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

Richter’s Syndrome with Hypercalcemia Induced by Tumor-Associated Production of Parathyroid Hormone-Related Peptide

Humoral hypercalcemia due to parathyroid hormone-related peptide (PTHrP) elevation is a well-known complication of various malignancies, but the situation is rare concerning hematological malignancies except for adult T-cell leukemia/lymphoma. We report a case of Richter’s syndrome with humoral hypercalcemia, and demonstrate by reverse transcription polymerase chain reaction (RT-PCR) that peripheral blood PTHrP levels were 2,500-fold higher compared to healthy controls. PTHrP production by tumor cells in chronic lymphocytic leukemia (CLL) and Richter’s syndrome has been previously demonstrated by nonquantitative methods such as immunohistochemistry and northern blot analysis, but this is the first report using the RT-PCR method. The presented case did not have hypercalcemia when initially diagnosed as small lymphocytic lymphoma (SLL), and as reported earlier, the development of hypercalcemia may be an indication of the transformation to Richter’s syndrome in patients with CLL/SLL

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

Phase I study of LJM716 in Japanese patients

Purpose: Human epidermal growth factor receptor 3 (HER3) has been identified as an important component of many receptor tyrosine kinase-driven cancers. LJM716 is a human IgG monoclonal antibody that binds HER3, trapping it in an inactive conformation. In this study, a phase I dose escalation was performed with a primary objective to establish the maximum tolerated dose and/or the recommended dose of LJM716 in Japanese patients with selected advanced solid tumors. Secondary objectives included the evaluation of the safety and tolerability, preliminary antitumor activity, and pharmacokinetics of LJM716 in Japanese patients. Methods: LJM716 was administered intravenously at doses of 10, 20, or 40 mg/kg once weekly, in 28-day cycles, to 12 patients with HER2-amplified breast cancer or gastric cancer, or with esophageal squamous cell carcinoma or squamous cell carcinoma of the head and neck, regardless of HER2 status. Results: The maximum tolerated dose was not reached and the recommended dose was established at 40 mg/kg. No dose-limiting toxicities were observed in the first cycle. The most frequently reported adverse events were diarrhea, fatigue, stomatitis, pyrexia, and paronychia. One unconfirmed partial response was observed in a patient with breast cancer and 50 % of the patients achieved stable disease as the best overall response. Exposure increased with ascending dose, and half-life was estimated to be 11–14 days. No anti-LJM716 antibodies were detected. Conclusions: LJM716 was well tolerated in Japanese patients, and a degree of tumor shrinkage was observed. Keywords: HER3; HER2; LJM716; monoclonal antibody; phase I Clinical trial information: ClinicalTrials.gov NCT0191193