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Background: Neratinib (HKI-272) is an oral irreversible pan-ErbB tyrosine kinase inhibitor that blocks downstream signaling of ErbB1, -2, and -4 by binding to the intracellular ATP binding sites of these receptors. Other available ErbB inhibitors include the ErbB2-specific monoclonal antibody trastuzumab and the reversible small molecule inhibitor lapatinib, which is directed against ErbB1 and -2. Neratinib may have advantages over other inhibitors because of its pan-ErbB inhibition and ability to irreversibly inhibit the intracellular tyrosine kinase domains. The objective of this ongoing multicenter, open-label, phase 1/2 study is to evaluate the safety, tolerability, and preliminary antitumor activity of neratinib in combination with capecitabine in patients with solid tumors.Material and Methods: Patients with advanced solid tumors are being enrolled in part 1 of this 2-part study to assess safety and tolerability (ie, adverse events and dose-limiting toxicities [DLTs]) and to determine the maximum tolerated dose (MTD) of neratinib in combination with capecitabine. Part 2 will further assess safety and tolerability, as well as objective response rates and pharmacokinetic parameters at the MTD in patients with metastatic or locally advanced ErbB2+ breast cancer. The dose escalation scheme for part 1 includes 3 ascending dose levels: neratinib 160 or 240 mg/day plus capecitabine 750 mg/m2 twice daily (bid) on days 1-14 of a 21-day cycle (levels 1 and 2) and neratinib 240 mg/day plus capecitabine 1,000 mg/m2 bid on days 1-14 of a 21-day cycle (level 3). Each patient participates at only 1 dose level. If dose level 1 is tolerated, but dose level 2 is not, an intermediate dose level of neratinib 200 mg plus capecitabine 750 mg/m2 bid can be evaluated as a potential MTD.Results: Data as of 1 May 2009 for patients treated at dose levels 1, 2, and 3 (n = 6, 5, and 4, respectively) are presented. Median (range) ages for patients at the respective dose levels were 46 (37-69), 56 (41-58), and 53 (39-80) years. Two DLTs have been observed at dose level 3; one patient each experienced grade 3 elevated alanine aminotransferase and grade 3 diarrhea. Common treatment-emergent adverse events (all grades, ≥10% of patients) included diarrhea (50.0%), nausea (25.0%), vomiting (25.0%), fatigue (16.7%), and pyrexia (16.7%). One patient at dose level 3 experienced a drug-related adverse event of grade ≥3 diarrhea. No patients have withdrawn from the study because of adverse events; 3 patients have died (disease progression, n = 3).Discussion: Based on preliminary results from part 1, the combination of neratinib and capecitabine was well tolerated. Accrual of patients will continue and a fourth cohort of patients (neratinib 200 mg/day plus capecitabine 1,000 mg/m2 bid) will be added to further evaluate this therapeutic combination and establish a recommended dose level for part 2 of this study and for future later-stage clinical studies. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5108.

e19082 Background: Poor performance status is a negative prognostic variable for survival and a risk for increased toxicities with standard chemotherapy. A phase 2 study combining erlotinib (E) and bevacizumab (B) demonstrated encouraging efficacy in the treatment of recurrent NSCLC with acceptable toxicity. We, therefore, tested this regimen in untreated PS 2 patients with advanced NSCLC. Methods: Single-arm phase 2 trial in treatment-naïve patients with advanced non-squamous NSCLC and either a PS of 2 or age >75. Only patients eligible for bevacizumab per label were allowed onto study. Patients received E 150 mg orally daily and B 15 mg/kg IV on day 1 every 21 days for up to 6 cycles. The primary end-point was the rate of non progressive disease at 4 months (alternative hypothesis P>60%). Other end-points included overall survival, progression free survival (PFS), toxicity evaluations and patient-reported PS (PRPS) measures. Results: 25 patients were enrolled. Patient characteristics: 56% female, median age 77 years (range: 52–90); 88% stage IV; 92% were PS 2; 20% were never or remote smokers (> 30 years) The PRPS was 1, 2, 3 in 32%, 52%, 8% respectively with data on 2 patients missing. The rate of non-progression at 4 months was 40%; overall best response: 5% PR, 40% SD, 50% PD and 5% unevaluable; median PFS 2.6 months, 95% CI (1.3–5.1); MST 5.8 months, 95% CI (3.8- 8.7). 2 patients had G3 rash. G3 diarrhea, G3 hemorrhage, G3 proteinuria, G3 duodenal ulcer and G3 pneumonitis each developed in one patient. Conclusions: E + B is an active regimen with an acceptable toxicity profile; however, this study did not meet its’ primary endpoint. Further study of this combination will not be pursued in the Hoosier Oncology Group for this patient population. [Table: see text]

Background The genetic polymorphism of thiopurine methyltransferase (TPMT) is well characterized in most populations. Four common polymorphic alleles are associated with impaired activity of the enzyme. These are TPMT*2 (238G>C), TPMT*3B (c.460G>A), TPMT*3A (c.460G>A and c.719A>G) and TPMT*3C (c.719A>G). The aim of the present study was to determine the frequency of TPMT polymorphisms and their association with the occurrence of adverse events, during 6-mercaptopurine therapy in pediatric acute lymphoblastic leukemic (ALL) patients in Gaza Strip. Methods A total of 56 DNA samples from all pediatric ALL patients admitted to the pediatric hematology departments of Gaza strip hospitals were analyzed. Genomic DNA from peripheral blood leukocytes was isolated and the TPMT*2, TPMT*3B TPMT*3A and TPMT*3C allelic polymorphism was determined by PCR-RFLP and allele specific PCR technique. Results No TPMT*2, *3B or *3C alleles were detected. Only one, out of 56 patients, was found heterozygous for the TPMT*3A allele. Thus, the frequency of TPMT*3A allele was calculated to be 0.89%. Fourteen patients of ALL were suffering from myelotoxicity during 6-MP therapy. From our results, no significant association could be established between clinical and laboratory data and/or the presence of the mutation in TPMT gene. Conclusion TPMT*3A was the only deficiency allele detected in our population with an allelic frequency of 0.89%. Other polymorphic alleles in TPMT gene, or factors other than TPMT polymorphisms may be responsible for the development of myelosuppression in cases that don’t carry the investigated TPMT alleles (*2, *3A, *3B and *3C). Therefore, more studies are recommended to study such factors.