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Cancer Therapy: Clinical |
Authors' Affiliations: 1 Department of Interdisciplinary Oncology, Experimental Therapeutics Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida; 2 Division of Hematology/Oncology, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California; 3 Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, Texas; 4 British Columbia Cancer Agency, Vancouver Cancer Center, Vancouver, British Columbia, Canada; and 5 Pfizer Global Research and Development, New London, Connecticut
Requests for reprints: Pamela N. Munster, Department of Interdisciplinary Oncology, Experimental Therapeutics Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612. Phone: 813-745-8948; Fax: 813-745-1984; E-mail: Pamela.Munster{at}moffitt.org.
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Abstract |
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Experimental Design: A phase I trial evaluated escalating doses of CP-724,714, administered daily in 21-day cycles. Pharmacokinetics/pharmacodynamics were evaluated in serial blood samples and in pretreatment and posttreatment tumor and skin biopsies.
Results: Thirty female patients [median age, 51 years (range, 37-71); median performance status, 1 (range, 0-1)] received CP-724,714 at four dose levels: 250 mg once daily (4 patients), 250 mg twice daily (15 patients), 250 mg thrice daily (6 patients), and 400 mg twice daily (5 patients). Dosing at 400 mg twice daily and 250 mg thrice daily was not feasible due to reversible, cholestatic liver dysfunction. Treatment-related adverse events were nausea (58%), asthenia (23%), hyperbilirubinemia (27%), elevated transaminases (30%), and skin rash (30%); neither diarrhea nor cardiomyopathy was observed. No objective responses were observed in 28 evaluable patients; 8 (29%) patients had stable disease. Twenty-seven (96%) patients received prior trastuzumab and were heavily pretreated (median prior chemotherapy, 6; range, 1-11). Systemic exposure exceeded the in vivo efficacy threshold required in preclinical studies.
Conclusions: Dose-limiting toxicities included hyperbilirubinemia, elevated alanine aminotransferase, thrombocytopenia and pulmonary embolus. Although the protocol-specified maximum tolerated dose of CP-724,714 was 250 mg thrice daily, the recommended phase II dose was 250 mg twice daily due to excessive late-cycle hepatotoxicity. Despite extensive prior treatment, 29% of patients had stable disease. A phase II trial has been initiated in patients with breast cancer.
Although there is no consensus on the exact mechanism of action of trastuzumab, either direct inhibition of HER2-mediated signaling or immunologic, preclinical, and clinical studies have validated HER2 as a target, rendering the development of small-molecule inhibition directed against HER2 a rational strategy (9–11). Several agents directed against HER2 or EGF receptor (EGFR; HER1), such as erlotinib (OSI-774, Tarceva), gefitinib (ZD1839, Iressa), lapatinib, and the pan-erbB receptor tyrosine kinase inhibitor, CI-1033, have shown efficacy in preclinical and clinical studies (12–17). However, whether the more specific inhibition of an individual receptor kinase or the inhibition of multiple receptor kinases that signal through dimerization will evolve as a better strategy is currently unknown. Further studies are needed to determine whether kinase inhibitors are cross-resistant in patients who failed trastuzumab and where to best place the kinase inhibitors in the sequence of treatments.
Kinase inhibitors may provide several advantages over trastuzumab. The different nature of these compounds may avoid the cardiotoxicity associated with trastuzumab (18). Furthermore, the oral route may facilitate administration.
This study evaluates the first clinical phase I trial of CP-724,714, 2-methoxy-N-[(2E)-3-[4-[3-methyl-4-[(6-methyl-3-pyridinyl)oxy]phenylamino]-6-quinazolinyl]-2-propenyl]-acetamide, butanedioic acid (C27H27N503 . 1.5 C4H6O4), an oral selective inhibitor of HER2, for patients with HER2-overexpressing solid tumors (Fig. 1
). In vitro studies suggested that CP-724,714 was selective for HER2 and inhibited HER2 kinase phosphorylation with an inhibitory concentration (IC50) of 3.8 ng/mL and the growth of SKBr-3 cells, a well-established HER2-dependent breast cancer cell line, at 25 ng/mL (19). CP-724,714 is >500-fold selective relative to the concentrations required to inhibit the EGFR intracellular domain. Similarly, CP-724,714 is approximately >1,000-fold selective relative to the concentrations required to inhibit the activity of the platelet-derived growth factor receptor, insulin receptor, insulin-like growth factor-I receptor, vascular endothelial growth factor receptor-2, abl, src, and met kinases (19). In vivo studies showed oral bioavailability and antitumor activity in FRE erbB2 tumors and in HER2-overexpressing breast (BT-474), lung (Calu-3), ovary (SK-OV-3), and pancreatic (Panc-1) xenograft models (Pfizer investigators' brochure) at doses of 100 mg/kg twice daily. This dose range had acceptable toxicity in Sprague-Dawley rats and Beagle dogs (19). The projected efficacious CP-724,714 concentration was based on both ex vivo inhibition of erbB2 autophosphorylation and in vivo tumor growth inhibition studies in FRE erbB2, BT-474, and SK-OV-3 tumors in athymic mice. Based on these studies, the desired Cmax concentration of CP-724,714 in humans was estimated to be 
500 ng/mL and predicted to require daily doses of 250 mg, which is <10% of the dose associated with severe irreversible toxicities in dogs and rodents. Planned dose escalations were up to 1,200 mg per day. Preclinical studies suggested predominantly gastrointestinal and hepatic toxicities as well as anemia, electrocardiographic changes (QT prolongation), and tremor. The gastrointestinal toxicities consisted mainly of emesis, loose stools, intestinal hemorrhage, and inflammation and were dose limiting in both dogs and rats. Hepatic toxicities included hepatocellular necrosis, Kupffer cell hypertrophy, increased serum hepatic transaminases, and 
-glutamyl transpeptidase and total bilirubin. These liver abnormalities were reversible with discontinuation of drug. Similarly to other quinazoline small-molecule inhibitors of the HER family, cardiomyopathy associated with CPI-724,714 has not been observed in the preclinical models (investigator's brochure).
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Materials and Methods |
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18 years old and had an Eastern Cooperative Oncology Group performance status of 1. Patients were required to have adequate bone marrow function (absolute neutrophil count >1,500 cells/mm3 and platelets >100,000 cells/mm3), renal function (serum creatinine <1.5x upper limit of normal or a calculated creatinine clearance of >60 mL/min), and liver function (bilirubin <1.5 mg/dL and liver transaminases and alkaline phosphatases not greater than grade 2 by common toxicity criteria version 2.0). Normal cardiac function, defined as 12-lead electrocardiogram without significant changes, a QTc interval <460 ms, a left ventricular ejection fraction (LVEF) of >50% (by multigated nuclide analysis scan or echocardiogram), and no prior history of torsade des pointes or other symptomatic QTc abnormalities, was required. Patients must have had at least one prior treatment, and patients with breast cancer must have failed prior therapy with trastuzumab. Patients with central nervous system disease (brain metastases or leptomeningeal involvement) or other serious medical or psychiatric illness that would limit full compliance were excluded. Informed consent was obtained in accordance with good clinical practice and institutional guidelines under a protocol approved by the responsible institutional review board by each participating site. Study treatment. In a phase I, open-label, multicenter, dose-escalation trial, the safety, tolerability, as well as the pharmacokinetic/pharmacodynamic of CP-724,714 were evaluated. Patients received oral daily dosing of CP-724,714 without interruptions. Each cycle consisted of 21 days (3 weeks) for a predefined maximal duration of 17 cycles. Starting at 250 mg once daily, dose escalation steps were determined based on a modified Fibonacci schema. The dosing schedule (daily, twice daily, or thrice daily) was guided by real-time (pharmacokinetic) assessment during the dose escalation. The MTD was defined as the highest dose level at which <33% of subjects experienced dose-limiting toxicities (DLT) in cycle 1. Subjects were expected to receive treatment for at least two cycles, at which time the first evaluation for efficacy occurred. At the MTD or the highest dose level, tumor biopsies before and after dosing were required to evaluate pharmacodynamic effects on HER2 receptor tyrosine kinase phosphorylation status. At the MTD, the cohort was to be expanded to at least six HER2-positive breast cancer patients amenable to mandatory biopsies.
Treatment assessment. Safety and toxicity evaluation at baseline included a physical exam, review of systems, vital signs (Eastern Cooperative Oncology Group performance status, blood pressure, pulse rate, body temperature, and weight), 12-lead electrocardiogram, complete blood cell count with differential, hepatic {transaminases [alanine aminotransferase (ALT), aspartate aminotransferase (AST)]}, and renal function assessment, coagulation profiles, and urine analysis. These studies were repeated weekly in the first cycle and then every 3 weeks. Efficacy was evaluated by the measurements of all visible and palpable tumors by either chest radiographs, computer tomography, bone scans, or magnetic resonance scans every two cycles using the same method of assessment from baseline throughout the study. The cardiac function was assessed after every two cycles by either multigated nuclide analysis scan or echocardiogram.
Pharmacokinetic studies. Blood samples were collected at times 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 24, 32, and 48 h following administration of a single dose of CP-724,714 of day 1 in cycle 1 (for single-dose pharmacokinetics) and cycle 2 (for steady-state pharmacokinetics). Regular dosing of CP-724,714 was resumed on day 3 of these cycles. The primary pharmacokinetic end points were Cmax (maximum observed serum concentration), AUC 0-t(last) (area under the serum concentration-time curve from time 0 to the time of the last quantifiable concentration), and Tmax (time of first occurrence of Cmax). The observed arithmetic means were reported for all pharmacokinetic variables, except that the median was reported for Tmax. Individual serum concentrations of CP-724,714 from each period were summarized in tabular and graphical form.
Serum samples were assayed for CP-724,714 concentration using validated, sensitive liquid chromatography-tandem mass spectrometry method by the Clinical Assay Group at Pfizer, Inc. (New London, CT). In brief, blood specimens were centrifuged to obtain serum fractions, and serum samples were immediately frozen and stored at temperature less than or equal to –20°C until analysis. Aliquots (150 µL) of serum, 50 µL of the internal standard CE-245,346, and 200 µL of 0.1 N HCl were added, in sequence, to one well of a 96-well block. The drug and internal standard were extracted using a 96-well ANSYS MP1 15 mg extraction plate. The sample was washed with 0.1 N HCl and 100% methanol and eluted with 200 µL 95:5 methanol/ammonium hydroxide. The eluent was isolated, evaporated to dryness, and reconstituted in 100 µL 82:18 acetonitrile/10 mmol/L ammonium acetate containing 0.05% formic acid. Separation was done by high-performance liquid chromatography isocratic conditions. The mobile phase was a binary mixture (82:18) of acetonitrile and 10 mmol/L ammonium acetate. The analytic column was a Phenomenex (Torrance, CA) Luna 5 m cyano 2.00 x 50 mm high-performance liquid chromatography column. The analysis was done on a Perkin-Elmer (Waltham, MA) SCIEX API 3000 triple quadrupole mass spectrometer operated in the positive ion mode. The TurboIonSpray ion source was operated at 1,500 V, with a temperature of 350°C and 6 L/s nitrogen gas. Nitrogen nebulizer gas was set to 8 and curtain gas was set to 8. Collision gas was set to 6. Product ions at m/z 272.0 were monitored for both drug and internal standard. The assay was linear from 1.0 to 500 ng/mL. The bias and precision (%CV) of both intrabatch and interbatch runs were within ±15% and ±8%, respectively. Stability of CP-724,714 to repeated freeze-thaw had been established at 3.00 and 400 ng/mL by preparing QCs; the mean assayed value of high and low QC samples was within 15% of their nominal values.
Pharmacodynamic studies. Blood samples (5 mL) were collected to quantify circulating HER2 ECD, a serum marker of HER2 tumor burden. If screening HER2 ECD was >15 ng/mL, above the normal level as suggested by Schwartz et al. (20), further samples (5 mL) were drawn after each two cycles with restaging studies. Serum samples for HER2 were stored frozen and sent to LabCorp (Research Triangle Park, NC) where they were assayed using the HER2/neu quantitative ELISA kit from DakoCytomation (Carpinteria, CA). In a subset of patients, skin and tumor biopsies by fine-needle aspirations were done on day 1 of cycle 1 before and 3 h after the first dose of CP-724,714. Three central laboratories were used for this study: (a) immunochemistry and analysis of tumor biopsies was done at IMPATH Predictive Oncology, Inc. (Los Angeles, CA); (b) blood specimens for pharmacogenomic analyses were stored at CRL Medinet (Lenexa, KS); and (c) serum samples for HER2 ECD evaluation were sent to LabCorp.
Analytic methods. Patients were evaluable for safety if at least one dose of study medication was received. Adverse events and laboratory tests were summarized by worst common toxicity criteria grade (version 2.0) for "cycle one" and "all cycles." Cumulative dose, dose intensity, and overall dose were summarized descriptively (n, median, range). Tumor response included rates of objective response (complete and partial response) and stable disease by WHO criteria. Objective response and stable disease rate were defined as the percentage of subjects based on the total number of response-evaluable subjects. Evaluation of efficacy was a secondary objective of this clinical phase I study.
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Results |
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Safety assessment. A total of 242 adverse events was reported, with 114 events (47%) being study drug related. Grade 3 and 4 treatment-related toxicities were recorded in nine patients. Nine episodes of severe adverse events were observed in a total of seven patients; three resulted in death. All three deaths were attributed to progression of the underlying disease. One death occurred in close proximity to two events that were treatment related: bilateral pulmonary emboli and thrombocytopenia. The death was believed to be attributed to disease progression; however, study drug relatedness cannot entirely be ruled out. DLTs included hyperbilirubinemia, liver enzyme elevations, and pulmonary emboli, which were seen in four patients (Table 2). In the 250 mg twice daily cohort, one patient experienced grade 3 thrombocytopenia and grade 4 pulmonary emboli. At the 250 mg thrice daily dose, one patient had a grade 3 increase in ALT, and two patients at the 400 mg twice daily dose experienced a grade 3 hyperbilirubinemia and ALT elevation. At the 250 mg thrice daily dose, one of six patients experienced DLTs with a grade 3 elevation of ALT in cycle 1. As discussed above, the excessive postcycle 1 liver toxicities were felt to be unacceptable. The 250 mg twice daily dose of CP-724,714 was therefore considered the recommended phase II dose and the 250 mg twice daily cohort was expanded to a total of 15 patients.
Toxicity assessment. For all subjects, regardless of treatment group or adverse event grade, treatment-emergent adverse events during study with the highest frequencies (>20%) were nausea (60%), asthenia (43.3%), abdominal pain (33.3%), rash (33.3%), increased ALT (33.3%), increased AST (33.3%), bilirubinemia (26.7%), respiratory tract infection (23.3%), and vomiting (23.3%). The majority of treatment-emergent (59.9%) and treatment-related (70%) adverse events were reported during cycle 1 of this trial. Adverse events that were study drug related were nausea (56.7%), rash (30%), increased AST (30%), increased ALT (30%), bilirubinemia (26.7%), and asthenia (23.3%; Table 3 ).
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Most shifts in hematologic laboratory variables were to the level of grade 1 or 2. Laboratory abnormalities of grade 3 or 4 were reported much less frequently. There were treatment-related grade 1 or 2 hemoglobin decreases from baseline in approximately two of three of subjects across all dosing cohorts. One subject had a grade 4 on-treatment decrease in hemoglobin. No subjects experienced an on-treatment elevation to a grade 4 for any serum chemistry variable. Treatment-related grade 3 toxicities as measured by hepatic laboratory tests (total bilirubin, AST, ALT, and -glutamyl transpeptidase) occurred in a few subjects, but in the majority of subjects on treatment, values for these variables did not increase beyond grade 2.
Cardiac safety. QTc prolongations beyond 60 ms from baseline or absolute QTc prolongations >480 ms were not observed. The baseline assessment was not available in one patient. All 30 patients had a baseline assessment of their LVEF. Multigated nuclide analysis scans were repeated before cycle 3 and then every four cycles. No incidences of congestive heart failure were observed during the study. In 26 patients, the baseline LVEF was >55%, in 3 patients the baseline LVEF was 50% to 55%, and in 1 patient the baseline LVEF was <50%. The latter patient improved her LVEF during treatment. A decrease in the LVEF to <50% was observed in one (3%) patient. However, the treating physicians of this patient reported that LVEF fractions below 50% were noted in the patient's history before initiation of the trial; hence, a clear association with CP-724,714 could not be clearly established. In 10 (33.3%) patients, repeat multigated nuclide analysis scans were not reported because patients were withdrawn from study before reassessment of multigated nuclide analysis scans due to progression of disease.
Efficacy results. Twenty-eight of 30 subjects were evaluable for tumor response. Two patients (one at the 250 mg twice daily dose and one at the 400 mg daily dose) were inevaluable because they did not receive a minimum of two cycles of study treatment. One patient was withdrawn due to early toxicity and one patient had declining Eastern Cooperative Oncology Group performance status. Among the 28 subjects who were evaluable for tumor responses, no complete or partial responses were observed. Eight (29%) had stable disease after two cycles of treatment as their best overall response. Of the eight subjects, seven experienced stable disease in 
6 months and one had stable disease for >6 months (Table 2). The eight subjects all had a primary diagnosis of breast cancer at study entry. Twenty subjects (71%) of the evaluable patients had progressive disease after two cycles.
Pharmacodynamic analysis. HER2, HER2 phosphorylation, and EGFR family members were evaluated by immunohistochemistry from tumor biopsies obtained before and on day 1 of CP-724,714 (see Materials and Methods). Serial tumor biopsies for phosphorylated HER2 and several other downstream markers could be obtained in only six pairs of biopsies. However, the immunohistochemical analysis was very limited partly due to poor tissue preservation and low cell count. In the setting of a limited number of samples and the absence of any response, no meaningful correlations could be inferred.
Serum analyses of circulating HER2 ECD were obtained in patients who had a baseline HER2 ECD of >15 ng/mL (20). Baseline and postcycle 2 data were obtained from 11 of 30 patients. Three of these patients were treated with CP-724,714 and were stable for at least 12 weeks and eight patients were treated for <12 weeks. The average change in serum HER ECD for patients with stable disease was 1.7-fold (±0.26-fold). The average increase in the patients treated for <12 weeks was 1.5-fold (±0.34-fold). There was no statistical difference for the two groups.
Pharmacokinetic analysis. CP-724,714 was rapidly absorbed after oral administration. The mean systemic exposure variables (Cmax and AUC) of CP-724,714 increased with dose in an approximate dose proportional manner after single and multiple oral dosing. There was some accumulation of CP-724,714 in the twice daily and thrice daily dosing regimens, with a mean accumulation ratio ranging from 1.2 to 1.5. Interpatient variability in the systemic variables was moderate (CV, 31-65%; Table 4
). Figure 2
shows the mean serum concentration-time profiles of CP-724,714 after a single oral dose (day 1 of cycle 1) and at steady state (day 1 of cycle 2) following multiple oral dosing. Median Tmax was 1 h after a single dose and 1 to 2 h at steady state (day 1 of cycle 2) across dose levels and regimens evaluated. After reaching Cmax, serum CP-724,714 concentrations declined biexponentially. The terminal half-life ranged from 4.31 to 4.80 h and was similar across the dose range from 250 to 400 mg. At steady state, mean serum CP-724,714 concentrations were above the predicted efficacious concentration for approximately 12.5%, 25%, and 37.5% of tau for 250 mg daily, twice daily, and thrice daily dose regimens, respectively. Mean serum CP-724,714 concentrations were above the predicted Ceff for 50% of tau for the 400 mg twice daily dose regimen.
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Discussion |
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This study describes the pharmacokinetic and pharmacodynamic profile of the selective HER2 receptor tyrosine kinase inhibitor CP-724,714 tested in a first-in-human study. This compound was administered orally in a continuous exposure to women with HER2-overexpressing tumors. All but two patients enrolled in this trial had metastatic breast cancer. One patient had a HER2-overexpressing colorectal cancer and one had bladder cancer. All but one of the breast cancer patients had failed prior therapy with trastuzumab for metastatic disease. Furthermore, patients were enrolled onto this study after a median number of 6 (range, 1-11) prior chemotherapy regimens. Ninety percent of the patients were exposed to prior anthracyclines. None of the patients had been treated with prior hormonal therapy in the metastatic setting. No responses were seen in the 30 patients treated with CP-724,714. Although disappointing, the extent of exposure to prior therapies in these patients renders responses less likely and does not rule out the possibility that CP-724,714 may be an active agent in less extensively pretreated patients. Furthermore, 7 of 30 patients had stable disease for 3 to 6 months and 1 patient had stable disease for >6 months, suggesting a clinical benefit of CP-724,714 despite the extensive prior therapy.
The MTD (prespecified per protocol) of CP-724,714 was 250 mg thrice daily. The maximally administered dose of CP-724,714 in this study was 400 mg twice daily. DLTs were thrombocytopenia (grade 3) and pulmonary embolus (grade 3) seen in 1 of 30 patients and an increase in liver function enzymes and hyperbilirubinemia in 3 patients. Although it is not certain whether the pulmonary embolus and the thrombocytopenia observed in this study were clearly study drug related, the hepatic and cholestatic toxicities were unequivocally drug related and prohibited further dose escalation beyond the 250 mg dose. Patients were able to better tolerate the 250 mg thrice daily dosing but unable to tolerate higher doses, suggesting that peak levels rather than cumulative exposure determined the observed liver toxicity.
The reported toxicities were predicted from the preclinical studies in both rodents and dogs. Similar adverse effects have been reported with other HER2 or EGFR pathway inhibitors, such as the small-molecule inhibitors erlotinib (Tarceva), gefitinib (ZD1839, Iressa), and even the geldanamycin analogues that target HER2 by inhibiting heat shock proteins (HSP90; ref. 21). Hepatic toxicities are uncommon in patients treated with trastuzumab (4). Other toxicities of CP-724,714 included rash, asthenia, and nausea. These toxicities were similar to those seen in the preclinical studies. However, QT prolongations or a decrease in LVEFs was not observed in the clinical study. The occurrence of a rash has been a predictor of response in some of the trials involving EGFR inhibitors (16). The size of this small study and the absence of responses do not support any valid conclusions determining rash as a predictive factor. Taken together, these findings suggest that the toxicity profile of this small-molecule inhibitor directed selectively against the HER2 kinase is more similar to those seen with nonselective HER2 kinase inhibitors rather than with the monoclonal antibody directed against HER2.
Mean systemic pharmacokinetic variables increased with dose, suggesting a linear drug disposition across the dose range evaluated. The mean terminal half-life was 4.5 h and seemed to be independent of the administered dose from 250 to 400 mg. There was some accumulation of CP-724,714 in the twice daily and thrice daily dosing regimens, with a mean accumulation ratio ranging from 1.2 to 1.5, which was consistent with the half-life. There was a considerable overlap of both Cmax and AUC among treatment groups as expected for a narrow dose range examined. Systemic exposure at the 250 mg twice daily and thrice daily dosing exceeded the predicted efficacious level, which supported evaluation of CP-724,714 efficacy in phase II studies. Based on safety findings from this phase I trial, the drug seemed to be better tolerated at 250 mg thrice daily, where a lower mean Cmax and AUC was observed, when compared with 400 mg twice daily. However, given the limited number of patients and the pharmacokinetic variability (CV, 31-65%) observed in this trial, caution in the interpretation of the safety and pharmacokinetic differentiation of these two doses is warranted.
The 250 mg thrice daily dose was the MTD. However, at the 250 mg thrice daily dosing, the liver toxicity was unacceptably high. The 250 mg twice daily dosing exceeded concentrations required for antitumor activity in preclinical models, and based on the findings presented here, the recommended phase II dose was defined as 250 mg twice daily.
The presented pharmacokinetic data suggest that plasma concentrations required for in vivo efficacy are obtainable. The absence of documented responses may therefore not be explained by subtherapeutic plasma levels. However, given the extensive prior treatment exposure, it may be difficult to assess the efficacy of CP-724,714, and this compound is currently being studied in limited phase II trials in patients with less prior therapy.
Biomarker/pharmacodynamic data did not provide conclusive data. Although pretreatment and posttreatment tumor biopsies were part of this trial, the biopsies were optional and tumor biopsies were collected in only six patients on this trial. The analysis was further hampered by the fact that fine-needle aspirations resulted in a very limited amount of tumor tissue with poor immunohistochemical staining.
These findings support other reports, suggesting that, although optional tumor biopsies in a trial may facilitate enrollment, this may also result in inconclusive correlative/pharmacodynamic analyses. Much more emphasis should be placed on mandatory tumor biopsies, particularly at dose levels of study drug that exceed the concentrations required for in vitro/in vivo efficacy.
Measurements of serum HER2 ECD were done in patients with baseline levels of 15 ng/mL (20) and were done at times of restaging studies. Paired samples were obtained in 11 of 30 patients. In this limited data set, there was no statistical difference in the relative change in HER2 ECD after cycle 2 in patients who were treated for >12 weeks versus those treated for <12 week (data not shown). However, data interpretation is limited by the small sample and the absence of objective responses. Furthermore, although elevated HER2 ECD has been reported to be associated with poorer outcome, it has not been clearly related to response to therapy (22, 23).
This is the first study involving the selective HER2 kinase inhibitor CP-724,714. This compound has acceptable tolerability and safety at 250 mg twice daily. Plasma concentrations exceed those required for efficacy in preclinical models. The predominant toxicities seen were hepatic cholestatic related and skin rash. These are more comparable with other nonselective small-molecule kinase inhibitors than to trastuzumab. Although 8 of 30 patients had stable disease, no responses were seen, which may at least in part be explained by the extensive prior treatment of these patients. These findings suggest that CP-724,714 and similar compounds should be further evaluated in patients at an earlier stage of their disease. The limited data on biomarkers in this trial warrant further assessment of the biological behavior of this compound in future studies.
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Acknowledgments |
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Footnotes |
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Received 6/26/06; revised 11/14/06; accepted 12/ 1/06.
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