A multi-national, randomised, open-label, parallel, phase III non-inferiority study comparing NK105 and paclitaxel in metastatic or recurrent breast cancer patients.

BACKGROUND: NK105 is a novel nanoparticle drug delivery formulation that encapsulates paclitaxel (PTX) in polymeric micelles. We conducted an open-label phase III non-inferiority trial to compare the efficacy and safety of NK105 and PTX in metastatic or recurrent breast cancer. METHODS: Patients were randomly assigned in a 1:1 ratio to receive either NK105 (65 mg/m2) or PTX (80 mg/m2) on days 1, 8 and 15 of a 28-day cycle. The primary endpoint was progression-free survival (PFS), with a non-inferiority margin of 1.215. RESULTS: A total of 436 patients were randomised and 211 patients in each group were included in the efficacy analysis. The median PFS was 8.4 and 8.5 months for NK105 and PTX, respectively (adjusted hazard ratio: 1.255; 95% confidence interval: 0.989-1.592). The median overall survival and overall response rates were 31.2 vs. 36.2 months and 31.6% vs. 39.0%, respectively. The two groups exhibited similar safety profiles. The incidence of peripheral sensory neuropathy (PSN) was 1.4% vs. 7.5% (≥Grade 3) for NK105 and PTX, respectively. The patient-reported outcomes of PSN were significantly favourable for NK105 (P < 0.0001). CONCLUSIONS: The primary endpoint was not met, but NK105 had a better PSN toxicity profile than PTX. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT01644890.

Safety and efficacy of CT-P13 in Japanese patients with rheumatoid arthritis in an extension phase or after switching from infliximab.

OBJECTIVES: This study aimed to evaluate the safety of CT-P13 in patients with rheumatoid arthritis (RA) during long-term treatment or after switching from innovator infliximab (IFX). METHODS: Patients who completed 54 weeks of treatment in a phase I/II study (PI/II) received CT-P13 at an initial dose of 3 mg/kg at Week 62, with dose increases permitted up to 10 mg/kg. The primary endpoint was adverse event (AE) incidence. RESULTS: Thirty-four of 38 patients in the maintenance group and 29 of 33 in the switch group reported at least one AE. Safety profiles in both groups were similar to those in PI/II. Eleven of 28 patients who were positive for anti-drug antibodies (ADA) at Week 62 discontinued the study before Week 110. Forty-one of 43 ADA-negative patients remained negative, and 10 of 28 ADA-positive patients became negative during the study. The mean DAS28 (ESR) at Week 134 was 3.166 in the maintenance group and 3.955 in the switch group. CONCLUSIONS: CT-P13 was well tolerated in patients who maintained the treatment after 54 weeks and in patients who switched to CT-P13 after 54 weeks of IFX treatment. The study also demonstrated a stable clinical efficacy of CT-P13 in RA patients.

Phase I study of NK105, a nanomicellar paclitaxel formulation, administered on a weekly schedule in patients with solid tumors.

Previous studies have established the rationale for NK105, a nanomicellar formulation of paclitaxel, administered every 3 weeks. The aim of this phase I study was to determine the recommended dose and pharmacokinetics of weekly administered NK105. NK105 was administered by a 30-min infusion once weekly for three consecutive weeks in each 4-week cycle. In the dose-escalation phase, three to seven patients with solid tumors were enrolled to each of the four dose levels (50-100 mg/m2; n = 16). At a dose level of 100 mg/m2, predefined dose-limiting toxicity (DLT) manifested in only one out of six evaluable patients, whereas a dose delay due to neutropenia during the first course occurred two patients. None of the three patients given 80 mg/m2 had a dose reduction, while a dose delay occurred in two. NK105 exhibited linear pharmacokinetics at doses of 50-100 mg/m2, and approximately 5 % of total paclitaxel was released from micelles. Thus, the recommended dose was set at 80 mg/m2, and an additional 10 advanced breast cancer (ABC) patients were given this dose in the dose-expansion phase. DLT manifested in two patients, and grade ≥ 3 neutropenia was found in eight patients. Among the nine patients who completed the first cycle, four had a dose reduction, mostly because of neutropenia. Of the 10 patients, six achieved partial response (PR), and four achieved stable disease (SD) status. Overall, weekly NK105 was well tolerated and had a desirable antitumor activity profile. Further investigations of NK105 in ABC patients are currently underway.

Feasibility study on combination chemotherapy using nogitecan hydrochloride (topotecan) and cisplatin for patients with metastatic, persistent, or recurrent uterine cervical cancer.

BACKGROUND: The standard chemotherapeutic regimen for stage IVB, persistent, or recurrent uterine cervical cancer is platinum-based combination chemotherapy such as cisplatin (CDDP)/paclitaxel and CDDP/nogitecan hydrochloride (NGT, topotecan). Because it is unclear whether the CDDP/NGT combination chemotherapy is tolerable for Japanese patients, we conducted the present study to assess the feasibility of CDDP/NGT combination chemotherapy. METHODS: Between June 2012 and April 2014, 15 patients with stage IVB, persistent, or recurrent uterine cervical cancer were enrolled in this study. Patients underwent six cycles of NGT at a dose of 0.75 mg/m2, followed immediately by CDDP at a dose of 50 mg/m2 on day 1 by intravenous infusion, and then NGT at a dose of 0.75 mg/m2 on days 2 and 3. RESULTS: Of 15 patients, 9 patients underwent at least 6 cycles of NGT/CDDP combination chemotherapy. Of a total of 83 cycles, 70 cycles (84.3 %) of NGT/CDDP combination chemotherapy could be continued at the starting dose of NGT (0.75 mg/m2). Grade 3/4 hematological toxicities included leukopenia in 10 patients (66.7 %), neutropenia in 15 (100 %), anemia in 6 (40.0 %), thrombocytopenia in 4 (26.7 %), and febrile neutropenia in 4 (26.7 %). The response rate according to RECIST was 27 % (3/11), with partial response in 3 patients. CONCLUSIONS: NGT/CDDP combination chemotherapy may be a tolerable and effective regimen for Japanese patients with stage IVB, persistent, or recurrent uterine cervical cancer. Based on the results of this study, NGT/CDDP combination chemotherapy was approved in Japan in November 2015.

A phase I dose escalation study of NK012, an SN-38 incorporating macromolecular polymeric micelle.

PURPOSE: This study evaluated the safety, tolerability, pharmacokinetics, and maximum tolerated dose (MTD) and recommended phase II dose (RD) of NK012, a macromolecular polymeric micelle formulation of SN-38 (the active metabolite of irinotecan). PATIENTS AND METHODS: Patients with previously treated advanced solid tumors and acceptable organ function were administered NK012 as a 30-min infusion every 21 or 28 days without premedications. Patients were screened for UGT1A1 *28 polymorphism prior to enrollment. Patients homozygous for UGT1A1*28 allele (*28/*28 genotype patients) were treated at a reduced dose level with the potential for dose escalation based on toxicities. Pharmacokinetic samples were obtained during cycles 1 and 2. RESULTS: Thirty-nine patients were enrolled, and thirty-eight patients were treated with NK012. NK012 was escalated from 9 to 37 mg/m(2) in patients with UGT1A1*28 allele genotype of wt/wt and wt/*28. The MTD/RD of a Q21D regimen was determined to be 28 mg/m(2) where the dose-limiting toxicity is myelosuppression, which appears to be cumulative and limits timely subsequent dosing. Based on delayed neutrophil recovery, the NK012 dose of 28 mg/m(2) administered on an every 28 days schedule was confirmed as the RD. Gastrointestinal toxicities were mild, with no grade 3 diarrhea reported. The T1/2z value of polymer-unbound SN-38 was significantly prolonged compared to that of SN-38 metabolized from CPT-11, indicating a sustained high systemic SN-38 concentration. Six patients had confirmed partial responses. Eighteen additional patients had stable disease as their best response to treatment. CONCLUSIONS: The recommended phase II dose of NK012 for UGT1A1 wt/wt and wt/*28 genotype patients is 28 mg/m(2) every 28 days. Additional clinical development as a single agent in specific patient populations or in combination with other chemotherapy agents is warranted.

Transarterial embolization of hypervascular tumors using trisacryl gelatin microspheres (Embosphere): a prospective multicenter clinical trial in Japan.

PURPOSE: To evaluate the feasibility and safety of transarterial embolization (TAE) using trisacryl gelatin microspheres (TGMs) for hypervascular tumors. MATERIALS AND METHODS: This was a prospective multicenter clinical trial involving five institutions. TAE using TGMs was performed for hypervascular tumors in various locations. The primary endpoint was the technical success. The secondary endpoints included catheter accessibility, preservation of the feeding arteries, local tumor response based on the Response Evaluation Criteria in Cancer of the Liver (RECICL) and adverse events related to TAE based on the Common Terminology Criteria for Adverse Events, version 4.0. RESULTS: Twenty-three patients with liver tumors (n = 9), uterine fibroids (n = 3) and other tumors (n = 11) were enrolled. The technical success rate was 95.7 % (22 of 23 patients). Catheter accessibility and preservation of the feeding arteries were obtained in all 55 target vessels (100 %). Local tumor response rates were 46.7 and 55.8 % at 4 and 12 weeks, respectively. Eighteen (78.3 %) patients developed 53 symptomatic events including grade ≧3 events: hypertension 21.7 %, pain 8.7 %, vomiting 4.3 % and anorexia 4.3 %, all related to postembolization syndromes. CONCLUSION: TAE using TGMs was technically feasible and safe for devascularization of hypervascular tumors.

Quantum key distribution over 120 km using ultrahigh purity single-photon source and superconducting single-photon detectors.

Advances in single-photon sources (SPSs) and single-photon detectors (SPDs) promise unique applications in the field of quantum information technology. In this paper, we report long-distance quantum key distribution (QKD) by using state-of-the-art devices: a quantum-dot SPS (QD SPS) emitting a photon in the telecom band of 1.5 µm and a superconducting nanowire SPD (SNSPD). At the distance of 100 km, we obtained the maximal secure key rate of 27.6 bps without using decoy states, which is at least threefold larger than the rate obtained in the previously reported 50-km-long QKD experiment. We also succeeded in transmitting secure keys at the rate of 0.307 bps over 120 km. This is the longest QKD distance yet reported by using known true SPSs. The ultralow multiphoton emissions of our SPS and ultralow dark count of the SNSPD contributed to this result. The experimental results demonstrate the potential applicability of QD SPSs to practical telecom QKD networks.

Transcatheter arterial embolization of hypervascular tumors with HepaSphere: prospective multicenter open label clinical trial of microspheres in Japan.

PURPOSE: To evaluate the feasibility and safety of transcatheter arterial embolization (TAE) with the use of HepaSphere microspheres for hypervascular tumors. MATERIALS AND METHODS: This was a prospective multicenter open label clinical trial involving six institutions in Japan. TAE was performed with the HepaSphere microspheres for hypervascular tumors in various locations. The endpoint of the study was the feasibility and safety of the procedure. The feasibility and safety were evaluated according to technical success and adverse events, respectively. Adverse events that were related to TAE were evaluated by using the Common Terminology Criteria for Adverse Events, version 4.0. RESULTS: Twenty-four patients were enrolled. The technical success rate was 100 % (24/24). Twenty-two (92 %) patients developed a total of 50 symptomatic adverse events, including 30 grade 1 events, 17 grade 2 events, and 3 grade 3 events. The most frequent adverse event was fever with an incidence of 63 %, followed by abdominal pain (25 %). CONCLUSION: TAE for hypervascular tumors with the HepaSphere microspheres was feasible and rarely caused major adverse events. TRIAL REGISTRATION: This trial was registered in JAPIC Clinical Trials Information (JapicCTI-111534).

Time-bin entangled photon pair generation from Si micro-ring resonator.

We demonstrate time-bin entanglement generation in telecom wavelength using a 7 µm radius Si micro-ring resonator pumped by a continuous wave laser. The resonator structure can enhance spontaneous four wave mixing, leading to a photon pair generation rate of about 90-100 Hz with a laser pump power of as low as -3.92 dBm (0.41 mW). We succeed in observing time-bin entanglement with the visibility over 92%. Moreover, wavelength-tunability of the entangled photon pair is demonstrated by changing the operation temperature.

Evaluation of the pharmacokinetic equivalence and 54-week efficacy and safety of CT-P13 and innovator infliximab in Japanese patients with rheumatoid arthritis.

OBJECTIVES: To demonstrate the pharmacokinetic equivalence of CT-P13 and its innovator infliximab (IFX) in Japanese patients with rheumatoid arthritis (RA), and to compare the efficacy and safety of these drugs, administered for 54 weeks. METHODS: In a randomized, double-blind, parallel-group, multicenter study, 3 mg/kg of CT-P13 or IFX, in combination with methotrexate (MTX) (6-16 mg/week), was administered for 54 weeks to Japanese active RA patients with an inadequate response to MTX, to demonstrate the pharmacokinetic equivalence, based on the area under the curve (AUC(τ)) (weeks 6-14) and C(max) (week 6) of these drugs, and to compare their efficacy and safety. RESULTS: The CT-P13-to-IFX ratios (90% confidence intervals) of the geometric mean AUC(τ) and C(max) values in patients negative for antibodies to infliximab at week 14 were 111.62% (100.24-124.29%) and 104.09% (92.12-117.61%), respectively, demonstrating the pharmacokinetic equivalence of these drugs. In the full analysis set, CT-P13 and IFX showed comparable therapeutic effectiveness, as measured by the American College of Rheumatology, Disease Activity Score in 28 joints, the European League Against Rheumatism, and other efficacy criteria, at weeks 14 and 30. The incidence of adverse events was similar for these drugs. CONCLUSION: CT-P13 and IFX, administered at a dose of 3 mg/kg in combination with MTX to active RA patients, were pharmacokinetically equivalent and comparable in efficacy and safety.

Modified E91 protocol demonstration with hybrid entanglement photon source.

We report on an experimental demonstration of the modified Ekert 91 protocol of quantum key distribution using a hybrid entanglement source with two different degrees of freedoms, a 1550 nm time-bin qubit and 810 nm polarization qubit. The violation of the Clauser-Horne-Shimony-Holt inequality could be demonstrated for the entanglement between the polarization qubit in free space and the time-bin qubit through 20 km fiber transmission. The secure key rate in our system is estimated 70-150 bps.

High-speed wavelength-division multiplexing quantum key distribution system.

A high-speed quantum key distribution system was developed with the wavelength-division multiplexing (WDM) technique and dedicated key distillation hardware engines. Two interferometers for encoding and decoding are shared over eight wavelengths to reduce the system's size, cost, and control complexity. The key distillation engines can process a huge amount of data from the WDM channels by using a 1 Mbit block in real time. We demonstrated a three-channel WDM system that simultaneously uses avalanche photodiodes and superconducting single-photon detectors. We achieved 12 h continuous key generation with a secure key rate of 208 kilobits per second through a 45 km field fiber with 14.5 dB loss.

Dose-escalation study of pemetrexed in combination with carboplatin followed by pemetrexed maintenance therapy for advanced non-small cell lung cancer.

INTRODUCTION: The primary objectives of this study were to determine the recommended dose of pemetrexed and carboplatin in patients with chemo-naive advanced non-small cell lung cancer (NSCLC). METHODS: Patients received escalated doses of carboplatin area under the concentration-time curve (AUC) of 5 (cohort 1) or 6 (cohort 2) and pemetrexed 500 mg/m(2) every 3 weeks for six cycles. For patients with objective response and stable disease, pemetrexed were continued until disease progression or unacceptable toxicity. RESULTS: In cohort 1, a dose-limiting toxicity (DLT) was observed in one of the six patients: grade 4 thrombocytopenia. No DLTs were seen in the first 6 patients of cohort 2, and thus the combination of pemetrexed 500 mg/m(2) plus carboplatin at AUC 6 was determined as the recommended dose. Among a total of 20 patients, 8 patients received a median of four cycles of pemetrexed monotherapy in a maintenance setting without unexpected or cumulative toxicities. No complete responses and 12 partial responses were observed, giving an overall response rate of 60.0% [95% confidence interval (CI), 36.1-80.9%]. Median progression-free survival time for all patients was 7.6 months (95% CI: 4.8-8.0 months). CONCLUSIONS: Pemetrexed 500 mg/m(2) plus carboplatin AUC 6 combination therapy followed by pemetrexed maintenance therapy, is generally tolerable, and shows encouraging antitumor activity in chemotherapy-naive patients with advanced NSCLC.

Phase II study of gemcitabine monotherapy as a salvage treatment for Japanese metastatic breast cancer patients after anthracycline and taxane treatment.

OBJECTIVE: This Phase II study was conducted to evaluate efficacy and safety of gemcitabine monotherapy in anthracycline and taxane pre-treated Japanese metastatic breast cancer patients. METHODS: At Step 1, twelve patients were divided into two groups of six patients each and the dose-limiting toxicity was evaluated at gemcitabine 1000 and 1250 mg/m(2) to determine the dose for Step 2. At Step 2, an additional 56 patients were assessed for efficacy and safety of gemcitabine monotherapy. Patients were treated with gemcitabine on days 1 and 8 of a 21-day cycle and explored incidence of adverse events graded by Common Terminology Criteria for Adverse Events (CTCAE) version 3.0, overall response rate (RR), time to progression disease and overall survival time. RESULTS: Gemcitabine 1250 mg/m(2) was determined as the dose for Step 2. Adverse events reported in this study were similar in type, frequency and toxicity grades as seen in other tumor types. Of the 62 patients at 1250 mg/m(2), 1 complete response (1.6%), 4 partial response (6.5%) and 20 stable disease (32.3%) were achieved, yielding an RR of 8.1% (95% CI: 2.7%, 17.8%). Median time to progression was 92.0 days (range: 29-651 days). The median survival time was 17.8 months (95% CI: 14.9 months to incalculable). CONCLUSION: Gemcitabine at 1250 mg/m(2) on days 1 and 8 of a 21-day cycle was tolerable and can be a salvage treatment option for Japanese metastatic breast cancer patients previously treated with anthracyclines and taxanes.

Efficacy differences of pemetrexed by histology in pretreated patients with stage IIIB/IV non-small cell lung cancer: review of results from an open-label randomized phase II study.

INTRODUCTION: Recent pivotal phase III studies in patients with advanced non-small cell lung cancer (NSCLC) consistently showed greater survival benefit of pemetrexed in patients with nonsquamous cell carcinoma histology (nonsquamous histology) compared with those with squamous cell carcinoma histology (squamous histology). To confirm the efficacy differences of pemetrexed by histologic type, we conducted an additional subgroup analysis of data from a Japanese randomized phase II study evaluating the efficacy and safety of pemetrexed 500 mg/m2 (P500) and 1000 mg/m2 (P1000) in patients with advanced NSCLC previously treated with chemotherapy. The efficacy and safety results of original phase II study have already been reported (Ohe et al., Clin Cancer Res 2008;14:4206-4212). METHODS: Objective response rates (ORRs), overall survival time, and progression-free survival time were analyzed by subgroup of histology, squamous, and nonsquamous, for the dose groups combined and separately. RESULTS: A total of 216 patients were evaluable for efficacy. One hundred sixty-eight patients had nonsquamous and 48 had squamous histology. ORRs were 20.8% and 2.1% (p < 0.001); median survival times (MST) were 16.0 and 8.5 months (p < 0.001); and median progression-free survival times (PFS) were 3.1 and 1.6 months (p < 0.001) for nonsquamous and squamous histology, respectively. In patients who were randomized to the P500 group, ORR were 23.5% and 0% (p = 0.0062); MST were 19.4 and 7.9 months (p < 0.001); and PFS were 3.1 and 1.4 months (p < 0.001) for nonsquamous and squamous histology, respectively. In patients who were randomized to the P1000 group, ORR were 18.1% and 4.0% (p = 0.1113); MST were 13.5 months and 8.6 months (p = 0.0971); and PFS were 3.1 and 1.7 months (p = 0.0024) for nonsquamous and squamous histology, respectively. There were no clinically relevant differences in the incidence of toxicities between histology groups. CONCLUSIONS: This study showed the difference of pemetrexed efficacy by histologic type, and this result supports the treatment-by-histology effect observed in the past pivotal phase III studies. Higher dose of pemetrexed resulted in similar outcomes both in patients with nonsquamous histology and squamous histology. Pemetrexed is not as effective as alternative therapies for previously treated squamous histology; however, pemetrexed should be the key agent for the treatment of patients with nonsquamous histology.

[Drug interactions in medical oncology].

Cytotoxic anti-neoplastic drugs are some of the strongest acting drugs. They have a complex pharmacological profile, narrow therapeutic window, steep dose-toxicity curve, and many pharmacokinetic and pharmacodynamic differences both within and between patients. This makes it difficult to avoid adverse effects. These drugs are approved for usage based on their clinical benefit to risk ratio. The recommended dose is usually close to the maximally-tolerated dose in order to achieve maximum therapeutic effect. Therefore, there is more concern about drug interactions affecting the pharmacokinetics of anti-neoplastic drugs than drugs in general. Any physician taking care of oncology patients must understand not only the pharmacokinetic profile(absorption, protein binding, metabolism and excretion)of the anti-neoplastic drugs their using, but also the many factors that affect the pharmacokinetic profile such as hepatic and renal function, and co-administered drugs. Expertise to achieve a good balance between safety and efficacy in medical treatment with proper knowledge in supportive care as well as an understanding of pharmacokinetics, pharmacodynamics and pharmacogenomics is essential for medical oncologists. In this review, we have summarized the drug-drug interactions important for the management of cancer patients. The types of interactions covered are pharmaceutical interactions and interactions at the level of absorption, protein binding, metabolism and excretion.

A landmark point analysis with cytotoxic agents for advanced NSCLC.

INTRODUCTION: As a result of recent publications, we hypothesized that period of 8 weeks after initiation of treatment is a useful landmark point for cytotoxic agents for advanced non-small cell lung cancer (NSCLC). To test this hypothesis, we conducted landmark analyses with clinical trials employing cytotoxic agents. Our goal was to assess the proper design of clinical trials with cytotoxic agents for NSCLC for maximizing patients' benefit. METHODS: We conducted landmark analyses of a phase II study of pemetrexed in locally advanced or metastatic NSCLC and a phase III study of Four-Arm Cooperative Study for advanced NSCLC. A total of 806 patients who received chemotherapy (pemetrexed, cisplatin and irinotecan, paclitaxel and carboplatin, cisplatin and gemcitabine, cisplatin and vinorelbine) were included in this assessment. RESULTS: Tumor-shrinkage rate at 8 weeks was significantly associated with longer survival in the study with pemetrexed (p = 0.043), whereas tumor-shrinkage rate at 4 weeks did not correlated with survival (p = 0.139). Similarly, using the Four-Arm Cooperative Study data, the optimal landmark point was 8 weeks (p = 0.002), not 4 weeks (p = 0.190). CONCLUSION: The landmark point for NSCLC was 8 weeks with all cytotoxic agents in our analysis when the therapy was given as a frontline or subsequent therapy. Our result suggests the concept of a disease-specific landmark point, which may lead to a change of phase II/III clinical study design to evaluate cytotoxic agents and clinical investigators, and their sponsors may consider an early look to assess the efficacy of cytotoxic agents for NSCLC.

Ultra fast quantum key distribution over a 97 km installed telecom fiber with wavelength division multiplexing clock synchronization.

We demonstrated ultra fast BB84 quantum key distribution (QKD) transmission at 625 MHz clock rate through a 97 km field-installed fiber using practical clock synchronization based on wavelength-division multiplexing (WDM). We succeeded in over-one-hour stable key generation at a high sifted key rate of 2.4 kbps and a low quantum bit error rate (QBER) of 2.9%. The asymptotic secure key rate was estimated to be 0.78- 0.82 kbps from the transmission data with the decoy method of average photon numbers 0, 0.15, and 0.4 photons/pulse.

Efficacy and safety of two doses of pemetrexed supplemented with folic acid and vitamin B12 in previously treated patients with non-small cell lung cancer.

PURPOSE: The objective of this study was to evaluate the efficacy and safety of two doses of pemetrexed supplemented with folic acid and vitamin B(12) in pretreated Japanese patients with advanced non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: Patients with an Eastern Cooperative Oncology Group performance status 0 to 2, stage III or IV, and who received previously one or two chemotherapy regimens were randomized to receive 500 mg/m(2) pemetrexed (P500) or 1,000 mg/m(2) pemetrexed (P1000) on day 1 every 3 weeks. The primary endpoint was response rate. RESULTS: Of the 216 patients evaluable for efficacy (108 in each arm), response rates were 18.5% (90% confidence interval, 12.6-25.8%) and 14.8% (90% confidence interval, 9.5-21.6%), median survival times were 16.0 and 12.6 months, 1-year survival rates were 59.2% and 53.7%, and median progression-free survival were 3.0 and 2.5 months for the P500 and P1000, respectively. Cox multiple regression analysis indicated that pemetrexed dose was not a significant prognostic factor. Drug-related toxicity was generally tolerable for both doses; however, the safety profile of P500 showed generally milder toxicity. Main adverse drug reactions of severity grade 3 or 4 were neutrophil count decreased (20.2%) and alanine aminotransferase (glutamine pyruvic transaminase) increased (15.8%) in P500 and neutrophil count decreased (24.3%), WBC count decreased (20.7%), and lymphocyte count decreased (18.0%) in P1000. One drug-related death from interstitial lung disease occurred in the P500. CONCLUSION: P500 and P1000 are similarly active with promising efficacy and acceptable safety outcomes in pretreated patients with NSCLC. These results support the use of P500 as a second- and third-line treatment of NSCLC.

Efficacy and safety of pemetrexed in combination with cisplatin for malignant pleural mesothelioma: a phase I/II study in Japanese patients.

BACKGROUND: Pemetrexed in combination with cisplatin (Pem/Cis) is used globally for the treatment of malignant pleural mesothelioma (MPM). This Phase I/II study was conducted to determine the recommended dose (RD) (Phase I) of Pem/Cis, and evaluate the efficacy and safety (Phase II) in Japanese MPM patients. METHODS: Key eligibility criteria were histologic diagnosis of MPM incurable by surgery, no prior chemotherapy, and a performance status 0-1. Under full vitamin supplementation, pemetrexed was intravenously administered on Day 1 of a 21-day cycle, followed by cisplatin. A cohort of six patients, starting from pemetrexed 500 mg/m(2) and cisplatin 75 mg/m(2) (Level 1), were studied in the dose-escalation Phase I (Step 1). The RD determined in Step 1 was carried forward into Phase II (Step 2). Planned number of patients treated with Pem/Cis was 18-38. RESULTS: In Step 1, 13 patients were enrolled: seven in Level 1 and six in Level -1 (pemetrexed 500 mg/m(2), cisplatin 60 mg/m(2)). Two of six evaluable patients had dose-limiting toxicities (pneumonitis and neutropenia) in Level 1, establishing Level 1 as the RD. In Step 2, 12 patients were enrolled, for a total of 19 patients treated at the RD. Seven patients achieved a partial response among these patients, for a response rate of 36.8% (95% confidence interval: 16.3-61.6); overall survival was 7.3 months. One drug-related death occurred due to worsening of a pre-existing pneumonia. Common grade 3/4 toxicities were neutropenia and decreased-hemoglobin. CONCLUSION: The Pem/Cis combination provides promising activity and an acceptable safety profile for chemonaive Japanese MPM patients with the same recommend dosage and schedule used in rest of the world.