Phase I study of veliparib in combination with gemcitabine.

BACKGROUND: Veliparib (ABT-888) is an oral PARP inhibitor expected to increase gemcitabine activity. This phase I determined the maximal tolerable dose (MTD), dose-limiting toxicities (DLT), antitumor activity, pharmacokinetics (PK), and pharmacodynamics (PD) of veliparib combined with gemcitabine. METHODS: Patients with advanced solid tumors received veliparib (10-40-mg PO BID) on chemotherapy weeks with gemcitabine 500-750-mg/m2 IV on days 1, 8, and 15 (28-day cycle), or on days 1 and 8 (21-day cycle). The MTD, DLT, adverse events, PK, and PD were evaluated. RESULTS: Eleven patients were enrolled on the 28-day schedule. The 28-day schedule was considered intolerable and amended to a 21-day schedule, with 20 patients enrolled. Grade ≥ 3 adverse events were myelosuppression-related. The MTD was determined to be 750-mg/m2 gemcitabine IV on days 1 and 8- and 20-mg PO veliparib BID days 1-14 on a 21-day schedule. Of 27 patients evaluable for response, 3 had PR and 15 had SD. There was no evidence of any major drug-drug interaction, and PK parameter values for veliparib, gemcitabine, and dFdU were as expected. Analysis of PBMCs showed evidence of PARP inhibition and DNA damage associated with therapy. CONCLUSIONS: Gemcitabine at 750-mg/m2 IV on days 1 and 8 combined with veliparib at a dose of 20-mg PO BID days 1-14 on a 21-day schedule is relatively well-tolerated, with manageable, expected toxicities. Clinical responses were observed in a pretreated population of patients, suggesting that this combination should be further evaluated in the phase II setting.

Long-term recurrence-free survival after an unplanned reduction in radiotherapy for HPV-positive oropharyngeal SCC: Two cases and a review of the literature.

There is currently no clear distinction between the treatment of HPV-positive and HPV-negative oropharyngeal squamous cell carcinoma (OPSCC). HPV-positive OPSCC has been demonstrated to be more radiosensitive than its HPV-negative counterpart. Despite this, patients with HPV-positive OPSCC continue to receive a full dose of radiation (70 Gy) outside clinical trials. However, this high dose comes with considerable morbidities, including severe mucositis, dysphagia, and xerostomia. We describe the cases of 2 patients with HPV-positive OPSCC who received two cycles of high-dose cisplatin at 100 mg/m2 on 3 separate days, along with concurrent radiotherapy at 50 Gy in 25 fractions for one and 46 Gy in 23 fractions for the other. During treatment, both patients experienced significant acute-phase toxicities-including grade 3 mucositis, grade 3 nausea, and grade 2 dermatitis-and their treatment regimen was stopped before its planned completion. Nevertheless, after a follow-up of 75 and 78 months, respectively, neither patient exhibited any evidence of disease. Late toxicities included grade 1 xerostomia, grade 1 pharyngeal-phase dysphagia, and grade 1 dysgeusia with some foods. We conclude that de-escalating the dose of radiation for HPV-positive patients by 30% and identifying which patients can safely be treated with this level of dose reduction warrants further study.

A week in the life of lung cancer survivors: Daily reports of stress, worry, mood, and symptoms.

This study examined the day-to-day lives of early stage lung cancer survivors who were discharged from treatment between 2 and 24 months prior to the study. Lung cancer survivors were called on eight consecutive nights and completed an interview about their daily experiences. Repeated measures, multilevel analysis of the phone interview data was conducted. Survivors reported few daily stressor exposures or somatic symptoms. Daily moods were generally positive, and survivors reported living quite independently. Lung cancer survivors did not report experiencing health-related worry on a daily basis. The findings from this study create a much more positive picture of lung cancer survivorship relative to prior studies.

Progress in Immunotherapy of Head and Neck Squamous Cell Carcinoma.

Squamous cell carcinoma of the mucosal surfaces of the head and neck area exhibits a complex interaction with the host immune system that plays an important part in the evolution of the malignant process, in the resistance to different therapeutic modalities, and the ability of tumor cells to metastasize to distant organs. The recent advances in tumor immunology have transformed the field in onco-immunology from using non-specific immune-stimulant agents such as interferon and interleukins to the area of rationally targeted immunotherapy such as immune checkpoint inhibitors, which have shown promising results in early phase clinical trials.

Impact of genetic markers on treatment of non-small cell lung cancer.

Non-small cell lung cancer represents a group of heterogeneous diseases. The last decade witnessed significant progress in improving our understanding of the biology of non-small cell lung cancer, which led to the identification of several genetic targets. Those genetic targets were utilized to explain clinical phenomena, such as the occurrence of non-small cell lung cancer in never-smokers, to predict response to conventional chemotherapy and biological agents, and to explain and predict resistance to therapy. The progress in the treatment of non-small cell lung cancer in the last few years was based on a new generation of population-enriched clinical trials that utilized genetic targets such as somatic EGFR mutations and ALK-EML4 mutations. In this review we will discuss the available information about the key genetic markers of non-small cell lung cancer and the pivotal clinical trials that validate the use of those genetic markers in non-small cell lung cancer patients.

Volociximab in cancer.

INTRODUCTION: Volociximab is a first-in-class chimeric monoclonal antibody that targets α5ß1 integrin. Preclinical studies have shown the ability of volociximab to inhibit tumor neoangiogenesis by blocking the interaction between α5ß1 and fibronectin. Volociximab's safety profile, pharmacokinetics and pharmacodynamics have been established. Ongoing clinical trials are evaluating its efficacy in the treatment of different types of solid tumors as a single agent or in combination with chemotherapy. In this review we focus on the biological effect of volociximab and results of completed clinical trials. AREAS COVERED: This review summarizes the structures and functions of integrin α5ß1 and its ligand fibronectin, provides an overview of the early development of volociximab, a targeted monoclonal antibody that specifically binds and inhibits activation of integrin α5ß1, and discusses the relevant data from pre-clinical and clinical studies. EXPERT OPINION: Volociximab has been well tolerated as monotherapy or in combination with chemotherapy. It has shown promising activity in different types of cancer. Randomized trials are required to validate those early results.