KSP in vivo.
The high rate of KSP immunoreactivity in the archival tissue specimens suggests that KSP would otherwise be an appropriate target for inhibition. However, while ispinesib is not subject to changes in tubulin structure, point mutations in KSP may confer resistance by altering inhibitor binding sites while retaining the enzymatic activity of KSP [22]. At the same time, complete loss of the spindle assembly checkpoint is lethal to cancer cells, while partial loss of this function causes aneuploidy and promotes tumorigenesis. At least in vitro, defects in the spindle assembly checkpoint are a mechanism of resistance to KSP inhibitors [14].
Prolonged KSP inhibition results in apoptosis, but requires a competent spindle assembly checkpoint and exit from mitosis into a pseudo-G1 phase, mitotic slippage. Both events are necessary to activate Bax and the intrinsic apoptotic pathway [14, 23, 24]. The inherent resistance of melanoma to apoptosis could account for resistance to ispinesib [25]. Perhaps of particular relevance to the action of KSP inhibitors, sustained spindle checkpoint arrest is de- pendent on the presence of the anti-apoptotic protein survivin [26], which is strongly expressed in melanoma [27].
Early in vitro studies suggest that ispinesib may be a substrate for MRPs, although whether this is relevant to resistance in vivo is not known.
Inhibitors of KSP continue to be of interest, although preliminary reports of ispinesib in breast cancer, head and neck cancer, colorectal cancer, ovarian cancer and renal cell
carcinoma have not indicated significant response rates in these tumor types [28–32]. KSP does not appear to be a useful target in treatment of metastatic melanoma. Further evaluation of ispinesib in patients with metastatic melano- ma, either alone or in combination with other agents, is not supported by the results of this trial.
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