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Schaefer E.S.,Highlands Oncology Group | Baik C.,University of Washington
Cancer Management and Research | Year: 2016

Anaplastic lymphoma kinase (ALK) gene fusions occur in 3%–7% of non-small-cell lung cancer (NSCLC) cases. Ceritinib, a once-daily, oral ALK inhibitor, has activity against crizotinib-resistant and crizotinib-naïve NSCLC, including brain metastases. Ceritinib (Zykadia™) was granted accelerated approval by the US Food and Drug Administration in 2014 for treating crizotinib-resistant ALK-positive NSCLC. Adverse events (AEs), particularly gastrointestinal (GI) AEs, are commonly experienced at the recommended dose of 750 mg/d and ∼38% of patients require dose interruption or reduction for GI AEs. This case study details our experience with the use of proactive GI AE management regimens in patients treated with ceritinib (750 mg/d) across two study sites. Proactive Regimens A and B were implemented in patients with metastatic ALK-positive NSCLC treated with ceritinib to manage drug-related GI AEs. Regimen A comprised ondansetron and diphenoxylate/atropine or loperamide, taken 30 minutes prior to ceritinib dose. Regimen B included dicyclomine (taken with the first ceritinib dose), ondansetron (taken 30 minutes prior to ceritinib dose for the first seven doses), and loperamide (taken as needed with the onset of diarrhea). The proactive medications were tapered off depending on patient tolerability to ceritinib. Nine patient cases are presented. Starting Regimens A or B before the first dose of ceritinib, or as soon as GI symptoms were encountered, prevented the need for dose reduction due to GI toxicity in eight of the nine patients. Using these regimens, 78% of patients were able to remain on 750 mg/d fasting. Two patients received 23 months and 16 months of therapy and remain on ceritinib 750 mg/d and 600 mg/d, respectively. Although not currently recommended or implemented in clinical studies, based on the patients evaluated here, upfront or proactive treatment plans that address AEs early on can allow the majority of patients to remain on the approved 750 mg/d ceritinib dose. © 2016 Schaefer and Baik. Source


Brufsky A.M.,University of Pittsburgh | Harker W.G.,Utah Cancer Specialists | Beck J.T.,Highlands Oncology Group | Bosserman L.,Wilshire Oncology Medical Group Inc. | And 7 more authors.
Cancer | Year: 2012

Background: Postmenopausal breast cancer (BC) patients receiving adjuvant aromatase inhibitor therapy are at risk of progressive bone loss and fractures. Zoledronic acid inhibits osteoclastic bone resorption, is effective in maintaining bone health, and may therefore be beneficial in this setting. Methods: Overall, 602 postmenopausal women with early, hormone receptor-positive BC receiving adjuvant letrozole were randomized (301 each group) to receive upfront or delayed-start zoledronic acid (4 mg intravenously every 6 months) for 5 years. The primary endpoint was the change in lumbar spine (LS) bone mineral density (BMD) at month 12. Secondary endpoints included changes in LS BMD, total hip BMD, and bone turnover markers at 2, 3, and 5 years; fracture incidence at 3 years; and time to disease recurrence. Results: At month 61, the adjusted mean difference in LS and total hip BMDs between the upfront and delayed groups was 8.9% and 6.7%, respectively (P <.0001, for both). Approximately 25% of delayed patients received zoledronic acid by month 61. Only 1 patient experienced grade 4 renal dysfunction; no confirmed cases of osteonecrosis of the jaw were reported. Fracture rates (upfront, 28 [9.3%]; delayed, 33 [11%]; P =.3803) and Kaplan-Meier disease recurrence rates (upfront, 9.8 [95% confidence interval (CI), 6.0-10.3]; delayed, 10.5 [95% CI, 6.6-14.4]; P =.6283) were similar at month 61. Conclusions: Upfront zoledronic acid seems to be the preferred treatment strategy versus delayed administration, as it significantly and progressively increases BMD in postmenopausal women with early BC receiving letrozole for 5 years, and long-term coadministration of letrozole and zoledronic acid is well tolerated. © 2011 American Cancer Society. Source


Iyer S.P.,Cornell College | Beck J.T.,Highlands Oncology Group | Stewart A.K.,Mayo Medical School | Shah J.,University of Texas M. D. Anderson Cancer Center | And 5 more authors.
British Journal of Haematology | Year: 2014

Dickkopf-1 (DKK1), expressed by myeloma cells, suppresses osteoblast function and plays a key role in bone disease in multiple myeloma. BHQ880, a human neutralizing IgG1 anti-DKK1 monoclonal antibody, is being investigated for its impact on multiple myeloma-related bone disease and as an agent with potential anti-myeloma activity. The primary objectives of this Phase IB study were to determine the maximum tolerated dose (MTD) of BHQ880 and to characterize the dose-limiting toxicity (DLT) of escalating doses in combination with anti-myeloma therapy and zoledronic acid. Twenty-eight patients were enrolled and received BHQ880 at doses of 3-40 mg/kg. No DLTs were reported, therefore, the MTD was not determined. The recommended Phase II dose was declared as 10 mg/kg, based mainly on saturation data. There was a general trend towards increased bone mineral density (BMD) observed over time; specific increases in spine BMD from Cycle 12 onwards irrespective of new skeletal-related events on study were observed, and increases in bone strength at the spine and hip were also demonstrated in some patients. BHQ880 in combination with zoledronic acid and anti-myeloma therapy was well tolerated and demonstrated potential clinical activity in patients with relapsed or refractory multiple myeloma. © 2014 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd. Source


Saura C.,University of Barcelona | Bendell J.,Sarah Cannon Research Institute | Jerusalem G.,CHU Sart Tilman | Su S.,Novartis | And 13 more authors.
Clinical Cancer Research | Year: 2014

Purpose: Phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway activation in patients with HER2-positive (HER2+) breast cancer has been implicated in de novo and acquired trastuzumab resistance. The purpose of this study was to determine the clinical activity of the PI3K inhibitor buparlisib (BKM120) in patients with HER2+ advanced/metastatic breast cancer resistant to trastuzumab-based therapy. Experimental Design: In the dose-escalation portion of this phase I/II study, patients with trastuzumabresistant locally advanced or metastatic HER2+ breast cancer were treated with daily oral doses of buparlisib and weekly intravenous trastuzumab (2 mg/kg). Dose escalation was guided by a Bayesian logistic regression model with overdose control. Results: Of 18 enrolled patients, 17 received buparlisib. One dose-limiting toxicity of grade 3 general weakness was reported at the 100-mg/day dose level (the single-agent maximum tolerated dose) and this dose level was declared the recommended phase II dose (RP2D) of buparlisib in combination with trastuzumab. Common (>25%) adverse events included rash (39%), hyperglycemia (33%), and diarrhea (28%). The pharmacokinetic profile of buparlisib was not affected by its combination with trastuzumab. At the RP2D, there were two (17%) partial responses, 7 (58%) patients had stable disease (≥6 weeks), and the disease control rate was 75%. Pharmacodynamic studies showed inhibition of the PI3K/AKT/mTOR and RAS/MEK/ERK pathways. Conclusions: In this patient population, the combination of buparlisib and trastuzumab was well tolerated, and preliminary signs of clinical activity were observed. The phase II portion of this study will further explore the safety and efficacy of this combination at the RP2D. ©2014 AACR. Source


Beck J.T.,Highlands Oncology Group | Ismail A.,University of Arkansas for Medical Sciences | Tolomeo C.,University of Arkansas for Medical Sciences
Cancer Treatment Reviews | Year: 2014

Squamous cell lung carcinoma accounts for approximately 30% of all non-small cell lung cancers (NSCLCs). Despite progress in the understanding of the biology of cancer, cytotoxic chemotherapy remains the standard of care for patients with squamous cell lung carcinoma, but the prognosis is generally poor. The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is one of the most commonly activated signaling pathways in cancer, leading to cell proliferation, survival, and differentiation. It has therefore become a major focus of clinical research. Various alterations in the PI3K/AKT/mTOR pathway have been identified in squamous cell lung carcinoma and a number of agents targeting these alterations are in clinical development for use as single agents and in combination with other targeted and conventional treatments. These include pan-PI3K inhibitors, isoform-specific PI3K inhibitors, AKT inhibitors, mTOR inhibitors, and dual PI3K/mTOR inhibitors. These agents have demonstrated antitumor activity in preclinical models of NSCLC and preliminary clinical evidence is also available for some agents. This review will discuss the role of the PI3K/AKT/mTOR pathway in cancer and how the discovery of genetic alterations in this pathway in patients with squamous cell lung carcinoma can inform the development of targeted therapies for this disease. An overview of ongoing clinical trials investigating PI3K/AKT/mTOR pathway inhibitors in squamous cell lung carcinoma will also be included. © 2014 Elsevier Ltd. Source

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