Hironobu Minami

Zoledronic Acid Significantly Reduces Skeletal Complications Compared With Placebo in Japanese Women With Bone Metastases From Breast Cancer: A Randomized, Placebo-Controlled Trial

PURPOSE To investigate the efficacy and safety of zoledronic acid for the treatment of bone metastases from breast cancer. PATIENTS AND METHODS Women with bone metastases (N = 228) were randomly assigned to receive 4 mg zoledronic acid (n = 114) or placebo (n = 114) via 15-minute infusions every 4 weeks for 1 year. The primary efficacy end point was the skeletal-related event (SRE) rate ratio between treatment groups. An SRE was defined as pathologic fracture, spinal cord compression, and radiation or surgery to bone. Secondary end points included percentage of patients with at least one SRE, time-to-first SRE, and Andersen-Gill multiple-event analysis. RESULTS The SRE rate ratio at 1 year (excluding HCM and adjusted for prior fracture) was 0.61 (permutation test; P = .027), indicating that zoledronic acid reduced the rate of SRE by 39% compared with placebo. The percentage of patients with at least one SRE (excluding HCM) was significantly reduced by 20% by zoledronic acid (29.8% v 49.6% for placebo; P = .003). Zoledronic acid significantly delayed time-to-first SRE (median not reached v 364 days; Cox regression; P = .007) and reduced the risk of SREs by 41% in multiple event analysis (risk ratio = 0.59; P = .019) compared with placebo. Zoledronic acid was well tolerated with a safety profile similar to placebo. No patient treated with zoledronic acid had grade 3 or 4 serum creatinine increase. CONCLUSION Zoledronic acid significantly reduced skeletal complications compared with placebo across multiple end points in Japanese women with bone metastases from breast cancer.

UGT1A1 Haplotypes Associated with Reduced Glucuronidation and Increased Serum Bilirubin in Irinotecan‐administered Japanese Patients with Cancer

A comprehensive haplotype analysis of UGT1A1 in the Japanese population was conducted, and the effects of these haplotypes were investigated with respect to UGT1A1‐related phenotypic parameters in patients with cancer who received irinotecan.

Irinotecan pharmacokinetics/pharmacodynamics and UGT1A genetic polymorphisms in Japanese: roles of UGT1A1*6 and *28.

Objectives SN-38, an active metabolite of irinotecan, is detoxified by glucuronidation with UGT1A isoforms, 1A1, 1A7, 1A9, and 1A10. The pharmacogenetic information on UGT1A haplotypes covering all these isoforms is important for the individualized therapy of irinotecan. Associations between UGT1A haplotypes and pharmacokinetics/pharmacodynamics of irinotecan were investigated to identify pharmacogenetic markers. Methods Associations between UGT1A haplotypes and the area under concentration curve ratio (SN-38 glucuronide/SN-38) or toxicities were analyzed in 177 Japanese cancer patients treated with irinotecan as a single agent or in combination chemotherapy. For association analysis, diplotypes of UGT1A gene segments [(1A1, 1A7, 1A9, 1A10), and Block C (common exons 2–5)] and combinatorial haplotypes (1A9-1A7-1A1) were used. The relationship between diplotypes and toxicities was investigated in 55 patients treated with irinotecan as a single agent. Results Among diplotypes of UGT1A genes, patients with the haplotypes harboring UGT1A1*6 or *28 had significantly reduced area under concentration curve ratios, with the effects of UGT1A1*6 or *28 being of a similar scale. A gene dose effect on the area under concentration curve ratio was observed for the number of haplotypes containing *28 or *6 (5.55, 3.62, and 2.07 for 0, 1, and 2 haplotypes, respectively, P<0.0001). In multivariate analysis, the homozygotes and double heterozygotes of *6 and *28 (*6/*6, *28/*28 and *6/*28) were significantly associated with severe neutropenia in 53 patients who received irinotecan monotherapy. Conclusions The haplotypes significantly associated with reduced area under concentration curve ratios and neutropenia contained UGT1A1*6 or *28, and both of them should be genotyped before irinotecan is given to Japanese and probably other Asian patients.

Association between gain-of-function mutations in PIK3CA and resistance to HER2-targeted agents in HER2-amplified breast cancer cell lines

BACKGROUND The mechanism of resistance to human epidermal growth factor receptor 2 (HER2)-targeted agents has not been fully understood. We investigated the influence of PIK3CA mutations on sensitivity to HER2-targeted agents in naturally derived breast cancer cells. MATERIALS AND METHODS We examined the effects of Calbiochem (CL)-387,785, HER2 tyrosine kinase inhibitor, and trastuzumab on cell growth and HER2 signaling in eight breast cancer cell lines showing HER2 amplification and trastuzumab-conditioned BT474 (BT474-TR). RESULTS Four cell lines with PIK3CA mutations (E545K and H1047R) were more resistant to trastuzumab than the remaining four without mutations (mean percentage of control with 10 microg/ml trastuzumab: 58% versus 92%; P = 0.010). While PIK3CA-mutant cells were more resistant to CL-387,785 than PIK3CA-wild-type cells (mean percentage of control with 1 microM CL-387,785: 21% versus 77%; P = 0.001), CL-387,785 retained activity against BT474-TR. Growth inhibition by trastuzumab and CL-387,785 was more closely correlated with changes in phosphorylation of S6K (correlation coefficient, 0.811) than those of HER2, Akt, or ERK1/2. Growth of most HER2-amplified cells was inhibited by LY294002, regardless of PIK3CA genotype. CONCLUSIONS PIK3CA mutations are associated with resistance to HER2-targeted agents. PI3K inhibitors are potentially effective in overcoming trastuzumab resistance caused by PIK3CA mutations. S6K phosphorylation is a possibly useful pharmacodynamic marker in HER2-targeted therapy.

A Phase I Dose-Escalation Study of ZD6474 in Japanese Patients with Solid, Malignant Tumors

Introduction: ZD6474 (vandetanib) is an orally available inhibitor of vascular endothelial growth factor receptor, epidermal growth factor receptor, and RET receptor tyrosine kinase activity. This study assessed the safety and tolerability of escalating doses of ZD6474 in Japanese patients with solid, malignant tumors. Methods: Adult patients with solid tumors refractory to standard therapy received a once-daily oral dose of ZD6474 (100–400 mg) in 28-day cycles, until disease progression or unacceptable toxicity was observed. Results: Eighteen patients were treated at doses of 100 mg (n = 3), 200 mg (n = 6), 300 mg (n = 6), and 400 mg (n = 3). Dose-limiting toxicities at the completion of cycle 2 were hypertension (n = 3), diarrhea (n = 1), headache (n = 1), toxic skin eruption (n = 1), and alanine aminotransferase increase (n = 1). A dose of 400 mg/day was considered to exceed the maximum tolerated dose (MTD). Toxicities were manageable with dose interruption and/or reduction. Objective tumor response was observed in four of nine patients with non-small cell lung cancer (NSCLC) at doses of either 200 or 300 mg. Terminal half-life was about 90–115 hours. Plasma trough concentrations achieved steady-state conditions after approximately 1 month of daily dosing. Conclusions: It was concluded that a dose of 400 mg/day was considered to exceed the MTD, and doses for phase II study were thought to be not more than 300 mg/day. The objective response observed in some NSCLC patients is encouraging for further studies in this tumor type.

Prognostic value of performance status assessed by patients themselves, nurses, and oncologists in advanced non-small cell lung cancer

Accuracy in the assessment of performance status by oncologists has not been well evaluated. We investigated possible discrepancies in the assessment of performance status among patients, nurses, and oncologists, and evaluated the prognostic importance of each assessment. Two hundred and six inpatients with inoperable, advanced non-small cell lung cancer were investigated prospectively. Weighted Kappa statistics for inter-observer agreement were 0.53 between oncologists and patients and 0.63 between oncologists and nurses. There was a significant difference among the assessments by the three groups (P < 0.001). Oncologists gave the healthiest performance status assessment, nurses an intermediate assessment, and patients the poorest. When included separately in the Cox model, the assessment by each group was significantly correlated with survival. However, the assessment by the patients themselves failed to distinguish survival of patients with performance status 1 and 2. Among the three models including patient-, nurse-, and oncologist-assessed PS, that including oncologist-assessed PS best fitted to the observed survival data. These results showed that the assessment by the patients themselves is different from those by the nurses and the oncologists and provided additional support for the use of the assessment by oncologists in clinical oncology.

Genetic polymorphisms of CYP2B6 affect the pharmacokinetics/pharmacodynamics of cyclophosphamide in Japanese cancer patients.

Objective To evaluate the effects of genetic polymorphisms of drug metabolizing enzymes on the pharmacokinetics of cyclophosphamide and its active metabolite, 4-hydroxycyclophosphamide, and on the pharmacodynamics. Experimental Design One hundred and three Japanese patients with malignant lymphoma or breast cancer treated with cyclophosphamide (500–750 mg/m2) participated in this study. The plasma concentrations of cyclophosphamide and 4-hydroxycyclophosphamide were determined by high-performance liquid chromatography, and pharmacokinetic parameters were calculated. The genotypes of CYP2B6, CYP2C19, CYP3A4, CYP3A5, ALDH1A1, GST genes were determined by allele-specific polymerase chain reaction or polymerase chain reaction–restriction-fragment length polymorphism. Results A large interindividual difference (54-fold) was observed in the area under the curve ratio of 4-hydroxycyclophosphamide/cyclophosphamide calculated as the metabolic index. We first proved that leukocytopenia and neutropenia were significantly (P<0.01) related to the area under the curve of 4-hydroxycyclophosphamide. We found that the homozygotes of CYP2B6*6 (Q172H and K262R) showed significantly (P<0.05) higher clearance and shorter half-life of cyclophosphamide than heterozygotes and homozygotes of CYP2B6*1. The small sample size, however, limited the impact. On the other hand, it was clearly demonstrated that the patients possessing the single nucleotide polymorphisms of the CYP2B6 gene, g.−2320T>C, g.−750T>C (5′-flanking region), g.15582C>T (intron 3), or g.18492T>C (intron 5), had significantly lower area under the curve ratios of 4-hydroxycyclophosphamide/cyclophosphamide, indicating a decreased cyclophosphamide 4-hydroxylation. Of particular importance was the finding that leukocytopenia was significantly related to the single nucleotide polymorphisms g.−2320T>C, g.−750T>C, and g.18492T>C in CYP2B6 gene, which are highly linked. No relationship was observed between the pharmacokinetics of cyclophosphamide or 4-hydroxycyclophosphamide and genetic polymorphisms of the other enzymes. Conclusions We clarified that the single nucleotide polymorphisms in the promoter region or introns in the CYP2B6 affect the potency of cyclophosphamide activation to 4-hydroxycyclophosphamide. This information would be valuable for predicting adverse reactions and the clinical efficacy of cyclophosphamide.

Phase I and pharmacokinetic study of sorafenib, an oral multikinase inhibitor, in Japanese patients with advanced refractory solid tumors

Sorafenib is a novel oral multikinase inhibitor that targets Raf serine/threonine and receptor tyrosine kinases, and inhibits tumor cell proliferation and angiogenesis. We have conducted a phase I study of sorafenib to determine the safety, tolerability, pharmacokinetics, and potential efficacy of this agent in 31 Japanese patients with advanced refractory solid tumors. Sorafenib (100–600 mg) was given as a single dose followed by a 7‐day wash‐out period, and then administrated twice daily (bid). The most frequent drug‐related adverse events were rash/desquamation (61%), hand–foot skin reactions (39%), diarrhea (36%), and elevations of serum lipase (36%) and amylase (26%) levels. Dose‐limiting toxicities (DLTs) were grade 3 diarrhea at 200 mg bid and grade 3 fatigue at 600 mg bid. Grade 3 and 4 pancreatic enzyme elevations were observed at 200–600 mg bid, but they were not deemed dose‐limiting because they were asymptomatic and were not associated with pancreatitis or chronic damage to the pancreas. The AUC and Cmax of sorafenib increased linearly with dose up to 400 mg bid. Partial responses were observed in one of 10 patients with non‐small cell lung cancer and one of three patients with renal cell carcinoma. In conclusion, sorafenib 400 mg bid was well tolerated in Japanese patients with advanced refractory solid tumors. The recommended dose for future clinical trials is 400 mg bid. (Cancer Sci 2008; 99: 1492–1498)

Haplotype structures of the UGT1A gene complex in a Japanese population.

Genetic polymorphisms of UDP-glucuronosyltransferases (UGTs) are involved in individual and ethnic differences in drug metabolism. To reveal co-occurrence of the UGT1A polymorphisms, we first analyzed haplotype structures of the entire UGT1A gene complex using the polymorphisms from 196 Japanese subjects. Based on strong linkage disequilibrium between UGT1A8 and 1A10, among 1A9, 1A7, and 1A6, and between 1A3 and 1A1, the complex was divided into five blocks, Block 8/10, Block 9/6, Block 4, Block 3/1, and Block C, and the haplotypes for each block were subsequently determined/inferred. Second, using pyrosequencing or direct sequencing, additional 105 subjects were genotyped for 41 functionally tagged polymorphisms. The data from 301 subjects confirmed the robustness of block partitioning, but several linkages among the haplotypes with functional changes were found across the blocks. Thus, important haplotypes and their linkages were identified among the UGT1A gene blocks (and segments), which should be considered in pharmacogenetic studies.

Indirect-response model for the time course of leukopenia with anticancer drugs

Because both the nadir count and the duration of leukopenia after chemotherapy with anti‐cancer drugs are important, a pharmacodynamic model describing the entire time course of leukopenia is valuable. In this study, a pharmacodynamic model was developed to simulate leukopenia.