Administration of CI-1033, an Irreversible Pan-Erbb Tyrosine

7112 Vol. 10, 7112–7120, November 1, 2004 Clinical Cancer Research Featured Article Administration of CI-1033, an Irreversible Pan-erbB Tyrosine Kinase Inhibitor, Is Feasible on a 7-Day On, 7-Day Off Schedule: A Phase I Pharmacokinetic and Food Effect Study Emiliano Calvo,1 Anthony W. Tolcher,1 sorption and elimination adequately described the pharma- Lisa A. Hammond,1 Amita Patnaik,1 cokinetic disposition. CL/F, apparent volume of distribution ؎ ؎ 1 2 (Vd/F), and ka (mean relative SD) were 280 L/hour ؎Johan S. de Bono, Irene A. Eiseman, ؎ ؊1 2 2 33%, 684 L 20%, and 0.35 hour 69%, respectively. Stephen C. Olson, Peter F. Lenehan, C values were achieved in 2 to 4 hours. Systemic CI-1033 1 3 max Heather McCreery, Patricia LoRusso, and exposure was largely unaffected by administration of a high- 1 Eric K. Rowinsky fat meal. At 250 mg, concentration values exceeded IC50 1Institute for Drug Development, Cancer Therapy and Research values required for prolonged pan-erbB tyrosine kinase in- Center, University of Texas Health Science Center at San Antonio, hibition in preclinical assays. 2 San Antonio, Texas, Pfizer Global Research and Development, Ann Conclusions: The recommended dose on this schedule is Arbor Laboratories, Ann Arbor, Michigan, 3Wayne State University, University Health Center, Detroit, Michigan 250 mg/day. Its tolerability and the biological relevance of concentrations achieved at the maximal tolerated dose war- rant consideration of disease-directed evaluations. This in- ABSTRACT termittent treatment schedule can be used without regard to Purpose: To determine the maximum tolerated dose of meals. administrating CI-1033, an oral 4-anilinoquinazoline that irreversibly inhibits the tyrosine kinase domain of all erbB subfamilies, on an intermittent schedule, and assess the INTRODUCTION interaction of CI-1033 with food on the pharmacokinetic The frequency of overexpression and/or aberrations of at behavior. least one member of the erbB receptor family in human nonhe- Experimental Design: Escalating doses of CI-1033 from matological epithelial malignancies is high, approaching almost a dose level of 300 mg/day for 7 days every other week were 90% in some studies (1, 2). Ligand binding to the extracellular administered to patients with advanced solid malignancies. domain of the erbB receptor results in phosphorylation of tyro- Plasma concentration-time data sets from all evaluable pa- sine residues in the tyrosine kinase (TK) domain, which medi- tients were used to develop a population pharmacokinetic ates cell proliferation, survival, angiogenesis, and metastasis model. Noncompartmental methods were used to independ- (3–5). Additionally, the magnitude of erbB expression has been ently assess the effect of a high-fat meal on CI-1033 absorp- consistently shown to be an adverse prognostic determinant in tion and bioavailability. patients with carcinomas of the breast (6–10), ovary (11, 12), Results: Twenty-four patients were treated with 69 prostate (13, 14), stomach (15, 16), head and neck (17), lung twenty-eight day courses. The incidence of unacceptable (18), brain (19), and melanoma (20), and has served in part as toxicity, principally diarrhea and skin rash, was observed at the rationale for developing various therapeutic strategies the 300 mg/day dose level. At the 250 mg/day level, toxicity against erbB (21). was manageable, and protracted administration was feasi- On the basis of the results of disease-directed studies with ble. A one-compartment linear model with first-order ab- both monoclonal antibody and small-molecule therapeutics targeting erbB1, it is clear that the magnitude of the resultant anticancer activity is disproportionately less than the magnitude of target expression, and both erbB signaling and determinants of therapeutic response are complex (21). This complexity is Received 6/17/04; revised 7/29/04; accepted 7/30/04. illustrated by extensive cooperation and interactions between The costs of publication of this article were defrayed in part by the erbB subfamily members, particularly cross-activation, het- payment of page charges. This article must therefore be hereby marked erodimerization, and cross-talk, in proliferative signal transduc- advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. tion and malignant transformation, which challenges the notion Note: Presented at the 22nd annual meeting of the American Society of of developing broadly effective therapeutic strategies by target- Clinical Oncology, Chicago, Illinois, May 31-June 3, 2003. ing any single erbB subfamily member. Targeting erbB1 alone Requests for reprints: Eric K. Rowinsky, Institute for Drug Develop- in malignancies that are not driven by constitutive erbB1 aber- ment, Cancer Therapy and Research Center, 7979 Wurzbach Road, 4th Floor Zeller Building, San Antonio, TX 78229. Phone: 210-616-5945; rations neglects the importance of other erbB subfamily mem- Fax: 210-616-5865; E-mail: [email protected]. bers such as erbB2 and erbB3 that play unique roles as receptor ©2004 American Association for Cancer Research. dimerization partners and also neglects their importance in Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2004 American Association for Cancer Research. Clinical Cancer Research 7113 tuning, amplifying, and diversifying signals (22). The multiplic- ter signaling partners from other signaling-competent receptors ity of erbB receptors and their ability to engage in cross-talk also by stabilizing inactive erbB homo- and heterodimers (3, 30, 31), confers redundancy in the signaling pathway and resistance the agent could theoretically provide greater efficacy and a against attempts to target specific pathway elements. Further- broader spectrum of antitumor activity. more, although the advent of potent and specific quinazoline- In preclinical studies, CI-1033 showed prominent antican- based small molecules that competitively inhibit ATP binding in cer activity in a broad range of in vivo and in vitro assessments. the TK domain of erbB has provided the foundation for devel- In the human tumor cloning assay, CI-1033 inhibited the growth oping many of the erbB TK inhibitors in clinical development, of clonogenic cells derived from a variety of tissue types. Broad the high intracellular concentration of ATP has been raised as a and impressive activity against human tumor xenografts of potential impediment in achieving sustained inhibition of erbB 4 colon, lung, breast, and glial origin was also observed. Further- signaling with competitive inhibitors (23). more, notable regression of well established erbB1-dependent CI-1033 (canertinib dihydrochloride; Pfizer Global Re- A431 human vulvar carcinoma xenografts associated with near- search and Development, Ann Arbor, MI; Fig. 1), an orally maximal suppression of erbB1 tyrosine phosphorylation oc- available 3-chloro, 4-fluoro, 4-anilinoquinazoline, was devel- oped to irreversibly bind to the TK domain of all erbB members. curred, even at the lowest dose tested, which was associated When bound into the ATP pocket, the acrylamide side-chain at with Cmax values approaching 66 ng/mL. Antitumor activity position C6 of CI-1033 is brought into close proximity with was shown to be independent of dose fractionation, with signif- cysteine 773 of erbB1 (or the analogous cysteines 784 and 778 icant in vivo activity noted on both intermittent (weekly) and 4 of erbB2 and erbB4, respectively), which facilitates the rapid continuous daily treatment schedules. formation of a covalent bond that permanently inactivates the The toxicological and pharmacologic profiles of CI-1033 catalytically active erbB1, erbB2, and erbB4 family members have been evaluated in rodents and monkeys.4 In both species, and effectively blocks erbB3-dependent signaling because of the toxicity was consistent with modulation of the intended targets. unavailability of catalytically active heterodimerization part- Diarrhea and emesis, which were associated with erosion/atro- ners. The covalent binding of CI-1033 within the ATP pocket of phy of the gastrointestinal mucosa and blunting of intestinal the receptor results in a more prolonged suppression of erbB villi, were the principal toxicities that precluded dose escalation activity compared with reversible inhibitors in preclinical stud- of CI-1033 on single- and multiple-dose oral schedules. With ies (24, 25). Furthermore, although CI-1033 binds covalently to protracted treatment, cutaneous toxicity was prominent in ro- erbB, it retains selectivity and is inactive against an extensive dents but not in monkeys. Absolute oral bioavailability ranged panel of other protein kinases (5). Moreover, the irreversible from moderate in the rat (35%–39%) to low in the monkey inhibition of erbB by CI-1033 has been shown to facilitate (7%), and Cmax values were achieved within 3 hours after receptor tagging with ubiquitin and degradation (26). In this treatment. At CI-1033 doses up to 100 mg/kg, pharmacokinetics setting, the reversibility of downstream proliferative signaling were proportional to dose. CI-1033 was highly bound to plasma may be more dependent on the resynthesis of receptors rather proteins (Ͼ 99%) and biliary elimination was the principal route than on pharmacokinetic parameters (e.g., clearance). In es- of excretion of radioactivity in radiolabeled drug disposition sence, these features may afford a greater therapeutic advantage studies. to CI-1033 relative to other erbB TK inhibitors, which have The unique

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