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Nemunaitis J.,Mary Crowley Cancer Research Centers | Mita A.,Cancer Therapy and Research Center | Stephenson J.,Cancer Centers of the Carolinas | Mita M.M.,Cancer Therapy and Research Center | And 6 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2013

Purpose: Omacetaxine mepesuccinate is a first-in-class cephalotaxine demonstrating clinical activity in chronic myeloid leukemia. A subcutaneous (SC) formulation demonstrated efficacy and safety in phase 1/2 trials in patients previously treated with ≥1 tyrosine kinase inhibitor. This study assessed pharmacokinetics and safety of SC omacetaxine in patients with advanced cancers. Methods: Omacetaxine 1.25 mg/m2 SC was administered BID, days 1-14 every 28 days for 2 cycles, until disease progression or unacceptable toxicity. Blood and urine were collected to measure omacetaxine concentrations and inactive metabolites. Adverse events, including QT interval prolongation, were recorded. Tumor response was assessed at cycle 2 completion. Results: Pharmacokinetic parameters were estimated from cycle 1, day 1 data in 21 patients with solid tumors or hematologic malignancies and cycle 1, day 11 data in 10 patients. Omacetaxine was rapidly absorbed, with mean peak plasma concentrations observed within 1 h, and widely distributed, as evidenced by an apparent volume of distribution of 126.8 L/m2. Plasma concentration versus time data demonstrated biexponential decay; mean steady-state terminal half-life was 7 h. Concentrations of inactive metabolites 4′-DMHHT and cephalotaxine were approximately 10 % of omacetaxine and undetectable in most patients, respectively. Urinary excretion of unchanged omacetaxine accounted for <15 % of the dose. Grade 3/4 drug-related adverse events included thrombocytopenia (48 %) and neutropenia (33 %). Two grade 2 increases in QTc interval (>470 ms) were observed and were not correlated with omacetaxine plasma concentration. No objective responses were observed. Conclusions: Omacetaxine is well absorbed after SC administration. Therapeutic plasma concentrations were achieved with 1.25 mg/m2 BID, supporting clinical development of this dose and schedule. © 2012 The Author(s).

Infante J.R.,Tennessee Oncology PLLC | Reid T.R.,University of California at San Diego | Cohn A.L.,Rocky Mountain Cancer Centers | Edenfield W.J.,Cancer Centers of the Carolinas | And 10 more authors.
Cancer | Year: 2013

BACKGROUND In this multicenter, open-label, randomized phase 2 trial, the authors evaluated the vascular endothelial growth factor receptor inhibitor axitinib, bevacizumab, or both in combination with chemotherapy as first-line treatment of metastatic colorectal cancer (mCRC). METHODS Patients with previously untreated mCRC were randomized 1:1:1 to receive continuous axitinib 5 mg twice daily, bevacizumab 5 mg/kg every 2 weeks, or axitinib 5 mg twice daily plus bevacizumab 2 mg/kg every 2 weeks, each in combination with modified 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX-6). The primary endpoint was the objective response rate (ORR). RESULTS In all, 126 patients were enrolled from August 2007 to September 2008. The ORR was numerically inferior in the axitinib arm (n = 42) versus the bevacizumab arm (n = 43; 28.6% vs 48.8%; 1-sided P =.97). Progression-free survival (PFS) (11.0 months vs 15.9 months; 1-sided P =.57) and overall survival (OS) (18.1 months vs 21.6 months; 1-sided P =.69) also were numerically inferior in the axitinib arm. Similarly, efficacy endpoints for the axitinib/bevacizumab arm (n = 41) were numerically inferior (ORR, 39%; PFS, 12.5 months; OS, 19.7 months). The patients who received axitinib had fewer treatment cycles compared with other arms. Common all-grade adverse events across all 3 treatment arms were fatigue, diarrhea, and nausea (all ≥49%). Hypertension and headache were more frequent in the patients who received axitinib. Patients in the bevacizumab arm had the longest treatment exposures and the highest rates of peripheral neuropathy. CONCLUSIONS Neither the addition of continuous axitinib nor the axitinib/bevacizumab combination to FOLFOX-6 improved ORR, PFS, or OS compared with bevacizumab as first-line treatment of mCRC. © 2013 American Cancer Society.

Robert N.J.,Virginia Cancer Specialists | Paul D.,Rocky Mountain Cancer Center | Generali D.,Senologia e Breast Unit | Gressot L.,Northwest Cancer Center | And 11 more authors.
Clinical Breast Cancer | Year: 2011

Introduction: A multicenter, open-label phase III study was conducted to test whether sunitinib plus paclitaxel prolongs progression-free survival (PFS) compared with bevacizumab plus paclitaxel as first-line treatment for patients with HER2- advanced breast cancer. Patients and Methods: Patients with HER2- advanced breast cancer who were disease free for ≥ 12 months after adjuvant taxane treatment were randomized (1:1; planned enrollment 740 patients) to receive intravenous (I.V.) paclitaxel 90 mg/m2 every week for 3 weeks in 4-week cycles plus either sunitinib 25 to 37.5 mg every day or bevacizumab 10 mg/kg I.V. every 2 weeks. Results: The trial was terminated early because of futility in reaching the primary endpoint as determined by the independent data monitoring committee during an interim futility analysis. At data cutoff, 242 patients had been randomized to sunitinib-paclitaxel and 243 patients to bevacizumab-paclitaxel. Median PFS was shorter with sunitinib-paclitaxel (7.4 vs. 9.2 months; hazard ratio [HR] 1.63 [95% confidence interval (CI), 1.18-2.25]; 1-sided P =.999). At a median follow-up of 8.1 months, with 79% of sunitinib-paclitaxel and 87% of bevacizumab-paclitaxel patients alive, overall survival analysis favored bevacizumab-paclitaxel (HR 1.82 [95% CI, 1.16-2.86]; 1-sided P =.996). The objective response rate was 32% in both arms, but median duration of response was shorter with sunitinib-paclitaxel (6.3 vs. 14.8 months). Bevacizumabpaclitaxel was better tolerated than sunitinib-paclitaxel. This was primarily due to a high frequency of grade 3/4, treatment-related neutropenia with sunitinib-paclitaxel (52%) precluding delivery of the prescribed doses of both drugs. Conclusion: The sunitinib-paclitaxel regimen evaluated in this study was clinically inferior to the bevacizumabpaclitaxel regimen and is not a recommended treatment option for patients with advanced breast cancer. © 2011 Elsevier Inc. All rights reserved.

Pokrzywinski R.,United Biosource Corporation | Secord A.A.,Duke University | Havrilesky L.J.,Duke University | Puls L.E.,Cancer Centers of the Carolinas | And 6 more authors.
Gynecologic Oncology | Year: 2011

Objectives: A phase II clinical trial compared docetaxel in combination with carboplatin to sequential single agent docetaxel followed by carboplatin for treatment of recurrent platinum-sensitive ovarian, peritoneal, or tubal cancer. This manuscript reports prospectively collected health-related quality of life (HRQL). Methods: Participants were randomized to either weekly docetaxel 30 mg/m 2/days 1 and 8 and carboplatin AUC 6/day 1 every 3 weeks (cDC) or docetaxel 30 mg/m 2/days 1 and 8, repeated every 3 weeks for 6 cycles followed by carboplatin AUC 6/day 1 every 3 weeks for 6 cycles or until disease progression (sDC). The primary HRQL endpoint was the trial outcome index (TOI) score of the Functional Assessment of Cancer Therapy-Ovarian (FACT-O) instrument, and was assessed as an intent-to-treat analysis. The secondary HRQL endpoints included the FACT-O total score, the FACT-General, and several domain scores of the FACT-O instrument (physical well-being (PWB), social/family well-being (SWB), emotional well-being (EWB), functional well-being (FWB), and the ovarian cancer specific (OCS) module). The FACT-O was administered at randomization, prior to each of 6 cycles of treatment, and at study endpoint. Results: One hundred forty-eight participants were randomized to each group. Sequential docetaxel followed by carboplatin (sDC) was associated with significant improvements in the FACT-O TOI (p = 0.013), FACT-O total score (p = 0.033), and OCS (p = 0.029) compared to the combination docetaxel and carboplatin group (cDC). Conclusions: Sequential single agent docetaxel followed by carboplatin is associated with improved HRQL when compared to cDC. The improved progression-free survival observed with cDC should be weighed against lower quality of life during treatment. © 2011 Elsevier Inc. All rights reserved.

Reynolds C.,Ocala Oncology | Reynolds C.,McKesson | Spira A.I.,Virginia Cancer Specialists | Spira A.I.,McKesson | And 6 more authors.
Investigational New Drugs | Year: 2013

Background Some elderly patients may have reduced tolerance the standard therapy (chemotherapy doublets) for stage III/IV non-small cell lung cancer (NSCLC). Sunitinib malate (S), an oral, multitargeted kinase inhibitor, shows promise as 2nd-line NSCLC treatment. This study explored the safety/efficacy of S in elderly patients with previously untreated NSCLC. Methods Primary objective: disease control rate (DCR) at six-weeks. Secondary objectives: overall response (OR, CR+PR), progression-free survival (PFS), time to progression (TTP), one-yr survival, quality of life (QOL), and safety. Treatment: S 37.5 mg daily/42-day cycle until PD or intolerable toxicity. Key inclusion: chemo-naïve stage IIIB/IV NSCLC (nonsquamous histology); ECOG PS = 0-1; ≥70 years; normal organ function. Exclusion: hemoptysis, anticoagulation, or clotting diathesis. Other standard S-specific criteria applied. Results 63 patients enrolled/60 treated. Demographics: 51 % male, 95 % white, median age 78 years (range, 70-88), 73 % ECOG = 1, 97 % Stage IV, 83 % adenocarcinoma, 44 % prior surgery, 19 % prior radiation. With a median of 2 cycles (range, 1-16), DCR = 63 %, OR = 7 % (0 CR, 4 PR). Median follow-up = 5.8 months (all; 15.9 months survivors), median PFS = 3.0 months (range, <1-25.1), median TTP = 4.5 months (range, <1-25.1), and 1-year survival = 26.4 % [95 % CI: 15.9, 38.2]. QOL declined initially, but improved over time. Treatment-related adverse events included: fatigue (48.3 %); diarrhea (38.3 %); thrombocytopenia (33.3 %), anorexia (26.7 %), mucositis (25.0 %); nausea (25.0 %), dysgeusia (20.0 %), and neutropenia (20.0 %). Conclusions The study met its primary endpoint. S produced acceptable DCR and QOL improved; however, OR was disappointing (7 %) and toxicity was greater than expected. A biomarker to identify patients more likely to benefit from S is needed. © 2013 Springer Science+Business Media New York.

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