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© 2001 American Society for Clinical Oncology Phase I and Pharmacokinetic Study of PKC412, an Inhibitor of Protein Kinase CFrom the Cancer Research Campaign Department of Medical Oncology, Beatson Oncology Centre, Glasgow; Imperial Cancer Research Fund Laboratories, Lincoln’s Inn Fields, London, United Kingdom; and Novartis Pharma AG Basel, Switzerland. Address reprint requests to A.L. Harris, MD, ICRF Medical Oncology Unit, University of Oxford, Churchill Hospital, Headington, Oxford OX3 7LJ, United Kingdom; email: a.harris{at}icrf.icnet.uk
PURPOSE: N-Benzoyl staurosporine (PKC412) is a protein kinase C inhibitor with antitumor activity in laboratory models. We determined the toxicity of oral PKC412 administered daily for repeat cycles of 28 days. PATIENTS AND METHODS: Thirty-two patients with advanced solid cancers were treated at seven dose levels (12.5 to 300 mg daily) for a total of 68 cycles.
RESULTS: The most frequent treatment-related toxicities were nausea, vomiting, fatigue, and diarrhea. At the two top dose levels (225 and 300 mg/d), 15 of 16 patients experienced nausea/vomiting (common toxicity criteria [CTC], version 1), grade 2 in nine of 16 and grade 3 in three of 16 patients; and six of 16 patients developed CTC grade 2 diarrhea. After 1 month of treatment, there were significant reductions in circulating lymphocyte (P < .02) and monocyte (P < .01) counts in patients receiving doses CONCLUSION: PKC412 can be safely administered by chronic oral therapy, and 150 mg/d is suitable for phase II studies. The pharmacokinetics and lack of conventional toxicity indicate that pharmacodynamic measures may be additionally needed to optimize the drug dose and schedule.
PROTEIN KINASE C family members (PKCs) are intimately involved in processes that are perturbed in cancer cells, including growth factor–mediated signal transduction, nuclear oncogene activity, cell cycle control, and topoisomerase activity.1-3 Tumor promoters activate PKC, and PKC activities are elevated in a variety of tumors.4 High levels of PKC have been found in breast, lung, and stomach carcinomas, but low levels have been described in other tumors such as colon.4-7 Manipulation of various PKC isoenzymes by transfection and antisense oligonucleotide experiments indicate a role in tumorigenicity and cell differentiation that is likely to be dependent on isoenzyme expression.2 Whether effects on particular PKC isoenzymes would enable selective tumor targeting is unknown. Given the multifunctional role of PKCs in tumour biology, the inhibition of PKC function would be expected to interfere with some signal transduction pathways critical for continued tumor growth and survival. We describe here our early clinical experience with the PKC inhibitor N-Benzoyl staurosporine (PKC412).
PKC412 is an N-Benzoyl derivative of the naturally occurring alkaloid staurosporine.8 It is an inhibitor of several kinases but predominantly the PKC enzyme family. PKC enzymes comprise more than 12 isoenzymes which can be classified into the following three main groups: (1) conventional calcium- and diacylglycerol (DAG)-dependent; (2) calcium-independent but DAG-dependent; and (3) calcium-independent and DAG-unresponsive.9 The various PKC subtypes show distinct enzymologic properties, differential tissue expression, and have different modes of activation and oncogenic potential. PKC412 preferentially inhibits the conventional PKCs PKC412 is an effective antiproliferative agent against various tumor and normal cell lines in vitro and in xenograft models.8,15-17 It synergizes with conventional cytotoxic agents without overt toxicity and is able to reverse p glycoprotein–-mediated multidrug resistance in vitro18,19 and in vivo.20 The 50% inhibitory concentration (IC50) for PKC412 against malignant cells using in vitro proliferation assays was between 0.2 and 0.7 µmol/L8, and this concentration may represent a minimal target for in vivo efficacy. In dogs and mice, no toxicologic effects were observed after 3 months of treatment at doses of 1 and 10 mg/kg/d, respectively.21 At daily doses of 20 mg/kg/d in rats and 3 mg/kg/d in dogs, suppressive effects were observed on proliferating tissues, particularly bone marrow, testes, and intestine. Variable duration and prolongation of the ECG PQ interval was observed with high-dose therapy in dogs (30 mg/kg/d). Single-dose pharmacokinetic studies in healthy human volunteers showed maximum plasma concentrations 1 to 3 hours after dosing, with variable terminal elimination half-lives of between 5 and 31 hours. Because of the potential anticancer activity of PKC412, we performed a phase I dose escalation study in patients with tumors refractory to conventional chemotherapy or for whom there was no conventional treatment available. PKC412 was initially given once daily and during dose escalation increased to three times daily. Patients were closely assessed for drug tolerability by both clinical and laboratory criteria.
Patients Patients had histologically proven cancer that was either refractory to conventional chemotherapy or unresponsive to standard treatment. Other eligibility criteria included the following: age greater than 18 years, World Health Organization performance status  2, life expectancy of more than 3 months, and no chemotherapy or investigational agents in the previous 30 days (40 days for mitomycin C or nitrosoureas). Patients with uncontrolled heart failure, severe ischemic heart disease, and any degree of atrioventricular block were ineligible. Eligible patients had to have a neutrophil count  2 x 109/L, hemoglobin 10 g/dL, platelet count 100 x 109/L, a normal serum creatinine and bilirubin, and serum transaminases two times the upper limit of normal.
Study Design
A treatment cycle comprised 28 days of daily dosing with PKC412, followed by a 7-day treatment-free period. During the first 24 hours of treatment, patients were observed in the hospital. If PKC412 was tolerated in the first treatment cycle and there was no evidence of disease progression, patients continued for a second cycle to a planned maximum of six. Because of prolongation of the ECG PQ interval observed in dogs receiving high-dose PKC412, patients were monitored for cardiac conduction changes by 24-hour continuous ECG before and during the first 24 hours of therapy.
Toxicity and Response Measurements
Treatment Compliance
Pharmacokinetics
Ethical Considerations
Statistics
Thirty-two patients entered the study. Their demographic details are listed in Table 2. A total of 68 cycles were given (median, two cycles; range, one to 12 cycles). Fifteen patients received a single cycle, 13 received two cycles, and four received more than two cycles (four, five, six, and 12 cycles). Eight patients did not complete the first treatment cycle, three because of nausea and vomiting and five because of progressive disease; although three of these five patients did receive the full 28-day treatment.
The majority of patients (n = 22) were withdrawn from the study because of progressive disease. Five were withdrawn because of nausea and vomiting, not controlled by standard antiemetic therapy. A further three patients withdrew consent. One patient with cholangiocarcinoma treated at dose level 2 (25 mg/d) attained shrinkage in his omental metastasis that fulfilled criteria for a partial response lasting 4 months. The disease had previously progressed on fluorouracil treatment. He continued on treatment for 12 cycles but was withdrawn after a cerebral vascular accident. This was attributed to a cancer associated thrombotic tendency that was manifest before starting PKC412 therapy. A second patient with cholangiocarcinoma, who had progressive disease on cisplatin-based chemotherapy before starting PKC412 300 mg/d, attained stable disease for 4.5 months.
Toxicity
Dose-Limiting Toxicity and MTD Hematologic toxicity was uncommon, affecting only two heavily pretreated patients. In one patient (225 mg/d), grade 2 leukopenia occurred after 4 weeks of treatment, which did not recur after a one-level dose reduction. The second patient developed grade 2 leukopenia and grade 1 neutropenia during the second treatment cycle. The drug was stopped for 4 days, and there was no recurrence on restarting the drug at the same dose (300 mg/d). Pooling data from all patients, comparison of circulating neutrophil, lymphocyte, and monocyte counts at baseline and after 1 month of treatment showed a significant decrease only in lymphocyte counts (1.38 ± 0.54 v 1.09 ± 0.52 x 109/L, respectively; P < .05). Further analysis showed that there was a dose effect of PKC412 on differential WBC counts. There were no significant changes in differential counts for patients receiving less than 100 mg/d PKC412. In patients receiving 100 mg or more per day, lymphocyte counts (1.28 ± 0.43 at baseline v 0.8 ± 0.49 x 109/L after 1 month; P < .02) and monocyte counts (0.37 ± 0.18 at baseline v 0.28 ± 0.27 x 109/L after 1 month, P < .01) were significantly lower after 1 month of treatment. No cardiac conduction abnormalities were observed by 24-hour ECG monitoring during the first 24 hours of therapy. There were no significant effects on biochemical liver or renal function.
Compliance
Pharmacokinetics Pharmacokinetic data for PKC412 were determined for 30 patients ( Fig 1A and 1B). Mean plasma concentrations in patients at each dose level, between 1 to 24 hours after first dose on day 1, were in the range of 0.3 to 7.0 µmol/L ( Fig 2). Cmax and AUC0-24 hours increased with increasing dose, the increase being less than dose proportional. Despite the less than proportional increase with dose, there was a linear relationship between daily dose and AUC0-24 hours and Cmax (Fig 1A and 1B). There was considerable interpatient variation in PKC412 plasma levels (Fig 1A and 1B). PKC412 was rapidly absorbed (Fig 2), and steady-state levels for PKC412 were apparent after 1 week of daily dosing ( Fig 3). The weekly drug concentrations gradually declined throughout the 4-week treatment cycle, and there were no significant differences between weekly plasma concentrations for the top three dose levels (Fig 3). In the treatment-free intervals, PKC412 concentrations decreased to near zero in most patients.
Plasma concentrations of all patients with grade 2 or greater nausea/vomiting who completed the first 28 days of treatment were analyzed in case this had affected drug compliance. Neither day 1 concentrations of PKC412 and/or metabolites nor the weekly trough levels of these patients were significantly different from the values of other patients with respect to absolute value or rate of increase or decrease in levels. The estimated median elimination half-life of PKC412 was 1.6 days (range, 0.9 to 4.0 days; n = 12). This compared with 0.7 days (range, 0.2 to 1.3 days) in healthy volunteers (n = 14). There was no accumulation of PKC412 (Fig 3). The plasma elimination half-life of the major PKC412 metabolite (M) was slow (median half-life of 36 days; range, 27 to 164 days). A concentration time course for PKC412 and the major metabolite in a patient receiving 25 mg daily over a 4-month period is shown in Fig 4. The biologic and chemical characteristics of PKC412 metabolites are not yet fully characterized. In vitro comparison of the effects of PKC412 and its metabolites on the activity of various PKC isoforms indicated that the metabolites had little activity compared with PKC412. Generally, the IC50 for the metabolites was at least five times greater than that for PKC412.
Preclinical experiments had shown an extensive binding of PKC412 to human plasma proteins, with approximately 88% to 98% protein binding, depending on the drug concentration. Binding to human (but not rodent) AAG, in particular, was significant. To understand the differences in pharmacokinetics between healthy human volunteers and study patients, plasma AAG concentrations were measured and compared with total PKC412 and metabolite concentrations. Plasma AAG levels were elevated in 21 of 24 patients in whom baseline values were obtained, and values tended to remain constant in most patients over the course of the study.
The principle toxicities in this phase I dose escalation study of PKC412 were nausea/vomiting and fatigue. Additional significant side effects were diarrhea, anorexia, and headache. At most dose levels, patients experienced some mild to moderate adverse events, but the toxicities were more prominent at the higher dose levels. Other toxicities were uncommon, and there was no clinically important myelosuppression. There was, however, significant dose-related suppression in circulating lymphocyte and monocyte levels after 28 days of treatment in patients receiving PKC412 100 mg or more per day. Nevertheless, this myelosuppression did not manifest as significant NCI-CTC toxicity, even in patients who continued for more than one treatment cycle. This is an important observation because of the likely chronic schedule for administering this drug. No individual toxicity reached the predefined MTD of two out of six patients with NCI-CTC grade 3 toxicity. Nevertheless, the prevalence of symptomatic toxicities at the top two dose levels (225 and 300 mg/d) clearly exclude these doses for chronic administration, whereas 150 mg/d would be an acceptable dose. The absence of a dose-limiting toxicity, as it is usually defined, contrasts with trials of conventional cytotoxic agents and indicates that it may not be appropriate to apply conventional phase I criteria to forthcoming trials of biologic response modifying agents. In general it was apparent, within the first week of treatment, whether patients were able to tolerate the drug. Symptoms such as nausea, vomiting, and lethargy did not worsen with prolonged treatment. The nausea and vomiting could be caused by drug effects on brain tissue PKC isoenzymes. Conversely, given the diarrhea, which developed early in treatment, local effects on gastrointestinal mucosa are possible. It was not established whether dose reduction in patients who had adverse symptoms was of benefit because doses were maintained according to protocol. In the patients who continued the drug for more than one cycle, no further side effects emerged. The pharmacokinetic data suggests that PKC412 displays less than proportional increases in plasma concentrations with increasing dose. Steady-state concentrations were reached within approximately 7 days. The decrease in weekly drug levels from 24 hours after first-dose to day 15 suggests some degree of induction of PKC412 metabolism. Thereafter, concentrations seemed to remain stable. There was considerable interpatient variation in plasma drug concentrations, particularly at the three highest dose levels, where there were no significant differences between mean weekly drug levels. Differences in gastrointestinal tract absorption and plasma protein binding may explain this variability. At the top three dose levels, plasma concentrations were consistently five to 10 times the cellular IC50 for PKC412 of 0.2 to 0.7 µmol/L8. The plasma concentrations of PKC412 were higher and the half-life was longer than predicted from animal studies and single-dose kinetics studies in healthy volunteers.21 The major metabolite (M) had a particularly long half-life. Two patients received prolonged treatment; one received 25 mg/d for 13 cycles and the other 150 mg/d for six cycles, but there was no evidence that the major metabolite accumulation produced either cumulative or delayed toxicity. The higher than predicted plasma drug levels suggests greater protein binding than anticipated. Preclinical experiments had shown extensive binding of PKC412 to human plasma proteins, with approximately 88% to 98% protein binding, depending on the drug concentration. Binding to AAG in particular was significant. It is possible that PKC412 and its metabolite preferentially bind to AAG in vivo. AAG levels were elevated in 21 of 24 patients tested, and this could account for the longer than anticipated plasma half-life. Recently, the staurosporine analog UCN-01 (7-hydroxystaurosporine) has been reported to exhibit strong AAG binding and to have similarly unusual pharmacokinetics, not predicted by animal studies.24 Whatever the explanation, although in humans PKC412 is more protein bound than animal studies had predicted, the drug was metabolised and associated with adverse effects as well as dose-dependent pharmacodynamic changes, as discussed below. The dynamics of dissociation from plasma proteins and tissue distribution of PKC412 are likely to be complex, and plasma levels may not be an appropriate reflection of drug concentration in target tissues. In parallel studies, we assessed whether the drug might have inhibitory effects on PKC signalling pathways in vivo.25 This was assessed by measuring cytokine release from phytohemagglutinin-stimulated fresh whole-blood cells obtained from patients at various time points during treatment. The release of tumor necrosis factor and interleukin-6 were both significantly inhibited in a time- and dose-dependent manner. The inhibition of cytokine release at doses of 100 mg/d and above was highly consistent. At the same time points, Western blots of peripheral-blood lymphocyte lysates showed marked downregulation of extracellular signal-regulated kinase 2 (ERK2) at all PKC412 dose levels tested (50 to 300 mg/d). PKCs are involved in the regulation of these cytokines and in ERK2 phosphorylation,26-28 suggesting that PKC412 has inhibitory effects on PKCs in vivo. Although this was a phase I study, tumor responses were assessed. It is, however, likely that conventional methods of assessing disease response are less valid with biologic response modifying agents than conventional cytotoxic agents. This is one of the inherent difficulties in their assessment, and other end points need to be developed. Measurement of changes in tumor metabolism by positron emission tomography using 18[F]-fluoro-deoxyglucose imaging is a potential suitable end point.29 Biopsy of tumor to assess changes in target molecules and measurement of levels of circulating markers of tumor invasion, such as markers of angiogenesis, are other potentially useful approaches. All these techniques, however, require validation. Two patients with cholangiocarcinoma were treated in this study; one at a low dose (25 mg/d) and the other at a high dose (300 mg/d). The first patient attained a partial response. Before commencing PKC412, this patient had clear evidence of progressive disease both on and off conventional fluorouracil-based chemotherapy. The second patient attained stable disease, having had progressive disease with conventional cytotoxic agents. Whether PKCs are abnormally activated in cholangiocarcinomas and the role of PKCs in the etiology and progression of cholangiocarcinomas are unknown. Bile acids are potent activators of PKC,30 and speculatively, this effect could have been blocked by the drug. Signal blocking agents represent a novel approach to treating cancer. PKC412 synergizes with conventional cytotoxic agents and is able to reverse P glycoprotein–mediated multidrug resistance in vitro18,19 and in vivo.20 In clinical practice, PKC412 could have synergistic effects when given by chronic oral administration during a course of conventional cytotoxic chemotherapy. There was little significant hematologic toxicity, suggesting that it could be safely combined with conventional cytotoxic agents without significant overlapping toxicity. It is, however, important to note that in vitro data indicate that synergy between biologic response modifiers and cytotoxic agents can be schedule-dependent31,32 and an important consideration in combination studies. The study suggests that PKC412 150 mg/d would be well tolerated chronically, a dose associated with plasma concentrations five to 10 times the cellular IC50. It is of interest to note that two pharmacodynamic end points, suppression of mitogen-induced cytokine release and peripheral-blood mononuclear-cell ERK2 levels, and suppression of circulating lymphocytes and monocytes occurred at the same doses as significant symptomatic toxicity, suggesting similar processes could underlie these effects. Further studies examining dose and schedule in combination with conventional chemotherapeutic agents are in progress. Because plasma pharmacokinetic evaluation is complicated by protein binding and metabolism, use of biologic markers of PKC inhibition will contribute to optimizing PKC412 administration.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
, ß, 
, and the calcium-independent PKCs 
, 
, and 
.
