Van Cutsem E.,University Hospitals Gasthuisberg |
Eng C.,University of Texas M. D. Anderson Cancer Center |
Nowara E.,Instytut im. M. Sklodowskiej Curie |
Swieboda-Sadlej A.,Medical University of Warsaw |
And 16 more authors.
Clinical Cancer Research | Year: 2014
Purpose: Panitumumab, a fully human anti-epidermal growth factor receptor monoclonal antibody (mAb), has demonstrated efficacy in patients with wild-type KRAS metastatic colorectal cancer (mCRC). Rilotumumab and ganitumab are investigational, fully human mAbs against hepatocyte growth factor (HGF)/scatter factor and IGF1R, respectively. Here we evaluate combining rilotumumab or ganitumab with panitumumab in previously treated patients with wild-type KRAS mCRC. Experimental Design: Part 1 was a phase Ib dose-finding study of panitumumab plus rilotumumab. The primary endpoint was the incidence of dose-limiting toxicities (DLT). Part 2 was a randomized phase II trial of panitumumab in combination with rilotumumab, ganitumab, or placebo. The primary endpoint was objective response rate (ORR); safety, progression-free survival (PFS), and overall survival (OS) were secondary endpoints. Archival tissue specimens were collected for exploratory correlative work. Results: In part 1, no DLTs were reported. A recommended phase II dose of 10 mg/kg rilotumumab was selected. In part 2, for the panitumumab plus rilotumumab (n = 48), panitumumab plus ganitumab (n = 46), and panitumumab plus placebo arms (n = 48), the ORRs were 31%, 22%, and 21%, respectively. The median PFS was 5.2, 5.3, and 3.7 months and median OS 13.8, 10.6, and 11.6 months, respectively. Adverse events were tolerable. Exploratory biomarker analyses, including MET and IGF-related protein expression, failed to indicate conclusive predictive evidence on efficacy endpoints. Conclusions: Panitumumab plus rilotumumab met the prespecified criterion for improvement in ORR whereas ganitumab did not. This is the first study to suggest a benefit for combining an HGF inhibitor (rilotumumab) with panitumumab in previously treated patients with wild-type KRAS mCRC. ©2014 AACR.
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.,Denver CO |
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.
Gerecitano J.F.,Sloan Kettering Cancer Center |
Stephenson J.J.,Cancer Centers of the Carolinas |
Lewis N.L.,Thomas Jefferson University |
Osmukhina A.,Astrazeneca |
And 7 more authors.
Investigational New Drugs | Year: 2013
Summary: Background This Phase I study assessed the safety and maximum tolerated dose (MTD) of the kinesin spindle protein inhibitor AZD4877 in patients with relapsed/refractory solid tumors and lymphoma. Methods In this multicenter study, a standard 3 + 3 dose-escalation design was used. AZD4877 was given as an intravenous infusion on days 1, 4, 8 and 11 of each 21-day cycle. Responses were assessed with CT scans +/- PET after 6 and 12 weeks, then every 12 weeks while on therapy. An additional four patients with lymphoma were enrolled at the MTD. Results 29 patients were enrolled and 22 patients received at least one dose of AZD4877 and were evaluable for safety. The MTD was 11 mg. Dose-limiting toxicity was neutropenia (n = 2 patients, 15 mg cohort). The most common adverse events were grade 1/2 fatigue, nausea, neutropenia and dyspnea. AZD4877 exposure generally increased with dose, with mean elimination half-life approximately 16 h at the MTD. Pharmacodynamic analyses demonstrated moderate correlation between plasma drug concentrations at 6 or 24 h and monoaster formation in peripheral blood mononuclear cells (PBMCs). Conclusions AZD4877 is generally well-tolerated with pharmacodynamic evidence of target inhibition in circulating PBMCs. © 2012 Springer Science+Business Media, LLC.
PubMed | University of Kansas Medical Center, Fred Hutchinson Cancer Research Center, University of Florida, Yale Cancer Center and 4 more.
Type: Clinical Trial, Phase I | Journal: Leukemia | Year: 2016
CC-486, the oral formulation of azacitidine (AZA), is an epigenetic modifier and DNA methyltransferase inhibitor in clinical development for treatment of hematologic malignancies. CC-486 administered for 7 days per 28-day treatment cycle was evaluated in a phase 1 dose-finding study. AZA has a short plasma half-life and DNA incorporation is S-phase-restricted; extending CC-486 exposure may increase the number of AZA-affected diseased target cells and maximize therapeutic effects. Patients with lower-risk myelodysplastic syndromes (MDS) received 300mg CC-486 once daily for 14 days (n=28) or 21 days (n=27) of repeated 28-day cycles. Median patient age was 72 years (range 31-87) and 75% of patients had International Prognostic Scoring System Intermediate-1 risk MDS. Median number of CC-486 treatment cycles was 7 (range 2-24) for the 14-day dosing schedule and 6 (1-24) for the 21-day schedule. Overall response (complete or partial remission, red blood cell (RBC) or platelet transfusion independence (TI), or hematologic improvement) (International Working Group 2006) was attained by 36% of patients receiving 14-day dosing and 41% receiving 21-day dosing. RBC TI rates were similar with both dosing schedules (31% and 38%, respectively). CC-486 was generally well-tolerated. Extended dosing schedules of oral CC-486 may provide effective long-term treatment for patients with lower-risk MDS.
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.
PubMed | Brown University, Comprehensive Cancer Centers Of Nevada And Us Oncology Research, Dana-Farber Cancer Institute, Progenics Pharmaceuticals Inc. and 2 more.
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2017
119 Background: The abundant expression of prostate specific membrane antigen (PSMA) on prostate cancer cells provides a rationale for antibody therapy. PSMA ADC, a fully human antibody to PSMA linked to the microtubule disrupting agent monomethyl auristatin E (MMAE), binds PSMA and is internalized within the prostate cancer cell where cleavage by lysosomal enzymes release free MMAE, causing cell cycle arrest and apoptosis. We have completed a phase 1 dose escalation study of PSMA ADC in subjects with taxane-refractory mCRPC.Eligibility requirements include progressive mCRPC following taxane-containing chemotherapy and ECOG status of 0 or 1. PSMA ADC was administered by IV infusion Q3W for up to 4 cycles. Safety, pharmacokinetics (PK), PSA, circulating tumor cells (CTC), clinical disease progression and immunogenicity to PSMA ADC were assessed. Serum PSMA ADC and total antibody were measured by ELISA, and free MMAE was measured by LC/MS/MS.The dosing cohorts ranged from 0.4 mg/kg to 2.8 mg/kg.52 subjects with mCRPC were dosed in nine dose levels. All subjects received prior docetaxel, 5 also received cabazitaxel and 3 subjects also received paclitaxel. PSMA ADC was generally well tolerated with the most commonly seen adverse events being anorexia and fatigue. Peripheral neuropathy was reported by 7 subjects after repeated doses. Two were grade 3. Dose limiting toxicities (DLT) seen at 2.8 mg/kg were neutropenia (one death) and reversible liver function tests (LFTs) elevations. Antitumor activity was manifested as reductions either in PSA or CTCs at 1.8 mg/kg PSMA ADC in approximately 50% of patients. Exposure to PSMA ADC increased with dose and was ~1,000-fold greater than MMAE exposure and no accumulation was observed.PSMA ADC in this study was generally well tolerated in doses up to 2.8 mg/kg every three weeks in subjects with mCRPC, previously treated with taxane. Antitumor activity was seen at higher dose levels. DLTs were neutropenia and reversible LFT abnormalities. The maximum tolerated dose of PSMA ADC was determined to be 2.5 mg/kg. A phase 2 trial in taxane refractory mCRPC has been initiated.NCT01414283.
A multicenter, randomized, phase 2 clinical trial to evaluate the efficacy and safety of combination docetaxel and carboplatin and sequential therapy with docetaxel then carboplatin in patients with recurrent platinum-sensitive ovarian cancer
Secord A.A.,Duke University |
Berchuck A.,Duke University |
Higgins R.V.,Carolinas Medical Center |
Nycum L.R.,Forsyth Regional Cancer Center |
And 6 more authors.
Cancer | Year: 2012
BACKGROUND: The aim of this randomized clinical trial was to evaluate the efficacy and safety of combination (cDC) and sequential (sDC) weekly docetaxel and carboplatin in women with recurrent platinum-sensitive epithelial ovarian cancer (EOC). METHODS: Participants were randomized to either weekly docetaxel 30 mg/m 2 on days 1 and 8 and carboplatin area under the curve (AUC) = 6 on day 1, every 3 weeks or docetaxel 30 mg/m 2 on days 1 and 8, every 3 weeks for 6 cycles followed by carboplatin AUC = 6 on day 1, every 3 weeks for 6 cycles or until disease progression. The primary endpoint was measurable progression-free survival (PFS). RESULTS: Between January 2004 and March 2007, 150 participants were enrolled. The response rate was 55.4% and 43.2% for those treated with cDC and sDC, respectively. The median PFS was 13.7 months (95% confidence interval [CI], 9.9-16.8) for cDC and 8.4 months (95% CI, 7.1-11.0) for sDC. On the basis of an exploratory analysis, patients treated with sDC were at a 62% increased risk of disease progression compared to those treated with cDC (hazard ratio = 1.62; 95% CI, 1.08-2.45; P =.02). The median overall survival time was similar in both groups (33.2 and 30.1 months, P =.2). The incidence of grade 2 or 3 neurotoxicity and grade 3 or 4 neutropenia was higher with cDC than with sDC (11.7% vs 8.5%; 36.8% vs 11.3%). The sDC group demonstrated significant improvements in the Functional Assessment for Cancer Therapy-Ovarian, Quality of Life Trial Outcome Index scores compared with the combination cohort (P =.013). CONCLUSIONS: Both cDC and sDC regimens have activity in recurrent platinum-sensitive EOC with acceptable toxicity profiles. The cDC regimen may provide a PFS advantage over sDC. © 2011 American Cancer Society.
PubMed | Provonix LLC., Samsung, ICON Clinical Research, Asan Medical Center and 3 more.
Type: Journal Article | Journal: Clinical pharmacology in drug development | Year: 2016
The aqueous solubility of lapatinib declines significantly at pH >4, suggesting that its bioavailability might be lowered by acid-reducing drugs. A study was therefore conducted to assess the effects of esomeprazole on lapatinib pharmacokinetics (PK). Women with metastatic human epidermal growth factor receptor 2 positive (HER2(+) ) breast cancer were enrolled. Patients received 1,250mg lapatinib once daily (QD) in the morning on Days 1-7 (Period 1) and Days 8-14 (Period 2) with 40mg esomeprazole QD at bedtime 3hours after dinner on Days 8-14. Lapatinib PK sampling occurred during the 24-hour steady-state dosing intervals on Day 7 (lapatinib alone) and Day 14 (lapatinib with esomeprazole). Esomeprazole treatment resulted in decreased lapatinib bioavailability (mean 26%, range 6-49%) that was inversely associated with patient age as a significant covariate.
Chung K.Y.,Cancer Centers of the Carolinas |
Saito K.,Taiho Pharma United States |
Zergebel C.,Taiho Pharma United States |
Hollywood E.,Sloan Kettering Cancer Center |
And 2 more authors.
Oncology | Year: 2011
Background: S-1 is a novel oral agent combining the 5-fluorouracil (FU) prodrug tegafur with gimeracil and oteracil, which inhibit 5-FU degradation by dihydropyrimidine dehydrogenase and phosphorylation within the gastrointestinal tract, respectively. The study was designed to identify the maximum tolerable dose and the dose-limiting toxicities of two schedules of S-1 combined with oxaliplatin and bevacizumab, in advanced solid tumor patients. Methods: Schedule A: S-1 was administered orally at 20 mg/m 2 twice daily for 14 consecutive days, escalated by 5 mg/m 2, with fixed-dose intravenous bevacizumab 7.5 mg/kg and oxaliplatin 130 mg/m 2 on day 1 of each 3-week cycle. Schedule B: S-1 was administered at 25 mg/m 2 twice daily for 7 consecutive days, escalated by 5 mg/m 2, with fixed-dose intravenous bevacizumab 5 mg/kg and oxaliplatin 85 mg/m 2 on day 1 of each 2-week cycle. Results: The maximum tolerated dose and recommended phase II dose of S-1 was 25 mg/m 2 twice daily for 14 days for schedule A and 35 mg/m 2 twice daily for 7 days for schedule B. The most common dose-limiting toxicities were grade 3 diarrhea. Both regimens were well tolerated. No pharmacokinetic interactions between oxaliplatin and S-1 components were observed. Conclusions: S-1, oxaliplatin and bevacizumab can be administered with acceptable safety and tolerability and without evidence of pharmacokinetic interactions. Copyright © 2011 S. Karger AG.