Junichi Tomomatsu

Incidence of Pneumothorax in Advanced and/or Metastatic Soft Tissue Sarcoma Patients during Pazopanib Treatment

Sird After pazopanib’s approval for the treatment of soft tissue sarcomas, pneumothorax was reported as an unexpected adverse event linked to pazopanib treatment. Pneumothorax was rarely reported in the pre-approval clinical trials of pazopanib [1], so the incidence of pneumothorax during pazopanib treatment has not yet been established. We retrospectively reviewed the cases of 32 soft tissue sarcoma patients treated with pazopanib between November 2012 and December 2013 at our institute. The median follow-up time was 3.1 months (range 0.3e9.6

A comparison of weekly paclitaxel and cetuximab with the EXTREME regimen in the treatment of recurrent/metastatic squamous cell head and neck carcinoma

BACKGROUND The effectiveness of the combination chemotherapy of weekly paclitaxel and cetuximab has not yet been compared to that of the current standard regimen, EXTREME (combination of 5-fluorouracil, cisplatin and cetuximab). METHODS We retrospectively reviewed the clinical records of R/M SCCHN patients who received cetuximab-containing chemotherapy as a first-line therapy; from these, patients receiving a weekly paclitaxel and cetuximab regimen (cohort A) and the EXTREME regimen (cohort B) were extracted. The responses, prognoses and adverse events of these two cohorts were evaluated. RESULTS A total of 86 patients were included (cohort A, 49; cohort B, 36). Patients with histories of platinum-based chemotherapy were more frequently given the cohort A treatment. Though the response rates were similar in the two cohorts (45% in cohort A and 51% in cohort B; p=0.83), the progression-free survival (PFS) was significantly more favorable in cohort A by the log-rank test (6.0monthsvs 5.0months; p=0.027). In the Cox-regression hazard analyses, male gender (hazard ratio [HR]=2.1, p=0.010), older age (≥ 70 yo) (HR=5.0, p=0.018), PS 0 (HR=2.2, p=0.027), no history of platinum chemotherapy (HR=3.2, p=0.003) and the presence of a tracheostomy (HR=2.3, p=0.039) were favorable factors within cohort A. CONCLUSION In selected R/M SCCHN patients, the combination of weekly paclitaxel and cetuximab could be the better treatment option than the EXTREME regimen.

SAFETY AND TOLERABILITY OF VANDETANIB IN JAPANESE PATIENTS WITH MEDULLARY THYROID CANCER: A PHASE I/II OPEN-LABEL STUDY

OBJECTIVE In a phase III trial, Western patients with medullary thyroid cancer (MTC) treated with the oral multikinase inhibitor vandetanib showed significantly improved progression-free survival (PFS) and objective response rate (ORR) compared with placebo. The biology of MTC and pharmacokinetics (PK) are similar for Japanese and Western patients; therefore, similar clinical benefit is anticipated in the Japanese population. This study evaluated the safety and tolerability of vandetanib in Japanese patients with unresectable locally advanced or metastatic MTC. METHODS This was a phase I/II, open-label, nonrandomized study. Patients received vandetanib (300 mg daily) until objective disease progression. The primary endpoints were safety and tolerability. Secondary endpoints included efficacy and PK. Final data analysis was conducted once all patients with measurable baseline disease had been followed to progression, or for 56 weeks. RESULTS Fourteen patients received vandetanib. All patients experienced at least one adverse event (AE), and 7 patients (50%) experienced grade ≥3 AEs. Common AEs included diarrhea (79%), hypertension (64%), and rash (43%). Four patients reported a total of five serious AEs (SAEs). Eleven patients (79%) had dose interruptions, and 8 patients (57%) had dose reductions. One patient discontinued treatment because of an SAE (interstitial lung disease). No patients met the prespecified criterion for QTc prolongation. The ORR was 38% and PFS at 12 months was 85%. CONCLUSION Safety and efficacy data were comparable to those previously reported, and AEs were generally manageable by standard clinical practice or dose modifications. Overall, vandetanib was considered to be beneficial for Japanese MTC patients. ABBREVIATIONS AE = adverse event CI = confidence interval Css,max = maximum steady-state plasma concentration DCR = disease control rate EGFR = epidermal growth factor receptor ILD = interstitial lung disease MTC = medullary thyroid cancer ORR = objective response rate PFS = progression-free survival PK = pharmacokinetics RECIST = Response Evaluation Criteria in Solid Tumors RET = re-arranged during transfection SAE = serious adverse event VEGFR = vascular endothelial growth factor receptor.

Abstract C120: Phase I study of the safety and tolerability of LJM716 in Japanese patients with advanced solid tumors

Background: Human epidermal growth factor receptor 3 (HER3) is implicated in tumor growth, proliferation, drug resistance, and metastasis. LJM716 is a fully humanized anti-HER3 IgG1 monoclonal antibody with single-agent and combination anti-tumor activity in HER2-amplified and neuregulin-expressing xenografts. This open-label dose escalation Phase I study evaluated the safety and tolerability of single-agent LJM716 in Japanese patients (pts) with HER2+ advanced/metastatic breast (BC) or gastric cancer (GC), and recurrent/metastatic esophageal squamous cell carcinoma (ESCC) or squamous cell carcinoma of the head and neck (SCCHN) regardless of HER2 status. Methods: Pts (aged ≥18 years, ECOG PS 0‒2) received intravenous (IV) once-weekly (QW) LJM716 in 28 day cycles. The primary objective was to determine the maximum tolerated dose (MTD) and/or recommended dose (RD). Secondary objectives included safety and tolerability, preliminary anti-tumor activity, and pharmacokinetics. Dose escalation decisions were made based on a synthesis of all relevant data, guided by an adaptive Bayesian logistic regression model (BLRM) on dose limiting toxicities (DLTs). Results: At the data cutoff date of Jun 3, 2015, 12 pts (SCCHN [n = 2], ESCC [n = 2], and HER2+ BC [n = 6] or GC [n = 2]) were enrolled (median age 58 years, 50% male, 58% ECOG PS 0). Pts were treated in 3 dose cohorts of 10‒40 mg/kg QW; the median duration of exposure to LJM716 was 14.0 weeks (range 4.0‒48.1). No DLT was reported during Cycle 1; at 40 mg/kg QW 1 pt experienced a DLT of Grade (Gr) 3 pneumonia aspiration during Cycle 2. The BLRM with overdose control supported the tolerability of LJM716 up to 40 mg/kg QW based on DLTs occurring during Cycle 1. However, DLTs occurring after Cycle 1 were also clinically considered, and 40 mg/kg QW was declared as the RD in Japanese pts; the MTD was not reached. One or more adverse event (AE) suspected as drug related were experienced by 10 (83%) pts; most commonly (≥25%) diarrhea (6 pts [50%]), stomatitis, paronychia, fatigue, and pyrexia (3 pts [25%] each). Four pts (33%) experienced ≥1 Gr 3/4 drug-related AEs (all at 40 mg/kg QW): pneumonia aspiration and neutropenia (1 pt [8%] each) and lymphocyte count decreased (2 pts [17%]). Serious AEs were experienced by 2 pts (17%); Gr 2 nausea and Gr 1 vomiting (not suspected as drug related) and Gr 3 pneumonia aspiration (suspected as drug related). One pt died within the follow up period after the last dose of study drug due to disease progression. LJM716 plasma concentration increased with dose, and mean AUClast and Cmax were similar to those found in Western pts. There were no complete or partial responses; stable disease was reported in 6 (50%) pts. Conclusion: LJM716 was well tolerated with a manageable safety profile, and the RD of LJM716 was established at 40 mg/kg QW IV in Japanese pts - the same RD as determined in Western pts in a separate clinical trial. Clinical trials identifier: NCT01911936. Citation Format: TAITO ESAKI, HISANOBU ODA, TATSUHIRO KAJITANI, TAKAYUKI KOBAYASHI, JUNICHI TOMOMATSU, TOMOYUKI KAKIZUME, TAKAHIRO WATANABE, HIROMI TAKEUCHI, KOICHI FUKINO, SHUNJI TAKAHASHI. Phase I study of the safety and tolerability of LJM716 in Japanese patients with advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C120.

Outcome for Advanced or Metastatic Soft Tissue Sarcoma of Nonextremities Treated with Doxorubicin-Based Chemotherapy: A Retrospective Study from a Single Cancer Institution

Background Doxorubicin is the key drug for treatment of advanced soft tissue sarcoma (STS). The appropriate dosage of doxorubicin, regarding monotherapy or the role of combination therapy, is unclear. Methods We retrospectively reviewed patients with advanced or metastatic STS of nonextremities who were treated with doxorubicin-based chemotherapies in our institution. Time to treatment failure (TTF), overall survival (OS), overall response, and prognostic factors for OS were evaluated. Results Seventy-five patients were enrolled. The median TTF was 4.7 months, and the median OS was 20.1 months. The overall response rate was 20%. Doses of doxorubicin monotherapy did not show significant difference either in TTF or in OS. There were no significant differences in OS between combination therapy and monotherapy, but the TTF with combination therapy was better than monotherapy. The overall response for combination therapy indicated a better response rate. Less number of involved organs, no bulky mass, and a normal CRP level were independent favorable prognostic factors for OS. Conclusions Combination therapy showed better response and TTF than monotherapy but did not show better OS. Possible prognostic factors for OS were indicated. This retrospective study was approved by the institutional review board. This trial is registered with UMIN000028787.

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.

O1-7-5Incidence and risk factors of interstitial lung disease (ILD) of head and neck cancer patients treated with Cetuximab

Yongchel Ahn, Cheon-Soo Park, HyukJai Jang, JiHwan Lee, Mikyong Byun, Byung-Gon Park, Woon-Seob Shin, Yoon-Sun Park, Seokjoon Lee, Daeho Kwon Department of Hematology and Oncology, Gangneung Asan Hospital, University of Ulsan College of Medicine, Korea, Department of Surgery, Gangneung Asan Hospital, University of Ulsan College of Medicine, Medical Research Center, Gangneung Asan Hospital, University of Ulsan College of Medicine, Department of Nursing, Korea University College of Nursing, Department of Physiology, Catholic Kwandong University College of Medicine, Department of Pharmacology, Catholic Kwandong University College of Medicine, Department of Microbiology, Catholic Kwandong University College of Medicine

P1-293Eight patients with mucosal malignant melanoma treated by nivolumab: a retrospective analysis in a single institution

Methotrexate and azathioprine had been administered to the patients with RA and MCTD, respectively. All 6 patients were histologically diagnosed as diffuse large B cell lymphoma. Because of the use of immunosuppressive drugs, 2 patients with RA and MCTD were classified as “other iatrogenic immunodeficiency-associated lymphoproliferative disorders” according to WHO classification (2008). The Ann Arbor clinical stages were II AE for 3 non-AD patients, and IV AE for 3 patients with ADs. According to the International Prognostic Index, all patients with ADs were classified as high risk. All patients received R-CHOP-like chemotherapy along with central nervous system (CNS) prophylaxis. Except for one patient who is receiving chemotherapy, all the patients achieved complete remission after the first chemotherapy regimen. Relapse was observed in two patients including one patient who experienced relapse in the CNS and the skin. Three patients have maintained complete remission at present, including one patient who is in the second complete remission for more than 8 years after salvage therapy for relapse. In cases with ADs, immunosuppressant was discontinued. There was no symptomatic worsening of ADs after chemotherapy.