Hiroshi Wakui

Phase I study of ipilimumab in phased combination with paclitaxel and carboplatin in Japanese patients with non-small-cell lung cancer.

SummaryBackground Ipilimumab is an antibody that targets the cytotoxic T-lymphocyte antigen-4 to potentiate an antitumor response. Adding ipilimumab 10xa0mg/kg to paclitaxel (PTX) and carboplatin (CBDCA) in a phased schedule improved progression-free survival in a phase II non-small-cell lung cancer (NSCLC) study. Methods This dose-escalating, phase I study was designed to identify the recommended dose of ipilimumab (3 or 10xa0mg/kg) by evaluating dose-limiting toxicity (DLT; Cycles 3 and 4) in phased combination with PTX (175xa0mg/m2) and CBDCA (area under the curveu2009=u20096) in Japanese patients with advanced NSCLC. Treatment was administered intravenously every 3xa0weeks initially, followed by some eligible patients receiving maintenance ipilimumab once every 12xa0weeks. Additional endpoints included safety, tumor response, pharmacokinetics, and immunogenicity. Results Fifteen patients were enrolled and 12 received ipilimumab (nu2009=u20096, 3xa0mg/kg; nu2009=u20096, 10xa0mg/kg) in combination with PTX and CBDCA. DLTs occurred in 2 patients (ipilimumab 3xa0mg/kg) and 1 patient (ipilimumab 10xa0mg/kg). The most common grade 3/4 adverse events (AEs) were decreased hemoglobin, leukopenia, and neutropenia. The most common immune-related AEs affected the skin, gastrointestinal, and nervous system. The safety profile was similar in both cohorts. Three patients in each cohort achieved a partial response. The pharmacokinetic (PK) profile of ipilimumab in Japanese patients was similar to that observed in previous studies in non-Japanese patients. Conclusions The recommended dose of ipilimumab in phased combination with PTX and CBDCA in Japanese patients with NSCLC was identified as 10xa0mg/kg. The safety profile was consistent with the previously defined AE profile.

Phase 1 and dose-finding study of patritumab (U3-1287), a human monoclonal antibody targeting HER3, in Japanese patients with advanced solid tumors.

PurposePatritumab (U3-1287) is a human epidermal growth factor receptor-3 (HER3)-targeted antibody that blocks ligand-associated activation of HER3. This open-label, phase 1 and dose-finding study (ClinicalTrials.jp Identifier: JapicCTI-101262) aimed to assess the safety, pharmacokinetics, incidence of anti-patritumab antibody, recommended dose for subsequent clinical studies, preliminary efficacy, and patritumab-related biomarkers in Japanese patients with advanced solid tumors.MethodsPatients received patritumab 9 or 18xa0mg/kg intravenously every 3xa0weeks until disease progression or intolerable toxicity occurred. Adverse events (AEs) were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE version 4.0). Dose-limiting toxicities (DLTs) were evaluated from the initial dose to Cycle 1 Day 21. Tumor response was assessed with Response Evaluation Criteria in Solid Tumors (RECIST version 1.1).ResultsNine patients received patritumab 9xa0mg/kg (nxa0=xa03) or 18xa0mg/kg (nxa0=xa06). Five patients were male, all patients had Eastern Cooperative Oncology Group performance status (PS)xa0≤xa01, and median (range) age of 67 (50–69) years. No DLTs were reported. Patritumab-related AEs reported in ≥2 patients were ALT increase (three patients), thrombocytopenia, diarrhea, stomatitis, cheilitis, rash maculo-papular and AST increase (two each). Pharmacokinetics profile was similar to the preceding US phase 1 study. Soluble HER3 concentration in serum unexpectedly increased in all patients. These changes did not correlate with clinical response. Four patients had a best response of stable disease. All patients tested had negative for anti-patritumab antibody formation.ConclusionsPatritumab was well tolerated up to 18xa0mg/kg without DLTs in Japanese patients with advanced solid tumors. Soluble HER3 increased in all patients.

Short Hydration in Chemotherapy Containing Cisplatin (≥75 mg/m2) for Patients with Lung Cancer: A Prospective Study

OBJECTIVEnWe previously reported that 22% of lung cancer patients experienced a Grade 2 or 3 elevation in creatinine after chemotherapy containing cisplatin. We conducted a Phase II trial to evaluate the safety and efficacy of short hydration.nnnMETHODSnThe major eligibility criteria included patients with lung cancer for whom a ≥75 mg/m(2) cisplatin-based regimen was indicated and adequate organ function. Cisplatin was administered with pre- and post-hydration containing 10 mEq of potassium chloride in 500 ml of fluid over a 60-min period. Immediately before the administration of cisplatin, mannitol (20%, 200 ml) was administered as forced diuresis over 30 min. And magnesium sulfate (8 mEq) was added to pre-hydration.nnnRESULTSnForty-four patients were enrolled between April and December 2011. The patients included 29 men and 15 women with a median (range) age of 64 (42-74) years. Twenty patients received cisplatin and pemetrexed as their most frequent regimen and 38 patients received three to four cycles of chemotherapy. The median (range) duration and volume of the chemotherapies were 4.0 (3.3-6.8) h and 1600 (1550-2050) ml, respectively. Of the 44 patients, 43 (97.8%) completed the cisplatin-based chemotherapy without Grade 2 or higher renal dysfunction. The only patient who had Grade 2 elevation in creatinine (maximum value 1.7 mg/dl) had prompt improvement in creatinine levels and completed four cycles of chemotherapy.nnnCONCLUSIONSnThe short hydration is safe without severe renal toxicities in regimens containing cisplatin (≥75 mg/m(2)) for patients with lung cancer.

A phase 1 study of lenvatinib, multiple receptor tyrosine kinase inhibitor, in Japanese patients with advanced solid tumors.

PurposeThis phase 1 study aimed to assess the tolerability, safety, pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy of lenvatinib capsules in Japanese patients with solid tumors when administered orally up to 24xa0mg on a once-daily (QD) continuous schedule.MethodsPatients were enrolled in one of the two sequential cohorts (20 or 24xa0mg) of lenvatinib on a 28-day cycle based on the conventional 3xa0+xa03 dose escalation design. Adverse events (AEs) were graded using the Common Terminology Criteria for Adverse Events, version 4.0. Tolerability was judged based on dose-limiting toxicities (DLTs) during Cycle 1. The drug was defined as tolerable when the incidence of DLTs was less than 33xa0%.Results Nine patients received lenvatinib [20xa0mg (nxa0=xa03); 24xa0mg (nxa0=xa06)]. No DLTs were observed. The most common AEs were thrombocytopenia, blood thyroid stimulating hormone increased, and hypertension (89xa0%), followed by leukopenia, headache, and proteinuria (78xa0%). The area under the concentration–time curve and maximum observed concentration increased dose proportionally. The PK profiles were similar to those in non-Japanese phase 1 studies. One patient with leiomyosarcoma showed a partial response, and three patients have maintained stable disease for more than 6xa0months.ConclusionsThe 24-mg QD continuous dose of lenvatinib was determined to be tolerable with encouraging anti-tumor activity in Japanese patients with solid tumors.

A phase 1 and dose-finding study of LY2523355 (litronesib), an Eg5 inhibitor, in Japanese patients with advanced solid tumors

PurposeEg5, a mitotic motor kinesin protein, plays an essential role in bipolar spindle formation in the M phase of the cell cycle. LY2523355 (litronesib) is an allosteric inhibitor of Eg5. This phase 1 and dose-finding study aimed to assess the safety, pharmacokinetics (PK), recommended dose for further studies, and preliminary efficacy in Japanese patients with advanced solid tumors.MethodsLY2523355 was given on days 1, 2, and 3 every 3xa0weeks at one of three dose levels: 2, 4, and 5xa0mg/m2/day. Toxicity was assessed according to NCI-CTCAE version 4.0, and tumor response according to RECIST version 1.1. granulocyte colony-stimulating factor (G-CSF) was used only for grade 4 neutropenia or grade 3 febrile neutropenia.ResultsTwelve patients were treated at doses of 2 (nxa0=xa03), 4 (nxa0=xa03), and 5 (nxa0=xa06) mg/m2/day. Most frequent treatment-related adverse events were neutropenia and leukopenia (100xa0%). Grade 4 neutropenia was observed in 83xa0%, but all recovered to above 500 neutrophils/μl within 7xa0days. All patients at 4 and 5xa0mg/m2/day required G-CSF support. No dose-limiting toxicities were reported up to 5xa0mg/m2/day. In PK analysis, LY2523355 exposure increased in a dose-dependent manner. The PK parameters for LY2523355 were similar to those observed in Western populations. No objective tumor responses were observed.ConclusionsThe recommended dose of LY2523355 with therapeutic G-CSF use for further studies was determined to be 5xa0mg/m2/day in Japanese patients with advanced solid tumors.

Phase I study of the anti-MET antibody onartuzumab in patients with solid tumors and MET-positive lung cancer

SummaryOnartuzumab is a monovalent, humanized, monoclonal antibody that showed significant survival benefits in combination with erlotinib in MET-positive non-small-cell lung cancer (NSCLC) in pre-specified subgroup analyses of a randomized phase II study. We conducted a two-stage, open-label, multicenter, phase I study of onartuzumab in Japanese patients. Stage 1 investigated the safety, tolerability, pharmacokinetics (PK), and recommended dose of onartuzumab in patients with solid tumors, and Stage 2 determined the safety, tolerability, and PK of onartuzumab plus erlotinib in patients with MET-positive NSCLC. Nine patients received onartuzumab monotherapy (4, 15, or 30xa0mg/kg on Day 1 of each 21-day cycle) in Stage 1, and six patients received onartuzumab (15xa0mg/kg) plus erlotinib (150xa0mg/day) in Stage 2. There were no dose-limiting toxicities in either stage. Serious adverse events (AEs) occurred in one patient in Stage 1 (convulsion), and two patients in Stage 2 (once case each of diarrhea, vomiting, and pulmonary embolism), but there were no grade 4 AEs or AEs leading to death. Onartuzumab PKs were linear in the dose range of 4 to 30xa0mg/kg, and were not affected by co-administration with erlotinib. PK parameters of onartuzumab were similar to those reported in non-Japanese patients. A partial response was observed in a patient with MET immunohistochemistry 3+ NSCLC without MET gene amplification. Based on these results, the recommended dose of onartuzumab in Japanese patients with solid tumors is 15xa0mg/kg every 21xa0days. The combination of onartuzumab with erlotinib is feasible in Japanese patients with MET-positive lung cancer.

Phase I trial of volasertib, a Polo-like kinase inhibitor, in Japanese patients with advanced solid tumors

SummaryPurpose This trial evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics, and clinical effects of volasertib, a selective Polo-like kinase inhibitor that induces mitotic arrest and apoptosis, in Japanese patients with advanced solid tumors (NCT01348347; 1230.15). Methods In this phase I, open-label, dose-escalation trial, sequential patient cohorts (3u2009+u20093 dose-escalation design) received volasertib (200–350xa0mg) as a single dose by intravenous infusion over 2xa0h on day 1 every 21xa0days until disease progression or unacceptable toxicity. The primary endpoint was the MTD of volasertib in Japanese patients with an advanced solid tumor; secondary endpoints included safety, pharmacokinetics, and clinical benefit. Results Fifteen patients with an advanced solid tumor were treated. Dose-limiting toxicities of grade 4 neutropenia for ≥7xa0days and grade 4 thrombocytopenia were both experienced by 2/6 patients in the 350xa0mg cohort. The MTD of volasertib in Japanese patients was 300xa0mg. The most common (≥3 patients) drug-related non-hematologic adverse events included fatigue, decreased appetite, and nausea. Exposure to volasertib and its metabolite increased with increasing doses. A partial response in a patient with gastric cancer and stable disease in eleven patients were observed. Conclusions Volasertib had a manageable safety profile up to the MTD determined as 300xa0mg. Exposure to volasertib and its metabolite increased with increasing doses. The safety profile of volasertib in Japanese patients is comparable with those previously obtained in Caucasian patients. These data support enrollment of Japanese patients in global clinical trials without dose modification.

Phase I and pharmacokinetics/pharmacodynamics study of the MEK inhibitor RO4987655 in Japanese patients with advanced solid tumors

RO4987655 is an oral and selective inhibitor of MEK, a key enzyme of the mitogen-activated protein kinase (MAPK) signaling pathway. This phase I dose-escalation study of RO4987655 in Japanese patients with advanced solid tumors aimed to determine maximum tolerated dose (MTD) and to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity. Patients received a single dose of RO4987655 (1, 2, 4, 5, or 6.5xa0mg) followed by continuous once-daily dosing (1, 2, or 4xa0mg QD) or twice-daily dosing (4, 5, or 6.5xa0mg BID) in 28-day cycles. A 3u2009+u20093 dose-escalation design was used. PD was evaluated by pERK inhibition in peripheral blood mononuclear cells (PBMCs). In dose-escalation, 25 patients were enrolled. After the MTD was determined, a further six patients were administered the MTD for further confirmation of safety. MTD was determined as 8xa0mg/day (4xa0mg BID) due to a total of four dose-limiting toxicities (DLTs) of grade 3 creatine phosphokinase (CPK) elevation (2 DLTs each in 10xa0mg/day and 13xa0mg/day). Most commonly related adverse events included dermatitis acneiform, CPK elevation, and eye disorders. Plasma concentration of RO4987655 appeared to increase in a dose-proportional manner with a plasma half-life of 4.32 to 21.1xa0h. Following multiple dose administration, a steady-state condition was reached by Cycle 1 Day 8. The inhibitory effects of RO4987655 on pERK in PBMCs increased in a dose-dependent manner. One esophageal cancer patient had confirmed partial response and seven patients showed progression-free survival for longer than 16xa0weeks. The MTD of RO4987655 for Japanese patients was determined as 8xa0mg/day (4xa0mg BID). RO4987655 was tolerated up to the MTD with a favorable PK/PD profile in Japanese patients with advanced solid tumors.

Abstract C68: Phase I study of administration of LY2523355, an Eg5 inhibitor, for 3 consecutive days every 3 weeks in Japanese patients with refractory solid tumors.

Background: Eg5, a mitotic motor kinesin, plays an essential role in bipolar spindle formation. Clinical studies on LY2523355 (Litronesib), an allosteric Eg5 inhibitor, were ongoing in several countries. This Phase I study evaluated the tolerability, safety and pharmacokinetics of LY2523355 in Japanese patients with refractory solid tumors to determine the recommended dose for further studies. Methods: This was an open-label, dose-escalation study. LY2523355 was intravenously administered over 60 min on days 1, 2, and 3 every 3 weeks at 1 of 3 dose levels: 2, 4, and 5 mg/m2/day. Doses were escalated in a classic 3 + 3 design. Toxicity was assessed with NCI-CTCAE. Tumor responses were assessed according to the RECIST. Dose-limiting toxicity (DLT) was defined as grade 4 neutropenia for >7 days, grade 4 thrombocytopenia or grade 3 thrombocytopenia requiring platelet transfusion, a neutrophil count of 38.5°C that lasted for >2 days, or grade ≥3 non-hematologic toxicity. G-CSF was used to treat grade 4 neutropenia or grade 3 febrile neutropenia. Results: Twelve patients were treated at doses of 2 (n = 3), 4 (n = 3), and 5 (n = 6) mg/m2/day. The male-to-female ratio was 7:5 and the median age was 61.5 years. The tumor types were non-small cell lung cancer (n = 2), colorectal cancer (n = 3), small cell lung cancer (n = 2), angiosarcoma (n = 1), breast cancer (n = 1), esophageal cancer (n = 1), gastric cancer (n = 1), and ovarian cancer (n = 1). The main toxicities were neutropenia and leukopenia (100%). Grade 4 neutropenia was observed in 83% of patients; neutrophil levels recovered to >500/μL within 7 days with G-CSF support in all patients. Grade 3 febrile neutropenia was observed in 2 (66%) patients at 4 mg/m2/day and in 6 (100%) patients at 5 mg/m2/day, but these were manageable with appropriate antibiotics administration. DLT was not noted up to 5 mg/m2/day, the dose used in parallel overseas Phase II studies. In pharmacokinetic analysis, exposure of LY2523355 increased dose-proportionally across these doses. None of the predictive factors, including gender, were associated with pharmacokinetic parameters or toxicity. The pharmacokinetic parameters were similar to those observed in Western populations. No objective tumor responses were observed. Conclusions: The recommended dose of LY2523355 with therapeutic G-CSF use for further studies was determined to be 5 mg/m2/day on days 1, 2, and 3 with a manageable safety profile in Japanese patients with refractory solid tumors. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C68. Citation Format: Yutaka Fujiwara, Hiroshi Nokihara, Noboru Yamamoto, Yasuhide Yamada, Hiroshi Wakui, Shinji Nakamichi, Hidenori Mizugaki, Satoru Kitazono, Hironori Kanda, Kohei Suzuki, Shiro Akinaga, Tomohide Tamura. Phase I study of administration of LY2523355, an Eg5 inhibitor, for 3 consecutive days every 3 weeks in Japanese patients with refractory solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C68.

Abstract C26: A phase 1 multiple ascending dose study of cabozantinib (XL184) monotherapy in Japanese patients with advanced solid tumors.

Background: Cabozantinib is a potent orally available small molecule inhibitor of multiple receptor tyrosine kinases with growth promoting and angiogenic properties. The primary targets of cabozantinib are MET and VEGFR2. In preclinical models, cabozantinib demonstrated significant tumor growth inhibition in multiple tumor models including human medullary thyroid cancer (MTC), human breast cancer, human lung carcinoma and rat glioblastoma. Anti-tumor activity in patients has been observed across a broad range of tumor types including MTC, prostate, ovarian and breast cancer, non-small cell lung cancer (NSCLC), hepatocellular carcinoma, melanoma and glioblastoma. The primary objectives of this open-label phase 1 study are determination of the maximum tolerated dose (MTD) and recommended phase 2 dose in Japanese patients. Methods: Patients with advanced solid malignancies are enrolled in successive cohorts to receive escalating doses of cabozantinib in a 3+3 trial design. Patients are treated with continuous 4-week cycles of cabozantinib administered orally (PO) once daily (QD). Dose limiting toxicities (DLTs) are determined using Cycle 1 data. Response is assessed on Day 29 and every 8 weeks thereafter by modified RECIST v1.0 criteria and patients with stable disease (SD) or objective response receive continued therapy. Pharmacokinetic (PK) parameters of cabozantinib and relevant plasma markers including VEGF-A, sVEGFR2 and PlGF are being evaluated. Results: As of 1 September 2011, 6 patients with advanced malignancies have been enrolled: NSCLC (n=3), colorectal cancer, gastrointestinal stromal tumor (GIST), leiomyosarcoma (n=1 each). Patients were pretreated with a median of 3 prior regimens (range, 2 − 7). Patients have been treated at 2 dose levels of 40mg and 60mg free base equivalents (salt strengths of 50mg and 75mg, respectively) PO QD. There have been no DLTs or serious adverse events reported to date. The MTD has not yet been defined. Observed adverse events were generally mild to moderate and include hypertension, palmer-plantar erythrodysesthesia, diarrhea, mucositis, rash, edema and headache. Laboratory abnormalities include elevated AST/ALT, neutropenia, thrombocytopenia and increases in alkaline phosphatase, LDH, lipase and TSH. Results of preliminary PK analysis at the 40mg QD dose level showed that cabozantinib appeared to reach steady-state plasma concentrations by Day 15 and there was evidence of 6- to 7-fold accumulation on Day 19. One patient with NSCLC has had a confirmed partial response with 38% reduction in the sum of target lesions. Three pretreated patients including 2 with NSCLC and 1 with GIST have had SD with reductions in the sum of target lesions of 20, 13 and 16% respectively, and continue treatment with cabozantinib. Conclusions: Cabozantinib appears well tolerated at doses tested to date. Early signs of antitumor activity including prolonged stable disease and response have been observed in the initial dosing cohorts. Determination of the MTD is ongoing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C26.