Phase I/II study of inhaled doxorubicin combined with platinum-based therapy for advanced non-small cell lung cancer.

PURPOSE: We have shown the feasibility of administering inhaled doxorubicin to patients with cancer. This study evaluated inhaled doxorubicin combined with cisplatin and docetaxel in patients with non-small cell lung cancer. The principal objective was to determine safety and, secondarily, efficacy. EXPERIMENTAL DESIGN: Patients who had chemo-naïve advanced non-small cell lung cancer were enrolled in the study. Adequate organ and pulmonary function was required: diffusing capacity for carbon monoxide/forced expiratory volume in 1 second/forced vital capacity > or =50%, resting/exercise O(2) saturation > or =90%/85%. In phase I, doxorubicin was escalated: dose level 1 (6 mg/m(2)) and level 2 (7.5 mg/m(2)). Escalation was permitted if < or =2 of 6 patients experienced pulmonary dose-limiting toxicity (grade 2 Radiation Therapy Oncology Group lung morbidity; resting O(2) saturation of <85%; decrease in diffusing capacity for carbon monoxide, forced vital capacity, or forced expiratory volume in 1 second of > or =20% from baseline or < or =30% of predicted; or grade 3 Common Terminology Criteria for Adverse Events version 3.0 pulmonary toxicity). Doses of cisplatin and docetaxel were 75 mg/m(2). Treatments and pulmonary function tests were repeated every 21 days, with up to eight cycles for responding patients. RESULTS: Twenty-eight patients were treated at level 1 and eight patients at level 2. Doxorubicin was escalated to 7.5 mg/m(2), however, after two patients developed pulmonary dose-limiting toxicity; the remainder were treated at 6.0 mg/m(2). Twenty-four evaluable patients received at least two courses or had progressive disease following the first course at the phase II dose. Toxicity was associated with i.v. chemotherapy although one patient had delayed pulmonary toxicity responding to corticosteroids and oxygen. Seven (29%) evaluable patients responded (six partial responses and one complete response) and 13 (54%) patients had stable disease for up to eight cycles. CONCLUSION: Although this combination was safe, the primary objective was not met and will not be pursued further.

Phase 1 study of aflibercept administered subcutaneously to patients with advanced solid tumors.

PURPOSE: To determine the maximum tolerated dose or maximal administered dose and pharmacokinetic and safety profiles of s.c. administered vascular endothelial growth factor Trap (aflibercept), a novel antiangiogenic agent. EXPERIMENTAL DESIGN: In this open-label, dose-escalation study, patients with advanced solid tumors were treated with subcutaneous doses of aflibercept at seven dose levels. Patients received a single dose of aflibercept and then underwent safety and pharmacokinetic assessments over the next 4 weeks. Patients then received weekly or biweekly treatment over the subsequent 6 weeks. Patients tolerating and benefiting could continue on aflibercept at the same dose and schedule until progression of disease. RESULTS: Thirty-eight patients received at least one dose of aflibercept. Maximum tolerated dose was not reached. Due to solubility/dosing limits with the subcutaneous formulation, 1,600 microg/kg/week was the maximal administered dose. The most common toxicities were proteinuria (37%), fatigue (32%), injection site reactions (18%), nausea (17%), myalgia and anorexia (16% each), hypertension (13%), and voice hoarseness (11%). Drug-related grade 3 to 4 toxicity was uncommon (7%) and reversible: dehydration, cerebral ischemia, proteinuria, hypertension, leukopenia, and pulmonary embolism. We identified dose-proportional increases in plasma concentrations of aflibercept bound to vascular endothelial growth factor with a t(1/2) of 18 days. No antiaflibercept antibodies were detected. Stable disease was maintained for at least 10 weeks in 18 patients (47%), and 2 patients maintained on study for >1 year. CONCLUSION: Subcutaneous aflibercept was well tolerated and had manageable side effects. Its favorable pharmacokinetic profile and potential antitumor activity warrants further evaluation.

Phase II study of cisplatin plus etoposide and bevacizumab for previously untreated, extensive-stage small-cell lung cancer: Eastern Cooperative Oncology Group Study E3501.

PURPOSE: To investigate the efficacy and safety of bevacizumab plus cisplatin and etoposide in patients with extensive-stage disease, small-cell lung cancer (ED-SCLC). PATIENTS AND METHODS: In this phase II trial, 63 patients were treated with bevacizumab 15 mg/kg plus cisplatin 60 mg/m(2) and etoposide 120 mg/m(2), which was followed by bevacizumab alone until death or disease progression occurred. The primary end point was the proportion of patients alive at 6 months without disease progression (ie, progression-free survival [PFS]). Secondary end points included overall survival (OS), objective response rate, and toxicity. Correlative studies were performed to explore the relationship between baseline and changes in plasma vascular endothelial growth factor (VEGF), soluble cell adhesion molecules (ie, vascular cell adhesion molecule [VCAM], intercellular cell adhesion molecule [ICAM], and E-selectin) and basic fibroblast growth factor and outcome. RESULTS: The 6-month PFS was 30.2%, the median PFS was 4.7 months, and OS was 10.9 months. The response rate was 63.5%. The most common adverse event was neutropenia (57.8%). Only one patient had grade 3 pulmonary hemorrhage. Patients who had high baseline VCAM had a higher risk of progression or death compared with those who had low baseline VCAM levels. No relationships between outcome and any other biomarkers were seen. CONCLUSION: The addition of bevacizumab to cisplatin and etoposide in patients with ED-SCLC results in improved PFS and OS relative to historical controls who received this chemotherapy regimen without bevacizumab. This regimen appears to be well tolerated and has minimal increase in toxicities compared with chemotherapy alone. Baseline VCAM levels predicted survival, but no other relationships among treatment, biomarkers, and outcome were identified.

Surface-enhanced Raman spectral measurements of 5-fluorouracil in saliva.

The ability of surface-enhanced Raman spectroscopy (SERS) to measure 5-fluorouracil (5-FU) in saliva is presented. The approach is based on the capacity of Raman spectroscopy to provide a unique spectral signature for virtually every chemical, and the ability of SERS to provide microg/mL sensitivity. A simple sampling method, that employed 1-mm glass capillaries filled with silver-doped sol-gels, was developed to isolate 5-FU from potential interfering chemical components of saliva and simultaneously provide SERSactivity. The method involved treating a 1 mL saliva sample with 1 mL of acetic acid, drawing 10 microL of sample into a SERS-active capillary by syringe, and then measuring the SER spectrum. Quality SER spectra were obtained for samples containing as little as 2 microg of 5-FU in 1 mL saliva. The entire process, the acid pretreatment, extraction and spectral measurement, took less than 5 minutes. The SERS of 5-fluorouridine and 5-fluoro-2'-deoxyuridine, two major metabolites of 5-FU, were also measured and shown to have unique spectral peaks. These measurements suggest that disposable SERS-active capillaries could be used to measure 5-FU and metabolite concentrations in chemotherapy patient saliva, thereby providing metabolic data that would allow regulating dosage. Tentative vibrational mode assignments for 5-FU and its metabolites are also given.

Phase II trial of weekly docetaxel/irinotecan combination in advanced pancreatic cancer.

BACKGROUND: Docetaxel and irinotecan have activity in pancreatic cancer. The combination of docetaxel and irinotecan is attractive because of preclinical evidence of synergy between the two drugs. We have previously demonstrated the safety of docetaxel 35 mg/m(2) and irinotecan 50 mg/m(2) given on days 1, 8, 15, and 21 of a 35-day schedule. PATIENTS AND METHODS: Patients who had unresectable or metastatic adenocarcinoma of the pancreas, bidimensionally measurable disease, Eastern Cooperative Oncology Group (ECOG) performance status 0-2, and normal bilirubin levels were eligible. Tumor assessment was performed with computed tomography, computed tomographic angiography, or magnetic resonance imaging every 2 cycles. Response was graded according to World Health Organization criteria. RESULTS: We enrolled 37 eligible patients. Principal grade 3/4 toxicities were diarrhea (21%), neutropenia (30%), and hyperglycemia (30%). There were 3 patients with febrile neutropenia and no toxic deaths. There were 4 early deaths. Among 36 evaluable patients, 9 (24%) attained a partial response and 1 (3%) attained a complete response for an objective response rate of 27%. One patient enrolled because she had been deemed to have unresectable disease but then underwent resection with negative margins after attaining a confirmed partial response. Median survival for all eligible patients is 9.4 months (range 0-68+ months) with minimum follow-up for surviving patients of 23.4 months. One-year survival is 43%. The patient who attained a complete response is alive with recurrent disease at 68 months. CONCLUSIONS: The docetaxel/irinotecan combination given on a weekly schedule is an active treatment for advanced pancreatic cancer.

Perforated viscus in a patient with non-small cell lung cancer receiving bevacizumab.

Bowel metastasis and perforation in patients with non-small cell lung cancer is rare. Bevacizumab has emerged as a new therapy in the treatment of metastatic non-small cell lung cancer. Bowel perforation associated with its use has been described in colon and ovarian cancers. The exact mechanism by which perforation occurs is under debate, and many theories exist. In this report, we present the first known case of visceral perforation in a patient with metastatic non-small cell lung cancer after treatment with bevacizumab.

Phase I study of inhaled Doxorubicin for patients with metastatic tumors to the lungs.

PURPOSE: To evaluate the toxicity profile of inhalational doxorubicin in patients with malignant disease in the lung. EXPERIMENTAL DESIGN: The OncoMyst Model CDD-2a inhalation device aerosolizes compounds to particles of 2 to 3 mum and prevents exhaled aerosol from escaping into the environment. Deposition efficiency of inhaled Technetium 99m was used to predict deposition of doxorubicin and calculate dose. Treatment was repeated every 3 weeks. No more than moderate pulmonary dysfunction was permitted (forced expiratory volume in 1 s, forced vital capacity, and diffusing capacity for carbon monoxide, all >50% predicted; resting SaO(2) >90%). RESULTS: Fifty-three patients were enrolled at 13 dose levels ranging from 0.4 to 9.4 mg/m(2). The most common histologic diagnoses were sarcoma (n = 19) and non-small cell lung cancer (n = 16). Dose-limiting toxicity (DLT) was observed at the 9.4 mg/m(2) dose level when two of four patients experienced pulmonary DLT. Of 11 patients treated at the 7.5 mg/m(2) dose level, only one showed DLT consisting of a decline in forced vital capacity of >20% from baseline. No significant systemic drug-related toxicity was observed. Several patients experienced declines in pulmonary function test variables, which were attributed to progressive disease. Observed activity included a partial response in a patient with metastatic soft tissue sarcoma previously treated with i.v. doxorubicin and ifosfamide. CONCLUSIONS: Inhaled doxorubicin is safe up to a dose of 7.5 mg/m(2) every 3 weeks in patients with cancer who had normal to moderately impaired pulmonary function.

Further delineation of the continuous human neoplastic enterochromaffin cell line, KRJ-I, and the inhibitory effects of lanreotide and rapamycin.

Small intestinal carcinoids (SICs) are the most prevalent gastrointestinal carcinoid and characterized by local invasion metastasis and protean symptomatology. The proliferative and secretory regulation of the cell of origin, the enterochromaffin (EC) cell has not been characterized. The absence of either a pure preparation of normal EC cells or human EC carcinoid cell lines has hindered the development of therapeutic agents. We therefore further characterized the neoplastic SIC cell line, KRJ-I by assessing its secretory (serotonin (5-HT)) and proliferative responses and defining its log growth phase transcriptome. Electron microscopy demonstrated oval, lobulated nuclei and substance P, and 5-HT-positive cytoplasmic vesicles. RT-PCR detected transcripts for chromogranin A (CHGA), VMAT1 (SLC18A1), tryptophan hydroxylase (TPH1), substance P (TAC1), guanylin (GUCA2A), and SERT (SLC6A4). By immunohistochemistry, all cells were positive for CHGA, SERT, VMAT1, and TPH1. Transcriptome analysis (Affymetrix U133 Plus chips) identified somatostatin SSTR2/3, adrenergic alpha1C and beta1, dopamine D2, nicotinic-type cholinergic A5, A6, B1, muscarinic acetylcholine M4, and 5-HT-2A receptors. The presence of transcripts for SSTR1, SSTR2, and SSTR3 receptors was confirmed by RT-PCR and sequencing. Isoproterenol (ISO) resulted in a dose-dependent increase in intracellular cAMP (EC50=340 nM) and 5-HT (EC50=81 nM) which was completely inhibited by the cAMP antagonist 2',5'-dideoxyadenosine (10 microM). Preincubation with a SSTR agonist, lanreotide, inhibited Ip-stimulated 5-HT secretion (IC50=420 nM). Both lanreotide (10 nM) and rapamycin (50 nM) inhibited proliferation (20+/-12 and 35+/-5% respectively) in serum-free medium whereas gefitinib (1 nM-10 microM) inhibited proliferation at micromolar concentrations. KRJ-I is a neoplastic EC cell line that can be used as an in vitro model of SICs as it will allow elucidation and clarification of the secretory and proliferative mechanism(s) of neoplastic EC cells and the molecular signatures that characterize each of these responses.

Oxaliplatin induces a delayed immune-mediated hemolytic anemia: a case report and review of the literature.

We report a case of a 59-year-old woman with metastatic carcinoma of the ileocecal region who received FOLFOX(oxaliplatin/leucovorin/5-fluorouracil) and bevacizumab therapy and exhibited a partial remission with minimal side effects. She developed a mild self-limited episode of immune-mediated hemolytic anemia during her 16th cycle of chemotherapy, which precluded her from receiving further oxaliplatin. We review the literature on oxaliplatin-induced immune-mediated hemolysis, including its mechanism, presenting symptoms, laboratory features, management, and implications for future therapy.

Evaluation of irinotecan plus paclitaxel in patients with advanced non-small cell lung cancer.

PURPOSE: We conducted a phase II study to evaluate the efficacy and safety of the combination of irinotecan and paclitaxel in patients with advanced stage non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients were eligible if they had histologically confirmed chemotherapy naïve stage IV NSCLC or stage IIIB disease that was not suitable for combined modality therapy. Patients were treated with irinotecan 50 mg/m2 and paclitaxel 75 mg/m2 on days 1 and 8 of a 21-day cycle. If the patient did not experience >grade 1 toxicity during the first cycle, the dose of irinotecan could be escalated to 60 mg/m(2). Patients were evaluated for tumor response rate, time to progression (TTP), overall survival (OS) and toxicity. RESULTS: Twenty-three eligible patients were treated. Two (9%) patients achieved a partial response. Eight patients (35%) had stable disease. The median number of cycles given per patient was four (range 1-29). The major toxicities were grade >or=3 neutropenia (26%) and grade 3 diarrhea (5%). The median time to progression was 2.8 months (range 0.5-21.8 months) for all patients and 4.3 months for the patients who had either stable disease or a partial response. The median overall survival was 9.2 months (range 0.5-40 months). The one- and two-year survival rates were 39% and 13%, respectively. CONCLUSION: The combination of irinotecan and paclitaxel is safe in advanced NSCLC and affords a survival similar to other non-platinum as well as platinum-based doublets. However, this combination does not have sufficient activity to justify further study in an unselected population. If biomarkers are developed that can guide the selection of chemotherapy in an individual patient, there may be a rationale for further evaluation of this regimen.

Comparison of health-related quality of life questionnaires in ambulatory oncology.

The purpose of this study is to compare three commonly used health-related quality of life (HR-QOL) questionnaires for their ease of use, accuracy, and patient preference; identify factors related to patient preference; identify differences in patient completion rates; and to identify factors associated with patient completion of these questionnaires. Three psychometrically sound measures, the Symptom Distress Scale (SDS), Medical Outcome Study Short Form-36 (SF-36), and Functional Assessment of Cancer Therapy (FACT), were tested. Seventy-nine patients completed questionnaires in the ambulatory oncology setting. No significant differences in patient ratings were found in ease of use and accuracy among the questionnaires. All of the questionnaires were rated as easy to use and accurate. Patient ratings on preference were marginally significant (p = 0.07). Forty-six percent of participants indicated that they preferred the SDS, whereas 27% and 39% preferred the SF-36 and the FACT. No significant differences in patient completion rates were found among the questionnaires. One hundred percent completion rates ranged from 88.6% for the SDS to 78.5% for the SF-36, and 80% completion rates ranged from 98.7% for the SDS to 94.9% for the SF-36. Administration of standardized HR-QOL questionnaires is feasible in the clinical setting.

Severe irinotecan-induced toxicities in a patient with uridine diphosphate glucuronosyltransferase 1A1 polymorphism.

Irinotecan is an analogue of camptothecin, a topoisomerase I inhibitor, that has an important role in the management of advanced colorectal cancer. It is approved as first-line therapy in combination with 5-fluorouracil and leucovorin or as monotherapy in the second-line setting. Its clinical use has been associated with variability in terms of pharmacokinetic behavior and toxicities, especially myelosuppression and diarrhea. Irinotecan is metabolized to the active compound SN-38; it is now known that the metabolism of irinotecan and the inactivation of SN-38 by glucuronidation are mediated by genetic differences, which contributes to the variability. In this article, a case is presented that illustrates this, and there is a brief discussion of the clinical pharmacology of irinotecan and some of the genetic variations that affect its cellular metabolism.

A phase I and pharmacokinetic study of VNP40101M, a new alkylating agent, in patients with advanced or metastatic cancer.

PURPOSE: VNP40101M is a new alkylating agent that demonstrated broad anti-tumor activity in murine tumor models. A phase I trial was initiated to determine the toxicities, maximum tolerated dose, and pharmacokinetics of VNP40101M by short IV infusion. STUDY DESIGN: The starting dose was 3 mg/m(2) every four weeks, and was escalated in successive cohorts as follows: 6, 12, 24, 40, 60, 80, and 100 mg/m(2). Beyond 100 mg/m(2), dose increments were 25%. Initially, 1-2 patients were assigned to a dose level. Intra-patient dose escalation was permitted. With the first instance of a drug-related > or = grade 2 adverse event, all dose levels required assessment of 3-6 patients. Pharmacokinetic parameters were assessed in the first cycle and any cycle with a change in dose. RESULTS: Twenty-six patients in 13 dose levels ranging from 3-305 mg/m(2) were evaluated. Dose-related thrombocytopenia was the major toxicity, with the nadir occurring at a median of day 27. At 305 mg/m(2), six of eight patients developed grade 3 thrombocytopenia, including one event that met the definition for DLT. Other dose-related toxicities included moderate granulocytopenia, anemia, and a mild infusion-related syndrome consisting of acute headache and facial flushing. The granulocyte nadir occurred at a median of day 34, and recovery of both thrombocytopenia and neutropenia to < grade 2 occurred at a median of day 43. VNP40101M peak plasma concentrations and AUC were linear with dose. The elimination half-life was short and estimated to be approximately 15 minutes. CONCLUSIONS: The MTD and recommended dose for phase II trials is 305 mg/m(2) every six weeks. Phase II trials in less heavily pre-treated patient populations are warranted.

AN-9 (Titan).

Titan is developing AN-9 for the potential treatment of various cancers. AN-9 is a histone deacetylase inhibitor analog of butyric acid that causes apoptosis of cancer cells through signaling cellular differentiation. In March 2001, a phase I/II study involving patients with liver tumors was initiated. By November 2001, enrollment had been completed in a second phase II study of refractory non-small-cell lung cancer (NSCLC). In June 2003, Titan began enrollment for a phase IIb trial of AN-9 in combination with docetaxel in patients with NSCLC.

Progress in the therapy of small cell lung cancer.

Small cell lung cancer (SCLC) accounts for approximately 14% of all cases of lung cancer. Combination chemotherapy is the most effective treatment modality for SCLC and recently, several new active drugs have emerged. Combinations of platinum agents with CPT-11 or gemcitabine have been successfully compared in phase III trials against the cisplatin/etoposide standard. Modest improvements in the outcome of patients with SCLC have been noted over the last two decades. Thoracic irradiation given concurrently with chemotherapy improves survival compared with sequential chemotherapy and radiation, but this approach is associated with more toxicity. Moreover, the optimal doses and fractionation of thoracic irradiation remain to be determined. Three-dimensional treatment planning is under investigation. Prophylactic cranial irradiation (PCI) has established a role in the management of patients who have achieved a complete response to the initial therapy. Novel molecular targeted therapies are among the strategies currently being investigated in SCLC.

A phase II study of topotecan and cyclophosphamide with G-CSF in patients with advanced small cell lung cancer.

PURPOSE: We conducted a multicenter phase II study to evaluate the efficacy and safety of the combination of topotecan and cyclophosphamide for patients with advanced small cell lung cancer (SCLC). PATIENTS AND METHODS: Patients were eligible if they had newly diagnosed extensive stage SCLC or if they had SCLC that progressed more than three months after completion of the first chemotherapy regimen. Patients were treated every 21 days with cyclophosphamide 600 mg/m2 IV on day 1 and topotecan 1.0 mg/m2 on days 1 to 5. Filgrastim was administered for 10 days starting on day 6. Patients were evaluated for objective tumor response, time to tumor progression, overall survival and toxicity. RESULTS: Forty-two eligible patients were treated. Seventeen patients (40.5%) had an objective response including 4 (9.5%) complete remissions (CR). Fifteen patients (35.7%) had stable disease. There are 2 patients known to be alive at the time of this report: one with stable disease at 26 months and another with a CR at 37 months. The median number of cycles completed was 6 (range 1-12). The major toxicities were grades 3 and 4 neutropenia (73.8%), grades 3 and 4 anemia (35.7%) and grades 3 and 4 thrombocytopenia (50%). Five patients died during the first cycle of chemotherapy. The median time to progression was 3 months (range 5 days-36 months) (CI: 51-135 days) and the median overall survival was 9 months (5 days-37 months) (CI: 210-330 days). The two-year survival rate was 21%. CONCLUSIONS: The combination of topotecan and cyclophosphamide is highly active in small cell lung cancer. Myelosuppression is the major toxicity and is rapidly reversible in most patients. The incidence of treatment-related mortality was comparable to some other intensive chemotherapy regimens. This incidence is unacceptably high and indicates better selection criteria are needed in order to exclude patients at excessive risk of morbidity.

Phase I and pharmacokinetic study of triapine, a potent ribonucleotide reductase inhibitor, administered daily for five days in patients with advanced solid tumors.

PURPOSE: A Phase I study in patients with advanced cancer was conducted to determine the safety, pharmacokinetics, and maximum tolerated dose of Triapine, a new, potent small-molecule inhibitor of ribonucleotide reductase. EXPERIMENTAL DESIGN: Triapine was administered by 2-h i.v. infusion daily for 5 days. Courses were repeated every 4 weeks. The starting dose was 5 mg/m(2)/day, but was reduced to 2 mg/m(2)/day after the first patient developed a hepatic adverse event. The dose was subsequently escalated using a modified Fibonacci scheme in cohorts of 3-6 patients. After the 12 mg/m(2)/day dose level, the study design was amended to permit 100% dose escalation in single-patient cohorts until the first episode of a drug-related grade 2 adverse event or dose-limiting toxicity (DLT). On reaching a dose of 96 mg/m(2)/day, the study was amended to determine the safety and tolerability of the 96-mg/m(2) dose administered daily for 5 days every 2 weeks in an expanded cohort of patients. RESULTS: A total of 32 patients received treatment. During the dose escalation phase of the study, grade 2-4 drug-related adverse events were first observed at a dose of 96 mg/m(2)/day. Grade 3-4 leukopenia was the primary toxicity observed among four patients treated at this dose, which occurred in the week after treatment and resolved to grade 1 or lower by day 15. Fifteen patients were subsequently treated at the 96-mg/m(2) dose, daily for 5 days, with courses repeated every 2 weeks. The most common nonhematological toxicities for the latter schedule were asthenia, fever, nausea and vomiting, mucositis, decreased serum bicarbonate, and hyperbilirubinemia, and were predominantly grade 1-2 in severity and rapidly reversible. Hematological toxicity on the every-other-week schedule consisted of leukopenia (grade 4 in 93% in at least one course) and anemia (grade 2 in 71%, grade 3 in 22%). Thrombocytopenia was less common and was grade 3-4 in severity in only 22%. Triapine showed linear pharmacokinetic behavior although interpatient variability was relatively high. Peak concentrations at the 96-mg/m(2)/day dose averaged 8 microM, and the mean elimination T(1/2) ranged from 35 min to 3 h, with a median value of approximately 1 h. Cumulative urinary recovery averaged 1-3% of the administered dose, suggesting that the elimination of Triapine was primarily through metabolism. No partial or complete responses were observed. CONCLUSIONS: Triapine administered at a dose of 96 mg/m(2) by 2-h i.v. infusion daily for 5 days on an every-other-week schedule demonstrates an acceptable safety profile. Serum concentrations that surpass in vitro tumor growth-inhibitory concentrations are achieved for brief periods of time each day and are sufficient to produce myelosuppression, the expected consequence of ribonucleotide reductase inhibition. Phase II trials are indicated but will proceed with a daily-for-4-days schedule to reduce the incidence of grade 4 leukopenia. The safety profile also supports the initiation of Phase I combination trials with other anticancer agents.

Lapatinib ditosylate GlaxoSmithKline.

Lapatinib ditosylate, an ErbB-2 and EGFR dual tyrosine kinase inhibitor, is being developed by GlaxoSmithKline plc for the potential treatment of solid tumors.

Erlotinib OSI/Roche/Genentech.

Erlotinib (CP-358774, OSI-774, Tarceva), a quinazoline derivative, is an orally active epidermal growth factor receptor tyrosine kinase inhibitor under development jointly by Genentech, OSI (formerly Oncogene Science) and Roche, both as monotherapy and combination therapy for the potential treatment of solid tumors, including non-small-cell lung cancer (NSCLC) and pancreatic, breast, head and neck cancers [203487]. Development of the compound is most advanced for NSCLC and pancreatic cancer; in July 2001, phase III combination trials were initiated for NSCLC [416835]. In October 2001, phase III monotherapy trials in NSCLC and phase III combination trials in pancreatic cancer were also initiated [426704]. In Japan, the compound was in phase I studies in January 2002 [439189].