Taito Esaki

Genotype-directed, dose-finding study of irinotecan in cancer patients with UGT1A1*28 and/or UGT1A1*6 polymorphisms.

Irinotecan‐induced severe neutropenia is associated with homozygosity for the UGT1A1*28 or UGT1A1*6 alleles. In this study, we determined the maximum‐tolerated dose (MTD) of irinotecan in patients with UGT1A1 polymorphisms. Patients who had received chemotherapy other than irinotecan for metastatic gastrointestinal cancer were enrolled. Patients were divided into three groups according to UGT1A1 genotypes: wild‐type (*1/*1); heterozygous (*28/*1, *6/*1); or homozygous (*28/*28, *6/*6, *28/*6). Irinotecan was given every 2 weeks for two cycles. The wild‐type group received a fixed dose of irinotecan (150 mg/m2) to serve as a reference. The MTD was guided from 75 to 150 mg/m2 by the continual reassessment method in the heterozygous and homozygous groups. Dose‐limiting toxicity (DLT) and pharmacokinetics were evaluated during cycle 1. Of 82 patients enrolled, DLT was assessable in 79 patients (wild‐type, 40; heterozygous, 20; and homozygous, 19). Dose‐limiting toxicity occurred in one patient in the wild‐type group, none in the heterozygous group, and six patients (grade 4 neutropenia) in the homozygous group. In the homozygous group, the MTD was 150 mg/m2 and the probability of DLT was 37.4%. The second cycle was delayed because of neutropenia in 56.3% of the patients given the MTD. The AUC0–24 h of SN‐38 was significantly greater (P < 0.001) and more widely distributed in the homozygous group. Patients homozygous for the UGT1A1*28 or UGT1A1*6 allele can receive irinotecan in a starting dose of 150 mg/m2, but many required dose reductions or delayed treatment in subsequent cycles. UMIN Clinical Trial Registration number: UMIN000000618. (Cancer Sci 2011; 102: 1868–1873)

Schedule-dependent reversion of acquired cisplatin resistance by 5-fluorouracil in a newly established cisplatin-resistant HST-1 human squamous carcinoma cell line

In vitro continuous stepwise exposure of HST‐I human squamous carcinoma cell line to cisplatin (CDDP) for 12 months resulted in a 3.5‐fold stably resistant subline designated HST‐I/CPO.2. Compared with parental cells, this cell line showed a 1.8‐fold increase in cellular glutathione (GSH) and a 50% reduction in initial numbers of DNA interstrand cross‐links (ICLs), despite similar levels of intracellular platinum accumulation. Evaluation of the kinetics of DNA ICL removal at nearly equivalent levels of DNA ICL formation indicated that HST‐I/CPO.2 cells appeared to remove DNA ICLs more rapidly than do HST‐I parental cells. Thus, both elevated cellular GSH and increased DNA repair capacity would be the major factors contributing to CDDP resistance. Pretreatment of HST‐I/CPO.2 cells with 5‐FU, with drug‐free intervals of 24 to 48 hr before exposure to CDDP, completely reversed CDDP resistance, or even increased the sensitivity to a level greater than that of parental cells, whereas the opposite sequence had no effect on resistance. In parallel with augmentation of the cytotoxicity, the levels of cellular GSH were significantly reduced over 48 hr by 5‐FU pretreatment. However, depletion of cellular GSH using buthionine sulfoximine resulted in partial reversal of CDDP resistance, indicating that reduction of cellular GSH alone is not sufficient for complete reversal of CDDP resistance. Our data, together with evidence that 5‐FU modulates the repair of platinum‐DNA cross‐links, suggest that schedule‐dependent, complete reversal of CDDP resistance by 5‐FU might be attributed to its inhibitory effects on both GSH levels and the repair of platinum‐DNA adducts. Thus, optimization for the drug administration schedule is important when aiming at therapeutic synergy and circumvention of acquired CDDP resistance.

Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G)

BACKGROUND FOLFIRI and FOLFOX have shown equivalent efficacy for metastatic colorectal cancer (mCRC), but their comparative effectiveness is unknown when combined with bevacizumab. PATIENTS AND METHODS WJOG4407G was a randomized, open-label, phase III trial conducted in Japan. Patients with previously untreated mCRC were randomized 1:1 to receive either FOLFIRI plus bevacizumab (FOLFIRI + Bev) or mFOLFOX6 plus bevacizumab (mFOLFOX6 + Bev), stratified by institution, adjuvant chemotherapy, and liver-limited disease. The primary end point was non-inferiority of FOLFIRI + Bev to mFOLFOX6 + Bev in progression-free survival (PFS), with an expected hazard ratio (HR) of 0.9 and non-inferiority margin of 1.25 (power 0.85, one-sided α-error 0.025). The secondary end points were response rate (RR), overall survival (OS), safety, and quality of life (QoL) during 18 months. This trial is registered to the University Hospital Medical Information Network, number UMIN000001396. RESULTS Among 402 patients enrolled from September 2008 to January 2012, 395 patients were eligible for efficacy analysis. The median PFS for FOLFIRI + Bev (n = 197) and mFOLFOX6 + Bev (n = 198) were 12.1 and 10.7 months, respectively [HR, 0.905; 95% confidence interval (CI) 0.723-1.133; P = 0.003 for non-inferiority]. The median OS for FOLFIRI + Bev and mFOLFOX6 + Bev were 31.4 and 30.1 months, respectively (HR, 0.990; 95% CI 0.785-1.249). The best overall RRs were 64% for FOLFIRI + Bev and 62% for mFOLFOX6 + Bev. The common grade 3 or higher adverse events were leukopenia (11% in FOLFIRI + Bev/5% in mFOLFOX6 + Bev), neutropenia (46%/35%), diarrhea (9%/5%), febrile neutropenia (5%/2%), peripheral neuropathy (0%/22%), and venous thromboembolism (6%/2%). The QoL assessed by FACT-C (TOI-PFC) and FACT/GOG-Ntx was favorable for FOLFIRI + Bev during 18 months. CONCLUSION FOLFIRI plus bevacizumab was non-inferior for PFS, compared with mFOLFOX6 plus bevacizumab, as the first-line systemic treatment for mCRC. CLINICAL TRIALS NUMBER UMIN000001396.

Burden on Oncologists When Communicating the Discontinuation of Anticancer Treatment

Objective Communicating the discontinuation of anticancer treatment to patients is a difficult task. The primary aim of this study was to clarify the level of oncologist-reported burden when communicating about discontinuation of an anticancer treatment. The secondary aims were (i) to identify the sources of burden contributing to their levels and (ii) to explore the useful strategies to alleviate their burden. Methods A multicenter nationwide questionnaire survey was conducted on 620 oncologists across Japan (response rate, 67%). Results High levels of perceived burden were reported by 47% of respondents, and 17% reported that they sometimes, often or always wanted to stop oncology work because of this burden. There was a significant association between high levels of burden and: a feeling that breaking bad news would deprive the patient of hope; concern that the patients family would blame the oncologist; concern that the patient may lose self-control; and a feeling that there was not enough time to break the bad news. Strategies perceived to be useful by oncologists included training in how to effectively communicate to patients discontinuation of anticancer treatment, a reduction in total workload to allow sufficient time to break bad news, and development of a multidisciplinary model to facilitate cooperation with other professionals and facilities. Conclusions Many oncologists reported high levels of burden relating to communication of discontinuation of anticancer treatment. A specific communication skills training program, sufficient time for communication and development of a multidisciplinary model could help alleviate the burden on oncologists.

Abstract LB-66: Results of two phase I multicenter trials of AZD5363, an inhibitor of AKT1, 2 and 3: Biomarker and early clinical evaluation in Western and Japanese patients with advanced solid tumors .

Background: AZD5363 is an oral, potent, and selective inhibitor of AKT1, 2 and 3, with activity in a wide range of tumor cell lines and xenografts dependent upon PI3K/AKT signaling. Methods: Two phase I studies (NCT01226316 [West], NCT01353781 [Japan]) were initiated to define the toxicity, pharmacokinetic (PK), and pharmacodynamic (PD) profile of AZD5363. Two schedules, continuous bid dosing (7/7) and an intermittent schedule bid dosing 4 days on 3 days off (4/7), were investigated. PD biomarkers of AKT signaling were assessed (using pre- and on-treatment samples) in plasma (pPRAS40, pGSK3β, pAKT, glucose, insulin), plucked hair (pPRAS40) and tumor tissue (pPRAS40, pGSK3β, pAKT). Results: At data cut-off (January 2013), 92 patients had been treated in the dose-escalation phases of both studies. In the Western study, the maximum tolerated dose (MTD) for each schedule was 320 mg bid (7/7) and 480 mg bid intermittent dosing (4/7). In the Japanese study, 320 mg bid (7/7) was not tolerated; the MTD for intermittent dosing (4/7) was 480 mg bid. The most commonly reported adverse events, of note, were hyperglycemia, rash, and diarrhea. The PK profile suggests a dose proportional increase in Cmax and AUC. Exposures achieved at doses of 320 mg bid (7/7) and 480 mg bid (4/7) and above are consistent with activity seen in xenograft models. At the doses described, target engagement was seen as evidenced by PD changes in normal tissue (>50% reduction in pPRAS40 in 7/10 patients on AZD5363 480 mg bid (4/7) in plucked hair samples and 30-50% reduction in pPRAS40 and >30% reduction in pGSK3β in platelet rich plasma). Importantly, 7/9 paired biopsies showed an increase in pAKT consistent with the non allosteric inhibition of AKT. Investigation of another intermittent schedule of AZD5363 bid, 2 days on/5 days off treatment, is ongoing. Exploratory mutation analyses of plasma samples are ongoing. Two partial responses were observed, one endometrioid cancer of the ovary and one cervical cancer, in patients on AZD5363 at 480 mg bid (4/7) and 400 mg bid (7/7), respectively. Mutation of either AKT1 or PIK3CA was identified in tumor tissue from both patients. A further patient, with endometrioid cancer of ovary (PIK3CA mutation), had stable disease (SD) for 156 days. Conclusions: AZD5363 administered at 480 mg bid (4/7) was generally well tolerated and showed a PK and PD profile consistent with activity in preclinical models. Partial responses were noted in patients with mutations driving the PI3K pathway. Footnote: AZD5363 was discovered by AstraZeneca subsequent to collaboration with Astex Therapeutics (and its collaboration with the Institute of Cancer Research and Cancer Research Technology Ltd). Citation Format: Udai Banerji, Malcolm Ranson, Jan HM Schellens, Taito Esaki, Emma Dean, Andrea Zivi, Ruud van der Noll, Paul K. Stockman, Marcelo Marotti, Michelle D. Garrett, Barry R. Davies, Paul Elvin, Andrew Hastie, Peter Lawrence, SY Amy Cheung, Christine Stephens, Kenji Tamura. Results of two phase I multicenter trials of AZD5363, an inhibitor of AKT1, 2 and 3: Biomarker and early clinical evaluation in Western and Japanese patients with advanced solid tumors . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-66. doi:10.1158/1538-7445.AM2013-LB-66

Oxaliplatin-induced allergic reaction in patients with colorectal cancer in Japan

BackgroundOxaliplatin is a platinum compound that is clinically effective for colorectal cancer (CRC), in combination with 5-fluorouracil (5-FU) and leucovorin (LV), and it is widely used for metastatic disease and for the adjuvant treatment of stage III CRC. With the increasing use of oxaliplatin in Japan, serious adverse events have been experienced other than hematologic and neurologic toxicities.MethodsIn order to clarify the clinical features of allergic reactions to oxaliplatin, we retrospectively investigated CRC patients who had received oxaliplatin-based chemotherapies.ResultsOne hundred and twenty-five CRC patients who had been treated with FOLFOX regimens (containing oxaliplatin, 5-FU, and LV) were examined, and 21 patients (17%) were found to have developed allergic reactions. Sixteen patients (13%) had grade 1/2 adverse events, classified according to the common terminology criteria for adverse events (CTC-AE) version 3.0 and 5 (4%) had grade 3/4 adverse events. The allergic reaction appeared after a median number of nine cycles (range, 2–15 cycles). Previous chemotherapy included 5-FU/LV, CPT-11, and S-1. All of the patients with allergic reactions recovered completely when treated with antiallergy drugs. Oxaliplatin was reintroduced in 11 patients, with the use of prophylactic agents; allergic reaction to the reintroduction was not observed in 8 patients and grade 1/2 allergic reactions developed in 3 patients. No correlation was identified between allergic reaction and patients’ background characteristics such as sex, history of allergy, and profile of other adverse events.ConclusionAllergic reactions to oxaliplatin remain an important issue for patients being able to safely continue effective chemotherapies; further analysis will be needed to establish methods for the prediction and prophylaxis of such reactions.

S-1 plus leucovorin versus S-1 plus leucovorin and oxaliplatin versus S-1 plus cisplatin in patients with advanced gastric cancer: a randomised, multicentre, open-label, phase 2 trial

BACKGROUND Although leucovorin enhances the efficacy of fluorouracil, the anti-tumour activity of S-1 and leucovorin and their combination with oxaliplatin for patients with advanced gastric cancer is unknown. We compared the activity and safety of S-1 plus leucovorin, S-1 plus leucovorin and oxaliplatin, and S-1 plus cisplatin as first-line chemotherapy for advanced gastric cancer. METHODS In this multicentre, randomised, open-label, phase 2 trial, we recruited chemotherapy-naive patients with unresectable or recurrent gastric cancer with measurable lesions aged 20 years or older from 25 general hospitals and specialist centres in Japan. Patients were randomly assigned (1:1:1) centrally to receive S-1 plus leucovorin (S-1 40-60 mg orally plus oral leucovorin 25 mg twice a day for 1 week, every 2 weeks), S-1 plus leucovorin and oxaliplatin (S-1 plus leucovorin and intravenous oxaliplatin 85 mg/m(2) on day 1, every 2 weeks), or S-1 plus cisplatin (S-1 40-60 mg orally twice a day for 3 weeks, plus intravenous cisplatin 60 mg/m(2) on day 8, every 5 weeks). Randomisation was done with the minimisation method using performance status (0 vs 1) and tumour stage (stage IV vs recurrent) as stratification factors. The primary endpoint was independently reviewed overall response in the full analysis set. This trial is registered with Japic CTI, number 111635. FINDINGS Between Oct 20, 2011, and Dec 17, 2012, we enrolled and randomly assigned 145 patients: 49 patients were assigned to S-1 plus leucovorin, 47 to S-1 plus leucovorin and oxaliplatin, and 49 to S-1 plus cisplatin. An objective response assessed by the independent review committee was achieved in 20 (43% [95% CI 28·3-57·8]) of the 47 patients in the S-1 plus leucovorin group, 31 (66% [50·7-79·1]) of the 47 patients in the S-1 plus leucovorin and oxaliplatin group, and 22 (46% [31·4-60·8]) of the 48 patients in the S-1 plus cisplatin group (Fishers exact test, p=0·84 for S-1 plus leucovorin vs S-1 plus cisplatin, p=0·063 for S-1 plus leucovorin and oxaliplatin vs S-1 plus cisplatin, and p=0·038 for S-1 plus leucovorin and oxaliplatin vs S-1 plus leucovorin). The most common grade 3-4 adverse events were neutropenia (three [6%] of 48 patients in the S-1 plus leucovorin group vs 12 [26%] of 47 patients in the S-1 plus leucovorin and oxaliplatin group vs 17 [35%] of 49 patients in the S-1 plus cisplatin group), decreased appetite (six [13%] vs 14 [30%] vs 12 [24%]), anaemia (five [10%] vs seven [15%] vs 13 [27%]), and hyponatraemia (two [4%] vs two [4%] vs nine [18%]). INTERPRETATION S-1 plus leucovorin and oxaliplatin was more active than S-1 plus leucovorin or S-1 plus cisplatin with acceptable toxic effects for patients with advanced gastric cancer. A phase 3 trial comparing S-1 plus leucovorin and oxaliplatin with S-1 plus cisplatin is underway. FUNDING Taiho Pharmaceutical.

A Phase II Clinical Study of mFOLFOX6 Plus Bevacizumab as First-line Therapy for Japanese Advanced/Recurrent Colorectal Cancer Patients

Objective In Japan, there had been no prospective clinical studies conducted in terms of modified FOLFOX6 + bevacizumab therapy. We performed a post-marketing Phase II multicenter clinical study to examine the efficacy and safety of this regimen as first-line therapy for Japanese patients with advanced/recurrent colorectal cancer. Methods Bevacizumab (5 mg/kg) was administered intravenously, and then oxaliplatin (85 mg/m2) and levofolinate calcium (200 mg/m2) were infused intravenously over 2 h. Subsequently, a bolus dose of 5-fluorouracil (400 mg/m2) was injected, followed by infusion of 5-fluorouracil (2400 mg/m2) for 46 h. This regimen was repeated every 2 weeks until 24 cycles unless there was disease progression, unacceptable toxicity or patient refusal. The primary end point was the response rate. Results Among the 70 patients enrolled, two patients withdrew the study before treatment, and 68 patients were eligible for analysis of efficacy and safety. The response rate was 51.5% (95% confidence interval: 39.0–63.8%). The median progression-free survival and median overall survival time were 12.6 months (95% confidence interval: 10.4–14.5 months) and 28.5 months [95% confidence interval: 23.1 months–(not applicable)], respectively. There were no treatment-related deaths observed. The most common Grade 3 and 4 adverse events included neutropenia in 35.3% of the patients, peripheral neuropathy in 16.2% and hypertension in 16.2%. All adverse events were manageable and tolerable. The exploratory analysis of polymorphisms of three genes, ERCC1, XPD and GSTP1, did not show any trends in terms of correlation with the efficacy or safety of modified FOLFOX6 + bevacizumab therapy. Conclusions Modified FOLFOX6 + bevacizumab therapy was manageable and tolerable in Japanese patients, achieving a high response rate.

Elevated antibodies to synthetic peptides of HTLV-1 envelope transmembrane glycoproteins in patients with HAM/TSP

We studied the antibody response to various kinds of well-characterized synthetic peptides of human T lymphotropic virus type 1 (HTLV-1) envelope glycoproteins in patients with HTLV-1 associated myelopathy (HAM)/tropical spastic paraparesis (TSP) and non-HAM/TSP HTLV-1 carriers. The serum antibody titers to most of the synthetic peptides were significantly higher in patients with HAM/TSP than those in non-HAM/TSP HTLV-1 carriers. However, the degree of the increase of antibody titers to the synthetic peptides corresponding to the transmembrane portions of HTLV-1 envelope glycoproteins (env-p20E), such as p20E 332-352, 374-392, 426-448 and 458-488, was greater than those to synthetic peptides of exterior portions of HTLV-1 envelope glycoproteins (env-gp46) in sera from patients with HAM/TSP. Antibodies to env-p20E 332-352 and 374-392 were elevated in the cerebrospinal fluid (CSF) only from patients with HAM/TSP but not from non-HAM/TSP HTLV-1 carriers. These data indicate that the increase of antibody titers to transmembrane portions of HTLV-1 envelope glycoproteins in sera and CSF is a characteristic feature of antibody response in patients with HAM/TSP and may be closely associated with the development of HAM/TSP from non-HAM/TSP HTLV-1 carriers.

Phase I Study to Assess the Safety, Tolerability and Pharmacokinetics of AZD4877 in Japanese Patients with Solid Tumors

Introduction AZD4877 is a potent Eg5 inhibitor that has been shown to have an acceptable tolerability profile in a Phase I study of Western patients with solid tumors. This study was conducted to evaluate the safety, pharmacokinetic (PK) profile, maximum tolerated dose (MTD) and efficacy of AZD4877 in a Japanese population with solid tumors. Methods In this Phase I, open-label, dose-escalation study, AZD4877 (10, 15, 20 or 25 mg) was administered as a 1-hour intravenous infusion on days 1, 8 and 15 of repeated 28-day cycles to Japanese patients with advanced solid tumors. Adverse events (AEs) were evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. PK variables were assessed pre- and post dosing. The MTD of AZD4877 was determined by evaluating dose-limiting toxicities (DLTs). Efficacy was evaluated by assessing best response according to Response Evaluation Criteria In Solid Tumors version 1.0. Results Of the 21 patients enrolled, 18 received at least one dose of AZD4877 (N = 3 in both the 10 and 15 mg cohorts, N = 6 in both the 20 and 25 mg cohorts). The most commonly reported AEs were fatigue and nausea (39% of patients each). One patient in each of the 20 and 25 mg cohorts experienced a DLT (neutropenia and febrile neutropenia). Dose escalation was halted at 25 mg and the MTD was not defined in this population. CTCAE grade ≥3 abnormal laboratory findings/vital signs were reported in 12 patients, with neutropenia (56%) and leukopenia (44%) being the most commonly reported. Exposure to AZD4877 was not fully dose proportional and AZD4877 clearance and elimination half-life appeared independent of dose. The best response to AZD4877 was stable disease in five of 16 evaluable patients. Conclusion AZD4877 up to doses of 25 mg was well tolerated in Japanese patients. There was little evidence of clinical efficacy.