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ABSTRACT: The role of tyrosine kinase inhibitors (TKIs) in the treatment of advanced malignancies is well established. Imatinib and vatalanib are oral TKIs with different mechanisms of action. This trial sought to establish the safety, tolerability, and maximum tolerated dose (MTD) of the two agents in combination. Secondary objectives included determination of potential pharmacologic interactions among vatalanib and imatinib and observation of antitumor activity. Patients with biopsy-proven advanced refractory solid tumors were enrolled in this single-center dose-escalation trial. Patients initially received imatinib and vatalanib once daily following a 14-day run-in period of daily oral vatalanib only, and were observed for a full 28-day treatment cycle prior to dose escalation. An amendment divided the vatalanib dose into two daily doses and gradually escalated the dose over a 2-3 week period. Patients continued combination therapy until disease progression or intolerable toxicity. Forty-five patients were enrolled between September 2004 and November 2007. As of September 2009, a total of 247 cycles of treatment had been administered (range: 1 -44+, median = 2 ). The MTD was determined to be vatalanib 1250 mg daily and imatinib 400 mg daily. Thirty-five patients (78%) were evaluable for response; 2 patients achieved PR, while 14 patients had SD ( 10 had stable disease ≥ 6 cycles). The combination of vatalanib and imatinib was well tolerated. Twice-daily vatalanib dosing improved tolerability and ease of full-dose administration. These results suggest that vatalanib-containing combinations may be active and tolerable, warranting further study.
Cancer Investigation 05/2011; 29(4):308-12. · 1.85 Impact Factor
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ABSTRACT: Patupilone is a novel microtubule-targeting cytotoxic agent with potential interaction with CYP3A4/CYP2C19 enzymes. Midazolam and omeprazole are primarily metabolized by CYP3A4 and CYP2C19, respectively. We evaluated the inhibitory effects of patupilone on the CYP3A4/CYP2C19 pathways.
This study had 2 parts: in an initial core phase, patients were randomly assigned to receive midazolam 4 mg or omeprazole 40 mg PO (days 1 and 29) and patupilone 10 mg/m(2) IV (days 8 and 29). Patients without progression continued patupilone every 3 weeks until disease progression or unacceptable toxicity (extension phase).
Forty-six patients were treated. The areas under the concentration-time curves (AUC)s of midazolam with or without patupilone co-administration were similar. The C (max) of midazolam when co-administered with patupilone was highly variable and was lower compared with midazolam alone; however, the oral clearance and terminal half-lives were similar. Both the C (max) and AUC of omeprazole when co-administered with patupilone were highly variable and lower than with omeprazole alone. However, the oral clearance and terminal half-lives were similar. The latter data suggest that patupilone decreased the absorption of omeprazole (by ~20%). The overall safety profile was consistent with that of previous single-agent patupilone studies; 2 partial responses (ovarian and pancreatic cancer) and 1 complete response (serous ovarian adenocarcinoma) were observed.
Patupilone was not a potent CYP3A4 or CYP2C19 inhibitor. No dose adjustment is required when omeprazole or midazolam is used in patients treated with patupilone. Patupilone exhibited promising antitumor activity in heavily pretreated patients with ovarian and pancreatic cancer.
Cancer Chemotherapy and Pharmacology 04/2011; 68(6):1507-16. · 2.83 Impact Factor
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E Claire Dees,
Jeffrey R Infante,
Roger B Cohen,
Bert H O'Neil,
Suzanne Jones,
Margaret von Mehren,
Hadi Danaee,
Yih Lee,
Jeffrey Ecsedy,
Mark Manfredi,
Katherine Galvin,
Bradley Stringer,
Hua Liu,
Omar Eton,
Howard Fingert, Howard Burris
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ABSTRACT: Aurora A kinase is critical in assembly and function of the mitotic spindle. It is overexpressed in various tumor types and implicated in oncogenesis and tumor progression. This trial evaluated the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of MLN8054, a selective small-molecule inhibitor of Aurora A kinase.
In this first-in-human, dose-escalation study, MLN8054 was given orally for 7, 14, or 21 days followed by a 14-day treatment-free period. Escalating cohorts of 3-6 patients with advanced solid tumors were treated until DLT was seen in ≥2 patients in a cohort. Serial blood samples were collected for pharmacokinetics and skin biopsies were collected for pharmacodynamics.
Sixty-one patients received 5, 10, 20, 30, or 40 mg once daily for 7 days; 25, 35, 45, or 55 mg/day in four divided doses (QID) for 7 days; or 55, 60, 70, or 80 mg/day plus methylphenidate or modafinil with daytime doses (QID/M) for 7-21 days. DLTs of reversible grade 3 benzodiazepine-like effects defined the estimated MTD of 60 mg QID/M for 14 days. MLN8054 was absorbed rapidly, exposure was dose proportional, and terminal half-life was 30-40 h. Three patients had stable disease for >6 cycles.
MLN8054 dosing for up to 14 days of a 28-day cycle was feasible. Reversible somnolence was dose limiting and prevented achievement of plasma concentrations predicted necessary for target modulation. A recommended dose for investigation in phase 2 trials was not established. A second-generation Aurora A kinase inhibitor is in development.
Cancer Chemotherapy and Pharmacology 04/2011; 67(4):945-54. · 2.83 Impact Factor
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Arijit Chakravarty,
Vaishali Shinde,
Josep Tabernero,
Andres Cervantes,
Roger B Cohen,
E Claire Dees, Howard Burris,
Jeffrey R Infante,
Teresa Macarulla,
Elena Elez, [......],
Jodi Pappas,
Lee Silverman,
Chris Simpson,
Bradley Stringer,
Stephen Tirrell,
Ole Petter Veiby,
Karthik Venkatakrishnan,
Katherine Galvin,
Mark Manfredi,
Jeffrey A Ecsedy
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ABSTRACT: The mitotic kinase Aurora A is an important therapeutic target for cancer therapy. This study evaluated new mechanism-based pharmacodynamic biomarkers in cancer patients in two phase I studies of MLN8054, a small-molecule inhibitor of Aurora A kinase. Patients with advanced solid tumors received MLN8054 orally for 7 consecutive days in escalating dose cohorts, with skin and tumor biopsies obtained before and after dosing. Skin biopsies were evaluated for increased mitotic cells within the basal epithelium. Tumor biopsies were assessed for accumulation of mitotic cells within proliferative tumor regions. Several patients in the highest dose cohorts showed marked increases in the skin mitotic index after dosing. Although some tumors exhibited increases in mitotic cells after dosing, others displayed decreases, a variable outcome consistent with dual mechanisms of mitotic arrest and mitotic slippage induced by antimitotics in tumors. To provide a clearer picture, mitotic cell chromosome alignment and spindle bipolarity, new biomarkers of Aurora A inhibition that act independently of mitotic arrest or slippage, were assessed in the tumor biopsies. Several patients, primarily in the highest dose cohorts, had marked decreases in the percentage of mitotic cells with aligned chromosomes and bipolar spindles after dosing. Evidence existed for an exposure-effect relationship for mitotic cells with defects in chromosome alignment and spindle bipolarity that indicated a biologically active dose range. Outcomes of pharmacodynamic assays from skin and tumor biopsies were concordant in several patients. Together, these new pharmacodynamic assays provide evidence for Aurora A inhibition by MLN8054 in patient skin and tumor tissues.
Cancer Research 02/2011; 71(3):675-85. · 7.86 Impact Factor
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ABSTRACT: Purpose. The aim of this study was to assess the safety and tolerability of motesanib (an orally administered small-molecule antagonist of vascular endothelial growth factor receptors 1, 2, and 3, platelet-derived growth factor receptor, and Kit) when administered in combination with panitumumab, gemcitabine, and cisplatin. Methods. This was an open-label, multicenter phase 1b study in patients with advanced solid tumors with an ECOG performance status ≤1 and for whom a gemcitabine/cisplatin regimen was indicated. Patients received motesanib (0 mg [control], 50 mg once daily [QD], 75 mg QD, 100 mg QD, 125 mg QD, or 75 mg twice daily [BID]) with panitumumab (9 mg/kg), gemcitabine (1250 mg/m(2)) and cisplatin (75 mg/m(2)) in 21-day cycles. The primary endpoint was the incidence of dose-limiting toxicities (DLTs). Results. Forty-one patients were enrolled and received treatment (including 8 control patients). One of eight patients in the 50 mg QD cohort and 5/11 patients in the 125 mg QD cohort experienced DLTs. The maximum tolerated dose was established as 100 mg QD. Among patients who received motesanib (n = 33), 29 had motesanib-related adverse events. Fourteen patients had serious motesanib-related events. Ten patients had motesanib-related venous thromboembolic events and three had motesanib-related arterial thromboembolic events, two of which were considered serious. One patient had a complete response and nine had partial responses as their best objective response. Conclusions. The combination of motesanib, panitumumab, and gemcitabine/cisplatin could not be administered consistently and, at the described doses and schedule, may be intolerable. However, encouraging antitumor activity was noted in some cases.
Journal of Oncology 01/2011; 2011:853931.
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ABSTRACT: nab-Paclitaxel has shown favorable efficacy and toxicity profiles compared to other taxanes in the treatment of metastatic breast cancer. In this pilot trial, we evaluated a nab-paclitaxel-containing adjuvant regimen in patients with early stage breast cancer. Patients with node-positive or high-risk node-negative early-stage breast cancer were eligible following completion of standard primary therapy. All the patients received four cycles, at 21-day intervals, of nab-paclitaxel (100 mg/m(2) IV days 1, 8, and 15) and cyclophosphamide (600 mg/m(2) IV day 1). HER2-positive patients also received trastuzumab 8 mg/kg IV on cycle 1 day 1, followed by 6 mg/kg every 21 days for a total of 52 weeks. The purpose of this trial was to evaluate feasibility and toxicity of this nab-paclitaxel-containing adjuvant regimen. 62 patients were treated between 2/08 and 11/08. The majority of the patients (87%) were HER2-negative. This adjuvant regimen was well tolerated, and full doses of all agents were administered in >90% of cycles. Grade 3/4 neutropenia occurred in 53% of the patients; however, only one episode of febrile neutropenia occurred in a total of 249 cycles administered. Other grade 3/4 adverse events occurred in less than 5% of patients. After short follow-up, all the patients remain alive and disease-free. The combination of nab-paclitaxel and cyclophosphamide, with or without trastuzumab, is feasible and well tolerated in patients with early stage breast cancer. Further investigation of the role of nab-paclitaxel in adjuvant breast cancer therapy is indicated, but definitive evaluation will require randomized phase III trials.
Breast Cancer Research and Treatment 09/2010; 123(2):471-5. · 4.43 Impact Factor
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Faye M Johnson,
Shruti Agrawal, Howard Burris,
Lee Rosen,
Navneet Dhillon,
David Hong,
Anne Blackwood-Chirchir,
Feng R Luo,
Oumar Sy,
Sanjeev Kaul,
Alberto A Chiappori
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ABSTRACT: The recently developed the Src and Abelson (Abl) kinase inhibitor dasatinib has antitumor effects in epithelial and mesenchymal tumors. Preclinical data have indicated that dasatinib is metabolized primarily through cytochrome P450 3A4 (CYP3A4) and may cause QT prolongation. In light of its improved tolerability, the authors were interested in the safety of a once-daily dasatinib regimen.
The authors conducted a phase 1 trial of dasatinib in 29 patients with advanced solid tumors. Segment 1 of the trial was short term and sequential and was designed to determine whether the coadministration of the potent CYP3A4 inhibitor ketoconazole had an effect on the pharmacokinetics of dasatinib. Segment 2 was designed to evaluate the safety of dasatinib as dosing was increased. QT intervals were monitored closely in both segments. Efficacy was assessed in Segment 2 using both positron emission tomography and computed tomography.
Hematologic toxicities were markedly less than those observed in patients with leukemia, whereas nonhematologic toxicities were similar. The authors determined that the maximum recommended dose was 180 mg once daily based on the incidence of pleural effusion. Coadministration of ketoconazole led to a marked increase in dasatinib exposure, which was correlated with an increase in corrected QT (QTc) values of approximately 6 msec. No adverse cardiac events were observed.
The dose-limiting toxic effect for dasatinib was pleural effusion. The pharmacokinetic and cardiac studies indicated that coadministration of dasatinib with potent CYP3A4 inhibitors or agents that prolong the QTc interval should be avoided if possible. Close monitoring for toxicity and dose reduction should be considered if the coadministration of such agents cannot be avoided.
Cancer 03/2010; 116(6):1582-91. · 4.77 Impact Factor
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Donna E Reece,
Dan Sullivan,
Sagar Lonial,
Ann F Mohrbacher,
Gurkamal Chatta,
Chaim Shustik, Howard Burris,
Karthik Venkatakrishnan,
Rachel Neuwirth,
William J Riordan,
Michael Karol,
Lisa L von Moltke,
Milin Acharya,
Peter Zannikos,
A Keith Stewart
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ABSTRACT: Characterize bortezomib pharmacokinetics/pharmacodynamics in relapsed myeloma patients after single and repeat intravenous administration at two doses.
Forty-two patients were randomized to receive bortezomib 1.0 or 1.3 mg/m(2), days 1, 4, 8, 11, for up to eight 21-day treatment cycles (n = 21, each dose group). Serial blood samples for pharmacokinetic/pharmacodynamic analysis were taken on days 1 and 11, cycles 1 and 3. Observational efficacy and safety data were collected.
Twelve patients in each dose group were evaluable for pharmacokinetics/pharmacodynamics. Plasma clearance decreased with repeat dosing (102-112 L/h for first dose; 15-32 L/h following repeat dosing), with associated increases in systemic exposure and terminal half-life. Systemic exposures of bortezomib were similar between dose groups considering the relatively narrow dose range and the observed pharmacokinetic variability, although there was no readily apparent deviation from dose-proportionality. Blood 20S proteasome inhibition profiles were similar between groups with mean maximum inhibition ranging from 70 to 84% and decreasing toward baseline over the dosing interval. Response rate (all 42 patients) was 50%, including 7% complete responses. The safety profile was consistent with the predictable and manageable profile previously established; data suggested milder toxicity in the 1.0 mg/m(2) group.
Bortezomib pharmacokinetics change with repeat dose administration, characterized by a reduction in plasma clearance and associated increase in systemic exposure. Bortezomib is pharmacodynamically active and tolerable at 1.0 and 1.3 mg/m(2) doses, with recovery toward baseline blood proteasome activity over the dosing interval following repeat dose administration, supporting the current clinical dosing regimen.
Cancer Chemotherapy and Pharmacology 03/2010; 67(1):57-67. · 2.83 Impact Factor
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ABSTRACT: Bevacizumab's role in the treatment of small cell lung cancer (SCLC) is unknown. A multicenter phase II trial with bevacizumab plus chemotherapy was conducted in patients with untreated extensive-stage SCLC.
Eligibility: no prior SCLC chemotherapy, no active brain metastases, no hemoptysis, and Eastern Cooperative Oncology Group performance status 0-1. Treatment consisted of irinotecan (60 mg/m2) administered intravenously (IV) on days 1, 8, 15; carboplatin area under the concentration-time curve = 4, IV, on day 1; bevacizumab (10 mg/kg, IV) on days 1 and 15 every 28 days for up to six cycles. Restaging was performed every two cycles (8 weeks). Patients with no progression received maintenance bevacizumab. Primary end point is 40% improvement in historical median time to progression (TTP) of 6 months.
Fifty-one patients were enrolled from February 2006 to March 2007 (22-month median follow-up). Baseline features: median age 66 years (range 46-81 years); male 57%; and Eastern Cooperative Oncology Group performance status 0-1 33/67%. Objective response rate 84% (95% CI 71-93%): 1 complete and 42 partial responses. Two patients (4%) had stable disease, and two patients had progressive disease. Four patients were unassessable because of treatment-related toxicity. Median TTP was 9.13 months (95% CI 7.36-9.46 months). Median overall survival was 12.1 months (95% CI 9.6-13.5 months); 1- and 2-year overall survivals were 51 and 14%, respectively. Grade 3/4 toxicity (> or = 10%): neutropenia (39%), thrombocytopenia (22%), dehydration (10%), diarrhea (31%), fatigue (20%), and pulmonary symptoms (10%). No significant bleeding occurred.
In this phase II trial, irinotecan, carboplatin, and bevacizumab achieved response, TTP, and survival outcomes that compare favorably with larger randomized trials using chemotherapy alone. Randomized trials can best assess bevacizumab's impact in the first-line treatment of extensive-stage SCLC.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 10/2009; 4(12):1555-60. · 4.55 Impact Factor
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Lecia V Sequist,
Panos M Fidias,
Jennifer S Temel,
Tatjana Kolevska,
Michael S Rabin,
Ralph V Boccia, Howard A Burris,
Robert J Belt,
Mark S Huberman,
Ostap Melnyk,
Glenn M Mills,
Craig W Englund,
David C Caldwell,
James G Keck,
Lisa Meng,
Marsha Jones,
Gail L Brown,
Martin J Edelman,
Thomas J Lynch
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ABSTRACT: We aimed to evaluate the safety and efficacy of canfosfamide in combination with carboplatin and paclitaxel as first-line therapy in patients with locally advanced or metastatic non-small cell lung cancer.
This was a phase 1-2a, multicenter, dose-ranging trial that enrolled patients with stage IIIB or IV non-small cell lung cancer with measurable disease. Patients received canfosfamide in doses ranging from 400 to 1000 mg/m2 intravenously (IV) with carboplatin at area under the curve 6 IV and paclitaxel at 200 mg/m2 IV day 1 every 3 weeks. The primary end point was objective response rate, and the secondary endpoints were safety and progression-free survival.
One hundred twenty-nine patients were treated with canfosfamide at dose levels of 400 (n = 3), 500 (n = 51), 750 (n = 54), and 1000 mg/m2 (n = 21). Objective tumor responses by RECIST were observed in 40 patients [34% (95% confidence interval [CI], 26-44)], the median progression-free survival was 4.3 months (95% CI, 3.7-5.2) and the median survival 9.9 months (95% CI, 7.7-11.9). The percent of patients alive at 1 year was 43.1%. The overall safety profile of the combination was acceptable and consistent with the profiles of the individual agents. In an exploratory analysis, patients receiving the optional maintenance canfosfamide therapy had a prolonged median survival of 16.8 months compared with those eligible for but not receiving maintenance therapy at 8.8 months (hazard ratio = 0.38, p < 0.001).
The combination of canfosfamide with carboplatin and paclitaxel chemotherapy is well tolerated and active. Maintenance canfosfamide may further improve outcomes. This regimen is worthy of additional study.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 08/2009; 4(11):1389-96. · 4.55 Impact Factor
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Azra Raza,
Naomi Galili,
Natalie Callander,
Leonel Ochoa,
Lawrence Piro,
Peter Emanuel,
Stephanie Williams, Howard Burris,
Stefan Faderl,
Zeev Estrov,
Peter Curtin,
Richard A Larson,
James G Keck,
Marsha Jones,
Lisa Meng,
Gail L Brown
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ABSTRACT: Ezatiostat hydrochloride liposomes for injection, a glutathione S-transferase P1-1 inhibitor, was evaluated in myelodysplastic syndrome (MDS). The objectives were to determine the safety, pharmacokinetics, and hematologic improvement (HI) rate. Phase 1-2a testing of ezatiostat for the treatment of MDS was conducted in a multidose-escalation, multicenter study. Phase 1 patients received ezatiostat at 5 dose levels (50, 100, 200, 400 and 600 mg/m2) intravenously (IV) on days 1 to 5 of a 14-day cycle until MDS progression or unacceptable toxicity. In phase 2, ezatiostat was administered on 2 dose schedules: 600 mg/m2 IV on days 1 to 5 or days 1 to 3 of a 21-day treatment cycle.
54 patients with histologically confirmed MDS were enrolled. The most common adverse events were grade 1 or 2, respectively, chills (11%, 9%), back pain (15%, 2%), flushing (19%, 0%), nausea (15%, 0%), bone pain (6%, 6%), fatigue (0%, 13%), extremity pain (7%, 4%), dyspnea (9%, 4%), and diarrhea (7%, 4%) related to acute infusional hypersensitivity reactions. The concentration of the primary active metabolites increased proportionate to ezatiostat dosage. Trilineage responses were observed in 4 of 16 patients (25%) with trilineage cytopenia. Hematologic Improvement-Erythroid (HI-E) was observed in 9 of 38 patients (24%), HI-Neutrophil in 11 of 26 patients (42%) and HI-Platelet in 12 of 24 patients (50%). These responses were accompanied by improvement in clinical symptoms and reductions in transfusion requirements. Improvement in bone marrow maturation and cellularity was also observed.
Phase 2 studies of ezatiostat hydrochloride liposomes for injection in MDS are supported by the tolerability and HI responses observed. An oral formulation of ezatiostat hydrochloride tablets is also in phase 2 clinical development.
Clinicaltrials.gov: NCT00035867.
Journal of Hematology & Oncology 06/2009; 2:20. · 3.99 Impact Factor
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Josep Tabernero,
Federico Rojo,
Emiliano Calvo, Howard Burris,
Ian Judson,
Katharine Hazell,
Erika Martinelli,
Santiago Ramon y Cajal,
Suzanne Jones,
Laura Vidal,
Nicholas Shand,
Teresa Macarulla,
Francisco Javier Ramos,
Sasa Dimitrijevic,
Ulrike Zoellner,
Pui Tang,
Michael Stumm,
Heidi A Lane,
David Lebwohl,
José Baselga
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ABSTRACT: Everolimus is a selective mammalian target of rapamycin (mTOR) inhibitor with promising anticancer activity. In order to identify a rationally based dose and schedule for cancer treatment, we have conducted a tumor pharmacodynamic phase I study in patients with advanced solid tumors.
Fifty-five patients were treated with everolimus in cohorts of 20, 50, and 70 mg weekly or 5 and 10 mg daily. Dose escalation depended on dose limiting toxicity (DLT) rate during the first 4-week period. Pre- and on-treatment steady-state tumor and skin biopsies were evaluated for total and phosphorylated (p) protein S6 kinase 1, eukaryotic initiation factor 4E (elF-4E) binding protein 1 (4E-BP1), eukaryotic initiation factor 4G (eIF-4G), AKT, and Ki-67 expression. Plasma trough levels of everolimus were determined on a weekly basis before dosing during the first 4 weeks.
We observed a dose- and schedule-dependent inhibition of the mTOR pathway with a near complete inhibition of pS6 and peIF-4G at 10 mg/d and >or= 50 mg/wk. In addition, pAKT was upregulated in 50% of the treated tumors. In the daily schedule, there was a correlation between everolimus plasma trough concentrations and inhibition of peIF4G and p4E-BP1. There was good concordance of mTOR pathway inhibition between skin and tumor. Clinical benefit was observed in four patients including one patient with advanced colorectal cancer achieving a partial response. DLTs occurred in five patients: one patient at 10 mg/d (grade 3 stomatitis) and four patients at 70 mg/wk (two with grade 3 stomatitis, one with grade 3 neutropenia, and one with grade 3 hyperglycemia).
Everolimus achieved mTOR signaling inhibition at doses below the DLT. A dosage of 10 mg/d or 50 mg/wk is recommended for further development.
Journal of Clinical Oncology 05/2008; 26(10):1603-10. · 18.37 Impact Factor
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ABSTRACT: To establish the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety and recommended Phase II dose of ixabepilone, administered weekly as an intravenous (IV) infusion to patients with solid tumors who have failed standard therapy.
This was an open-label, single-arm, Phase I, dose-escalation study.
The MTD of ixabepilone [30-min, weekly IV infusion on a 21-day schedule (N = 33)] was established at 25 mg/m(2). Grade 3 fatigue was the DLT in 2/4 patients treated at 30 mg/m(2). Ixabepilone was well tolerated at the MTD. Myelosuppression was rare, with no Grade 3/4 neutropenia. Due to the potential for cumulative neurotoxicity, the protocol was amended to a 1-h infusion, weekly for 3 weeks with a 1-week break. No DLT occurred at starting doses of 15, 20 and 25 mg/m(2) on this modified schedule (N = 51), although overall toxicity was less at 15 and 20 mg/m(2) than 25 mg/m(2). Five patients (2 on the 30-min/21-day schedule and 3 on the 60-min/28-day schedule) achieved durable objective partial responses across a variety of tumor types.
Ixabepilone had an acceptable safety profile at the MTD of 25 mg/m(2) (as a 30-min weekly infusion on a continuous 21-day schedule) and at 20 mg/m(2) (as a 1-h weekly infusion on a modified 28-day schedule). The clinical activity and acceptable tolerability profile warrant further single- or combination-agent evaluation.
Cancer Chemotherapy and Pharmacology 05/2008; 63(3):417-25. · 2.83 Impact Factor
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ABSTRACT: In advanced pancreatic cancer, single-agent gemcitabine became the standard therapy approximately 10 years ago. Subsequently, combinations of gemcitabine with fluorouracil, cisplatin, irinotecan, oxaliplatin, or pemetrexed produced no clear survival benefit. Among the newer approaches, targeting human epidermal growth factor receptor (HER-1/EGFR) shows promise. The U.S. Food and Drug Administration recently approved erlotinib (a HER-1/EGFR tyrosine kinase inhibitor) combined with gemcitabine for the first-line treatment of advanced pancreatic cancer. This combination showed a statistically significant survival benefit over gemcitabine alone in locally advanced or metastatic disease (the median overall survival time was 6.24 months versus 5.91 months; hazard ratio, 0.82; p = .038); however, the clinical significance of this survival difference has been questioned. Additionally, a large phase III trial where the addition of cetuximab (an anti-HER-1/EGFR monoclonal antibody [mAb]) to gemcitabine failed to result in a longer overall survival time than with gemcitabine alone has been reported. Targeting vascular endothelial growth factor (VEGF) with bevacizumab (a recombinant, humanized IgG1 mAb that binds to VEGF) in combination with gemcitabine was investigated in a phase II trial, with promising outcomes that were unfortunately not supported by a subsequent phase III study. While the future treatment of pancreatic cancer may be influenced by the potential of certain biomarkers to predict better response to molecular-targeted therapies, allowing individualization of patient therapy, there are currently no clear candidates, and this remains an interesting area for further investigation.
The Oncologist 04/2008; 13(3):289-98. · 3.91 Impact Factor
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ABSTRACT: Enzastaurin, an oral serine/threonine kinase inhibitor, suppresses protein kinase C (PKC) and protein kinase B/AK transforming (AKT) signaling, induces tumor cell apoptosis, and inhibits proliferation and angiogenesis. Increased PKC and AKT activity is associated with poor prognosis in non-small-cell lung cancer (NSCLC). This phase II trial of enzastaurin was conducted to determine the 6-month progression-free survival (PFS) rate in advanced, metastatic NSCLC.
Patients with metastatic (stage IV and wet IIIB) NSCLC, Eastern Cooperative Oncology Group performance status <or= 2, and <or= two prior systemic regimens (including one or more platinum-based chemotherapy regimens) received 500 mg of enzastaurin administered once daily.
Fifty-five patients were enrolled (55% male patients, 45% female patients; median age, 63 years; range, 44 to 82 years; 78% of patients having stage IV disease). Adenocarcinoma was the most common diagnosis (65%). Prior therapies included radiotherapy (73%) and epidermal growth factor inhibitors (29%). Median PFS was 1.8 months (95% CI, 1.7 to 1.9). Six-month PFS rate was 13% (95% CI, 3.9% to 21.5%). Median overall survival (OS) was 8.4 months (95% CI, 6.0 to 13.6 months). The 12-month OS rate was 44% (95% CI, 30.5% to 57.3%). Nineteen patients (35%) had stable disease. No objective responses were observed. Seven patients (13%) had PFS >or= 6 months, three of whom continued for more than 10 months. The most common toxicity was fatigue (grade <or= 3; n = 17). Grade 3 or worse toxicities were fatigue (n = 2), thromboembolism (n = 1), ataxia (n = 1), and anemia (n = 1). Two patients discontinued treatment because of drug-related fatigue and dizziness. Five patients died while enrolled in the study (non drug-related).
Although the primary end point of a 20% PFS rate was not achieved, 13% of the patients had PFS for >or= 6 months. Given the tolerability and survival data, evaluation of enzastaurin in combination with cytotoxic drugs is warranted in NSCLC.
Journal of Clinical Oncology 03/2008; 26(7):1135-41. · 18.37 Impact Factor
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Joe J Stephenson,
Charles Gregory, Howard Burris,
Tim Larson,
Udit Verma,
Allen Cohn,
Jeffrey Crawford,
Roger B Cohen,
Julie Martin,
Peggy Lum,
Xinqun Yang,
Rafael G Amado
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ABSTRACT: This study evaluated safety, pharmacokinetics, and efficacy of 2 dose schedules and 2 infusion times of panitumumab in patients with advanced solid malignancies.
This phase I multicenter, open-label study sequentially enrolled patients with advanced solid tumors refractory to standard therapy, or for which no standard therapy exists, to receive panitumumab 6 mg/kg every 2 weeks or 9 mg/kg every 3 weeks. Patients receiving panitumumab every 2 weeks received either all infusions over 60 minutes or a 60-minute infusion for the first dose followed by 30-minute infusions if the first infusion was well tolerated. Patients in the every-3-week cohort received 60-minute infusions. Safety outcomes included the incidence of adverse events and antipanitumumab antibody formation. Pharmacokinetic properties were determined. Efficacy endpoints included response rate and duration of response.
Eighty-six patients were enrolled; 84 (98%) received panitumumab. Treatment-related adverse events occurred in 90% of patients. Safety profiles were similar between patients receiving 30-minute (n = 20) and 60-minute (n = 43) infusions every 2 weeks and patients receiving panitumumab every 3 weeks (n = 21). Panitumumab exposure at steady state increased dose proportionally, and peak serum concentrations were similar in patients receiving either 30- or 60-minute infusions every 2 weeks. Objective responses were seen in 4 patients (5%) with colon, rectal, esophageal, and bladder cancers.
Similar drug exposures and safety profiles were observed in patients receiving panitumumab 6 mg/kg every 2 weeks with either 30- or 60-minute infusions and antitumor activity was seen in some patients. Exposure increased approximately dose proportionally at steady state.
Clinical Colorectal Cancer 02/2008; 8(1):29-37. · 1.68 Impact Factor
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Paula M Fracasso, Howard Burris,
Matthew A Arquette,
Ramaswamy Govindan,
Feng Gao,
Lisa P Wright,
Sherry A Goodner,
F Anthony Greco,
Suzanne F Jones,
Noel Willcut,
Catherine Chodkiewicz,
Amit Pathak,
Gregory M Springett,
George R Simon,
Daniel M Sullivan,
Raphaël Marcelpoil,
Shelley D Mayfield,
David Mauro,
Christopher R Garrett
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ABSTRACT: This phase 1 study evaluated the pharmacokinetic and pharmacodynamic effects of cetuximab on patients with epithelial malignancies.
Following a skin and tumor biopsy, patients with advanced epithelial malignancies were randomized to receive a single dose of cetuximab at 50, 100, 250, 400, or 500 mg/m2 i.v. Repeat skin (days 2, 8, 15, and 22) and tumor (day 8) biopsies were obtained. Immunohistochemical expression of epidermal growth factor receptor (EGFR) and its pathway members was done on biopsies. Blood samples were obtained over 22 days for pharmacokinetic analyses. After day 22, all patients received weekly 250 mg/m2 cetuximab until disease progression or unacceptable toxicity.
Thirty-nine patients enrolled. Rash was noted in 26 (67%) patients. Three patients (two with colon cancer and one with laryngeal cancer) achieved a partial response and 13 patients had stable disease. Pharmacokinetic data revealed mean maximum observed cetuximab concentrations and mean area under the concentration-time curve from time zero to infinity increased in a dose-dependent manner up to 400 mg/m2 cetuximab. Mean clearance was similar at cetuximab doses>or=100 mg/m2, supporting saturation of EGFR binding at 250 mg/m2. Pharmacodynamic evaluation revealed that patients with partial response/stable disease had a higher-grade rash and higher cetuximab trough levels than those with progressive disease (P=0.032 and 0.002, respectively). Administration of single doses (250-500 mg/m2) of cetuximab resulted in a dose-dependent decrease in EGFR protein expression levels in skin over time, supporting a minimal dose of cetuximab at 250 mg/m2 for a pharmacodynamic effect.
This study provides a pharmacokinetic and pharmacodynamic rationale for the dosing of cetuximab.
Clinical Cancer Research 03/2007; 13(3):986-93. · 7.74 Impact Factor
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Neil L Spector,
Wenle Xia, Howard Burris,
Herbert Hurwitz,
E Claire Dees,
Afshin Dowlati,
Bert O'Neil,
Beth Overmoyer,
Paul K Marcom,
Kimberly L Blackwell,
Deborah A Smith,
Kevin M Koch,
Andrew Stead,
Steven Mangum,
Matthew J Ellis,
Leihua Liu,
Albert K Man,
Troy M Bremer,
Jennifer Harris,
Sarah Bacus
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ABSTRACT: This was a pilot study to assess the biologic effects of lapatinib on various tumor growth/survival pathways in patients with advanced ErbB1 and/or ErbB2-overexpressing solid malignancies.
Heavily pretreated patients with metastatic cancers overexpressing ErbB2 and/or expressing ErbB1 were randomly assigned to one of five dose cohorts of lapatinib (GW572016) administered orally once daily continuously. The biologic effects of lapatinib on tumor growth and survival pathways were assessed in tumor biopsies obtained before and after 21 days of therapy. Clinical response was determined at 8 weeks.
Sequential tumor biopsies from 33 patients were examined. Partial responses occurred in four patients with breast cancer, and disease stabilization occurred in 11 others with various malignancies. Responders exhibited variable levels of inhibition of p-ErbB1, p-ErbB2, p-Erk1/2, p-Akt, cyclin D1, and transforming growth factor alpha. Even some nonresponders demonstrated varying degrees of biomarker inhibition. Increased tumor cell apoptosis (TUNEL) occurred in patients with evidence of tumor regression but not in nonresponders (progressive disease). Clinical response was associated with a pretreatment TUNEL score > 0 and increased pretreatment expression of ErbB2, p-ErbB2, Erk1/2, p-Erk1/2, insulin-like growth factor receptor-1, p70 S6 kinase, and transforming growth factor alpha compared with nonresponders.
Lapatinib exhibited preliminary evidence of biologic and clinical activity in ErbB1 and/or ErbB2-overexpressing tumors. However, the limited sample size of this study and the variability of the biologic endpoints suggest that further work is needed to prioritize biomarkers for disease-directed studies, and underscores the need for improved trial design strategies in early clinical studies of targeted agents.
Journal of Clinical Oncology 05/2005; 23(11):2502-12. · 18.37 Impact Factor
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ABSTRACT: To determine the response rate of trastuzumab as first-line therapy in patients with HER-2 overexpressing metastatic breast cancer. To assess the feasibility and toxicity of weekly paclitaxel/carboplatin with or without trastuzumab following initial treatment with trastuzumab.
Sixty-one patients received trastuzumab (8 mg/kg followed by 4 mg/kg/wk) for 8 weeks. Responding patients received 8 additional weeks of trastuzumab (4 mg/kg/wk), and then proceeded to receive trastuzumab (2 mg/kg) in combination with paclitaxel 70 mg/m(2) and carboplatin (area under the curve, 2) weekly for 6 weeks followed by 2 weeks rest. Stable patients after the initial 8 weeks of trastuzumab proceeded to treatment with trastuzumab, paclitaxel, and carboplatin. Patients with disease progression during the initial 8 weeks had the trastuzumab discontinued and were treated with weekly paclitaxel/carboplatin.
Weekly paclitaxel/carboplatin with or without trastuzumab was well tolerated. Fifty-two patients were assessable for response and all 61 patients were assessable for survival. Seventeen (33%) of 52 patients experienced a minor/partial response to single-agent trastuzumab and received 8 additional weeks of single-agent trastuzumab. Fifteen (29%) of 52 patients had stable disease and proceeded to receive paclitaxel/carboplatin/trastuzumab. Thirty-one patients with measurable disease were assessable for response after initial single-agent trastuzumab followed by paclitaxel/carboplatin/trastuzumab. An overall response rate of 84% (eight complete responses/18 partial responses), median time to progression of 14.2 months, and median overall survival of 32.2 months was reported with the triplet combination. In the patients treated with paclitaxel/carboplatin alone after disease progression on initial single-agent trastuzumab, an overall response rate of 69% (one complete response/10 partial responses), median time to progression of 8.3 months, and median overall survival of 22.2 months was reported. Median time to progression for all 61 patients is 10 months and the median overall survival is 26.7 months.
This trial confirms the activity and tolerability of weekly paclitaxel/carboplatin alone or in combination with trastuzumab in women with HER-2 overexpressing metastatic breast cancer.
Journal of Clinical Oncology 06/2004; 22(9):1621-9. · 18.37 Impact Factor
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David R Gandara,
Kari Chansky,
Kathy S Albain,
Bryan R Leigh,
Laurie E Gaspar,
Primo N Lara, Howard Burris,
Paul Gumerlock,
J Philip Kuebler,
James D Bearden,
John Crowley,
Robert Livingston
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ABSTRACT: To test the concept of taxane sequencing in combined-modality therapy, this phase II trial (S9504) evaluated consolidation docetaxel after concurrent chemoradiotherapy in patients with pathologically documented stage IIIB non-small-cell lung cancer (NSCLC). Results were compared with those of the predecessor study (S9019) with identical eligibility, staging criteria, and treatment, excepting docetaxel consolidation.
Treatment consisted of cisplatin 50 mg/m2 on days 1, 8, 29, and 36, etoposide 50 mg/m2 on days 1 through 5 and 29 through 33, and concurrent thoracic radiotherapy (total dose of 61 Gy). Consolidation docetaxel started 4 to 6 weeks after chemoradiotherapy at an initial dose of 75 mg/m2.
Stage subsets (tumor-node-metastasis system) in 83 eligible patients were as follows: T4N0/1, 31 patients (37%); T4N2, 22 patients (27%), and T1-3N3, 30 patients (36%). Concurrent chemoradiotherapy was generally well tolerated, but two patients died from probable radiation-associated pneumonitis. Neutropenia during consolidation docetaxel was common (57% with grade 4) and most frequent during escalation to 100 mg/m2. Median progression-free survival was 16 months, median survival was 26 months, and 1-, 2-, and 3-year survival rates were 76%, 54%, and 37%, respectively. Brain metastasis was the most common site of failure. In S9019, median survival was 15 months and 1-, 2-, and 3-year survival rates were 58%, 34%, and 17%, respectively.
Consolidation docetaxel after concurrent chemoradiotherapy in stage IIIB NSCLC is feasible and generally tolerable, and results compare favorably with the predecessor trial S9019. Nevertheless, this study remains hypothesis-generating and does not provide definitive evidence of the benefit of this approach. Phase III trials evaluating the S9504 regimen have been initiated to validate these results.
Journal of Clinical Oncology 06/2003; 21(10):2004-10. · 18.37 Impact Factor
