Yasutsuna Sasaki

Leucovorin, fluorouracil, and oxaliplatin plus bevacizumab versus S-1 and oxaliplatin plus bevacizumab in patients with metastatic colorectal cancer (SOFT): an open-label, non-inferiority, randomised phase 3 trial

BACKGROUNDnStudies done in Asia have shown that a regimen of S-1 plus oxaliplatin (SOX) has promising efficacy and safety in patients with metastatic colorectal cancer. We aimed to establish whether SOX plus bevacizumab is non-inferior to mFOLFOX6 (modified regimen of leucovorin, fluorouracil, and oxaliplatin) plus bevacizumab as first-line chemotherapy for metastatic colorectal cancer.nnnMETHODSnWe undertook an open-label, non-inferiority, randomised phase 3 trial in 82 sites in Japan. We enrolled individuals aged 20-80 years who had metastatic colorectal cancer, had an Eastern Cooperative Oncology Group performance status of 0 or 1, had assessable lesions, had received no previous chemotherapy or radiotherapy, could take drugs orally, and had adequate organ function. Eligible patients were randomly assigned (1:1) to receive either mFOLFOX6 plus bevacizumab (on day 1 of each 2-week cycle, 5 mg/kg intravenous infusion of bevacizumab and a simultaneous intravenous infusion of 85 mg/m(2) oxaliplatin, 200 mg/m(2)l-leucovorin, 400 mg/m(2) bolus fluorouracil, and 2400 mg/m(2) infusional fluorouracil) or SOX plus bevacizumab (on day 1 of each 3-week cycle, 7·5 mg/kg intravenous infusion of bevacizumab and 130 mg/m(2) intravenous infusion of oxaliplatin; assigned dose of S-1 twice a day from after dinner on day 1 to after breakfast on day 15, followed by 7-day break). Randomisation was done centrally with the minimisation method, with stratification by institution and whether postoperative adjuvant chemotherapy had been given. Participants, investigators, and data analysts were not masked to treatment assignment. The primary endpoint was progression-free survival (PFS), which was defined as the interval between enrolment and progressive disease (≥20% increase in sum of longest dimensions of target lesions from baseline, or appearance of new lesions) or death, whichever came first. The primary analysis was done by modified intention to treat. This trial is registered with the Japan Pharmaceutical Information Center, number JapicCTI-090699.nnnFINDINGSnBetween Feb 1, 2009, and March 31, 2011, 512 patients underwent randomisation. 256 patients assigned to receive SOX plus bevacizumab and 255 assigned to receive mFOLFOX6 plus bevacizumab were included in the primary analysis. Median PFS was 11·5 months (95% CI 10·7-13·2) in the group assigned to mFOLFOX6 plus bevacizumab and 11·7 months (10·7-12·9) in the group assigned to SOX plus bevacizumab (HR 1·04, 95% CI 0·86-1·27; less than non-inferiority margin of 1·33, pnon-inferiority=0·014). The most common haematological adverse events of grade 3 or higher were leucopenia (21 [8%] of 249 patients given mFOLFOX6 plus bevacizumab included in safety analysis vs six [2%] of 250 given SOX plus bevacizumab; p=0·0029) and neutropenia (84 [34%] vs 22 [9%]; p<0·0001). Grade 3 or higher anorexia (13 [5%] vs three [1%]; p=0·019) and diarrhoea (23 [9%] vs seven [3%]; p=0·0040) were significantly more common in patients given SOX plus bevacizumab than in those given mFOLFOX6 plus bevacizumab. We recorded seven treatment-related deaths (three in the group given mFOLFOX6 plus bevacizumab; four in that given SOX plus bevacizumab).nnnINTERPRETATIONnSOX plus bevacizumab is non-inferior to mFOLFOX6 plus bevacizumab with respect to PFS as first-line treatment for metastatic colorectal cancer, and could become standard treatment in Asian populations.nnnFUNDINGnTaiho.

The mechanism of the difference in cellular uptake of platinum derivatives in non-small cell lung cancer cell line (PC-14) and its cisplatin-resistant subline ( PC-14 CDDP)

A cisplatin‐resistant non‐small cell lung cancer cell line, PC‐14/CDDP, was established from PC‐14 by stepwise escalation of CDDP concentrations in vitro. PC‐14/CDDP cells were 11.4‐fold more resistant to CDDP compared with PC‐14 cells. This resistant cell line was cross‐resistant to platinum analogues, such as carboplatin (CBDCA) (X 3.5), cis‐diammine(glycolate‐O, O′)platinum(II) (254‐S) (X 5.6) and cis‐dichloro(ethylenediammine)platinum(II) (cis‐DEP) (X 4.2). On the other hand, relative resistance value to ormaplatin was only 1.4‐fold. To elucidate the mechanism(s) of CDDP resistance and of its circumvention by ormaplatin, we investigated the characteristics of this cell line. Total sulfhydryl content was slightly elevated in PC‐14/CDDP cells compared with PC‐14 cells. There was no significant difference in the DNA repair ability between the two cell lines. Cellular accumulations of CDDP, CBDCA, 254‐S, and cis‐DEP in PC‐14/CDDP cells were markedly decreased to 23%, 27%, 29%, and 32% of those in PC‐14 cells, respectively. However, the accumulation of ormaplatin in PC‐14/CDDP was almost the same as that in PC‐14. To elucidate the mechanisms of uptake of these platinum analogs in the cells, we studied the effects of ouabain, an Na+, K+ ‐ATPase inhibitor, on cellular drug uptake in both cell lines. Preincubation with 300 nM ouabain for 1 h inhibited approximately 60% of CDDP accumulation in PC‐14. However ouabain preincubation at any concentration up to 300 nM did not affect CDDP accumulation in PC‐14/CDDP. The accumulation of ormaplatin was not inhibited by ouabain in either of the cell lines. These data suggest that the mechanism of the uptake of ormaplatin is different from that of CDDP, and that ormaplatin exerts a cytotoxic effect in CDDP‐resistant cells which have defective cisplatin accumulation.

Phase II trial of nanoparticle albumin-bound paclitaxel as second-line chemotherapy for unresectable or recurrent gastric cancer

This multicenter phase II study first investigated the efficacy and safety of nanoparticle albumin‐bound paclitaxel (nab‐paclitaxel) when given every 3 weeks to patients with unresectable or recurrent gastric cancer who had received a prior round of fluoropyrimidine‐containing chemotherapy. Patients with unresectable or recurrent gastric cancer who experienced progression despite fluoropyrimidine‐containing treatment were studied. Nab‐paclitaxel was given i.v. at 260 mg/m2 on day 1 of each 21‐day cycle without anti‐allergic premedication until disease progression or study discontinuation. The primary endpoint was the overall response rate. The secondary endpoints were the disease control rate, progression‐free survival, overall survival, and safety. From April 2008 to July 2010, 56 patients were enrolled, 55 patients received the study treatment, and 54 patients were evaluable for responses. According to an independent review committee, the overall response rate was 27.8% (15/54; 95% confidence interval [CI], 16.5–41.6) and the disease control rate was 59.3% (32/54; 95% CI, 45.0–72.4). One patient had a complete response. The median progression‐free survival and overall survival were 2.9 months (95% CI, 2.4–3.6) and 9.2 months (95% CI, 6.9–11.4), respectively. The most common grade 3/4 toxicities were neutropenia (49.1%), leucopenia (20.0%), lymphopenia (10.9%), and peripheral sensory neuropathy (23.6%). There were no treatment‐related deaths. Nab‐paclitaxel, given every 3 weeks, showed promising activity against previously treated unresectable or recurrent gastric cancers, with well‐tolerated toxicities. (Trial registration, ClinicalTrials.gov: NCT00661167).

Regorafenib in Japanese patients with solid tumors: phase I study of safety, efficacy, and pharmacokinetics

The safety, pharmacokinetics, and antitumor activity of the multikinase inhibitor regorafenib in Japanese patients was assessed in this multicenter, single-arm, phase I trial. Fifteen patients with treatment-refractory advanced solid tumors received regorafenib 160xa0mg once daily for the first 3xa0weeks of each 4-week cycle until disease progression, unacceptable toxicity, or investigator or patient decision to stop. The median duration of treatment was 2.1xa0months (range, 0.9–20.1xa0months). At data cutoff, one patient was still receiving regorafenib in cycle 21. Reasons for treatment discontinuation were disease progression (nu2009=u200912) and adverse events (liver enzyme elevation nu2009=u20091; anemia nu2009=u20091). Adverse events necessitated dose reduction in six patients, interruption of daily treatment in seven patients, and cycle delay in four patients. All patients experienced at least one drug-related adverse event, particularly gastrointestinal (87xa0%), dermatologic (73xa0%), or hematologic (67xa0%) events. There was no significant change in time to maximum concentration or terminal half-life of regorafenib and its active metabolites M2 and M5 between single dosing and 21-day continuous dosing. The area under the concentration–time curve was 2.1-fold higher for regorafenib, 5.2-fold higher for M2, and 37.3-fold higher for M5, and the maximum concentration was 2.0-fold, 4.8-fold, and 36.0-fold higher, respectively, after continuous dosing than after single dosing. One patient had a partial response (duration 10.5xa0months) and seven patients had stable disease. This study indicates that regorafenib 160xa0mg orally once daily (21xa0days on/7xa0days off treatment) can be given to Japanese patients who have solid tumors, without undue toxicity.

Response rate as an endpoint for evaluating new cytotoxic agents in phase II trials of non-small-cell lung cancer

BACKGROUNDnResponse rate (RR) has been used as a defining endpoint of new-agent phase II trials for non-small-cell lung cancer (NSCLC). However, tumor responses to chemotherapy do not always result in prolonged survival of patients with this disease.nnnDESIGNnSingle-agent phase II trials were identified by a MEDLINE search of the period from 1976 to 1995. Associations between RR, median survival time (MST) and characteristics of patients who entered the trial, including tumor extent, performance status and prior chemotherapy, were studied by using the logistic regression model.nnnRESULTSnA total of 183 treatment arms in 176 trials (including 10 randomized phase II trials) were identified. The overall RR in the 6768 evaluable patients was 11%. Eleven drugs, cisplatin, epirubicin, ifosfamide, edatrexate, irinotecan, vinorelbine, docetaxel, paclitaxel, etoposide, vindesine, and 254-S, produced a RR of more than 20%. An MST of eight months or longer was obtained with 12 drugs, but there were cases in which no objective responses were produced by these drugs. MST was correlated with RR (r = 0.504, P < 0.0001), but ranged broadly at a given level of RR. Multiple linear regression analysis showed a significant correlation between RR and MST (regression coefficient = 0.60, P = 0.00003) after adjustment for other variables.nnnCONCLUSIONSnRR was significantly correlated with MST in single-agent phase II trials for NSCLC, but there is room for further consideration of the endpoint of these trials.

Phase 1 study of pazopanib alone or combined with lapatinib in Japanese patients with solid tumors

AbstractPurposenA phase 1 study of pazopanib alone or in combination with lapatinib was conducted to assess the safety, tolerability, and pharmacokinetics of these oral tyrosine kinase inhibitors in Japanese patients with solid tumors.MethodsIn part A (monotherapy), 7 patients initially received pazopanib 800xa0mg/day, the recommended dose for non-Japanese patients. Then, 3 patients received pazopanib 400xa0mg/day on day 1 followed by 800xa0mg/day from day 2 onward. Three other patients received pazopanib 1,000xa0mg/day. In part B (combination therapy), 17 patients received pazopanib plus lapatinib (pazopanib/lapatinib) at once-daily doses of 400/1,000xa0mg (4 patients), 800/1,000xa0mg (3 patients), 400/1,500xa0mg (3 patients), and then 600/1,250xa0mg (7 patients).ResultsThere was no dose-limiting toxicity during the study. In part A, most drug-related adverse events were grade 2 or lower, including neutropenia/neutrophil count decreased, thrombocytopenia/platelet count decreased, diarrhea, hypertension, aspartate aminotransferase increased, and lipase increased. In part B, rash, decreased appetite, and serum thyroid-stimulating hormone increased also occurred. In all dose groups, the plasma concentrations after multiple doses of pazopanib exceeded the target trough concentration for inhibition of vascular endothelial growth factor receptor-2 activity (20xa0μg/mL).ConclusionsThe pharmacokinetic profiles of pazopanib and lapatinib in Japanese patients were not apparently different from those reported in non-Japanese patients. There were no consistent trends in pharmacokinetic drug interactions between pazopanib and lapatinib. Pazopanib monotherapy at 800 and 1,000xa0mg once daily and pazopanib plus lapatinib once daily at any doses studied were well tolerated in Japanese patients.

A phase I study of farletuzumab, a humanized anti-folate receptor α monoclonal antibody, in patients with solid tumors

SummaryFarletuzumab is a humanized monoclonal antibody against folate receptor α (FRA). The purpose of the study is to assess safety and tolerability, the pharmacokinetic (PK) profile, and preliminary antitumor effect. Patients with ovarian cancer (OC) or FRA-expressing solid tumors who are resistant to standard treatments were eligible for the study. After single-dose administration for PK assessment, farletuzumab was administered by intravenous injection, repeating every week until disease progression. Dose-limiting toxicities (DLTs) were defined as grade 4 hematological and grade 3/4 nonhematological toxicities. Dose escalation was planned in 4 cohorts (50, 100, 200, and 400xa0mg/m2). Fourteen patients with OC and two patients with gastric cancer (GC) received farletuzumab infusion. Neither DLTs nor grade 3/4 toxicities were reported in all cohorts. Major adverse events, including grade 1/2 infusion related reaction (15 patients, 93.8xa0%), headache (seven patients, 43.8xa0%), and nausea and decreased appetite (five patients each, 31.3xa0%), were observed and medically managed. AUC and Cmax increased dose-dependently and linear PK profiles were observed. No tumor shrinkage was recorded, but long-term disease stabilization for 25 and 20xa0months was observed in one patient with clear cell OC (100xa0mg/m2) and one patient with GC (400xa0mg/m2), respectively. No cumulative toxicity occurred in any patient. Farletuzumab was well tolerated in Japanese patients with a similar PK profile as compared with the US population. Long-term disease stabilization was observed in a subpopulation of clear cell OC and GC; both of them were resistant and progressive after standard chemotherapies (ClinicalTrials.gov Identifier: NCT01049061).

Nab-paclitaxel versus solvent-based paclitaxel in patients with previously treated advanced gastric cancer (ABSOLUTE): an open-label, randomised, non-inferiority, phase 3 trial

BACKGROUNDnWeekly administration of solvent-based paclitaxel is one of the standard second-line chemotherapy regimens for advanced gastric cancer. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) was developed to improve the solubility of paclitaxel and does not need premedication to avoid infusion-related reactions associated with solvent-based paclitaxel. Additionally, higher doses of nab-paclitaxel can be administered over a shorter infusion time and at higher drug concentrations compared with solvent-based paclitaxel. We aimed to investigate the efficacy and safety of nab-paclitaxel versus solvent-based paclitaxel in patients with previously treated advanced gastric cancer.nnnMETHODSnWe did a randomised, open-label, non-inferiority, phase 3 trial at 72 institutions in Japan. Patients aged 20 years or older with advanced gastric adenocarcinoma refractory to a fluoropyrimidine-containing first-line chemotherapy regimen, with progressive disease or a relapse fewer than 24 weeks after the final dose of adjuvant chemotherapy were randomly assigned (1:1:1) to receive intravenous nab-paclitaxel (260 mg/m2) every 3 weeks (on day 1 of a 21-day cycle), weekly nab-paclitaxel (100 mg/m2, on days 1, 8, and 15 of a 28-day cycle), or weekly solvent-based paclitaxel (80 mg/m2, on days 1, 8, and 15 of a 28-day cycle). Randomisation was done with the minimisation method, with stratification for previous use of docetaxel, presence of peritoneal metastases, and Eastern Cooperative Oncology Group (ECOG) performance status. The primary endpoint was overall survival in the full analysis set, which included all randomly assigned patients who received at least one dose of study drug, with a non-inferiority margin of 1·25 for the hazard ratio. This trial is registered with Japan Pharmaceutical Information Center Clinical Trial, number JapicCTI-132059, and has been completed.nnnFINDINGSnBetween March 13, 2013, and May 14, 2015, 741 patients were randomly assigned to nab-paclitaxel every 3 weeks (n=247), weekly nab-paclitaxel (n=246), or weekly solvent-based paclitaxel (n=248). Median follow-up for overall survival was 9·99 months (IQR 6·05-15·05). Median overall survival was 10·3 months (95% CI 8·7-11·4) in the group that received in the nab-paclitaxel every 3 weeks, 11·1 months (9·9-13·0) in the weekly nab-paclitaxel group, and 10·9 months (9·4-11·8) in the weekly solvent-based paclitaxel group. Weekly nab-paclitaxel was non-inferior to weekly solvent-based paclitaxel (hazard ratio 0·97, 97·5% CI 0·76-1·23; non-inferiority one-sided p=0·0085), whereas nab-paclitaxel every 3 weeks was not non-inferior to solvent-based paclitaxel (1·06, 95% CI 0·87-1·31; non-inferiority one-sided p=0·062). The main grade 3 or worse adverse drug reactions were neutropenia (158 [65%] of 244 patients in the group that received nab-paclitaxel every 3 weeks vs 99 [41%] of 241 patients in the weekly nab-paclitaxel group vs 71 [29%] of 243 patients in the weekly solvent-based paclitaxel group), peripheral sensory neuropathy (49 [20%] vs six [2%] vs six [2%]), and febrile neutropenia (30 [12%] vs seven [3%] vs two [1%]). Hypersensitivity reactions were less frequent with nab-paclitaxel every 3 weeks (two [1%] patients) and weekly nab-paclitaxel (three [1%] patients) than with weekly solvent-based paclitaxel (13 [5%] patients). Four treatment-related deaths were reported overall (pneumonia in one patient in the group that received nab-paclitaxel every 3 weeks, febrile neutropenia/pneumonia in one patient, and septic shock in one patient in the weekly nab-paclitaxel group, and respiratory disease/interstitial lung disease in one patient in the weekly solvent-based paclitaxel group).nnnINTERPRETATIONnAs the trial showed that weekly nab-paclitaxel was non-inferior to weekly solvent-based paclitaxel in terms of overall survival, the advantages of the nab-paclitaxel formulation make it a potential regimen for second-line treatment of gastric cancer.nnnFUNDINGnTaiho Pharmaceutical.

Increased Plasma Concentrations of Unbound SN-38, the Active Metabolite of Irinotecan, in Cancer Patients with Severe Renal Failure

PurposeDelayed plasma concentration profiles of the active irinotecan metabolite SN-38 were observed in cancer patients with severe renal failure (SRF), even though SN-38 is eliminated mainly via the liver. Here, we examined the plasma concentrations of unbound SN-38 in such patients.MethodsPlasma unbound concentrations were examined by ultrafiltration. Physiologically-based pharmacokinetic (PBPK) models of irinotecan and SN-38 were established to quantitatively assess the principal mechanism for delayed SN-38 elimination.ResultsThe area under the plasma unbound concentration-time curve (AUCu) of SN-38 in SRF patients was 4.38-fold higher than that in normal kidney patients. The unbound fraction of SN-38 was also 2.6-fold higher in such patients, partly because SN-38 protein binding was displaced by the uremic toxin 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF). This result was supported by correlation of the unbound fraction of SN-38 with the plasma CMPF concentration, which negatively correlated with renal function. PBPK modeling indicated substantially reduced influx of SN-38 into hepatocytes and approximately one-third irinotecan dose for SRF patients to produce an unbound concentration profile of SN-38 similar to normal kidney patients.ConclusionThe AUCu of SN-38 in SRF cancer patients is much greater than that of normal kidney patients primarily because of the reduced hepatic uptake of SN-38.

Patritumab plus trastuzumab and paclitaxel in human epidermal growth factor receptor 2-overexpressing metastatic breast cancer.

Human epidermal growth factor receptor 3 (HER3) expression in lung and breast cancers has a negative impact on survival. Patritumab, a human anti‐HER3 mAb, has shown anticancer activity in preclinical models. This study examined the safety and pharmacokinetics of patritumab in combination with trastuzumab and paclitaxel in patients with HER2‐overexpressing metastatic breast cancer. In this open‐label, multicenter, dose‐escalation, phase Ib study, patients received patritumab 9 or 18 mg/kg plus trastuzumab and paclitaxel at known tolerated doses. Safety and tolerability were assessed based on dose‐limiting toxicities and other non‐life threatening adverse events. The pharmacokinetic profile for patritumab was determined based on the target trough level. Clinical efficacy was evaluated based on the overall response rate and progression‐free survival. Six patients received patritumab 9 mg/kg and 12 received 18 mg/kg. The most common adverse events were diarrhea, alopecia, leukopenia, neutropenia, and maculopapular rash. No dose‐limiting toxicities were observed. The target trough serum concentration was achieved in all patients at a dose of 18 mg/kg. Overall response rate was 38.9% and median progression‐free survival was 274 days. In conclusion, patritumab plus trastuzumab and paclitaxel was tolerable and efficacious at both doses. We recommend the dose level of 18 mg/kg for future phase II studies. (Clinical trial registration: JapicCTI‐121772.)