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

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 developed 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 mechanistic features of CI-1033 as an irrevers- reversible actions and target one specific erbB subfamily (27). In addition, given the multiplicity of erbB receptor expression in ible pan-erbB inhibitor, as well as its impressive preclinical individual cancers, the broad and highly specific inhibition of activity, served as the impetus for its clinical development. The the entire family of erbB receptors (28) by CI-1033, including feasibility of administering CI-1033 on both daily protracted inhibition of the constitutively active mutant epidermal growth and intermittent schedules has been evaluated in patients with factor receptor vIII (29), and the potential of CI-1033 to seques- advanced solid malignancies (5). Although intermittent schedules are appealing from a mechanistic standpoint, thrombocytopenia and rare hypersensitivity reactions have been noted in patients treated on an intermittent weekly dosing schedule (32, 33). The principal objectives of this study were to (a) determine the maximal tolerated dose of CI-1033 administered on an intermittent schedule in which CI-1033 is administered daily for 7 days every 2 weeks (7 days-on, 7 days-off) and recommend a dose for disease-directed trials, (b) characterize the toxicities associated with this schedule of administration, (c) describe the pharmacology including the effect of food on absorption, and (d) seek preliminary evidence of antitumor activity.

Fig. 1 Chemical structure of CI-1033. Note: The chemical groups in the dotted circles represent the reactive groups responsible for alkylation of cysteine in the TK domain of the erbB receptors. They are attached 4 Pfizer Global Research and Development. CI-1033 Investigator Bro- to a condensed quinazoline backbone. chure. Ann Arbor, Michigan, 2003.

PATIENTS AND METHODS event of DLT, patients could be retreated with CI-1033 at the Patient Selection. Patients with histologically docu- next lower dose level. Intrapatient dose escalation was not mented advanced-stage nonhematological malignancies that permitted. were refractory to standard therapy, or for whom no effective All patients were asked to refrain from eating for 2 hours therapy existed, were candidates for this study. Eligibility cri- before and after treatment. The subset of patients that partici- teria also included the following: (a) age Ն18 years; (b) Karnof- pated in an evaluation of the effects of food on CI-1033 absorp- sky performance status Ն50%; (c) life-expectancy of at least 12 tion and bioavailability were required to abstain from ingesting weeks; (d) no chemotherapy within 4 weeks before the first dose food and liquids for 8 hours before the administration of CI- of CI-1033 and no hormonal therapy, immunotherapy, or radio- 1033 with 6 fluid ounces (180 mL) of tap water on day 1 of therapy within 2 weeks; (e) adequate hematopoietic (absolute courses 1 and 2 (study day 29). On both days, the dose of CI-1033 was to be given at approximately the same time of day. neutrophic count Ն 1500/␮L, platelet count Ն 100,000/␮L), On day 1 of course 1, continued fasting from food and liquids hepatic (total bilirubin Յ 1.5 times institutional upper normal was required for 2 additional hours, after taking the study drug. limit, aspartate amino transaminase and alanine amino transam- On day 1 of course 2, CI-1033 was administered with a high-fat, inase Յ 3 times institutional normal upper limit); and renal high-calorie breakfast. This meal was adopted from the Food (calculated creatinine clearance Ն45 mL/minute according to and Drug Administration Draft Guidance for Industry “Food- the method of Cockcroft and Gault; ref. 34) functions; (f)no Effect Bioavailability and Bioequivalence Studies,” first issued history of swallowing disorders or gastrointestinal malabsorp- in October 1997 (37). Patients had 30 minutes to complete the tion that could interfere with bioavailability of the study drug; meal and were then immediately given CI-1033 (within 5 min- g and ( ) no concurrent serious infection or coexisting medical utes) with tap water. Additional food and liquids were prohib- problem of sufficient severity to potentially limit full compli- ited for 2 hours after administration of the drug. ance with the protocol. All patients gave written informed CI-1033 was supplied by Pfizer Global Research and De- consent before entry into the study in accordance with federal velopment (Ann Arbor, Michigan) as 5-mg, 25-mg, and 250-mg and institutional guidelines. tablets. An absolute dose was administered irrespective of the Dosage and Drug Administration. The starting dose of body surface area and weight of the patient based on the results CI-1033 was 300 mg daily for 7 days every other week, which of previous pharmacokinetic studies that did not show a rela- is equivalent to 66% of the maximal tolerated dose achieved tionship between clearance and either body weight or body when CI-1033 is administered for 14 consecutive days every 3 surface area.4 Doses were to be rounded down to the nearest weeks (35). Each 28-day period, which consisted of two 7-day available capsule strength. Patients were instructed to self- treatment periods, was arbitrarily defined as one course of administer CI-1033 at the same time of day according to the treatment. Because this dose level closely approximated those treatment schedule and to refrain from consuming food and doses associated with toxicity on alternate, albeit not widely beverages other than water for 2 hours before and 2 hours after disparate, CI-1033 schedules (33), a moderately conservative each CI-1033 dose. A diary that detailed the dates and times of dose escalation scheme in which the maximal dose escalation drug administration as well as relevant peritreatment events and increment was 40% was used. At least three patients were to be possible toxicities was kept by each patient and was required to treated at CI-1033 dose levels that did not result in dose-limiting be submitted before dispensing drug for each successive course. toxicity (DLT) during first courses. If one of the first three Pretreatment and Follow-Up Studies. Histories that in- patients experienced a DLT in course 1, at least three additional cluded recording of performance status and concurrent medica- patients were enrolled at the same dose level to verify its tions, physical examination, and routine laboratory evaluations validity. The maximal tolerated dose was defined as the highest were don before treatment and weekly. Routine laboratory eval- dose at which less than two of the first six patients experienced uations included complete blood counts, differential white blood consistent DLT during the first course of treatment. If the cell count, electrolytes, blood urea nitrogen, creatinine, glucose, incidence of dose-limiting events was shown to be unacceptably total protein, albumin, calcium, phosphate, uric acid, alkaline high in the first course of treatment at the first dose level, the phosphatase, total and direct bilirubin, transaminases, coagula- next cohort of new patients was to be treated with 250 mg of tion profile, and urinalysis. Pretreatment studies also included CI-1033, which represents a 17% dose reduction. DLT was an electrocardiogram, and relevant radiological studies for eval- defined as (a) any grade 4 hematologic toxicity; (b) an absolute uation of all measurable or evaluable sites of malignancy, as neutrophic count Ͻ 1000/␮L with a documented infection or well as an assessment of relevant tumor markers. An ophthal- fever Ͼ38.5°C; (c) any grade 3 or 4 nonhematological toxicity mological examination consisting of measurement of visual (excluding nausea, vomiting, or diarrhea associated with subop- acuity and slit lamp microscopy was done before treatment and timal premedication and/or management or tolerable cutaneous after every other course. Radiological studies for disease status toxicity); and (d) a delay exceeding 14 days in the initiation of assessments were also done after every other course or as a 7-day treatment period of CI-1033 because of toxicity that did needed to confirm response. Patients were able to continue not resolve to grade Յ1 or pretreatment levels. Patients were treatment if they did not develop progressive disease. A com- permitted to begin each successive 7-day treatment period as plete response was scored if there was disappearance of all long as drug-related toxicities had resolved to the levels speci- active disease on two measurements separated by a minimum fied previously, and there was no evidence of disease progres- period of 4 weeks and a PR required at least a 50% reduction in sion. Toxicity was graded according to the National Cancer the sum of the product of the bidimensional measurements of all Institute Common Toxicity Criteria, version 2.0 (36). In the lesions documented separated by at least 4 weeks. Any concur-

rent increase in the size of any lesion by Ն25% or the appear- Table 1 Patients characteristics ance of any new lesion was considered disease progression. Characteristic Number Stable disease was defined as best response if the criteria for Number of patients 24 either a complete or partial response were not met during the Median number of courses per patient (range) 2 (1–10) study, and if the criteria for progressive disease were not met Median age in years (range) 61 (44–82) during the first 8 weeks the patient was in the study. Gender (male:female) 17:7 Plasma Sampling and Assay. Except for the food effect Median performance status (Karnofsky) 90 90–100 16 component, pharmacokinetic profiling was accomplished with 70–80 6 sparse blood sampling. Blood samples in EDTA/ascorbic acid- 60 2 containing tubes were collected on day 15 of the first course, Previous therapy just before the beginning of the second 7-day treatment period, Chemotherapy 24 Ͻ3 regimens 6 and then 1, 3, and 6 hours after treatment. Those patients who Ն3 regimens 18 participated in the food effect component of the study under- Surgery 19 went blood sampling before and at 1, 2, 4, 6, 8, 12, and 24 hours Radiation therapy 14 after administration of CI-1033, on day 1 of course 1 (without Immunotherapy 4 food) and day 1 of course 2 (with food), which corresponded to Hormonal therapy 4 Tumor types study day 29. Colorectal 16 The samples were centrifuged at 3,000 rpm for 15 minutes Lung (non-small cell) 3 immediately after collection. The plasma was then transferred to Breast, appendix, endometrial, kidney, 1 each a sample tube, which was frozen at Ϫ20°C until assayed for mesothelioma CI-1033. An acetonitrile protein precipitation reaction with an alkene deuterated CI-1033 internal standard was used to isolate the serum from a 0.2-mL aliquot of plasma. Supernatant com- median number of courses administered to each patient was two pound separation was accomplished on an YMC Cyano 3.0 ϫ (range, 1–10). Ten patients required dose reduction (six pa- 50-mm column (YMC Co. Ltd., Milford, MA), and subsequent tients) or discontinuation (four patients) for intolerable toxicity. mass spectrometric analysis was done on a SCIEX Triple Qua- At the starting dose level of CI-1033, 300 mg/day, the drupole API 3000 (MDS Sciex, San Francisco, CA). The result- planned patient cohort size of three was increased to six after the ing range of quantitation for CI-1033 was 1 to 500 ng/mL. occurrence of DLT in course 1 in one of the first three individ- Overall precision [(percentage of coefficient of variation uals treated with CI-1033. Although three of the first six patients (%CV)] of quality control samples averaged 9.9%, with an experienced dose-limiting events [grade 3 asthenia (1 patient), overall accuracy [percentage of relative error (%RE)] of Ϫ7.7% grade 3 diarrhea (1 patient), and grade 3 rash (1 patient)], the to Ϫ1.6%. lack of consistency in the nature of the events permitted dose Pharmacokinetic Analysis. Population pharmacokinetic escalation according to the protocol. Instead, the cohort size was (PK) methods were used to pool and analyze all data, including increased to nine subjects to broaden the experience at the dose that obtained from patients participating in the food effect level. However, two of the final three patients developed grade portion of the study. We conducted the population analysis with 2 events, consisting of diarrhea and rash, after the first 7-day a one-compartment linear model with first-order absorption and treatment period. Although these events did not meet the strict elimination together with an absorption lag time using NON- definition of DLT as established in the protocol a priori, the MEM V and PREDPP ADVAN2 (38). Bayesian estimates were relatively high incidences of both moderate and severe events, obtained by conditioning on the individual concentrations with many of which were subjectively intolerable, in the first course allowance for interaction between subject level and residual of treatment were unacceptably high and projected to preclude chronic treatment with CI-1033 at this dose. Therefore, new effects. Model dependent parameters included Vd/F, apparent patients were treated at a reduced dose level of CI-1033, 250 clearance (Cl/F), and ka as well as their interindividual vari- ances. We assessed the effect of food on CI-1033 absorption mg/day. At 250 mg/day, 3 (20%) of 15 patients experienced grade 3 events in course 1, consisting of diarrhea (1 patient), using noncompartmental methods. Cmax and Tmax were recorded as observed. Area under the concentration-time curve extrapo- skin rash (1 patient), and both diarrhea and malaise (1 patient), but prophylactic and/or supportive antidiarrheal measures had lated to infinity (AUC0-ϱ) was determined by linear trapezoidal approximation. All descriptive summaries were generated with not been optimally used in both individuals who experienced SAS Version 8.0 (SAS Institute, Inc. Cary, NC, 1989–1996). isolated diarrheal events and further treatment was feasible in one patient after dose reduction and such measures were insti- tuted. Of 15 patients treated with CI-1033 at the 250 mg/day RESULTS dose level, three patients experienced DLT in course 1, four General. Twenty-four patients, whose pertinent charac- patients experienced DLT at any time during treatment, and 5 of teristics are displayed in Table 1, received 69 four-week courses 40 courses were associated with DLT. Only one patient had of CI-1033 at two dose levels. All patients were fully evaluable CI-1033 discontinued because of toxicity. On the basis of these for toxicity. The total numbers of new patients treated at each results, the maximal tolerated dose of CI-1033 was determined dose level, number of evaluable courses, rates of DLTs as to be 250 mg/day. functions of the numbers of first and total courses at each dose Toxicity. Cutaneous toxicity and diarrhea were the most level, and dose escalation scheme are depicted in Table 2. The common toxicities of CI-1033 and precluded dose escalation on

Table 2 Dose De-escalation scheme N of patients with DLTs No. of No. of Dose* patients courses First course All courses Type of DLTs Toxicity grade Comments 300 mg 9 29 5*/9 6*/29 Asthenia 3 Rash 3 Diarrhea 3 Rash 2 Non-DLT † Diarrhea 2 Non-DLT † 250 mg 15 40 3/15 4/40 Rash 3 (MTD) Diarrhea 3 Diarrhea, asthenia 3, 3 Same patient Abbreviations: DLT, dose-limiting toxicity; MTD, maximum tolerated dose; No., number. * The starting dose of CI-1033 was 300 mg daily for 7 days every other week. Each 28-day period was defined as one course of treatment. † Two episodes of grade 2 diarrhea and skin rash that were grade 2 by NCI-CTC; however, both events were considered intolerable, required dose reduction and/or treatment interruption, and were therefore considered dose-limiting.

this 7-day-on, 7-day-off schedule. The distributions of severest sive and were usually reported simultaneously. The preponder- grades of the most common adverse events experienced by each ance of episodes were mild or moderate (grade 1 or 2); however, study patient as a function of dose level are displayed in Table 3. two (8.3%) patients experienced grade 3 nausea and vomiting in Gastrointestinal. Adverse gastrointestinal events, partic- the absence of premedication. Most events were brief in dura- ularly nausea, vomiting, and diarrhea were the most common tion, typically beginning on the first day of the 7-day treatment toxicities reported during the study. With regard to both dose period and lasting a median of 2.5 days. Nausea and vomiting cohorts, diarrhea was the most pertinent toxicity of CI-1033. were also prevented and/or managed successfully with prochlor- Nineteen (79.2%) of 24 patients experienced diarrhea at some perazine or serotonin 5HT3 receptor antagonists, but routine time during treatment. The onset of symptoms was typically on premedication was not necessary because most events were the 3rd day of the 7-day treatment period and symptoms gen- nausea alone, mild in severity, brief, and sporadic. erally resolved completely or to a minimal severity level within Cutaneous Toxicity. Cutaneous toxicity was the most 2 to 3 days after the 7-day treatment period (median duration, common adverse event. It was experienced by 20 (83.3%) of 24 6.5 days). Most events were either self-limited or ameliorated patients. The cutaneous manifestations were qualitatively simi- with specific antidiarrheal measures such as loperamide. The majority of episodes were mild to moderate (grade 1 or 2) in lar in most affected individuals. The rash typically involved the severity. Although 6 (25%) patients experienced grade 3 diar- face in a periorificial distribution, as well as the upper trunk. rhea, including 3 of 9 patients treated at the 300-mg/day and 3 Cutaneous manifestations were initially noted rostrally with of 15 patients treated at the 250-mg/day dose levels, respec- progression caudally to involve the upper trunk. The typical tively, these events generally occurred in the absence of optimal appearance was that of an erythematous macular-papular rash. antidiarrheal medication and/or support in the first course of The onset of the rash and/or worsening of residual manifesta- treatment. Retreatment was usually feasible with greater toler- tions because of previous treatment were generally on the 5th ance after the institution of these supportive measures, consist- day on the 7-day treatment period, with worsening for 3 to 4 ing of forced oral hydration and electrolytes supplementation, days into the 7-day rest period. Next, the cutaneous lesions and loperamide 4 mg for the first dose, then 2 mg every 2 hours receded as manifested by decreased erythema and development during the daily hours and 4 mg every 4 hours during the night, of crusting, scar formation, and hyperpigmentation. This cycle until absence of loose stools was achieved during 12 hours. of progression and recession of lesions was noted throughout the Nausea and vomiting were also common in patients treated intermittent therapy; however, the magnitude and severity of the with CI-1033, with 18 (75%) and 9 (37.5%) patients experienc- cutaneous lesions progressively decreased with chronic admin- ing nausea and/or vomiting, respectively, at some time during istration. In most patients, the intensity of the rash was maximal treatment. However, these toxicities were not mutually exclu- during weeks 2 to 4, followed by gradual resolution despite

Table 3 Summary of toxicity during the study (all courses) Diarrhea Rash Nausea Vomiting Asthenia Stomatitis Thrombocyt. grade grade grade grade grade grade grade Dose (mg) Patient no. 1–2 3 1–2 3 1–2 3 1–2 3 1–2 3 1–2 3 1–2 3 300 9 335141214120 40 250 15 10 3 13 1 12 1 5 1 6 2 5 0 7 0 Totals (patients) 24 13 6 18 2 16 2 7 2 10 3 7 0 11 0 (%) 100 54 25 75 8 67 8 29 8 42 13 29 0 46 0 Abbreviations: Thrombocyt., thrombocytopenia.

further treatment with CI-1033 on this 7-day-on, 7-day-off (n ϭ 10, 41.76%), hypoalbuminemia (n ϭ 11, 45.8%), hypocal- schedule. cemia (n ϭ 8, 33.3%), and decreased bicarbonate (n ϭ 8, Symptoms attributable to the cutaneous effects of CI-1033 33.3%). Grade 3 events included hypoalbuminemia (four pa- were disproportionately less than appearance of the rash itself. tients), elevated aspartate aminotransferase, hyperglycemia, hy- Nevertheless, the maximal severity of the cutaneous toxicity permagnesemia, hypokalemia, and hypophosphatemia (two pa- was grade 1 or 2 in most individuals. However, grade 3 cuta- tients each). One patient experienced grade 4 hyponatremia. neous toxicity that required interruption of treatment was expe- Occult hematuria and/or proteinuria (Ն2ϩ) were observed in 10 rienced by one patient each at the 250 and 300 mg/day dose patients across both dose levels in the study. These abnormali- levels. In addition, one patient who was treated with CI-1033, ties were often present before treatment, suggesting that under- 300 mg/day, developed an intolerable rash that was considered lying disease was a contributory factor. No relationship to dose-limiting, albeit grade 2 in severity as defined by the Na- administration of the investigational drug could be established. tional Cancer Institute Common Toxicity Criteria. This was Antitumor Activity. No patient had objective evidence based on a subjective appreciation of the cosmetic appearance of of a major response. Three of the 10 evaluable patients with the cutaneous lesions, as well as discomfort. Although various colorectal carcinoma and the single patient with an advanced topical medications, including corticosteroids, were used to has- mesothelioma, all of whom had experienced progressive disease ten the resolution of the cutaneous effects in patients, it is not before treatment with CI-1033, had stable disease as their best clear whether any specific topical therapy was truly effective response. Two of the colorectal carcinoma patients were treated because the skin lesions tended to inherently recede over time. with CI-1033, 300 mg/day, whereas the two other individuals Miscellaneous. Mild to moderate (grade 1 or 2) mucosi- were treated with CI-1033 at the 250-mg dose level. The median tis, thrombocytopenia, and ocular manifestations that did not time to progression for these four patients was 6.5 months sem related to dose in the relatively narrow dose range were (range, 4.2–11). Another subject with colorectal carcinoma with common. Seven (29.1%) patients developed mucositis, charac- liver and lung metastases that had progressed during prior terized by swelling and soreness of the oral mucosa. These treatment with 5-fluorouracil, leucovorin, and irinotecan expe- manifestations typically peaked in severity at the end of the rienced a 44% reduction in measurable disease that lasted 11 7-day treatment period and resolved during the 7-day rest period months on CI-1033 treatment at the 300 mg/day dose level. without any specific measures. Eleven (45.8%) patients, includ- Pharmacokinetics. Consistent with its rapid clearance, ing 7 and 4 patients at the 250 and 300 mg/day dose levels, there was no evidence of drug accumulation over time. After respectively, experienced thrombocytopenia, which resulted in oral administration, absorption was slightly delayed; the absorp- neither dose reduction nor treatment interruption. Thrombocy- tion lag-time averaged 25 minutes, and maximal concentrations topenia occurred at a median of 4 days into each treatment were attained 2 to 4 hours after treatment. Estimated mean Ϯ Ϯ period, and its duration coincided closely with the duration of relative SD values for CL/F, Vd/F, and ka were 280 L/h 33%, CI-1033 treatment. In affected subjects, platelets usually re- 684 L Ϯ 20%, and 0.35 hoursϪ1Ϯ 69%, respectively. Table 4 turned to pretreatment levels during the 7-day rest period, and shows CI-1033 empirical Bayesian pharmacokinetic parameter there was no evidence of cumulative toxicity on this schedule. estimates by administered dose. At any given dose level, there Two patients, both treated with CI-1033 at the 250 mg/day dose was moderate variability in systemic exposure among patients level, complained of dryness of their eyes, which was diagnosed and between study days. Both CL/F and Vd/F values were as keratitis sicca (grades 1 and 2) and felt to be related to study dose-independent, suggesting dose-proportional drug disposi- drug. The symptoms responded to lubricating solutions and tion within the relatively narrow dose range evaluated in this treatment disruption was not required. No other ophthalmic study. At the recommended dose of 250 mg/day, mean Cmax of findings were evident on visual acuity and slit lamp microscopic the 12 patients with available PK data, including those partici- examinations. In addition, no clinically significant electrocar- pating in the food effect study, was 175.2 Ϯ 79.2 ng/mL. diographic abnormalities, hypersensitivity phenomena, or man- The administration of CI-1033 with a high-fat meal had ifestations compatible with drug-induced pulmonary toxicity little effect on its PK behavior when compared with adminis- were evident. tration under fasting conditions as shown by the mean CI-1033 Other events that were possibly related to CI-1033 included anemia, coagulation abnormalities, elevations in hepatic transaminases and/or alkaline phosphatase, and various abnormalities in clinical chemistry tests. Ten (41.7%) patients devel- Table 4 Mean (%RSD) CI-1033 empirical Bayesian oped anemia, but most events were mild or moderate (grade 1 or pharmacokinetic parameter estimates by administered dose 2) in severity. One patient developed grade 4 anemia (nadir Dose given, number of patients (%) hemoglobin, 6.4 g/dl) concurrent with progressive disease after two courses of CI-1033 at the 300-mg/day dose level. These 200 mg, 3 pt* 250 mg, 14 pt 300 mg, 4 pt effects were noted in patients treated at both dose levels of V/F (liters) 667 (2) 670 (7) 675 (7) Cl/F (L/hour) 270 (39) 266 (18) 319 (6) CI-1033, and definite temporal relationships could not be estab- Ϫ1 ka (hrs ) 0.39 (27) 0.50 (94) 0.42 (49) lished for any of these potential toxicities, indicating that the Half-life (hours) 1.9 (33) 1.8 (18) 1.5 (7) underlying malignant process may have contributed. Most Abbreviations: Cl/F, apparent clearance; RSD, relative SD; pt, changes in blood chemistry characteristics were also mild or patient; V/F, apparent volume of distribution. moderate (grade 1 or 2). The most frequently occurring changes * These patients were dose reduced because of adverse events included hyperglycemia (n ϭ 15, 62.5%), hypomagnesemia during first week of treatment, before plasma sampling for PK analysis.

Fig. 2 Mean CI-1033 plasma concentration-time curves after treatment with 250 mg of CI-1033 in a fasting state and after a high-fat meal.

concentration versus time plots done under fed and fasting inhibitors with favorable pharmacokinetic characteristics such conditions in Fig. 2. A slightly Ͼ1 hour increase in the mean as wide and protracted tissue distribution would have to over-

Tmax value from 3 to 4.3 hours, with no change in either AUC0-␣ come high intracellular ATP concentrations to impart protracted or Cmax values indicates that a high-fat meal delays the absorp- inhibition of receptor TKs. As an irreversible inhibitor of recep- tion of CI-1033 but does not affect the extent of its absorption. tor TK, CI-1033 has the potential advantage of lowering the High variability as well as a limited sample (n ϭ 6) precluded minimal plasma concentration at which activity occurs, mini- a rigorous statistical analysis. mizing the requirements for continuous drug administration and eliminating the requirements for therapeutics with long plasma DISCUSSION half-lives without compromising efficacy. As expected based on The erbB family of extracellular receptors mediates the its receptor binding characteristics, the activity of CI-1033 has transduction of proliferative signals that are essential for cell been shown to be independent of dose fractionation in preclin- proliferation of many types of human cancer (39). Today, tar- ical studies, with substantial activity achieved on dosing regi- geted therapy against these TK receptors is a reality with the mens ranging from once daily to once weekly. All of these availability of both monoclonal antibodies targeting the extra- considerations could also reduce toxicity because of any non- cellular domains of erbB1 and erbB2 and various small-mole- specific interactions that may occur at high or prolonged plasma cule, ATP-mimetic inhibitors of erbB1 TK. However, the ob- levels. Another major impetus for developing CI-1033 is its jective antitumor activity of these agents are disproportionately potential to irreversibly bind to the ATP-binding pocket of all lower than expectations based on the high rates of expression, erbB TKs, thereby inhibiting activation, cross-activation, and overexpression, and aberrations of erbB1 in human malignan- downstream signaling emanating from erbB1, erbB2, erbB3, cies, particularly carcinomas, with the robust responses limited and erbB4. Cross-activation or heterodimerization may occur to patients with gene mutations that drive tumor proliferation between distinct erbB receptors despite the inactivation of the (29, 40, 41). TK domain of one of the receptors. The rationale for developing the 4-anilinoquinazoline CI- This phase I and pharmacologic study was designed to 1033 that irreversibly inhibits all erbB TK is based on both in evaluate the feasibility of administering CI-1033 daily on a vitro and in vivo evidence that the antitumor activity of erbB- 7-day-on, 7-day-off schedule because intermittent schedules targeted therapeutics is maximum after prolonged suppression have been associated with prominent activity in preclinical of the receptor TK activity. It was felt that irreversible inhibitors studies, possibly due in part to the irreversible binding of the might be more advantageous than reversible inhibitors in per- agent to erbB TK. Furthermore, schedules in which CI-1033 is manently eliminating existing receptor TK activity that would administered either daily on a less interrupted schedule with regenerate only when new receptors are synthesized. Further- lower doses or weekly with higher doses have been associated more, it was hypothesized that even reversible receptor TK with preclusive toxicity (33, 42). The incidence and severity of

toxicities associated with CI-1033 at the recommended phase II PK behavior is not unexpected and is congruent with that dose, 250 mg/day, were tolerable. Furthermore, there was ade- observed in other studies (42, 44, 45). In the absence of accu- quate safety experience over multiple courses in patients treated mulation, Cmax values still exceed by 10-fold the IC50 values for at this dose level, with most of the adverse effects noted being prolonged pan-erbB TK inhibition and/or transactivation of all of grade 1 or 2. In contrast, an unacceptably high incidence of erbB receptor subfamily members, in in vitro studies. Further- early dose-limiting events occurred in patients treated with more, these concentrations almost triple the concentrations that CI-1033 at the next higher dose level, 300 mg/day. The principal produce maximal suppression of erbB-TK phosphorylation in toxicities of CI-1033 were cutaneous effects and diarrhea. Sim- animal models.4 ilar toxicities, mainly rash and diarrhea, have been observed The results of this phase I and pharmacological study with other erbB TK inhibitors, which suggests an erbB-mediated indicate that daily oral treatment with CI-1033 on a 7-day-on, mechanism of action for the pharmacodynamic effects of these 7-day-off schedule is well tolerated and devoid of relevant drugs (43). At the recommended dose of 250 mg/day, adverse hematologic toxicity and hypersensitivity reactions. In fact, the events were prevented or managed successfully in most cases principal toxicities of CI-1033 on this schedule, cutaneous tox- without the need for interruption of treatment. In most cases, icity and diarrhea, are similar to those of monoclonal antibodies diarrhea was well controlled by the intake of loperamide, and and small-molecule inhibitors of erbB1 TK. Furthermore, CI- skin rash generally improved or resolved within 3 weeks after 1033 plasma concentrations at the recommended phase II dose therapy without any need for interruption of the treatment. There of 250 mg/day exceed biologically relevant concentrations by at were no treatment-related deaths or grade 4 toxicity during the least one order of magnitude. Although major tumor regression study. Disease progression was the primary reason for discon- was not noted in the 14 patients evaluable for tumor response, tinuation and only four (16.7%) patients withdrew because of antitumor activity was not a primary end point in this phase I treatment-related adverse effects. study done in a heterogeneous patient population with malig- No treatment-related hypersensitivity reactions were noted nancies that undoubtedly possess a wide range of erbB expres- in the present study, but manifestations of hypersensitivity phe- sion and activation profiles. Large, multicenter disease-directed nomena have occurred in patients treated with other dosing studies in patients with advanced carcinomas of the lung, breast, schedules of CI-1033 (32, 33). Although thrombocytopenia was and ovary will provide an opportunity to benchmark the antitu- not observed previously in preclinical toxicology evaluations in mor activities of CI-1033 relative to those of more specific animals, it was an unexpected severe side effect in patients receiving higher doses of CI-1033 administered on days 1, 8, inhibitors of erbB1 TK as well as an opportunity to evaluate the and 15 every 28 days (33), possibly because of the greater potential for antitumor activity outside the range of specific chemical reactivity and kinase promiscuity of CI-1033 com- inhibitors of erbB1 TK that might be conferred by the pan-erbB pared with more restricted and reversible erbB1 TK inhibitors. inhibitory properties of CI-1033. 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