Phase 1 dose‐escalation study of single‐agent veliparib in Japanese patients with advanced solid tumors

Veliparib (ABT‐888) is a potent, orally bioavailable poly(ADP‐ribose) polymerase‐1 and ‐2 inhibitor. This phase 1 study evaluated the tolerability, pharmacokinetic profile, safety, and preliminary antitumor activity of single‐agent veliparib in Japanese patients with advanced solid tumors. Eligible patients were assigned to treatment with veliparib at 200 or 400 mg dose; veliparib was self‐administered orally twice daily on days 1–28 of 28‐day cycles. Dose escalation, following a 3 + 3 design, defined dose‐limiting toxicities, the maximum tolerated dose, and the recommended phase 2 dose. Sixteen patients were enrolled (median age, 59 years). Fourteen patients had high‐grade serous ovarian cancer, one had primary peritoneal cancer, and one had BRCA‐mutated breast cancer. The most frequent treatment‐emergent adverse events were nausea and vomiting (93.8% each), decreased appetite (62.5%), abdominal pain, diarrhea, and malaise (31.3% each). A grade ≥3 toxicity was observed in 50% of patients; one patient each in the 200 mg (n = 4) and 400 mg (n = 12) cohorts experienced serious adverse events. Dose‐limiting toxicities were observed for one patient at the 400 mg dose. No toxicities leading to death were reported. The recommended phase 2 dose was defined as 400 mg twice daily. The veliparib pharmacokinetic profile was consistent with that reported for the Western population. Two patients, both with ovarian cancer, had a RECIST partial response. Veliparib monotherapy showed manageable tolerability and safety profiles and a predictable pharmacokinetic profile at a 400 mg twice‐daily dose, and supports the inclusion of Japanese patients in the multinational phase 3 study (NCT02470585).     

Phase 1 study of capmatinib in MET‐positive solid tumor patients: Dose escalation and expansion of selected cohorts

Capmatinib is an oral, ATP‐competitive, and highly potent, type 1b MET inhibitor. Herein, we report phase 1 dose‐escalation results for capmatinib in advanced MET‐positive solid tumor patients and dose expansion in advanced non‐lung tumors. Capmatinib was well tolerated with a manageable safety profile across all explored doses. Dose‐limiting toxicities (DLT) occurred at 200 mg twice daily (bid), 250 mg bid, and 450 mg bid capsules; however, no DLT were reported at 600 mg bid (capsules). Capmatinib tablets at 400 mg bid had comparable tolerability and exposure to that of 600 mg bid capsules. Maximum tolerated dose was not reached; recommended phase 2 dose was 400 mg bid tablets/600 mg bid capsules; at this dose, C_trough >EC₉₀ (90% inhibition of c‐MET phosphorylation in animal models) is expected to be achieved and maintained. Among the dose‐expansion patients (N = 38), best overall response across all cohorts was stable disease (gastric cancer 22%, hepatocellular carcinoma 46%, other indications 28%); two other indication patients with gene copy number (GCN) ≥6 achieved substantial tumor reduction. Near‐complete immunohistochemically determined phospho‐MET inhibition (H‐score = 2) was shown following capmatinib 450 mg bid capsule in paired biopsies obtained from one advanced colorectal cancer patient. Incidence of high‐level MET GCN (GCN ≥6) and MET‐overexpressing (immunohistochemistry 3+) tumors in the expansion cohorts was 8% and 13%, respectively; no MET mutations were observed. Thus, the recommended phase 2 dose (RP2D) of capmatinib was 600 mg bid capsule/400 mg bid tablet. Capmatinib was well tolerated and showed antitumor activity and acceptable safety profile at the RP2D. (ClinicalTrials.gov Identifier: NCT01324479).     

Phase I,multicenter, open‐label,dose‐escalation study of sonidegib in Asian patients with advanced solid tumors

Sonidegib is a selective inhibitor of Smoothened receptor, which is a key regulator of the Hedgehog signaling pathway. The purpose of this study was to determine the maximum tolerated dose based on dose‐limiting toxicity (DLT) and the recommended dose (RD) of sonidegib in Asian patients with advanced solid tumors. This was an open‐label, single‐arm, multicenter, two‐group, parallel, dose‐escalation, phase I study undertaken in Asian patients; group 1 included patients from Japan and group 2 included patients from Hong Kong and Taiwan. Dose escalation was guided by a Bayesian logistic regression model dependent on DLTs in cycle 1 and other safety findings. A total of 45 adult Asian patients with confirmed advanced solid tumors were enrolled. Group 1 included 21 patients (12 treated with 400 mg q.d. [once daily] and 9 treated with 600 mg q.d.) and group 2 included 24 patients (12 treated with 400 mg q.d., 8 treated with 600 mg q.d., and 4 treated with 800 mg q.d.). Elevation in creatine kinase was the DLT in both groups. The most common adverse events suspected to be related to sonidegib in both patient groups were increase in creatine kinase levels, myalgia, fatigue, and abnormal hepatic function. The RD of 400 mg q.d. was defined in both groups. Difference in tolerability was noted between the East Asian patients and Western population. The RD in East Asian patients (400 mg q.d.) was lower than in patients from Europe and the USA (800 mg q.d. and 250 mg twice daily). (Registered with Clinicaltrials.gov : NCT01208831.)     

Phase I study of single‐agent ribociclib in Japanese patients with advanced solid tumors

The cyclin D‐CDK4/6‐INK4‐Rb pathway is frequently dysregulated in cancers. Ribociclib, an orally available, selective CDK4/6 inhibitor, showed preliminary clinical activity in a phase I study in the USA and Europe for patients with solid tumors and lymphomas. The present study aimed to determine the single‐agent maximum tolerated dose (MTD) and recommended dose for expansion (RDE) in Japanese patients with advanced solid tumors. Ribociclib safety, tolerability, pharmacokinetic profile, and preliminary antitumor activity were also assessed. Japanese patients with solid tumors that had progressed on prior therapies received escalating doses of single‐agent ribociclib on a 3‐weeks‐on/1‐week‐off schedule. Treatment continued until the development of toxicity or disease progression. A dose escalation was planned for patients with esophageal cancer. In the dose‐escalation phase, 4 patients received 400 mg ribociclib and 13 patients received 600 mg ribociclib. Four patients experienced dose‐limiting toxicities, 3 of whom were in the 600 mg group. The RDE was declared to be 600 mg, and the MTD was not determined. The most frequent adverse events were hematologic and gastrointestinal. Four patients achieved stable disease at the 600 mg dose; no patients achieved complete or partial response. All patients discontinued the study, the majority due to disease progression. No patients discontinued due to adverse events. Dose escalation was not pursued due to lack of observed efficacy in esophageal cancer. At the RDE of 600 mg/d on a 3‐weeks‐on/1‐week‐off schedule, ribociclib showed acceptable safety and tolerability profiles in Japanese patients with advanced solid tumors.     

Phase I study of olaratumab in Japanese patients with advanced solid tumors

Olaratumab (IMC‐3G3) is a fully human IgG1 monoclonal antibody that selectively binds the external domain of human platelet‐derived growth factor receptor‐α with high affinity and blocks ligand binding. This was a single‐center, dose‐escalation, phase I trial of olaratumab in Japanese patients with advanced/refractory solid malignancies. Three to six patients were enrolled into each of three cohorts: Patients received i.v. olaratumab: 10 mg/kg on days 1 and 8 every 3 weeks (cohort 1); 20 mg/kg every 2 weeks (cohort 2); and 15 mg/kg on days 1 and 8 every 3 weeks (cohort 3). Doses were escalated from cohort 1 through cohort 3. The primary objective was to establish the safety and pharmacokinetic profile of olaratumab. Sixteen patients were treated across three cohorts. There were no dose‐limiting toxicities, so the maximum tolerated dose was not reached. The most common olaratumab‐related treatment‐emergent adverse events (TEAEs) were proteinuria (25.0%) and elevated aspartate transaminase (12.5%). One patient (cohort 2) had two olaratumab‐related Grade 3 TEAEs (increased aspartate aminotransferase and tumor hemorrhage); otherwise, olaratumab‐related TEAEs were Grade 1/2. Seven patients (43.8%) had a best response of stable disease. Based on the pharmacokinetic concentration profile of olaratumab, the trough concentrations following single and multiple doses at 15 mg/kg on days 1 and 8 every 3 weeks (cohort 3) and multiple doses at 20 mg/kg every 2 weeks (cohort 2) were above the 155 μg/mL target. Thus, these two doses could represent an acceptable schedule for future trials in Japanese patients. Olaratumab had an acceptable safety profile and was well tolerated.     

Phase I,multicenter, dose‐escalation study of avadomide in adult Japanese patients with advanced malignancies

Non‐Hodgkin lymphoma (NHL) treated with chemoimmunotherapy has limited efficacy in some patients, resulting in relapsed or refractory disease. Avadomide (CC‐122) is a novel cereblon‐binding agent that exhibits antilymphoma and immune‐modulation activities with a biological profile distinct from similar agents, such as lenalidomide. This phase I multicenter study evaluated avadomide in Japanese patients with advanced solid tumors or NHL. Fourteen patients with NHL and one with a solid tumor (esophageal carcinoma), were enrolled in four dose‐escalation cohorts using a 3 + 3 design. Primary endpoints included safety, dose‐limiting toxicities (DLT), maximum‐tolerated dose and/or recommended phase II dose (RP2D), and pharmacokinetics. Secondary endpoints included overall response rate (ORR) and duration of response. One patient with NHL experienced DLT, which included face edema, pharyngeal edema, and tumor flare (all grade 1) that led to a dose reduction. Eleven patients had grade ≥3 treatment‐emergent adverse events, most frequently decreased neutrophil count (33%) and decreased lymphocyte count (20%). The ORR in patients with NHL (n = 13) was 54%, including four complete and three partial responses. The best response for the solid tumor patient was progressive disease. Avadomide dose intensity was consistent across cohorts, and the 3‐mg dose given five consecutive days/week was established as the RP2D. This phase I study identified a tolerable dose of avadomide, with an acceptable toxicity profile and clinically meaningful efficacy in Japanese patients with previously treated NHL.     

Phase I dose‐escalation study of buparlisib (BKM120), an oral pan‐class I PI3K inhibitor,in Japanese patients with advanced solid tumors

Buparlisib (BKM120) is an oral pan‐phosphatidylinositol 3‐kinase inhibitor, targeting all four isoforms of class I PI3K (α, β, γ and δ). This open‐label Phase I dose‐escalation study was conducted to determine the maximum tolerated dose of continuous daily buparlisib in Japanese patients with advanced solid tumors. Secondary objectives included safety and tolerability, pharmacokinetics, antitumor activity and pharmacodynamic marker changes. Fifteen patients were treated at 25 mg/day (n = 3), 50 mg/day (n = 3) and 100 mg/day (n = 9) dose levels. One dose‐limiting toxicity of Grade 4 abnormal liver function occurred at 100 mg/day. Considering the safety profile and the maximum tolerated dose in the first‐in‐man study of buparlisib in non‐Japanese patients, further dose escalation was stopped and 100 mg/day was declared the recommended dose. The most common treatment‐related adverse events were rash, abnormal hepatic function (including increased transaminase levels), increased blood insulin levels and increased eosinophil count. Hyperglycemia was experienced by two patients, one Grade 1 and one Grade 4, and mood alterations were experienced by three patients, two Grade 1 and one Grade 2. Pharmacokinetic results showed that buparlisib was rapidly absorbed in a dose‐proportional manner. Best overall response was stable disease for six patients, including one unconfirmed partial response. In these Japanese patients with advanced solid tumors, buparlisib had a manageable safety profile, with similar pharmacokinetics to non‐Japanese patients. The recommended dose of 100 mg/day will be used in future studies of buparlisib in Japanese patients.     

Phase I study of alpelisib (BYL719), an α‐specific PI3K inhibitor,in Japanese patients with advanced solid tumors

This phase I study aimed to determine tolerability and preliminary efficacy of single‐agent alpelisib (BYL719) in Japanese patients with advanced solid malignancies. The primary objective of the study was to estimate the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of oral alpelisib in patients with advanced solid tumors who had progressed despite standard therapy. The expansion part included patients with PIK3CA mutation/amplification; safety, preliminary efficacy, pharmacokinetic (PK)/pharmacodynamic profile, and food effect on the PK profile of alpelisib at the MTD/RP2D were determined. Oral alpelisib was given as a single agent on a continuous 28‐day treatment cycle once daily. Overall, 33 patients received alpelisib. Dose‐limiting toxicities were observed in 2 patients in the escalation part (at 400 mg/day) and 1 patient in the expansion part (at 350 mg/day). The RP2D of alpelisib was determined as 350 mg/day based on overall safety profile in the dose escalation part and previous data from a Western population; the MTD was not determined. The most common all‐grade treatment‐suspected adverse events were hyperglycemia and maculopapular rash (48.5% each) and diarrhea (45.5%). The PK of alpelisib in the Japanese population was similar to that reported in the Western population. The overall response rate, disease control rate, and median progression‐free survival at 350 mg/day were 3%, 57.6%, and 3.4 months, respectively. Alpelisib as single agent showed a favorable safety profile and encouraging preliminary efficacy in Japanese patients with advanced solid tumors.     

Dose‐finding study of the checkpoint kinase 1 inhibitor,prexasertib, in Japanese patients with advanced solid tumors

Prexasertib is a novel inhibitor of checkpoint kinase 1. The primary objective of this study was to evaluate prexasertib tolerability in Japanese patients with advanced solid tumors. This nonrandomized single‐arm open‐label phase 1 study of prexasertib consisted of 2 dose levels, 80 mg/m² and the global‐recommended dose based on a US study of 105 mg/m², administered intravenously once every 14 days (n = 6 for each dose). Transition to the higher dose proceeded if the frequency of dose‐limiting toxicity observed in cycle 1 was <33% at the lower dose. Safety measures, pharmacokinetics and antitumor activity were assessed. A total of 12 patients were treated. Two patients, one in each dose group, experienced dose‐limiting toxicities of febrile neutropenia, one grade 4 and the other grade 3; both patients recovered and continued the study treatment. The grade 4 treatment‐emergent adverse events related to study treatment were neutropenia (6 patients [50.0%]), leukopenia (4 patients [33.3%]), and 1 instance each (8.3%) of anemia, febrile neutropenia and thrombocytopenia. Neutropenia was generally transient and reversible; 11 patients (91.7%) required granulocyte colony‐stimulating factor treatment during the study. There were no discontinuations due to adverse events or deaths. The prexasertib pharmacokinetics displayed dose‐independent and time‐independent behavior across both dose levels, similar to the profile observed in the US‐based phase 1 study. Eight patients had a best overall response of stable disease. These data are consistent with the known safety profile for prexasertib and confirm its tolerability in Japanese patients with advanced solid tumors.     

Phase I dose‐escalation trial of Sym004, an anti‐EGFR antibody mixture,in Japanese patients with advanced solid tumors

Sym004 is a 1:1 mixture of two antibodies targeting non‐overlapping epitopes of the epidermal growth factor receptor that antagonizes ligand binding and induces receptor downregulation. In preclinical models, it has superior antitumor activity to cetuximab and panitumumab. Japanese adults aged ≥20 years with an Eastern Cooperative Oncology Group status of 0/1 and life expectancy ≥3 months were eligible. Patients in Part A (dose escalation) had refractory or recurrent late‐stage solid tumors and received Sym004 6 mg/kg/wk (n = 3), 9 mg/kg loading/6 mg/kg/wk (n = 6), 12 mg/kg/wk (n = 6), or 18 mg/kg biweekly (n = 6). Patients in expansion Part B (n = 30) had esophageal squamous cell carcinoma and received Sym004 at the dose recommended from Part A. Fifty‐one patients received Sym004. No dose‐limiting toxicities were observed in Part A. A dose of 12 mg/kg/wk was selected for Part B. All patients in Part B experienced treatment‐related adverse events, most commonly dermatitis acneiform (76.7%). Eighteen grade ≥3 treatment‐related adverse events and five serious adverse events occurred (cardiac arrest, lung infection, interstitial lung disease, toxic skin eruption, blood creatinine increase). Two patients had treatment‐related adverse events resulting in death (cardiac arrest and blood creatinine increase). Five patients in Part B had a best overall response of partial response, 12 stable diseases and 12 disease progression (1 not evaluable). The objective response rate was 16.7% (95% CI: 5.6%‐34.7%). Sym004 therapy was well tolerated with no dose‐limiting toxicities at any dose studied. Evidence of antitumor activity was seen in patients with esophageal squamous cell carcinoma. ClinicalTrials.gov Identifier: NCT01955473.     

Phase I dose escalation study of telatinib (BAY 57-9352) in patients with advanced solid tumours

Telatinib (BAY 57-9352) is an orally available, small-molecule inhibitor of vascular endothelial growth factor receptors 2 and 3 (VEGFR-2/-3) and platelet-derived growth factor receptor β tyrosine kinases. In this multicentre phase I dose escalation study, 71 patients with refractory solid tumours were enroled into 14 days on/7 days off (noncontinuous dosing) or continuous dosing groups to receive telatinib two times daily (BID). Hypertension (23%) and diarrhoea (7%) were the most frequent study drug-related adverse events of CTC grade 3. The maximum-tolerated dose was not reached up to a dose of 1500 mg BID continuous dosing. Telatinib was rapidly absorbed with median t_max of 3 hours or less. Geometric mean C_max and AUC₀₋₁₂ increased in a less than dose-proportional manner and plateaued in the 900–1500 mg BID dose range. Two renal cell carcinoma patients reached a partial response. Tumour blood flow measured by contrast-enhanced magnetic resonance imaging and sVEGFR-2 plasma levels decreased with increasing AUC₀₋₁₂ of telatinib. Telatinib is safe and well tolerated up to a dose of 1500 mg BID continuous dosing. Based on pharmacokinetic and pharmacodynamic criteria, 900 mg telatinib BID continuously administered was selected as the recommended phase II dose.     

Phase I study of taselisib in Japanese patients with advanced solid tumors or hormone receptor‐positive advanced breast cancer

Taselisib is a potent and selective phosphatidylinositide 3‐kinase (PI3K) inhibitor. The present article reports the first study of taselisib administration in Japanese patients. The aim of this 2‐stage, phase I, multicenter, open‐label, dose‐escalation study was to evaluate the safety, pharmacokinetics, and preliminary efficacy of taselisib as monotherapy in Japanese patients with advanced solid tumors (stage 1), and as part of combination therapy in Japanese patients with hormone receptor (HR)‐positive locally advanced or recurrent breast cancer (stage 2). In stage 1, oral taselisib tablets 2, 4, and 6 mg/d were given in 28‐day cycles. In stage 2, successive cohorts of patients received oral taselisib tablets (2 or 4 mg/d) with i.m. fulvestrant 500 mg. Nine and 6 patients were enrolled in stage 1 and stage 2, respectively. Taselisib was well tolerated. No dose‐limiting toxicities were experienced in any cohort of patients and no deaths were observed. The most common treatment‐related adverse events in stage 1 and stage 2, respectively, were rash (55.6%, 66.7%), diarrhea (44.4%, 66.7%), and stomatitis (44.4%, 66.7%). Taselisib was rapidly absorbed after dosage; its half‐life was 12.9‐32.0 hours in stage 1 and 16.1‐26.5 hours in stage 2. Two patients achieved partial response (PR), 5 patients had stable disease (SD) and 2 patients had progressive disease (PD) in stage 1, and 1 patient had PR and 3 patients had SD in stage 2. All patients with PR were positive for PIK3CA gene mutations. These preliminary data suggest that taselisib may be effective in patients with PIK3CA‐mutated solid tumors or HR‐positive advanced breast cancer.     

Phase I study of oral gemcitabine prodrug (LY2334737) in Japanese patients with advanced solid tumors

Purpose

LY2334737 is an oral gemcitabine prodrug. This Phase I study assessed the safety and tolerability of LY2334737 in Japanese patients with solid tumors and evaluated pharmacokinetics (PK), pharmacodynamics, and antitumor activity.

Methods

Patients with advanced/metastatic solid tumors received escalating doses of LY2334737 once daily for 14 days, followed by a 7-day drug-free period. Cycles were repeated until discontinuation criteria were met.

Results

Of 13 patients treated, 3 received 20 mg/day, 6 received 30 mg/day, 4 received 40 mg/day. On the 40 mg dose, 3 patients experienced dose-limiting toxicities (DLTs): hepatic toxicities (e.g., Grade [G]3/4 transaminase and G1–3 bilirubin elevation) and G4 thrombocytopenia; all 3 showed features of disseminated intravascular coagulation. One additional DLT occurred on the 30 mg dose (G3 transaminase elevation). Exploratory pharmacogenetic analyses identified a genetic variation in the CES2 gene potentially associated with these DLTs. PK data showed no clear relationship between the AUC of gemcitabine and its incorporation into leukocyte DNA; 2 of the 3 DLT patients had high incorporation. Two patients (30 mg/day) achieved stable disease with progression-free survival lasting 135 and 155 days.

Conclusions

LY2334737 was tolerated by Japanese patients up to 30 mg/day. The toxicities observed at the 40 mg dose may require the development of alternative dosing schedules.     

Phase I dose escalation study of topotecan combined with alternating schedules of paclitaxel and carboplatin in advanced solid tumors

Background:Combining topotecan with other cytotoxics has been problematic due to marrow suppression. A phase I trial was initiated to identify the optimal sequence and maximum-tolerated dose of topotecan in combination with paclitaxel and carboplatin. Patients and methods:Patients with advanced cancer and performance status ECOG 2. The starting dose was paclitaxel 175 mg/m² day 1, carboplatin AUC 6.0 day 1, and topotecan 0.5 mg/m² daily day 1–5 (early sequence). The next course of paclitaxel and carboplatin administration was delayed to day 5 (late sequence). Treatment was repeated every three weeks. After determining maximum-tolerated dose without cytokines, granulocyte colony-stimulating factor (G-CSF) was added and further dose escalation was pursued. Results:Fifty-one patients were entered; men : women ratio 30 : 21. Dose-limiting toxicity (DLT) for the early sequence was neutropenia at doses paclitaxel mg/m²/carboplatin AUC 5/topotecan mg/m² (PCT) 175/5/0.75 for four to five days. DLT for the late sequence was neutropenia at PCT doses of 175/5/1.0 for four days. G-CSF 5 µg/kg subcutaneously starting day 6 permitted further topotecan dose escalation. After adding G-CSF, late sequence DLT was neutropenia at doses 175/5/1.25 for four days. Forty-six patients were evaluable for response and of those, there were thirteen partial responses. Conclusions:The late sequence resulted in less toxicity and was better tolerated. The early sequence maximum-tolerated dose (MTD) was 175/6/0.5 for five days. The late sequence MTD was PCT 175/5/0.75 for five days. The late sequence MTD with G-CSF was 175/5/1.0 for four days. The recommended phase II PCT dose is the late sequence 175/5/1.0 for four days with G-CSF.     

Phase I study of TAS-102 treatment in Japanese patients with advanced solid tumours

Background:

TAS-102 consists of α, α, α-trifluorothymidine (TFT) and an inhibitor of thymidine phosphorylase (TPI). We conducted a dose-escalation phase I study in Japanese patients with advanced solid tumours.

Methods:

TAS-102 was administered twice daily on days 1–5 and days 8–12 in a 28-day cycle to patients with solid tumours refractory to standard chemotherapy, to determine its maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetics (PKs). MTD was evaluated in cycle 1.

Results:

Safety and PKs were evaluated in 21 patients treated with TAS-102 at 30, 40, 50, 60, or 70 mg m⁻² per day. DLTs, such as grade 4 leucopenia, grade 4 neutropenia, and grade 4 thrombocytopenia, were observed in two patients at doses of 30 and 70 mg m⁻². α, α, α-trifluorothymidine and TPI exposures increased dose dependently, and the percentage of decrease in neutrophil count and TFT exposure were significantly correlated. The disease control rate was 50.0% with a median progression-free survival of 2.4 months in 18 colorectal cancer patients. The dose of TAS-102 was not increased above 70 mg m⁻² per day because of the increased tendency for grade 3 and 4 neutropenia, and 70 mg m⁻² per day was the recommended dose for phase II studies.

Conclusions:

TAS-102 at 70 mg m⁻² per day was tolerated in Japanese patients with advanced solid tumours. Phase II studies are ongoing in patients with colorectal cancer.     

Phase II clinical trial of peptide cocktail therapy for patients with advanced pancreatic cancer: VENUS‐PC study

We previously conducted a phase I clinical trial combining the HLA‐A*2402‐restricted KIF20A‐derived peptide vaccine with gemcitabine for advanced pancreatic cancer (PC) and confirmed its safety and immunogenicity in cancer patients. In this study, we conducted a multicenter, single‐armed, phase II trial using two antiangiogenic cancer vaccines targeting VEGFR1 and VEGFR2 in addition to the KIF20A peptide. We attempted to evaluate the clinical benefit of the cancer vaccination in combination with gemcitabine. Chemotherapy naïve PC patients were enrolled to evaluate primarily the 1‐year survival rate, and secondarily overall survival (OS), progression free survival (PFS), response rate (RR), disease control rate (DCR) and the peptide‐specific immune responses. All enrolled patients received therapy without the HLA‐A information, and the HLA genotypes were used for classification of the patients. Between June 2012 and May 2013, a total of 68 patients were enrolled. No severe systemic adverse effects of Grade 3 or higher related to these three peptides were observed. The 1‐year survival rates between the HLA‐A*2402‐matched and ‐unmatched groups were not significantly different. In the HLA‐A*2402 matched group, patients showing peptide‐specific CTL induction for KIF20A or VEGFR1 showed a better prognosis compared to those without such induction (P = 0.023, P = 0.009, respectively). In the HLA‐A*2402‐matched group, the patients who showed a strong injection site reaction had a better survival rate (P = 0.017) compared to those with a weak or no injection site reaction. This phase II study demonstrated that this therapeutic peptide cocktail might be effective in patients who demonstrate peptide‐specific immune reactions although predictive biomarkers are needed for patient selection in its further clinical application.     

Phase I study of dasatinib (BMS-354825) in Japanese patients with solid tumors

Dasatinib is a potent oral inhibitor of tyrosine kinases including the SRC family kinases, which are activated in tumors, and implicated in invasion and bone metastasis. This phase I dose-escalation study assessed safety, tolerability, maximum tolerated dose (MTD), antitumor activity, pharmacokinetics and pharmacodynamics in Japanese patients with refractory, advanced solid tumors. Dasatinib was administered once daily at 100, 150 and 200 mg/day. Sixteen patients were treated with dasatinib in the following doses: 100 mg (nine patients), 150 mg (three patients) and 200 mg (four patients). The most frequent adverse events (AE; ≥ 50%) were anorexia, fatigue, pleural effusion, anemia, constipation, diarrhea, vomiting and increased aspartate aminotransferase (AST). The most frequent AE of grade ≥ 3 (≥ 10%) were anemia, decreased lymphocyte count, fatigue and increased blood magnesium. Dose-limiting toxicities were observed in two patients: grade 2 pleural effusion and bronchial wall thickening at the 100-mg level and grade 3 dyspnea at the 200-mg level. In addition, grade 2 pleural effusion was observed in all four patients treated with 200 mg. Therefore, 150 mg was determined to be the MTD. The pharmacokinetic parameters were comparable among the dose levels. As a pharmacodynamic study, markers of bone metabolism were assessed. Bone resorption markers, NTx and TRACP-5b, showed a decrease of 46.3% and 22.2%, respectively. No objective responses were observed, but three patients had stable disease that lasted for over 6 months. In this study population, the safety profile of dasatinib was generally acceptable and 150 mg of dasatinib administered once daily was determined to be the MTD.     

Phase I dose escalation and pharmacokinetic study of oral enzastaurin (LY317615) in advanced solid tumors

Enzastaurin is an oral serine/threonine kinase inhibitor that targets the protein kinase C (PKC) and phosphoinositide 3‐kinase/AKT pathways to induce apoptosis and suppress proliferation of various cancer cell lines. This phase I study evaluated the tolerability and pharmacokinetics of enzastaurin in Japanese patients with advanced solid tumors and determined the recommended dose for phase II. Eligible patients had advanced solid tumors and an Eastern Cooperative Oncology Group performance status of 0–2. Patients received enzastaurin orally once daily until disease progression (PD) or unacceptable toxicity occurred. Enzastaurin was started at 250 mg/day followed by stepwise dose increases based on the incidence of dose‐limiting toxicities (DLT). Twenty‐three patients (seven patients: 250 mg; six patients: 375 mg; six patients: 500 mg; four patients: 750 mg) were enrolled and received enzastaurin. The major tumor types were non‐small‐cell lung cancer (n = 5) and breast cancer (n = 3). No DLT was reported at doses of 500 mg or less. Because two DLT (grade 2 QTc prolongation lasting for a week) were observed at 750 mg enzastaurin, this was determined as the maximum tolerated dose. Multiple daily doses at 500 mg achieved the target plasma concentration to inhibit PKC activity (1400 nmol/L). Enzastaurin was well tolerated up to 500 mg in Japanese patients with advanced solid tumors. The recommended dose for phase II was determined to be 500 mg daily for a 28‐day cycle on the basis of safety and plasma exposures. (Cancer Sci 2010);     

Phase I study of tivantinib in Japanese patients with advanced hepatocellular carcinoma: Distinctive pharmacokinetic profiles from other solid tumors

A c‐Met inhibitor tivantinib is a candidate anticancer agent for patients with hepatocellular carcinoma (HCC), and CYP2C19 is the key metabolic enzyme for tivantinib. Previous Japanese phase I studies in patients with solid tumors (except HCC) recommend 360 mg twice daily (BID) and 240 mg BID for CYP2C19 extensive metabolizers (EM) and poor metabolizers (PM), respectively. In this study, Japanese patients with HCC in whom sorafenib treatment has failed were enrolled to evaluate the safety, tolerability and pharmacokinetics of oral tivantinib as a single agent. The dose was escalated separately in EM and PM, from 120 mg BID to 240 mg BID, in both capsule and tablet formulations. A total of 28 patients (EM: 21, PM: 7) received tivantinib. At a dose of 120 mg BID, dose‐limiting toxicities (DLT) did not develop in 12 EM (capsule: 6, tablet: 6) and 7 PM (capsule: 4, tablet: 3) during the DLT‐observation period (for 29 days after first dosing). At this dose, the pharmacokinetic profiles of tivantinib (AUC_0–12 and C_max) did not remarkably differ between EM and PM. When treated with 240 mg BID, 5 of 9 EM (capsule: 4 of 6, tablet: 1 of 3) developed neutropenia‐related DLT accompanying plasma tivantinib concentration higher than expected from the previous studies. Consequently, PM did not receive 240 mg BID. In conclusion, 120 mg BID of tivantinib is recommended among Japanese patients with HCC regardless of CYP2C19 phenotype.     

Phase 1 dose escalation study of docetaxel with filgrastim support in patients with advanced solid tumors

Docetaxel has demonstrated activity in a broad range of solid tumors. Phase I trials have shown 100 mg/m(2) every 21 d to be the recommended dose. This phase I trial was designed to define the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of docetaxel with granulocyte colony-stimulating factor (G-CSF) support in patients with advanced solid tumors. Eligible patients had advanced malignancies and up to two prior chemotherapy regimens, ECOG PS = 0 1, adequate organ function, and gave written, informed consent. Docetaxel was escalated in cohorts of patients starting at 100 mg/m(2) on a 21-d schedule. Prophylactic G-CSF was administered on d 3 10. The DLT was defined as grade IV neutropenia >4 d, febrile neutropenia, grade IV thrombocytopenia, any grade III nonhematologic toxicity, or the inability to receive cycle 2 because of ongoing toxicity. Twenty-three patients were enrolled at doses up to 145 mg/m(2). The median age was 59 yr and the median number of prior chemotherapy regimens was 1. No DLT was observed at 100 mg/m(2), and 2 of 11 patients at 120 mg/m(2) experienced DLT (neutropenic fever and stomatitis). At 145 mg/m(2), one of eight patients had DLT (fatigue). Two of eight patients at 145 mg/m(2) had brief grade IV neutropenia (without fever), and none had grade III-IV thrombocytopenia or anemia. The docetaxel dose can be safely escalated to 145 mg/m(2) every 21 d with GCSF support, a 45% increase above the standard recommended phase II dose. Further studies will clarify the role of dose-intensified docetaxel.