1 Department of Medicine, Institut Gustave-Roussy, Villejuif, France; 2 Department of Oncology, Umea, Sweden
Received 15 May 2003; revised 8 September 2003; accepted 17 September 2003
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ABSTRACT |
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PKC412 (N-benzoyl-staurosporine), an oral inhibitor of protein kinase C, is capable of cell cycle inhibition and is endowed with anti-angiogenic properties. This dose-finding phase I study was designed to establish the maximum tolerated dose (MTD) of PKC412 when combined with cisplatingemcitabine.
Patients and methods:
Escalating doses of PKC412 were given every day of a 4 week cycle with cisplatin 100 mg/m2 on day 2 and gemcitabine 1000 mg/m2 on days 1, 8 and 15 in patients with non-small-cell lung cancer. Dose escalation was based on a modified continuous reassessment method.
Results:
Twenty-three patients, assigned to four cohorts receiving PKC412 at a dose ranging from 25 to 150 mg/day were evaluable. Grade 3 diarrhea occurring in 3/4 patients at cycle 1 led us to define 150 mg/day as the MTD. The MTD based on multiple cycles was redefined as 100 mg/day, since prolonged grade 23 nausea/vomiting leading to treatment discontinuation occurred in 3/7 patients after repeated cycles. The next lower dose tested of 50 mg/day was therefore considered as the recommended dose for phase II trials. Among 33 cycles in eight patients, toxicity consisted of grade 12 diarrhea (12.5%) and asthenia (50%) with only one patient experiencing grade 3 headache at this dose level. A partial response was observed in three patients.
Conclusions:
The results of the present study indicate that PKC412 at a dose of 50 mg/day can be safely added to cisplatin and gemcitabine in patients with advanced non-small-cell lung cancer.
Key words: anti-angiogenesis, cell cycle inhibitor, protein kinase C
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Introduction |
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Based on single agent activity of PKC412 in NSCLC and the additive effects evidenced in vitro with cisplatin [15], a phase I study was designed using a cisplatingemcitabine regimen with escalating doses of PKC412. The primary objective was to determine the MTD of PKC412 combined with cisplatin and gemcitabine. Secondary objectives were as follows: (a) to define the DLT of PKC412 when combined with cisplatingemcitabine; (b) to establish the RD of PKC412 when combined with chemotherapy containing cisplatingemcitabine; (c) to characterize the pharmacokinetic (PK) profile of PKC412 at the RD; and (d) to report evidence for anti-tumor activity in patients with NSCLC.
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Patients and methods |
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Eligible patients fulfilled the following criteria for study entry: neutrophil count, 1.5 x 109/l; hemoglobin
10 g/dl; platelet count
100 x 109/l; serum creatinine <1.5 x upper limit of normal (ULN); and total bilirubin <1.5 x ULN with serum aspartate aminotransferase and alanine aminotransferase levels <2.0 x ULN.
All patients gave their written informed consent before treatment according to institutional and national guidelines. The study was performed according to French and Swedish drug regulations and complied with the principles of the Helsinki Declaration. The protocol was approved by the University of Kremlin-Bicêtre (France) and the University of Umea (Sweden) Ethics Committees.
The present analysis is based on the examination of the source case report forms by the participating investigators who had access to all study data.
Study design
Before entry onto the study, all patients were required to have a clinical history, physical examination, chest and abdominal computed tomography (CT) scan, complete blood work-up comprising complete blood count and serum chemistries (sodium, potassium, calcium, creatinine, urea, bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase and total protein) and an electrocardiogram. During treatment, a medical history, toxicity assessment and complete blood work-up were performed weekly. Toxicity grading was performed in accordance with the National Cancer Institutecommon toxicity criteria (NCICTC), version 2.0 [17]. Patients were evaluated for tumor response every two cycles. Standard Southwest Oncology Group (SWOG) criteria were used to determine response [18]. Criteria for withdrawing patients from the study included tumor progression, dose-limiting or unacceptable toxicity as determined by the treating physician and patient refusal.
Drug administration
PKC412 was supplied by Novartis (Basel, Switzerland) in soft gelatin capsules containing 25 mg of the active drug substance. Capsules were taken with water during or following meals. The first dose of PKC412 was taken before administering chemotherapy. PKC412 was given orally daily during a 28-day cycle without interruption during and between cycles. Scheduled dose levels were 25 mg (25 mg taken o.d.), 50 mg (25 mg taken b.i.d.), 75 mg (25 mg taken t.i.d.), 100 mg (50 mg taken b.i.d.), 150 mg (50 mg taken t.i.d.) and 225 mg (75 mg taken t.i.d.). Fractionation of the daily doses was empirically chosen to improve the digestive tolerability and to reduce the number of pills that needed to be swallowed at one time. Dosage of PKC412 was reduced by 50% at cycle two in case of grade 34 PKC412-related toxicities.
On days 1, 8 and 15, gemcitabine 1000 mg/m2 diluted in 100 ml of 0.9% NaCl was given as a 30-min intravenous infusion 1 h after the administration of PKC412. Antiemetic treatment before gemcitabine consisted of ondansetron 8 mg and methylprednisolone 125 mg. On day 2, cisplatin 100 mg/m2 diluted in 250 ml of 0.9% NaCl was given intravenously over 60 min and hydration with 3 l 0.9% NaCl, 1 h after the administration of PKC412. Anti-emetic treatment during cisplatin therapy consisted of ondansetron 8 mg per os twice to three times daily, that was continued, in case of prolonged nausea, with dexamethasone 20 mg with or without bromazepam 1 mg four times daily for 2 days. In case of prolonged nausea 2 days after cisplatin therapy, the anti-emetic regimen was intensified with prednisone 100 mg and metoclopramide 40 mg [19].
Gemcitabine dose was adjusted in case of hematological toxicity. If grade 2 neutropenia and/or thrombocytopenia occurred at day 8 and/or 15, 75% of the initial gemcitabine dose was given. If grade 3 or 4 neutropenia and/or thrombocytopenia occurred at days 8 and/or 15, gemcitabine was omitted and a decrease of 25% was made at the subsequent cycle. The next cycle was delayed until hematological recovery. Dose adjustments for non-hematological toxicities were as follows: a 50% decrease in the initial gemcitabine dose was recommended in case of grade 34 transaminase elevation at day 8 and/or 15. A 50% decrease in the cisplatin dose was recommended in case of grade 1 nephrotoxicity and no cisplatin was given until recovery if nephrotoxicity exceeded grade >1. Cisplatin was discontinued when grade 3 neurotoxicity and grade 2 ototoxicity occurred.
Dose escalation procedure
The starting dose of PKC412 was 25 mg daily, i.e. 1/6 of the recommended dose of single agent PKC412 established in the phase I study [11]. A modified continual reassessment method (MCRM) was used for dose escalation [20]. For dose-finding purposes, four patients were assigned sequentially to each cohort. The daily PKC412 dose increments foreseen, namely 25, 50, 75, 100, 150 and 225 mg, were based on a single agent phase I study [11].
DLTs were defined as grade 4 neutropenia lasting at least 7 days, grade 4 febrile neutropenia, grade 4 thrombocytopenia, grade 2 nephrotoxicity and any other grade 34 non-hematological toxicity (excepted alopecia and acute nausea/vomiting). Nausea/vomiting occurring during the first week of treatment were considered as acute and cisplatin related, while nausea/vomiting lasting >1 week and disappearing after discontinuation of PKC412 were considered as prolonged and PKC related. Prolonged nausea/vomiting that persisted for >1 week, despite an adapted anti-emetic regimen, and any other toxicity that required dose reduction or treatment discontinuation were considered as DLT.
Dose escalation was primarily designed to define the MTD based on acute DLT of PKC412 when combined with cisplatin and gemcitabine during cycle 1 of treatment. The MTD was defined as the highest dose of PKC412 at which >35% of the patient population would experience DLT during cycle 1. The DLT observed after treatment of each cohort of patients was noted and the dose-toxicity model defined by the MCRM was updated accordingly. If no DLT was observed in a group of four patients, then the dose escalation proceeded to a further dose level. If one of four patients experienced DLT at cycle 1, then four new patients had to be entered at this dose level. In that situation, dose escalation was allowed to resume to a further dose level if three or less patients of eight experienced DLT at cycle 1. The probability of DLT at each of the PKC412 dose levels under study was estimated. The next cohort of patients was administered the dose level at which the estimated probability of DLT was closest to the 35% threshold DLT rate, provided that the new dose level did not exceed double the previous dose. The final RD was based on the MTD based on multiple cycles, since a prolonged administration of PKC412 should be possible at that dose level.
Pharmacokinetics study
In humans, PKC412 has two main metabolites, the O-demethylation product of PKC412, CGP62221 (O-desmethyl-N-benzoyl-staurosporine) and 7-hydroxy-PKC412, referred to as CGP52421 (N-benzoyl-7-hydroxy-staurosporine) (Figure 1). CGP52421 is a mixture of two epimers (epimer 1, 62.5% of CGP52421; epimer 2, 37.5% of CGP52421) and has structural homology with UCN-01 [15]. CGP52421-epimer1 has a short half-life and cannot be measured in plasma. CGP52421-epimer2 has a long half-life and accumulates over time [11]. A 24-h PK profile was obtained on day 28 of the first cycle and day 1 of the second cycle, before administering the second cycle of chemotherapy. Blood samples were collected prior to the first dose and at 1, 2, 4 (prior to the midday dose), 6, 10 (prior to the evening dose) and 24 h after the first intake. Blood samples were processed rapidly and protected from light. Samples of venous blood (3 ml) were collected in heparinized tubes and immediately centrifuged at 4000 r.p.m. Plasma samples were stored at 20°C until analysis.
Determination of PKC412 and its two main metabolites CGP62221 and CGP52421-epimer2, in plasma was performed by HPLC with fluorescence detection. The plasma PKC412 levels were analyzed by Novartis Pharma AG (Basel, Switzerland) according to published procedures [21]. An Agilent HP 1090 and an Agilent HP1100 HPLC system with a LiChrospher 100 RP18ec, 250 x 4 mm, 5 µm column, protected by the same type of pre-column, were used. The lowest quantification limit was 75 ng/ml for PKC412, 100 ng/ml for CGP62221 and 38 ng/ml for CGP52421-epimer2. Non-compartmental pharmacokinetic parameters were calculated for PKC412 and its metabolites in order to define the maximum concentration (Cmax) and the area under the plasma concentration time curve over 24 h (AUC24h) for each dose level, using the software Turbochrom, versions 6.1.0 and 6.1.2 (Perkin-Elmer, Norwalk, CT, USA) and Microsoft Excel, version 97 SR-2 (Microsoft, Redmond, WA, USA).
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Results |
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At dose level 100 mg/day, three more patients were added to the four initially included to evaluate toxicities beyond the first cycle. The last three included patients who experienced prolonged grade 2 or 3 toxicities at cycle two. One patient experienced grade 3 fatigue beginning at day 2 of cycle 2 with grade 3 nausea/vomiting beginning at day 6 and lasting until discontinuation of PKC412 at day 10. The second patient experienced grade 2 nausea/vomiting during cycles 1 and 2; despite intensive anti-emetic regimens, PKC412 dose reduction (to 50 mg/day) was required at cycle two without symptom improvement and treatment was interrupted. The third patient also had long-lasting grade 2 vomiting during cycles 1 and 2 that disappeared after discontinuation of PKC412 at day 21 of cycle 2. At dose level 3, the last three patients included did not differ from the first four patients in terms of PS, metastatic sites, prior irradiation or concomitant medications. Since 3/7 patients required treatment discontinuation due to unacceptable toxicity after repeated cycles, we decided not to include additional patients at dose level III and this dose level was not considered as meeting criteria for the RD for phase II studies.
Thus, 50 mg/day, the next dose level tested below 100 mg/day was considered. In addition to DLT at cycle 1 at 50 mg/day, one patient had grade 3 nausea/vomiting during the first week of cycle two that lasted 2 weeks until discontinuation of PKC412. No dose reduction was performed. As a total of 2/8 patients experienced PKC412-related DLT at dose level II, the 50 mg/day dose level was considered as the RD for chronic administration of PKC412 combined with cisplatin and gemcitabine (see Table 2). At this dose level, PKC412 plasma concentrations were in the range of the IC50 for preclinical studies. This dose of 50 mg/day was near the MTD. For several kinase inhibitors the dose recommendation for phase I trials has been selected based on a compromise between toxicity, plasma concentrations and surrogate biological end points of antitumor activity, if any. For PKC412, there was no clear evidence to support an increase in dose above 50 mg/day in order to achieve higher activity against PKC enzymes in tumors. Therefore we decided not to investigate further doses >50 mg/day and consequently the dose level of 75 mg/day was not explored.
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Non-hematological toxicities
Table 4 shows non-hematological toxicities. At dose level II, the above described DLT was a grade 3 headache at cycle 1. Other PKC412-related toxicities at the RD were mild to moderate grade 12 diarrhea, asthenia/fatigue, headache and prolonged nausea/vomiting. As mentioned above, one patient had grade 3 nausea/vomiting that was considered related to PKC412. Other toxicities were either considered related to cisplatin and/or gemcitabine. They included grade 2 hearing loss in one patient at level I, grade 1 peripheral neuropathy in two patients at level II, grade 2 anorexia in two patients at level I and one patient at level II, grade 2 infections without neutropenia in two patients at level II and one patient at level IV. Five patients presented cisplatin-related grade 1 elevation of serum creatinine (three patients at dose level II, one patient at dose level I and one patient at dose level IV).
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Pharmacokinetics
The PKC412 pharmacokinetic profile was assessed in four patients at the 50 mg dose level. Figure 2 shows the mean plasma concentrationtime curves for PKC412, CGP62221 and CGP52421-epimer2 at dose level II (50 mg/day). At this dose level, the mean AUC24 of PKC412, CGP62221 and CGP52421-epimer2 was 11389 (range 644716739), 17923 (range 1094825049) and 1513 ng·h/ml (range 10751927), respectively. The mean Cmax of PKC412, CGP62221 and CGP52421-epimer2 was 799 (range 5011070), 861 (range 5691189) and 69 (range 4787) ng/ml, respectively.
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Discussion |
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PKC412 can be administered orally and it provided an opportunity to explore the effects of prolonged inhibition of PKC during a clinical trial in patients with advanced cancer. In a previously published phase I trial, the RD of single agent PKC412 was 150 mg daily with toxicities consisting of nausea/vomiting, diarrhea and lethargy/fatigue [11]. In our study, toxicities were either related to PKC412 or cisplatingemcitabine chemotherapy. Diarrhea was the main DLT of PKC412 when combined with chemotherapy and prohibited dose escalation >150 mg/day. As gemcitabine and cisplatin do not induce diarrhea, this toxicity was considered solely attributable to PKC412. Attempts to control diarrhea with loperamide were not satisfactory and treatment discontinuation was required in all patients experiencing diarrhea at a dose level of 150 mg/day. When re-challenged with PKC412, patients re-experienced grade 3 diarrhea and this strongly pointed to the role of PKC412 in this toxicity.
Nausea and vomiting were also frequently documented in our study and greatly influenced our recommendation for the definition of MTD and RD. Since PKC412 is given orally for a prolonged period of time, discomfort caused by persistent nausea/vomiting could have an impact on schedule compliance and the quality of life of patients in future phase II clinical trials. As cisplatin is also known to induce nausea and vomiting, we proposed considering grade 2 nausea and vomiting lasting >1 week as a DLT in our study, in addition to the classic grade 34 threshold for drug-induced DLT. At the dose of 100 mg/day, grade 23 nausea/vomiting lasting >1 week was observed in 3/7 patients who required treatment discontinuation or dose reduction. The frequency and severity of nausea/vomiting were also increased in other phase I studies when PKC412 was combined with paclitaxel and carboplatin [23] or protracted infusional 5-fluorouracil [24]. We had no alternative but to propose the daily dose of 50 mg as the RD in combination with cisplatin and gemcitabine in our study because of nausea and vomiting.
From the PKC412 single agent phase I study, we know that side-effects are dose related and usually occur within the first week of treatment. PKC isoenzymes are found in every tissue and the pattern and frequency of toxicities are identical when PKC412 is given as a single agent or in combination [11]. Toxicities, however, did occur at lower doses of PKC412 and a drug interaction at the PK level is suspected. However, as PK samples were scheduled only at day 28, we cannot confirm this hypothesis, as DLTs supervene earlier. However, at the pharmacodynamic level, we should be reminded that PKC412 caused nausea and vomiting as a single agent and it is not surprising to observe that the addition of an highly emetic drug such as cisplatin was probably responsible for the prolonged nausea and vomiting occurring at a much lower PKC412 dose level.
In our study, the adjunction of PKC412 had no influence on cisplatingemcitabine-induced hematological toxicity. At a daily dose of PKC412 50 mg, hematological toxicity was similar in intensity and frequency to that previously reported with cisplatingemcitabine chemotherapy. With the same schedule of administration for the gemcitabine-cisplatin regimen as in our study, Crinò et al. reported percentages of gemcitabine dose reduction or omission of 27% and 29%, respectively, compared with 20% and 29% in our phase I trial [25]. Only a larger randomized phase II trial comparing chemotherapy with and without PKC412 would allow a better assessment of the toxicities.
The three partial responses and the four long-lasting (>4 months) tumor stabilizations all occurred at the RD and below. At the RD, the mean PKC412 Cmax at day 28 was 799 ng/ml (range 5011070). The mean plasma PKC412 concentrationtime profiles (Figure 2) at the RD were consistently above the minimal target concentration required for cytotoxicity in all cell lines, i.e. an inhibitory concentration (IC50) of 285 ng/ml (range 114399). This target concentration level was reported to exert anti-proliferative and anti-tumor activity in human tumor models without the presence of human AAG and it is difficult to be confident of the potential value of this clinically achieved plasma concentration [26]. However, previously published data have shown that PKC412 pharmacokinetics are very complex due to the high-affinity protein binding of PKC412 and its metabolites. In the single-agent PKC412 study, the linear relationship between the dosage and plasma PKC412 level seen during the first week of treatment disappeared with prolonged drug intake. At day 28, no increase was observed in the plasma PKC412 level with increasing doses ranging from 150 to 300 mg/day. There was accumulation of CGP52421-epimer2, a 10-fold less active metabolite known for its very long elimination time (median half-life of 36 days; range 27164 days). CGP52421 has the highest affinity for human AAG (>99.9% binding) due to its structural homology with UNC-01 [10, 15, 27]. It is possible that CGP52421-epimer2 displaces PKC412 and CGP62221 from AAG and that further interaction with cisplatin protein adducts reinforces this mechanism [28]. Our trial was not designed to test further these drug interactions. In other studies, attempts were made to identify biological end points that would correlate with the biological anti-tumor activity of PKC412. Blood plasma TNF- and IL-6 levels and the level of extracellular signal-regulated kinase 2 using western blotting in peripheral blood mononuclear cells have been proposed as candidate surrogate end points for PKC412 [29], but have still not been validated for routine clinical trials.
In summary, the results of this study indicate that PKC412 at a dose of 50 mg/day can be safely added to cisplatingemcitabine chemotherapy in patients with advanced NSCLC. The plasma PKC412 levels achieved at the RD are in the IC50 range of preclinical models without the presence of human AAG. Further trials are warranted to evaluate the anti-tumor activity of PKC412 in the treatment of advanced NSCLC, either combined with cisplatingemcitabine or with other chemotherapies.
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Acknowledgements |
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FOOTNOTES |
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