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Clinical studies with non-iressa EGFR tyrosine kinase inhibitors
Lung Cancer (2003) 41, S43 /S48
www.elsevier.com/locate/lungcan
Clinical studies with non-iressa EGFR tyrosine kinase inhibitors Philip Bonomi* College of Medicine, Rush University, 600 South Paulina Street Suite 440, Chicago, IL 60612 3873, USA
KEYWORDS Clinical studies; Non-iressa; EGFR
Summary During the last five years there has been interest in developing noncytotoxic, targeted cancer treatments. This phenomenon has occurred as a result of increased information regarding factors which regulate tumor proliferation, survival, angiogenesis, invasiveness, and metastatic potential. In non-small cell lung cancer many investigators have focused their attention on the epidermal growth factor receptor (EGFR) because this membrane protein, which has an extracellular ligand binding domain, as well as, tyrosine kinase activity on the intracellular portion of the molecule, is expressed in a relatively high proportion of non-small cell lung cancers. Gefitinib which was the first EGFR specific tyrosine kinase inhibitor to be extensively tested in non-small cell lung cancer has shown single agent activity in non-small cell lung cancer. Subsequently, erlotinib, another EGFR specific tyrosine inhibitor, has also demonstrated single agent activity in non-small cell lung cancer. Phase III trials of erlotinib alone or in combination with chemotherapy have been completed, and data are being analyzed. Several dual inhibitors of erb B1 and erb B2 (PKI 166, GW 572016, EKB 569) have been or are being tested in phase I trials. In addition, CI 1033, a pan-erb inhibitor, is also being tested in phase I studies. Diarrhea and rash have been the predominant side effects of these agents. Life threatening toxicity has been rare. Although the erb tyrosine kinase inhibitors are attrative agents to use in treating nonsmall cell lung cancer because of their relatively benign toxicity profile, more data are needed to define the role of these agents in non-small cell lung cancer. – 2003 Elsevier Science Ireland Ltd and American Society of Clinical Oncology. Published by Elservier Ireland Ltd. All rights reserved.
1. Introduction Currently chemotherapy is the primary treatment for good performance stage IV NSCLC patients. A meta-analysis has shown that there is a modest improvement in survival for patients treated with cisplatin containing chemotherapy regimens compared with treatment with supportive care only [1]. More recently a meta-analysis has shown that third generation chemotherapy regi-
*Tel.: /1-312-942-7100; fax: /1-312-942-2219.
mens are slightly more effective than the older platinum based regimens [2]. Results from the most recent randomized trials comparing newer regimens have shown no significant survival differences suggesting [3,4] that continued testing of variations of the currently available cytotoxic agents is unlikely to produce a significant improvement in survival for stage IV NSCLC patients. Simultaneous with the somewhat disappointing results from trials evaluating the newer cytotoxic agents there has been increasing information regarding the distinguishing characteristics of neoplastic cells which include self sufficiency in
0169-5002/03/$ - see front matter – 2003 Elsevier Science Ireland Ltd and American Society of Clinical Oncology. Published by Elservier Ireland Ltd. All rights reserved. doi:10.1016/S0169-5002(03)00141-7
S44
growth signals, insensitivity to anti-growth signals, tissue invasion and increased metastatic potential, limitless replicative potential, sustained angiogenesis, and evasion of apoptosis. These characteristics, which have been called the ‘‘hallmarks of cancer’’ by Weinberg and Hannahan [5] have identified potential new therapeutic targets for anticancer treatments. Currently a variety of novel strategies are being tested in NSCLC clinical trials. The areas of most intense developmental have included strategies to inhibit angiogenesis, approaches to enhance apoptosis, attempts to inhibit tissue invasion and metastatic potential, and methods of inhibiting the epidermal growth factor receptor [6]. Both monoclonal antibodies directed against the extra-cellular portion of EGFR and small molecules which inhibit the intracellular tyrosine kinase activity of EGFR have been shown to reduce proliferation and enhance apoptosis in malignant cells [7]. In pre-clinical models EGFR inhibition also reduces tumor related angiogenesis and the invasive and metastatic potential of malignant tumors. These observations and the fact that EGFR is expressed in a relatively high percentage of nonsmall cell lung cancers [8] has led to the development of a number of small molecules which inhibit tyrosine kinase activity associated with EGFR (erbB1) alone or EGFR and other members of the erbB family. The EGFR tyrosine kinase inhibitions are unique among the biologic therapies which have been tested in non-small cell lung cancer because gefitinib [9,10] and erlotinib [11] the first compounds to be tested, have shown single agent activity. Gefitinib, which was the first EGFR tyrosine kinase inhibition to be tested in non-small cell lung cancer is discussed elsewhere in this monograph. The more recently developed erbB tyrosine kinase inhibitors including erlotinib are described briefly in this narrative.
2. Development of erlotinib Pre-clinical studies showed that erlotinib, which is a quinazoline, is capable of inhibiting phosphorylation of EGFR [12]. This effect was related to erlotinib’s ability to specifically inhibit the tyrosine kinase activity of the intracellular portion of EGFR with little affect on other tyrosine kinase inhibitors. In addition, erlotinib’s binding to EGFR appears to be reversible, because increasing concentrations of ATP reduce erlotinib’s inhibitory affect on EGFR tyrosine kinase. In cell cultures erlotinib was shown to increase the concentrations of non phosphorylated retinoblastoma protein, and
P. Bonomi
this phenomenon also was associated with decreased cellular proliferation. In addition to its anti-proliferative effect there was evidence that erlotinib increased apoptosis in DiFi colon cancer cells. Based on the encouraging observations Hidalgo et al. [13] conducted a phase I clinical trial with erlotinib. The first group of patients received erlotinib once daily at doses of 25 /100 mg on Monday, Wednesday, and Friday for 3 consecutive weeks with courses being repeated every 4 weeks. In the subsequent group patients received erlotinib 50 /200 mg daily as a single daily dose for 21 days out of a 28-day treatment cycle. In this group of patients diarrhea was found to be the dose limiting toxicity in patients receiving 200 mg daily. In addition many of the patients experienced cutaneous toxicity which generally involved a rash on the face and upper trunk and which was usually asymptomatic. In the third group of patients 150 mg was given as a single daily dose continuously. In this cohort 15 patients received a total of 54 courses. Grade I /II diarrhea was observed in six patients, and grade I /II cutaneous toxicity observed in seven patients. No grade III toxicity was noted in this group of patients. Diarrhea was self limited, or in some cases loperamide was required to control this symptom. Similarly, grade I /II rash occurred within the first 1 /2 weeks and it frequently resolved gradually despite continued therapy. Some patients received topical and systemic medications for the cutaneous toxicity, but there is no treatment which was identified as clearly effective. Other toxicities included mild mucositis and headaches and grade I hyperbilirubinemia which occurred in eight patients, six of whom had hepatic metastases. Pharmacokinetic studies revealed that the maximum concentration was achieved 3 h after taking a single dose, and there was no evidence of drug accumulation with continuous treatment [13]. The minimal study state concentration was 1.209/0.62 mg/ml. There was moderate inter-patient variability in the steady state concentration. The elimination half life was 24.4 h and the median area under the curve was 12 mg/h per ml. Patients who developed a rash had higher AUC0 24 values (18 vs. 11.5, P /0.02). Based on the results of this study the investigators recommended a single daily dose of 150 mg given on a continuous basis for evaluation in phase II trials. In the phase I trial there were minor tumor regressions observed in a single patient with renal cell carcinoma and a single colorectal cancer patient [13]. Stable disease lasting for at least 5 months was observed in two additional colorectal
Clinical studies with non-iressa EGFR tyrosine kinase inhibitors
cancer patients, and in single patients with NSCLC, prostate cancer, cervical cancer, and head and neck cancer [13]. A subsequent phase II NSCLC included patients who had progressive disease following treatment with a platinum based chemotherapy regimen [11]. Patients were allowed to receive multiple chemotherapy regimens provided they met the following eligibility requirements: NSCLC which was positive for EGFR expression, measurable disease, ECOG performance status 0 /2, and adequate organ function. EGFR positivity was defined as at least 10% of the malignant cells being 1/ positive for EGFR as determined by immunohistochemistry. Treatment consisted of erlotinib 150 mg as a single daily dose continuously. Most patients were ambulatory and had non-squamous histology. In addition, there were more women than men, and 70% of the patients received two or more chemotherapy regimens prior to starting erlotinib. Responses to erlotinib were as follows: complete remission one (2%), partial remission six (10%), and stable disease 20 (35%). The majority of the patients experienced skin toxicity, and diarrhea, but severe (grade III) rash occurred in only 2% of patients, and severe diarrhea (grade III) occurred in 2%. Other side effects included dry skin, nausea, and pruritus. The median survival was 36 weeks and 1 year survival rate was 48% [11]. Multivariate analysis revealed that longer time from the last chemotherapy treatment was associated with a higher chance of obtaining objective remission (P /0.001). EGFR levels defined by the percent of positive cells and the intensity of staining were not significantly related to objective response. In addition, the number of previous chemotherapy regimens was not significantly related to response. A longer time from initial diagnosis and a longer time from the last chemotherapy were associated with significantly longer survival with erlotinib. The EGFR levels and the number of previous chemotherapy regimens were not significantly related to survival [11]. Subsequently, two phase III trials in stage IV NSCLC patients have compared treatment with chemotherapy versus chemotherapy combined with erlotinib. In one of the trials paclitaxel and carboplatin was utilized, and in the other trial the chemotherapy regimen consisted of gemcitabine and cisplatin. In each study patients who were assigned to the chemotherapy-erlotinib arm received 150 mg of erlotinib daily starting with the first dose of chemotherapy, and erlotinib was continued after completion of chemotherapy. The accrual goals in each trial was 1000 patients. In
S45
addition to the first line trials of erlotinib combined with chemotherapy, the National Cancer Institute of Canada is conducting a phase III trial comparing erlotinib to placebo as third line therapy in NSCLC patients. This trial which has an accrual goal of 700 is nearing completion.
3. PKI 166 PKI 166 is a pyrolo-pyrimidine compound which competes with the ATP binding site on EGFR tyrosine kinase. At a low concentration (1 nm) PKI 166 inhibits EGFR auto-transphosphorylation, CFOS mRNA expression, and cell proliferation [14]. At higher concentrations (0.1 /1 mM) PKI 166 also inhibited autophosphorylation of erbB2. In animal studies PKI 166 showed good oral bio-availability, and it produced a marked reduction in autophosphorylation of EGFR in xenographs in nude mice following administration of EGF [14]. Recently, PKI 166 has been evaluated in three phase I trials [15 /17]. In the first study Hoekstra et al. [15] observed dose limiting elevations of serum transaminases at relatively low continuous doses. Subsequently, these investigators changed the schedule to daily for 14 consecutive days followed by a 14-day rest period. Five dose levels ranging from 50 to 900 mg daily were evaluated, and no dose limiting toxicities were observed up to 600 mg daily. The most common side effects observed were diarrhea, mild nausea, vomiting, fatigue, rash, myalgias, and reversible elevations of serum transaminases. No hematologic toxicity was noted. At a dose of 900 mg daily for 14 consecutive days dose limiting grade 3 elevations of transaminases, diarrhea, and rash were observed. No drug accumulation was noted at doses of 600 mg daily on days 1 /14. The AUC achieved at a 600 mg daily dose exceeded the level shown to be effective in preclinical models. The investigators suggested that either 600 or 750 mg will most likely be the dose tested in phase II trials evaluating the 2 week on/2 week off schedule [15]. In another phase I trial [16] PKI 166 was administered orally three times weekly on a continuous schedule. Sixteen patients were treated on this study, and dose-limiting reversible elevations of serum transaminases were observed at a dose of 400 mg given three times a week. Other sided effects included nausea, vomiting, diarrhea, fatigue, and rash. No hematologic toxicity was observed in this study trial. Stable disease was observed in three of 16 patients which included one patient with renal carcinoma, one with thyroid cancer, and one with unknown primary.
S46
In the third phase I trial conducted at MD Anderson 32 patients were treated with continuous daily doses for a minimum of 28 days [17]. The initial dose level was 50 mg daily. Most recently two patients have been treated at 600 mg/day. No dose limiting toxicity has been observed so far, but the investigators have observed diarrhea, rash, fatigue, and reversible elevations of serum tansaminases. Similar to the observations of other investigators, no hematologic toxicity was observed. Decreases in EGFR and EGFR phosphorylation in skin and tumor biopsies were found, and there was one partial remission in NSCLC.
4. GW572016 The fact that heterodimerizations is involved in signal transduction mediated by the erbB1 family members suggested that the development of agents which inhibit 2 or more of the erbB1 tyrosine kinases might produce greater anti-tumor effect than inhibiting erbB1 related tyrosine kinase alone. GW572016 has been developed for this purpose. GW572016 was tested against an EGFR over expressing malignant tumor and against an erbB2 over expressing tumor. Each of these tumors was injected into mice and biopsies were obtained from palpable tumors before and after oral administration of GW572016 [18]. In animals which were injected with HN5, which is an EGFR over expressing tumor, the investigators observed a decrease in phosphorylation of EGFR, ERK 1/2, and AKT. While significant decreases were detected in phosphorylation of each of these molecules, there was no difference in the oral concentration of each molecule. Similarly, pre and post treatment biopsies were obtained in nude mice which contained B1474 tumor which over expresses erbB2. Again oral administration of GW562016 produced reduction in phosphorylated erbB2 and ERK-1/2 without decreasing the total amounts of these molecules. The investigators concluded GW572016 produced a biologic effect on both erbB1 and erbB2, as well as, a biologic effect on several downstream markers ERK-1/2 which is involved in cell proliferation and AKT which is involved in the apoptosis pathway [18]. Two phase I trials of GW572016 [19,20] were conducted in healthy subjects. In the first trial [19] which was a double blind placebo control study, doses of GW572016 of 25, 100, and 175 mg daily were given for 8 days versus a single daily dose of placebo for 8 days. Twenty-seven patients were entered into this trial in which gastrointestinal gaseous symptoms, rash, headaches, and transient
P. Bonomi
increases in serum transaminases were observed. All of the toxicities were grade I except for 6% of patients who developed grade II reversible elevations of serum of the transaminases. Interestingly the patients on the placebo appeared to have similar frequencies of the same side effects. Using a single daily dose the half life of GW572016 was 8 h, and there was an average accumulation of the drug of at least 50% over the 8day period. The investigators concluded that a dose up to 175 mg daily for 8 days was well tolerated and resulted in accumulative levels of the drug [19]. In a second Phase I trial 16 healthy subjects participated in a double blind trial [20]. Each subject received single daily doses for 4 days */ three of the doses were (GW572016 and one was placebo). The first group of subjects doses of GW572016 were 10, 50, and 175 mg; and the second doses were 25, 100, and 250 mg of a single daily dose. Grade I /II headache which occurred in greater than 28% of the subjects was the most common symptom. In addition, 9% of the subjects developed grade I rash, and 4% developed grade I diarrhea. Like the other study patients receiving placebo showed no side effects. Peak serum levels were observed at 3 /4 h, and the serum half life was 6 /9 h. The investigators concluded that the single oral dose of GW572016 up to 250 mg was well tolerated [20].
5. EKB569 EKB 569 is an irreversible inhibitor of ErbB1 and erbB2. This compound, which is anilinoquinoline derivative is well absorbed orally. EKB569 has been tested as a single dose for 14 consecutive days followed by a 2 week rest period [21]. Thirty patients were treated on this schedule with doses ranging from 25 to 125 mg daily. Eight patients received at least four courses of EKB569. The most common side effects were diarrhea, rash, nausea and vomiting, stomatitis, and anorexia. These symptoms were generally mild and were always reversible. Dose limiting toxicity was diarrhea which occurred at the 125 mg dose. The investigators concluded that the maximum toleration was 75 mg daily for 14 days followed by a 14-day rest period. The half life of EKB569 is 20 /23 h, and on day 14 the peak serum concentration was approximately 2-fold higher the serum concentration achieved on day 1. Subsequently, the investigators are evaluating continuous daily dosing of this agent, and at a daily dose of 50 mg the maximum tolerated dose has not been reached [21].
Clinical studies with non-iressa EGFR tyrosine kinase inhibitors
S47
6. CI-1033
7. Summary
The CI-1033 is an irreversible pan erbB inhibitor. In a phase I trial 34 patients received a single daily dose on days 1, 8, 15, of a 28-day cycle [22]. Single weekly dose starting at 100 mg and increasing to 600 mg have been tested. The most common side effects were grade I /II nausea and vomiting, diarrhea, and rash. Dose limiting hypersensitivity reactions were observed in two patients at the 560 mg dose. Since that time the investigators have added prophylactic diphenhydramine and have treated additional patients at the 560 mg dose. Without hypersensitivity reactions stable disease was observed in a patient with osteogenic sarcoma who has received a total of 8 cycles. In another phase I trial the schedule consisted of a single daily doses on days 1 /7 repeated every 21 days [23]. Thirty-seven patients have been enrolled on this trial and the most common toxicities have been grade I /II rash, nausea and vomiting, and diarrhea. Three patients experienced reversible grade III thrombocytopenia. Similar to the observations in the other phase I trial, one patient at the 560 mg/day dose experienced a grade III hypersensitivity reaction. The peak serum concentration occurred 4 h after a single oral dose, and the half life was approximately 5 h. In the preliminary report of their study, these investigators noted significant decrease in ki 67 and increase a significant in P27 8 days after starting treatment with CI-1033. They also observed one partial remission in a primary skin tumor. The investigators concluded CI-1033 was well tolerated and that there was evidence that compound produced significant effect on biomarkers [23]. In a more recent publication, this group of investigators reported the results with CI-1033 in 53 patients [24]. The schedule again was days 1 /7 every 21 days. Fifty-three patients were enrolled, and they attempted to get pre and post treatment, skin and tumor biopsies. They found a median decrease of 44% in EGFR phosphorylation, a median decrease of 26% in ki 67, and a median increase of 56% in p27 in day 8 tumor biopsies. Skin biopsies were obtained in 23 patients, and they detected a 50% decrease in ki 67, 24% increase in p27, but there is no significant change in erbB1 while there was down regulation of erbB2. There was no correlation between the dose level of CI-1033 and the degree of biomarker modulation in tumors or the skin. Dose limiting toxicity and the maximum tolerating dose were not described in this protocol. However, the investigators stated that the protocol schedule had been amended to give a single daily dose of CI-1033 on days 1 /14 every 21 days [24].
Each of the small molecules which inhibit erbB related tyrosine kinases produces rash and diarrhea which is generally mild and reversible. PKI 166 has been associated with dose limiting, reversible elevations of serum transaminases. Less severe reversible elevations of transaminases have also occurred with GW572016. Both groups of investigators who tested GW572016 have reported the occurrence of headache in healthy subjects. This side effect was not described with the other EGFR tyrosine kinase inhibitors. Hypersensitivity reactions and thrombocytopenia were listed as side effects with CI 1033 but not with the other compounds. Erlotinib has produced single agent response rate of approximately 10% in previously treated nonsmall cell lung cancer, and it is being tested in two phase III trials in which patients are assigned to chemotherapy alone versus chemotherapy combined with erlotinib. In addition, the NCI Canada is comparing erlotinib to placebo in a phase III trial in non-small cell lung cancer patients who have received two previous chemotherapy regimens. Phase II data for PKI 166, GW572016, CI-1-33, and EKB 569 are not available.
References [1] Non-small cell lung cancer collaborative group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomized clinical trials. Br Med J 1995;311:899 /901. [2] Baggstram MQ, Socinski MA, Hensing TA, et al. Third generation chemotherapy regimens (3GR) improve survival over second generation regimens (2GR) in stage IIIB.IV nonsmall cell lung cancer (NSCLC): a meta-analysis of the published literature. Proc Am Soc Clin Oncol 2002;021:306a. [3] Kelly KK, Crowley J, Bunn PA, et al. Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced nonsmall cell lung cancer: a Southwest oncology group trial. J Clin Oncol 2001;19:3210 /8. [4] Schiller JH, Harrington D, Belani C, et al. Comparison of four chemotherapy regimens for advanced non-small cell lung cancer. New Engl J Med 2002;346:92 /8. [5] Hanahan D, Weinberg RS. The hallmarks of cancer. Cell 2000;100:57 /70. [6] Dy GK, Adjei AA. Novel targets for lung cancer therapy: Part I J Clin Oncol 2002;20:2881 /94; Part II J Clin Oncol 2002;20:3016 /28. [7] Mendelsohn J. Targeting the epidermal growth factor receptor for cancer therapy. David A Karnotsky Award Lecture. J Clin Oncol 2002;20(Suppl. 1):1s /13s. [8] Rusch V, Klimstra D, Vekatraman E, et al. Over-expression of the epidermal growth factor receptor and its ligand transforming growth factor alpha is frequent in resectable non-small cell lung cancer, but does not predict tumor progression. Clin Cancer Res 1997;3:515 /22.
S48 [9] Kris MG, Natale RB, Herbst RS, et al. A phase II trial of ZD 1839 (Iressa) in advanced non-small cell lung cancer (NSCLC) patients who had failed platinum and docetaxel based regimens (IDEAL 2). Proc Am Soc Clin Oncol 2002;21:292a. [10] Fukuoka M, Yano S, Giaccone G, et al. Final results from a phase II trial of ZD 1839 (Iressa) for patients with advanced non-small cell lung cancer (IDEAL I). Proc Am Soc Clin Oncol 2002;21:298a. [11] Perez-Soler R, Chachoua A, Huberman M, et al. A phase II trial of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor OSI-774, following platinum based chemotherapy in patients advanced EGFR expressing, nonsmall cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2001;21:310a. [12] Mayer HD, Barbacci EG, Iwata KK, et al. Induction of apoptosis and cell cycle arrest by CP-358-774, and inhibitor of epidermal growth factor receptor tyrosine kinase. Cancer Res 1992;57:4838 /48. [13] Hidalgo M, Siu LL, Neumanitis K, et al. Phase I and pharmacologic study of OSI-774, and epidermal growth factor receptor tyrosine kinase inhibitor in patients with advanced solid malignancies. J Clin Oncol 2001;19:3267 / 79. [14] Traxler P, Buchdunger E, Furet P, et al. Preclinical profile of PKI 166 */a novel potent EGFR tyrosine kinase inhibitor for clinical development. Clin Cancer Res 1999;5:3750S. [15] Hoekstra R, Dumez H, Van Oosteram AT, et al. A phase I and pharmacologic study of PKI 188, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, administered orally in a 2 weeks on, 2 weeks off scheme to patients with advanced cancer. Proc Am Soc Clin Oncol 2002;21:86a. [16] Dumez H, Hoekstra R, Eskens F, et al. A phase I and pharmacologic study of PKI 166, and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, administered orally 3 times a week to patients with advanced cancer. Proc Am Soc Clin Oncol 2002;21:86a.
P. Bonomi [17] Murren JR, Papadimitrakopoulou VA, Sizer KC, et al. A phase I dose escalating study to evaluate the biological activity and pharmacokinetics of PKI 166, a novel tyrosine kinase inhibitor in patients with advanced cancer. Proc Am Soc Clin Oncol 2002;21:95a. [18] Yia W, Mullin RJ, Keith BR, et al. Anti-tumor activity of GW 572016: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 pathways. Proc Am Soc Clin Oncol 2002;21:94a. [19] Adams VR, Bence AL, Anderson EB, et al. A phase I pharmacokinetic/pharmacodynamic study evaluating multiple doses of oral GW572016 in healthy subjects. Proc Am Soc Clin Oncol 2002;21:94a. [20] DeSimone PA, Bence AK, Anderson EB, et al. A phase I study to investigate the safety, tolerability, and pharmacokinetics of single oral escalating doses of GW572016 in healthy volunteers. Proc Am Soc Clin Oncol 2002;21:94a. [21] Hidalgo M, Erlichman C, Rawinsky EK, et al. Phase I trial of EKB-569, an irreversible inhibitor of the epidermal growth factor (EGFR) in patients with advanced solid tumors. Proc Am Soc Clin Oncol 2002;21:17a. [22] Garrison MA, Tolcher A, McGreery H, et al. A phase I pharmacokinetic study of CI-1033, a pan-erB tyrosine kinase inhibitor, given orally on days 1, 8 and 15 every 28 days to patients with solid tumors. Proc Am Soc Clin Oncol 2001;21:72a. [23] Shin DM, Neumanitis J, Zinner RG, et al. A phase I clinical and biomarker study of CI-1033, a novel pan erbB tyrosine kinase inhibitor in patients with solid tumors. Proc Am Soc Clin Oncol 2001;20:82a. [24] Zinner RG, Donato NJ, Neumanitis J, et al. Biomarker modulation in tumor and skin biopsy samples from patients with solid tumors following treatment with the pan-erB tyrosine kinase inhibitor, CI-1033. Proc Am Soc Clin Oncol 2002;21:15a.
www.elsevier.com/locate/lungcan
Clinical studies with non-iressa EGFR tyrosine kinase inhibitors Philip Bonomi* College of Medicine, Rush University, 600 South Paulina Street Suite 440, Chicago, IL 60612 3873, USA
KEYWORDS Clinical studies; Non-iressa; EGFR
Summary During the last five years there has been interest in developing noncytotoxic, targeted cancer treatments. This phenomenon has occurred as a result of increased information regarding factors which regulate tumor proliferation, survival, angiogenesis, invasiveness, and metastatic potential. In non-small cell lung cancer many investigators have focused their attention on the epidermal growth factor receptor (EGFR) because this membrane protein, which has an extracellular ligand binding domain, as well as, tyrosine kinase activity on the intracellular portion of the molecule, is expressed in a relatively high proportion of non-small cell lung cancers. Gefitinib which was the first EGFR specific tyrosine kinase inhibitor to be extensively tested in non-small cell lung cancer has shown single agent activity in non-small cell lung cancer. Subsequently, erlotinib, another EGFR specific tyrosine inhibitor, has also demonstrated single agent activity in non-small cell lung cancer. Phase III trials of erlotinib alone or in combination with chemotherapy have been completed, and data are being analyzed. Several dual inhibitors of erb B1 and erb B2 (PKI 166, GW 572016, EKB 569) have been or are being tested in phase I trials. In addition, CI 1033, a pan-erb inhibitor, is also being tested in phase I studies. Diarrhea and rash have been the predominant side effects of these agents. Life threatening toxicity has been rare. Although the erb tyrosine kinase inhibitors are attrative agents to use in treating nonsmall cell lung cancer because of their relatively benign toxicity profile, more data are needed to define the role of these agents in non-small cell lung cancer. – 2003 Elsevier Science Ireland Ltd and American Society of Clinical Oncology. Published by Elservier Ireland Ltd. All rights reserved.
1. Introduction Currently chemotherapy is the primary treatment for good performance stage IV NSCLC patients. A meta-analysis has shown that there is a modest improvement in survival for patients treated with cisplatin containing chemotherapy regimens compared with treatment with supportive care only [1]. More recently a meta-analysis has shown that third generation chemotherapy regi-
*Tel.: /1-312-942-7100; fax: /1-312-942-2219.
mens are slightly more effective than the older platinum based regimens [2]. Results from the most recent randomized trials comparing newer regimens have shown no significant survival differences suggesting [3,4] that continued testing of variations of the currently available cytotoxic agents is unlikely to produce a significant improvement in survival for stage IV NSCLC patients. Simultaneous with the somewhat disappointing results from trials evaluating the newer cytotoxic agents there has been increasing information regarding the distinguishing characteristics of neoplastic cells which include self sufficiency in
0169-5002/03/$ - see front matter – 2003 Elsevier Science Ireland Ltd and American Society of Clinical Oncology. Published by Elservier Ireland Ltd. All rights reserved. doi:10.1016/S0169-5002(03)00141-7
S44
growth signals, insensitivity to anti-growth signals, tissue invasion and increased metastatic potential, limitless replicative potential, sustained angiogenesis, and evasion of apoptosis. These characteristics, which have been called the ‘‘hallmarks of cancer’’ by Weinberg and Hannahan [5] have identified potential new therapeutic targets for anticancer treatments. Currently a variety of novel strategies are being tested in NSCLC clinical trials. The areas of most intense developmental have included strategies to inhibit angiogenesis, approaches to enhance apoptosis, attempts to inhibit tissue invasion and metastatic potential, and methods of inhibiting the epidermal growth factor receptor [6]. Both monoclonal antibodies directed against the extra-cellular portion of EGFR and small molecules which inhibit the intracellular tyrosine kinase activity of EGFR have been shown to reduce proliferation and enhance apoptosis in malignant cells [7]. In pre-clinical models EGFR inhibition also reduces tumor related angiogenesis and the invasive and metastatic potential of malignant tumors. These observations and the fact that EGFR is expressed in a relatively high percentage of nonsmall cell lung cancers [8] has led to the development of a number of small molecules which inhibit tyrosine kinase activity associated with EGFR (erbB1) alone or EGFR and other members of the erbB family. The EGFR tyrosine kinase inhibitions are unique among the biologic therapies which have been tested in non-small cell lung cancer because gefitinib [9,10] and erlotinib [11] the first compounds to be tested, have shown single agent activity. Gefitinib, which was the first EGFR tyrosine kinase inhibition to be tested in non-small cell lung cancer is discussed elsewhere in this monograph. The more recently developed erbB tyrosine kinase inhibitors including erlotinib are described briefly in this narrative.
2. Development of erlotinib Pre-clinical studies showed that erlotinib, which is a quinazoline, is capable of inhibiting phosphorylation of EGFR [12]. This effect was related to erlotinib’s ability to specifically inhibit the tyrosine kinase activity of the intracellular portion of EGFR with little affect on other tyrosine kinase inhibitors. In addition, erlotinib’s binding to EGFR appears to be reversible, because increasing concentrations of ATP reduce erlotinib’s inhibitory affect on EGFR tyrosine kinase. In cell cultures erlotinib was shown to increase the concentrations of non phosphorylated retinoblastoma protein, and
P. Bonomi
this phenomenon also was associated with decreased cellular proliferation. In addition to its anti-proliferative effect there was evidence that erlotinib increased apoptosis in DiFi colon cancer cells. Based on the encouraging observations Hidalgo et al. [13] conducted a phase I clinical trial with erlotinib. The first group of patients received erlotinib once daily at doses of 25 /100 mg on Monday, Wednesday, and Friday for 3 consecutive weeks with courses being repeated every 4 weeks. In the subsequent group patients received erlotinib 50 /200 mg daily as a single daily dose for 21 days out of a 28-day treatment cycle. In this group of patients diarrhea was found to be the dose limiting toxicity in patients receiving 200 mg daily. In addition many of the patients experienced cutaneous toxicity which generally involved a rash on the face and upper trunk and which was usually asymptomatic. In the third group of patients 150 mg was given as a single daily dose continuously. In this cohort 15 patients received a total of 54 courses. Grade I /II diarrhea was observed in six patients, and grade I /II cutaneous toxicity observed in seven patients. No grade III toxicity was noted in this group of patients. Diarrhea was self limited, or in some cases loperamide was required to control this symptom. Similarly, grade I /II rash occurred within the first 1 /2 weeks and it frequently resolved gradually despite continued therapy. Some patients received topical and systemic medications for the cutaneous toxicity, but there is no treatment which was identified as clearly effective. Other toxicities included mild mucositis and headaches and grade I hyperbilirubinemia which occurred in eight patients, six of whom had hepatic metastases. Pharmacokinetic studies revealed that the maximum concentration was achieved 3 h after taking a single dose, and there was no evidence of drug accumulation with continuous treatment [13]. The minimal study state concentration was 1.209/0.62 mg/ml. There was moderate inter-patient variability in the steady state concentration. The elimination half life was 24.4 h and the median area under the curve was 12 mg/h per ml. Patients who developed a rash had higher AUC0 24 values (18 vs. 11.5, P /0.02). Based on the results of this study the investigators recommended a single daily dose of 150 mg given on a continuous basis for evaluation in phase II trials. In the phase I trial there were minor tumor regressions observed in a single patient with renal cell carcinoma and a single colorectal cancer patient [13]. Stable disease lasting for at least 5 months was observed in two additional colorectal
Clinical studies with non-iressa EGFR tyrosine kinase inhibitors
cancer patients, and in single patients with NSCLC, prostate cancer, cervical cancer, and head and neck cancer [13]. A subsequent phase II NSCLC included patients who had progressive disease following treatment with a platinum based chemotherapy regimen [11]. Patients were allowed to receive multiple chemotherapy regimens provided they met the following eligibility requirements: NSCLC which was positive for EGFR expression, measurable disease, ECOG performance status 0 /2, and adequate organ function. EGFR positivity was defined as at least 10% of the malignant cells being 1/ positive for EGFR as determined by immunohistochemistry. Treatment consisted of erlotinib 150 mg as a single daily dose continuously. Most patients were ambulatory and had non-squamous histology. In addition, there were more women than men, and 70% of the patients received two or more chemotherapy regimens prior to starting erlotinib. Responses to erlotinib were as follows: complete remission one (2%), partial remission six (10%), and stable disease 20 (35%). The majority of the patients experienced skin toxicity, and diarrhea, but severe (grade III) rash occurred in only 2% of patients, and severe diarrhea (grade III) occurred in 2%. Other side effects included dry skin, nausea, and pruritus. The median survival was 36 weeks and 1 year survival rate was 48% [11]. Multivariate analysis revealed that longer time from the last chemotherapy treatment was associated with a higher chance of obtaining objective remission (P /0.001). EGFR levels defined by the percent of positive cells and the intensity of staining were not significantly related to objective response. In addition, the number of previous chemotherapy regimens was not significantly related to response. A longer time from initial diagnosis and a longer time from the last chemotherapy were associated with significantly longer survival with erlotinib. The EGFR levels and the number of previous chemotherapy regimens were not significantly related to survival [11]. Subsequently, two phase III trials in stage IV NSCLC patients have compared treatment with chemotherapy versus chemotherapy combined with erlotinib. In one of the trials paclitaxel and carboplatin was utilized, and in the other trial the chemotherapy regimen consisted of gemcitabine and cisplatin. In each study patients who were assigned to the chemotherapy-erlotinib arm received 150 mg of erlotinib daily starting with the first dose of chemotherapy, and erlotinib was continued after completion of chemotherapy. The accrual goals in each trial was 1000 patients. In
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addition to the first line trials of erlotinib combined with chemotherapy, the National Cancer Institute of Canada is conducting a phase III trial comparing erlotinib to placebo as third line therapy in NSCLC patients. This trial which has an accrual goal of 700 is nearing completion.
3. PKI 166 PKI 166 is a pyrolo-pyrimidine compound which competes with the ATP binding site on EGFR tyrosine kinase. At a low concentration (1 nm) PKI 166 inhibits EGFR auto-transphosphorylation, CFOS mRNA expression, and cell proliferation [14]. At higher concentrations (0.1 /1 mM) PKI 166 also inhibited autophosphorylation of erbB2. In animal studies PKI 166 showed good oral bio-availability, and it produced a marked reduction in autophosphorylation of EGFR in xenographs in nude mice following administration of EGF [14]. Recently, PKI 166 has been evaluated in three phase I trials [15 /17]. In the first study Hoekstra et al. [15] observed dose limiting elevations of serum transaminases at relatively low continuous doses. Subsequently, these investigators changed the schedule to daily for 14 consecutive days followed by a 14-day rest period. Five dose levels ranging from 50 to 900 mg daily were evaluated, and no dose limiting toxicities were observed up to 600 mg daily. The most common side effects observed were diarrhea, mild nausea, vomiting, fatigue, rash, myalgias, and reversible elevations of serum transaminases. No hematologic toxicity was noted. At a dose of 900 mg daily for 14 consecutive days dose limiting grade 3 elevations of transaminases, diarrhea, and rash were observed. No drug accumulation was noted at doses of 600 mg daily on days 1 /14. The AUC achieved at a 600 mg daily dose exceeded the level shown to be effective in preclinical models. The investigators suggested that either 600 or 750 mg will most likely be the dose tested in phase II trials evaluating the 2 week on/2 week off schedule [15]. In another phase I trial [16] PKI 166 was administered orally three times weekly on a continuous schedule. Sixteen patients were treated on this study, and dose-limiting reversible elevations of serum transaminases were observed at a dose of 400 mg given three times a week. Other sided effects included nausea, vomiting, diarrhea, fatigue, and rash. No hematologic toxicity was observed in this study trial. Stable disease was observed in three of 16 patients which included one patient with renal carcinoma, one with thyroid cancer, and one with unknown primary.
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In the third phase I trial conducted at MD Anderson 32 patients were treated with continuous daily doses for a minimum of 28 days [17]. The initial dose level was 50 mg daily. Most recently two patients have been treated at 600 mg/day. No dose limiting toxicity has been observed so far, but the investigators have observed diarrhea, rash, fatigue, and reversible elevations of serum tansaminases. Similar to the observations of other investigators, no hematologic toxicity was observed. Decreases in EGFR and EGFR phosphorylation in skin and tumor biopsies were found, and there was one partial remission in NSCLC.
4. GW572016 The fact that heterodimerizations is involved in signal transduction mediated by the erbB1 family members suggested that the development of agents which inhibit 2 or more of the erbB1 tyrosine kinases might produce greater anti-tumor effect than inhibiting erbB1 related tyrosine kinase alone. GW572016 has been developed for this purpose. GW572016 was tested against an EGFR over expressing malignant tumor and against an erbB2 over expressing tumor. Each of these tumors was injected into mice and biopsies were obtained from palpable tumors before and after oral administration of GW572016 [18]. In animals which were injected with HN5, which is an EGFR over expressing tumor, the investigators observed a decrease in phosphorylation of EGFR, ERK 1/2, and AKT. While significant decreases were detected in phosphorylation of each of these molecules, there was no difference in the oral concentration of each molecule. Similarly, pre and post treatment biopsies were obtained in nude mice which contained B1474 tumor which over expresses erbB2. Again oral administration of GW562016 produced reduction in phosphorylated erbB2 and ERK-1/2 without decreasing the total amounts of these molecules. The investigators concluded GW572016 produced a biologic effect on both erbB1 and erbB2, as well as, a biologic effect on several downstream markers ERK-1/2 which is involved in cell proliferation and AKT which is involved in the apoptosis pathway [18]. Two phase I trials of GW572016 [19,20] were conducted in healthy subjects. In the first trial [19] which was a double blind placebo control study, doses of GW572016 of 25, 100, and 175 mg daily were given for 8 days versus a single daily dose of placebo for 8 days. Twenty-seven patients were entered into this trial in which gastrointestinal gaseous symptoms, rash, headaches, and transient
P. Bonomi
increases in serum transaminases were observed. All of the toxicities were grade I except for 6% of patients who developed grade II reversible elevations of serum of the transaminases. Interestingly the patients on the placebo appeared to have similar frequencies of the same side effects. Using a single daily dose the half life of GW572016 was 8 h, and there was an average accumulation of the drug of at least 50% over the 8day period. The investigators concluded that a dose up to 175 mg daily for 8 days was well tolerated and resulted in accumulative levels of the drug [19]. In a second Phase I trial 16 healthy subjects participated in a double blind trial [20]. Each subject received single daily doses for 4 days */ three of the doses were (GW572016 and one was placebo). The first group of subjects doses of GW572016 were 10, 50, and 175 mg; and the second doses were 25, 100, and 250 mg of a single daily dose. Grade I /II headache which occurred in greater than 28% of the subjects was the most common symptom. In addition, 9% of the subjects developed grade I rash, and 4% developed grade I diarrhea. Like the other study patients receiving placebo showed no side effects. Peak serum levels were observed at 3 /4 h, and the serum half life was 6 /9 h. The investigators concluded that the single oral dose of GW572016 up to 250 mg was well tolerated [20].
5. EKB569 EKB 569 is an irreversible inhibitor of ErbB1 and erbB2. This compound, which is anilinoquinoline derivative is well absorbed orally. EKB569 has been tested as a single dose for 14 consecutive days followed by a 2 week rest period [21]. Thirty patients were treated on this schedule with doses ranging from 25 to 125 mg daily. Eight patients received at least four courses of EKB569. The most common side effects were diarrhea, rash, nausea and vomiting, stomatitis, and anorexia. These symptoms were generally mild and were always reversible. Dose limiting toxicity was diarrhea which occurred at the 125 mg dose. The investigators concluded that the maximum toleration was 75 mg daily for 14 days followed by a 14-day rest period. The half life of EKB569 is 20 /23 h, and on day 14 the peak serum concentration was approximately 2-fold higher the serum concentration achieved on day 1. Subsequently, the investigators are evaluating continuous daily dosing of this agent, and at a daily dose of 50 mg the maximum tolerated dose has not been reached [21].
Clinical studies with non-iressa EGFR tyrosine kinase inhibitors
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6. CI-1033
7. Summary
The CI-1033 is an irreversible pan erbB inhibitor. In a phase I trial 34 patients received a single daily dose on days 1, 8, 15, of a 28-day cycle [22]. Single weekly dose starting at 100 mg and increasing to 600 mg have been tested. The most common side effects were grade I /II nausea and vomiting, diarrhea, and rash. Dose limiting hypersensitivity reactions were observed in two patients at the 560 mg dose. Since that time the investigators have added prophylactic diphenhydramine and have treated additional patients at the 560 mg dose. Without hypersensitivity reactions stable disease was observed in a patient with osteogenic sarcoma who has received a total of 8 cycles. In another phase I trial the schedule consisted of a single daily doses on days 1 /7 repeated every 21 days [23]. Thirty-seven patients have been enrolled on this trial and the most common toxicities have been grade I /II rash, nausea and vomiting, and diarrhea. Three patients experienced reversible grade III thrombocytopenia. Similar to the observations in the other phase I trial, one patient at the 560 mg/day dose experienced a grade III hypersensitivity reaction. The peak serum concentration occurred 4 h after a single oral dose, and the half life was approximately 5 h. In the preliminary report of their study, these investigators noted significant decrease in ki 67 and increase a significant in P27 8 days after starting treatment with CI-1033. They also observed one partial remission in a primary skin tumor. The investigators concluded CI-1033 was well tolerated and that there was evidence that compound produced significant effect on biomarkers [23]. In a more recent publication, this group of investigators reported the results with CI-1033 in 53 patients [24]. The schedule again was days 1 /7 every 21 days. Fifty-three patients were enrolled, and they attempted to get pre and post treatment, skin and tumor biopsies. They found a median decrease of 44% in EGFR phosphorylation, a median decrease of 26% in ki 67, and a median increase of 56% in p27 in day 8 tumor biopsies. Skin biopsies were obtained in 23 patients, and they detected a 50% decrease in ki 67, 24% increase in p27, but there is no significant change in erbB1 while there was down regulation of erbB2. There was no correlation between the dose level of CI-1033 and the degree of biomarker modulation in tumors or the skin. Dose limiting toxicity and the maximum tolerating dose were not described in this protocol. However, the investigators stated that the protocol schedule had been amended to give a single daily dose of CI-1033 on days 1 /14 every 21 days [24].
Each of the small molecules which inhibit erbB related tyrosine kinases produces rash and diarrhea which is generally mild and reversible. PKI 166 has been associated with dose limiting, reversible elevations of serum transaminases. Less severe reversible elevations of transaminases have also occurred with GW572016. Both groups of investigators who tested GW572016 have reported the occurrence of headache in healthy subjects. This side effect was not described with the other EGFR tyrosine kinase inhibitors. Hypersensitivity reactions and thrombocytopenia were listed as side effects with CI 1033 but not with the other compounds. Erlotinib has produced single agent response rate of approximately 10% in previously treated nonsmall cell lung cancer, and it is being tested in two phase III trials in which patients are assigned to chemotherapy alone versus chemotherapy combined with erlotinib. In addition, the NCI Canada is comparing erlotinib to placebo in a phase III trial in non-small cell lung cancer patients who have received two previous chemotherapy regimens. Phase II data for PKI 166, GW572016, CI-1-33, and EKB 569 are not available.
References [1] Non-small cell lung cancer collaborative group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomized clinical trials. Br Med J 1995;311:899 /901. [2] Baggstram MQ, Socinski MA, Hensing TA, et al. Third generation chemotherapy regimens (3GR) improve survival over second generation regimens (2GR) in stage IIIB.IV nonsmall cell lung cancer (NSCLC): a meta-analysis of the published literature. Proc Am Soc Clin Oncol 2002;021:306a. [3] Kelly KK, Crowley J, Bunn PA, et al. Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced nonsmall cell lung cancer: a Southwest oncology group trial. J Clin Oncol 2001;19:3210 /8. [4] Schiller JH, Harrington D, Belani C, et al. Comparison of four chemotherapy regimens for advanced non-small cell lung cancer. New Engl J Med 2002;346:92 /8. [5] Hanahan D, Weinberg RS. The hallmarks of cancer. Cell 2000;100:57 /70. [6] Dy GK, Adjei AA. Novel targets for lung cancer therapy: Part I J Clin Oncol 2002;20:2881 /94; Part II J Clin Oncol 2002;20:3016 /28. [7] Mendelsohn J. Targeting the epidermal growth factor receptor for cancer therapy. David A Karnotsky Award Lecture. J Clin Oncol 2002;20(Suppl. 1):1s /13s. [8] Rusch V, Klimstra D, Vekatraman E, et al. Over-expression of the epidermal growth factor receptor and its ligand transforming growth factor alpha is frequent in resectable non-small cell lung cancer, but does not predict tumor progression. Clin Cancer Res 1997;3:515 /22.
S48 [9] Kris MG, Natale RB, Herbst RS, et al. A phase II trial of ZD 1839 (Iressa) in advanced non-small cell lung cancer (NSCLC) patients who had failed platinum and docetaxel based regimens (IDEAL 2). Proc Am Soc Clin Oncol 2002;21:292a. [10] Fukuoka M, Yano S, Giaccone G, et al. Final results from a phase II trial of ZD 1839 (Iressa) for patients with advanced non-small cell lung cancer (IDEAL I). Proc Am Soc Clin Oncol 2002;21:298a. [11] Perez-Soler R, Chachoua A, Huberman M, et al. A phase II trial of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor OSI-774, following platinum based chemotherapy in patients advanced EGFR expressing, nonsmall cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2001;21:310a. [12] Mayer HD, Barbacci EG, Iwata KK, et al. Induction of apoptosis and cell cycle arrest by CP-358-774, and inhibitor of epidermal growth factor receptor tyrosine kinase. Cancer Res 1992;57:4838 /48. [13] Hidalgo M, Siu LL, Neumanitis K, et al. Phase I and pharmacologic study of OSI-774, and epidermal growth factor receptor tyrosine kinase inhibitor in patients with advanced solid malignancies. J Clin Oncol 2001;19:3267 / 79. [14] Traxler P, Buchdunger E, Furet P, et al. Preclinical profile of PKI 166 */a novel potent EGFR tyrosine kinase inhibitor for clinical development. Clin Cancer Res 1999;5:3750S. [15] Hoekstra R, Dumez H, Van Oosteram AT, et al. A phase I and pharmacologic study of PKI 188, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, administered orally in a 2 weeks on, 2 weeks off scheme to patients with advanced cancer. Proc Am Soc Clin Oncol 2002;21:86a. [16] Dumez H, Hoekstra R, Eskens F, et al. A phase I and pharmacologic study of PKI 166, and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, administered orally 3 times a week to patients with advanced cancer. Proc Am Soc Clin Oncol 2002;21:86a.
P. Bonomi [17] Murren JR, Papadimitrakopoulou VA, Sizer KC, et al. A phase I dose escalating study to evaluate the biological activity and pharmacokinetics of PKI 166, a novel tyrosine kinase inhibitor in patients with advanced cancer. Proc Am Soc Clin Oncol 2002;21:95a. [18] Yia W, Mullin RJ, Keith BR, et al. Anti-tumor activity of GW 572016: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 pathways. Proc Am Soc Clin Oncol 2002;21:94a. [19] Adams VR, Bence AL, Anderson EB, et al. A phase I pharmacokinetic/pharmacodynamic study evaluating multiple doses of oral GW572016 in healthy subjects. Proc Am Soc Clin Oncol 2002;21:94a. [20] DeSimone PA, Bence AK, Anderson EB, et al. A phase I study to investigate the safety, tolerability, and pharmacokinetics of single oral escalating doses of GW572016 in healthy volunteers. Proc Am Soc Clin Oncol 2002;21:94a. [21] Hidalgo M, Erlichman C, Rawinsky EK, et al. Phase I trial of EKB-569, an irreversible inhibitor of the epidermal growth factor (EGFR) in patients with advanced solid tumors. Proc Am Soc Clin Oncol 2002;21:17a. [22] Garrison MA, Tolcher A, McGreery H, et al. A phase I pharmacokinetic study of CI-1033, a pan-erB tyrosine kinase inhibitor, given orally on days 1, 8 and 15 every 28 days to patients with solid tumors. Proc Am Soc Clin Oncol 2001;21:72a. [23] Shin DM, Neumanitis J, Zinner RG, et al. A phase I clinical and biomarker study of CI-1033, a novel pan erbB tyrosine kinase inhibitor in patients with solid tumors. Proc Am Soc Clin Oncol 2001;20:82a. [24] Zinner RG, Donato NJ, Neumanitis J, et al. Biomarker modulation in tumor and skin biopsy samples from patients with solid tumors following treatment with the pan-erB tyrosine kinase inhibitor, CI-1033. Proc Am Soc Clin Oncol 2002;21:15a.