Nozomu Fuse

Phase III study comparing oxaliplatin plus S-1 with cisplatin plus S-1 in chemotherapy-naïve patients with advanced gastric cancer

BACKGROUND We evaluated the efficacy and safety of S-1 plus oxaliplatin (SOX) as an alternative to cisplatin plus S-1 (CS) in first-line chemotherapy for advanced gastric cancer (AGC). PATIENTS AND METHODS In this randomized, open-label, multicenter phase III study, patients were randomly assigned to receive SOX (80-120mg/day S-1 for 2 weeks with 100mg/m2 oxaliplatin on day 1, every 3 weeks) or CS (S-1 for 3 weeks with 60mg/m2 cisplatin on day 8, every 5 weeks). The primary end points were noninferiority in progression-free survival (PFS) and relative efficacy in overall survival (OS) for SOX using adjusted hazard ratios (HRs) with stratification factors; performance status and unresectable or recurrent (+adjuvant chemotherapy) disease. RESULTS Overall, 685 patients were randomized from January 2010 to October 2011. In per-protocol population, SOX (n = 318) was noninferior to CS (n = 324) in PFS [median, 5.5 versus 5.4 months; HR 1.004, 95% confidence interval (CI) 0.840-1.199; predefined noninferiority margin 1.30]. The median OS for SOX and CS were 14.1 and 13.1 months, respectively (HR 0.958 with 95% CI 0.803-1.142). In the intention-to-treat population (SOX, n = 339; CS, n = 337), the HRs in PFS and OS were 0.979 (95% CI 0.821-1.167) and 0.934 (95% CI 0.786-1.108), respectively. The most common ≥grade 3 adverse events (SOX versus CS) were neutropenia (19.5% versus 41.8%), anemia (15.1% versus 32.5%), hyponatremia (4.4% versus 13.4%), febrile neutropenia (0.9% versus 6.9%), and sensory neuropathy (4.7% versus 0%). CONCLUSION SOX is as effective as CS for AGC with favorable safety profile, therefore SOX can replace CS. CLINICAL TRIAL NUMBER JapicCTI-101021.BACKGROUND We evaluated the efficacy and safety of S-1 plus oxaliplatin (SOX) as an alternative to cisplatin plus S-1 (CS) in first-line chemotherapy for advanced gastric cancer (AGC). PATIENTS AND METHODS In this randomized, open-label, multicenter phase III study, patients were randomly assigned to receive SOX (80-120 mg/day S-1 for 2 weeks with 100 mg/m(2) oxaliplatin on day 1, every 3 weeks) or CS (S-1 for 3 weeks with 60 mg/m(2) cisplatin on day 8, every 5 weeks). The primary end points were noninferiority in progression-free survival (PFS) and relative efficacy in overall survival (OS) for SOX using adjusted hazard ratios (HRs) with stratification factors; performance status and unresectable or recurrent (+adjuvant chemotherapy) disease. RESULTS Overall, 685 patients were randomized from January 2010 to October 2011. In per-protocol population, SOX (n = 318) was noninferior to CS (n = 324) in PFS [median, 5.5 versus 5.4 months; HR 1.004, 95% confidence interval (CI) 0.840-1.199; predefined noninferiority margin 1.30]. The median OS for SOX and CS were 14.1 and 13.1 months, respectively (HR 0.958 with 95% CI 0.803-1.142). In the intention-to-treat population (SOX, n = 339; CS, n = 337), the HRs in PFS and OS were 0.979 (95% CI 0.821-1.167) and 0.934 (95% CI 0.786-1.108), respectively. The most common ≥grade 3 adverse events (SOX versus CS) were neutropenia (19.5% versus 41.8%), anemia (15.1% versus 32.5%), hyponatremia (4.4% versus 13.4%), febrile neutropenia (0.9% versus 6.9%), and sensory neuropathy (4.7% versus 0%). CONCLUSION SOX is as effective as CS for AGC with favorable safety profile, therefore SOX can replace CS. CLINICAL TRIAL NUMBER JapicCTI-101021.

Phase I Study of NK012, a Novel SN-38–Incorporating Micellar Nanoparticle, in Adult Patients with Solid Tumors

Purpose: We conducted a first-in-human phase I study to determine the dose-limiting toxicity (DLT), evaluate the pharmacokinetic profile, and document any antitumor activity of NK012, a novel SN-38–incorporating micellar nanoparticle. Experimental Design: Patients with solid tumors refractory to standard therapy, or for which no standard therapy is available, were enrolled. NK012 was administered as a 30-minute infusion every 3 weeks. The starting dose was 2 mg/m2 as SN-38 equivalent, and an accelerated titration schedule was used. Pharmacokinetic analysis was conducted in cycles 1 and 2. Results: Twenty-four patients were enrolled in the study. No UGT1A1*28 homozygous patients were enrolled. Predominant toxicity was neutropenia. Nonhematologic toxicity, especially diarrhea, was mostly grade 1 or 2 during study treatments. Two of nine patients had DLT during cycle 1 at the 28 mg/m2 dose level. DLTs were mostly neutropenia or a related event. Polymer-bound SN-38 (NK012) and SN-38 released from NK012 were slowly eliminated from the plasma, with a terminal-phase half-life of approximately 140 and 210 hours, respectively. Systemic exposure to both polymer-bound SN-38 and SN-38 increased in proportion to the dose. A refractory esophageal cancer patient and a lung carcinoid tumor patient had an objective response and continued the study treatment for 5 and 12 months, respectively. Conclusions: NK012 was well tolerated and showed antitumor activity including partial responses and several occurrences of prolonged stable disease across a variety of advanced refractory cancers. Phase II studies are ongoing. Clin Cancer Res; 16(20); 5058–66. ©2010 AACR.

Role of chemotherapy for advanced/recurrent gastric cancer: An individual-patient-data meta-analysis

We conducted an individual-patient-data meta-analysis of the efficacy of chemotherapy on overall survival (OS) and progression-free survival (PFS) in advanced/recurrent gastric cancer (AGC). Our primary research question was whether the experimental arms of the trials included in the meta-analysis showed a benefit as compared with their corresponding control arms. MEDLINE (up to 2010), Cochrane Central Register of Controlled Trials, National Institutes of Health (NIH) trial registry and proceedings of major oncologic and gastrointestinal cancer meetings were searched. Randomised controlled trials for AGC closed to patient accrual before the end of 2006 were eligible. As of December 2010, individual patient data were available from 22 trials (4245 patients, representing 47% of the targeted data) of 55 eligible trials. The overall comparison of experimental arms with the corresponding control arms showed statistically significant differences in terms of both OS and PFS. Hazard ratio was 0.88 (95% confidence interval 0.82-0.94, P<0.0001) for OS and 0.81 (0.76-0.88, P<0.0001) for PFS. The results of the sub-analysis of adding a given chemotherapeutic agent to any chemotherapy confirm the results of the overall analysis, with a hazard reduction of 11% for OS (P<0.01) and 26% for PFS (P<0.0001). This meta-analysis of individual patient data shows that the additions of experimental chemotherapeutic agents to pre-existing control or standard regimens have produced a modest improvement in OS and PFS. Median survival remained below 1 year for all investigated chemotherapy regimens and none emerged as a clear standard.

Phase II study of oxaliplatin plus S-1 as first-line treatment for advanced gastric cancer (G-SOX study)

BACKGROUND The efficacy and safety of oxaliplatin combined with S-1 (SOX regimen) for unresectable advanced or recurrent gastric cancer were investigated. PATIENTS AND METHODS Oxaliplatin was administered i.v. (100 mg/m(2)) on day 1, while S-1 was administered orally (80 mg/m(2)/day, b.i.d.) for 14 days followed by a 7-day rest. This schedule was repeated every 3 weeks. RESULTS Among 55 patients enrolled, one patient received oxaliplatin for the other study, and three patients were considered unsuitable against the inclusion criteria. Accordingly, 51 patients were assessable for efficacy. The response rate was 59%, and the disease control rate was 84%. The median progression-free survival time was 6.5 months, the 1-year survival rate was 71%, and the median survival time was 16.5 months. In 54 patients assessed for safety, the major grade 3/4 toxic effects were neutropenia (22%), thrombocytopenia (13%), anemia (9%), anorexia (6%), fatigue (6%), and sensory neuropathy (4%). CONCLUSION These findings indicate that SOX regimen with oxaliplatin at a dose of 100 mg/m(2) is feasible and shows promising efficacy against advanced gastric cancer.

Progression-Free Survival as a Surrogate for Overall Survival in Advanced/Recurrent Gastric Cancer Trials: A Meta-Analysis

The traditional endpoint for assessing efficacy of chemotherapies for advanced/recurrent gastric cancer is overall survival (OS), but OS requires prolonged follow-up. We investigated whether progression-free survival (PFS) is a valid surrogate for OS. Using individual patient data from the GASTRIC meta-analysis, surrogacy of PFS was assessed through the correlation between the endpoints and through the correlation between the treatment effects on the endpoints. External validation of the prediction based on PFS was also evaluated. Individual data from 4069 patients in 20 randomized trials were analyzed. The rank correlation coefficient between PFS and OS was 0.853 (95% confidence interval [CI] = 0.852 to 0.854). The R (2) between treatment effects on PFS and on OS was 0.61 (95% CI = 0.04 to 1.00). Treatment effects on PFS and on OS were only moderately correlated, and we could not confirm the validity of PFS as a surrogate endpoint for OS in advanced/recurrent gastric cancer.

KRAS mutations detected by the amplification refractory mutation system–Scorpion assays strongly correlate with therapeutic effect of cetuximab

Background:We aimed to compare the sensitive and quality-controlled KRAS testing with direct sequencing and to assess the impact on decision making of treatment.Patients and methods:We analysed genomic DNA isolated from macrodissected formalin-fixed paraffin-embedded specimens by direct sequencing and an amplification refractory mutation system–Scorpion assay (ARMS/S) method. Cetuximab was administered to patients identified as having wild-type (WT) KRAS using direct sequencing. Therapeutic effects were evaluated according to their KRAS status as determined by ARMS/S.Results:Among the 159 patients, the overall mutation rate was determined to be 37.0% by direct sequencing and 44.0% by ARMS/S. For the patients diagnosed as WT by direct sequencing and treated with cetuximab (n=47), a response rate of 16.0% was observed for 38 ARMS/S WT patients, whereas 9 ARMS/S mutant (MUT) patients failed to respond. The ARMS/S WT patients showed significant improvement in progression-free survival (PFS) and overall survival (OS) compared with ARMS/S MUT patients (PFS median 5.0 vs 1.7 months, hazards ratio (HR)=0.29, P=0.001; OS median 12.1 vs 3.8 months, HR=0.26, P=0.001).Conclusion:Sensitive and quality-controlled KRAS testing may provide improved predictive power to determine the efficacy of anti-epidermal growth factor antibodies.

Photodynamic therapy as salvage treatment for local failure after chemoradiotherapy in patients with esophageal squamous cell carcinoma: a phase II study.

Local failure at the primary site is a major problem after chemoradiotherapy (CRT) in patients with esophageal squamous cell carcinoma (ESCC). Salvage surgery is the only treatment option with curative intent, but it is associated with high morbidity and mortality. The aim of this study was to evaluate the efficacy and safety of salvage photodynamic therapy (PDT) after CRT. Patients with histologically proven local failure limited to the submucosal layer, and without any metastasis after definitive CRT (≥50 Gy) for ESCC were enrolled in the study. PDT began with intravenous administration of 2 mg/kg of porfimer sodium followed 48–72 hr later by excimer dye laser irradiation with a fluence of 75 J/cm2. The primary endpoint was a complete response (CR) to treatment with PDT, and the secondary endpoints were toxicity related to PDT, progression‐free survival (PFS) and overall survival (OS). Twenty‐five patients were enrolled in the study. A CR was attained in 19 of 25 patients treated with PDT (CR rate, 76%; 95% CI, 55–91%). One treatment‐related death (4%) caused by gastrointestinal hemorrhage at the irradiated site occurred 33 days after PDT. No adverse events greater than grade 3 were related to PDT in the other patients. After a median follow‐up of 48 months after PDT, the PFS and OS at 3 years were 40% (95% CI, 21–59%) and 38% (95% CI, 17–60%), respectively. PDT is a potentially curative and tolerable salvage treatment after CRT for carefully selected patients with local failure without any metastasis.

Phase I first-in-human study of TAK-285, a novel investigational dual HER2/EGFR inhibitor, in cancer patients

Background:This phase I first-in-human study was conducted in Japanese patients to investigate the safety, pharmacokinetics (PKs), and determine the maximum tolerated dose (MTD) of oral TAK-285, a novel dual erbB protein kinase inhibitor that specifically targets human epidermal growth factor receptor (EGFR) and HER2.Methods:The TAK-285 dose was escalated until MTD was determined. A second patient cohort received TAK-285 at the MTD for at least 4 weeks.Results:In all, 26 patients received TAK-285 at doses ranging from 50 to 400 mg once daily (q.d.) or twice daily (b.i.d.); 20 patients made up the dose escalation cohort and the remaining 6 patients were the repeated administration cohort. TAK-285 was well tolerated. Dose-limiting toxicities noted in two patients who received 400 mg b.i.d. were grade 3 increases in aminotransferases and grade 3 decreased appetite. Consequently, the MTD was determined to be 300 mg b.i.d. Absorption of TAK-285 was rapid after oral dosing, and plasma exposure at steady-state increased in a dose-proportional fashion for doses ranging from 50 to 300 mg b.i.d. A partial response was observed for one patient with parotid cancer who received 300 mg b.i.d.Conclusion:The toxicity profile and PK properties of oral TAK-285 warrant further evaluation.

Clinical features of interstitial lung disease induced by standard chemotherapy (FOLFOX or FOLFIRI) for colorectal cancer

BACKGROUND Chemotherapy-induced interstitial lung disease (ILD) in colorectal cancer (CRC) patients is rarely reported, but its clinical features remain to be clarified. PATIENTS AND METHODS Using a computerized database, we retrospectively identified patients who developed ILD from 734 patients with CRC treated with infusional 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX) or infusional 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) from April 2005 to December 2008 at the National Cancer Center Hospital East. RESULTS Of 734 patients, 11 patients developed ILD (1.5%) and 4 of those patients died (0.54%). Of the 11 patients, 10 showed pulmonary shadows other than lung metastases before chemotherapy. ILD developed during FOLFOX in six patients, at 137 days after completion of FOLFOX in one patient, during oxaliplatin interruption of FOLFOX in one patient and during FOLFIRI in the remaining three patients. FOLFOX had been administered at some point for all ILD patients, with a median of 10 cycles (range 2-17 cycles) and a median dose of administered oxaliplatin of 850 mg/m(2) (range 170-1445 mg/m(2)). CONCLUSIONS ILD following FOLFOX or FOLFIRI is an uncommon but life-threatening complication. Care must be taken regarding the onset of ILD, not only during but also after chemotherapy for CRC.

KRAS mutations in primary tumours and post-FOLFOX metastatic lesions in cases of colorectal cancer

Background:KRAS mutations are predictive markers for the efficacy of anti-EGFR antibody therapies in patients with metastatic colorectal cancer. Although the mutational status of KRAS is reportedly highly concordant between primary and metastatic lesions, it is not yet clear whether genotoxic chemotherapies might induce additional mutations.Methods:A total of 63 lesions (23 baseline primary, 18 metastatic and 24 post-treatment metastatic) from 21 patients who were treated with FOLFOX as adjuvant therapy for stage III/IV colorectal cancer following curative resection were examined. The DNA samples were obtained from formalin-fixed paraffin-embedded specimens, and KRAS, NRAS, BRAF and PIK3CA mutations were evaluated.Results:The numbers of primary lesions with wild-type and mutant KRAS codons 12 and 13 were 8 and 13, respectively. The mutational status of KRAS remained concordant between the primary tumours and the post-FOLFOX metastatic lesions, irrespective of patient background, treatment duration and disease-free survival. Furthermore, the mutational statuses of the other genes evaluated were also concordant between the primary and metastatic lesions.Conclusion:Because the mutational statuses of predictive biomarker genes were not altered by FOLFOX therapy, specimens from both primary tumours and post-FOLFOX tumour metastases might serve as valid sources of DNA for known genomic biomarker testing.