Showing papers by "David R. Gandara published in 2007"
TL;DR: Assessment of ERCC1 mRNA expression in patient tumor tissue is feasible in the clinical setting and predicts response to docetaxel and cisplatin, and a multibiomarker profile predictive of patient outcome is refined.
Abstract: Purpose Although current treatment options for metastatic non–small-cell lung cancer (NSCLC) rely on cisplatin-based chemotherapy, individualized approaches to therapy may improve response or reduce unnecessary toxicity Excision repair cross-complementing 1 (ERCC1) has been associated with cisplatin resistance We hypothesized that assigning cisplatin based on pretreatment ERCC1 mRNA levels would improve response Patients and Methods From August 2001 to October 2005, 444 stage IV NSCLC patients were enrolled RNA was isolated from pretreatment biopsies, and quantitative real-time reverse transcriptase PCR assays were performed to determine ERCC1 mRNA expression Patients were randomly assigned in a 1:2 ratio to either the control or genotypic arm before ERCC1 assessment Patients in the control arm received docetaxel plus cisplatin In the genotypic arm, patients with low ERCC1 levels received docetaxel plus cisplatin, and those with high levels received docetaxel plus gemcitabine The primary end point
460 citations
TL;DR: This combined-modality approach is feasible and is associated with high rates of complete resection and pathologic CR in both T3 and T4 tumors, markedly improved relative to previous studies of radiation plus resection.
Abstract: Purpose Traditional treatment for superior sulcus non–small-cell lung cancers (SS NSCLC), radiation plus surgery, yields a 50% rate of complete resection and a 30% 5-year survival. On the basis of improved outcomes in other subsets of stage III NSCLC, this trial tested the feasibility of induction chemoradiotherapy for SS NSCLC. Patients and Methods Patients with T3-4, N0-1 SS NSCLC received two cycles of cisplatin and etoposide concurrently with radiation (45 Gy). Patients with stable or responding disease underwent thoracotomy. All patients received two more cycles of chemotherapy. Survival was calculated by the Kaplan-Meier method and prognostic factors were assessed by Cox regression analysis. Results From April 1995 to November 1999, 110 eligible patients (76 men, 34 women) were entered onto the study (78 T3, 32 T4 tumors). Induction therapy was completed by 104 (95%) patients. Of 95 patients eligible for surgery, 88 (80%) underwent thoracotomy, two (1.8%) died postoperatively, and 83 (76%) had compl...
386 citations
TL;DR: Long-term survival with untreated stage I NSCLC is uncommon, and the vast majority of untreated patients die of lung cancer, so treatment with surgical resection or other ablative therapies should not be delayed even in patients with small lung cancers.
295 citations
TL;DR: Single-agent erlotinib was not effective in MPM, despite high expression of EGFR, and activation of the ERK and phosphatidylinositol 3-kinase/Akt downstream pathways are possible resistance mechanisms to EGFR TKI.
Abstract: Purpose Malignant pleural mesothelioma (MPM) expresses high levels of epidermal growth factor receptor (EGFR), and preclinical studies have identified antitumor activity of EGFR tyrosine kinase inhibitors (TKIs) in MPM. We conducted a phase II trial of the EGFR TKI erlotinib in previously untreated patients with MPM. Patients and Methods Patients with measurable and nonmeasurable disease were treated with erlotinib 150 mg/d on days 1 through 28 of each 28-day dosing cycle. Archived patient tumors were analyzed for immunohistochemical expression of EGFR, phospho-EGFR, human epidermal growth factor receptor 2 (HER2), phospho–extracellular signal-regulated kinase (ERK), and phosphatase and tensin homolog (PTEN) and phosphorylation of members of the phosphatidylinositol 3-kinase/Akt signaling pathway. Results Sixty-three patients were treated on the study. EGFR was highly expressed in 75% of patient tumors, as was phospho-ERK (82%), phospho-Akt (84%), phospho–mammalian target of rapamycin (74%), and phospho-f...
209 citations
TL;DR: In phase II trials in MM, GC on a 21-day (D) schedule has response rates of 16%–26% and median overall survival (OS) of 9.6–13 months (mo).
Abstract: 7526 Background: In phase II trials in MM, GC on a 21-day (D) schedule has response rates of 16%–26% and median overall survival (OS) of 9.6–13 months (mo). Since VEGF has a key role in MM biology,...
95 citations
TL;DR: The results support the notion that circulating KRAS mutations originate from tumors and are prognostically relevant in lung cancer.
93 citations
TL;DR: Although well tolerated, perifosine did not meet prespecified PSA criteria for response as a single agent in biochemically recurrent prostate cancer, however, 20% of patients had evidence of PSA reduction, suggesting modest single-agent clinical activity.
93 citations
TL;DR: These studies provide a rationale for intermittent dosing of EGFR TKIs with chemotherapy in order to enhance cytotoxicity and pharmacodynamic separation of the 2 drug classes will ameliorate these effects.
80 citations
TL;DR: Bortezomib, a small-molecule proteasome inhibitor, has shown promising activity in lung cancer both as a single agent and in combination with agents commonly used in lung cancers.
Abstract: Bortezomib, a small-molecule proteasome inhibitor, has activity in lung cancer both as a single agent and in combination with agents commonly used in lung cancer. The ability of bortezomib to favorably modulate the expression of apoptosis-associated proteins, along with its moderate toxicity as a single agent, provides the basis for its combination with cytotoxic agents in the treatment of lung cancer. In non-small cell lung cancer, bortezomib as a single agent has limited activity but in combination with chemotherapy has shown encouraging activity without significantly adding to toxicity. Bortezomib as a single agent has shown minimal activity in small cell lung cancer. Although the role of bortezomib in lung cancer is uncertain, it is likely to have its greatest clinical benefit when given in combination with other therapeutics. Ongoing studies are focused on optimizing the scheduling of bortezomib with chemotherapy, investigating its combination with targeted agents and radiation, and examining its efficacy in a specific subgroup, bronchioloalveolar carcinoma.
78 citations
City of Hope National Medical Center1, University of Texas Health Science Center at San Antonio2, University of California, Davis3, Yeshiva University4, Case Western Reserve University5, University of Wisconsin-Madison6, New York University7, Memorial Sloan Kettering Cancer Center8, University of Pittsburgh9, University of Southern California10, National Institutes of Health11
TL;DR: Oxaliplatin at 130 mg/m2 every 3 weeks was well tolerated in all patients with impaired liver function and dose reductions of single-agent oxali Platin are not indicated in patients with hepatic dysfunction.
Abstract: Purpose: To determine the toxicities, pharmacokinetics, and maximally tolerated doses of oxaliplatin in patients with hepatic impairment and to develop formal guidelines for oxaliplatin dosing in this patient population. Experimental Design: Sixty adult cancer patients with variable hepatic function received i.v. oxaliplatin ranging from 60 to 130 mg/m 2 every 3 weeks. Patients were stratified by levels of total bilirubin, aspartate aminotransferase (AST), and alkaline phosphatase (AP) into five cohorts based on the degree of hepatic dysfunction: control group A [bilirubin, AST, and AP ≤ upper limit of normal (ULN)], mild dysfunction group B (bilirubin ≤ ULN, ULN 2.5 × ULN, or AP > 5 × ULN), severe dysfunction group D (bilirubin > 3.0 mg/dL, any AST, and any AP), and liver transplantation group E (any bilirubin, any AST, and any AP). Doses were escalated in cohorts of three patients, and urine and plasma ultrafiltrates were assayed for platinum concentrations. Results: Dose escalation of single-agent oxaliplatin to 130 mg/m 2 was well tolerated in all cohorts. Platinum clearance did not correlate with any liver function test. Two of 56 assessable patients with a diagnosis of laryngeal carcinoma and cervical adenocarcinoma experienced partial responses lasting 3 and 5.5 months. Conclusions: Oxaliplatin at 130 mg/m 2 every 3 weeks was well tolerated in all patients with impaired liver function. Dose reductions of single-agent oxaliplatin are not indicated in patients with hepatic dysfunction.
53 citations
TL;DR: These chemotherapy regimens were associated with an encouraging disease-control rate (54%) in patients 80 years or older with advanced NSCLC, with good tolerance, and Selected octogenarians with advanced NCI may benefit from single-agent chemotherapy.
TL;DR: The results of this study suggest this carboplatin/docetaxel chemotherapy regimen is active for outpatient treatment of recurrent SCCHN patients with good performance status.
Abstract: Carboplatin/docetaxel chemotherapy was evaluated in advanced squamous cell carcinoma of the head and neck (SCCHN). Eligibility included patients with recurrent, persistent, or metastatic SCCHN with...
TL;DR: This independent blinded analysis of the TRIBUTE study identified fatal ILD in 0.6% of cases treated with the combination of erlotinib plus chemotherapy, possibly higher than previous reports of EGFR TKIs alone in the non-Japanese population.
TL;DR: A phase II clinical trial of concurrent paclitaxel, carboplatin, and radiation with or without surgery as an alternative to the standard cisplatin-based CRT for localized and metastatic esophageal cancer is conducted.
TL;DR: The standard of care for resected stage II-IIIA non-small cell lung cancer (NSCLC) now includes adjuvant chemotherapy based on the results of three phase III studies using cisplatin-based regimens--the International Adjuvant Lung Trial, the National Cancer Institute of Canada JBR.10 trial, and the Adjuance International Trialist Association trial.
Abstract: The standard of care for resected stage II-IIIA non-small cell lung cancer (NSCLC) now includes adjuvant chemotherapy based on the results of three phase III studies using cisplatin-based regimens--the International Adjuvant Lung Trial, the National Cancer Institute of Canada JBR.10 trial, and the Adjuvant Navelbine International Trialist Association trial. The role of adjuvant chemotherapy for stage I disease remains controversial. A recent meta-analysis (the Lung Adjuvant Cisplatin Evaluation) showed potential harm with the addition of adjuvant cisplatin for stage IA disease and no survival benefit for this modality in stage IB disease. Updated results from the Cancer and Leukemia Group B 9633 trial, the only trial to focus exclusively on stage IB patients, no longer show a statistically significant survival benefit from adjuvant chemotherapy in this population, except for the subgroup of patients with larger tumors. It may be that trials have been underpowered to detect a small benefit for patients with stage IB disease, or there may really not be benefit to adding adjuvant therapy for this stage of disease. Additional markers, such as tumor size or the presence or absence of certain tumor proteins like ERCC1, may help to determine which patients with resected stage I NSCLC may benefit from adjuvant chemotherapy. Strategies such as inhibition of angiogenesis pathways and the epidermal growth factor receptor are under exploration.
TL;DR: Pemetrexed with bortezomib is feasible and tolerable at recommended single-agent doses and, based on the observed efficacy, a phase II study in non-small cell lung cancer is warranted.
TL;DR: The biologic rationale for developing new combination strategies based on patient selection by molecular and clinical factors, or by pharmacodynamic parameters is explored.
TL;DR: The histone deacetylase inhibitor vorinostat is well tolerated over long durations of therapy, and shows promising activity against relapsed/refractory follicular and marginal zone lymphoma.
TL;DR: Oblimersen given in this dose and schedule with α-IFN does not appear sufficiently active to warrant further study in advanced renal cancer, and combined with newer targeted agents may show greater promise.
Abstract: Purpose
Oblimersen is an 18-base oligodeoxynucleotide encoding antisense to the gene for bcl-2, an anti-apoptotic protein that is upregulated in renal and other cancers. This study was designed to evaluate the combination of oblimersen with α-Interferon in advanced renal cancer. Trial endpoints were antitumor efficacy and toxicity, pharmacokinetics, and evidence of apoptosis in peripheral blood mononuclear cells.
TL;DR: It is shown that subset analysis has uniformly shown the greatest efficacy for patients with stage II and III disease and the least benefit for patient with stage I disease.
TL;DR: Estimating the response rate of 26-h continuous infusion cyclosporine A (CSA) combined with carboplatin (CBDCA) and subcutaneous alpha-interferon (IFN) in recurrent ovarian cancer (OC) and measuring their effects on CBDCA pharmacokinetics concluded that Steady-state levels of >1 μg/mL CSA (HPLC assay) are achievable in vivo.
Abstract: The purpose of this study was to estimate the response rate of 26-h continuous infusion cyclosporine A (CSA) combined with carboplatin (CBDCA) and subcutaneous alpha-interferon (IFN), in recurrent ovarian cancer (OC), and to measure their effects on CBDCA pharmacokinetics. OC patients relapsing following platinum-based chemotherapy received CBDCA area under the curve (AUC 3) with CSA and IFN, every 3 weeks. The pharmacokinetics of CSA and CBDCA were determined in a subset of patients. Thirty patients received 84 courses of therapy. Three partial responses were observed. Nine patients were stable for >4 months. Toxicity was similar to that observed in our previously reported phase I study and consisted of myelosuppression, nausea, vomiting, and headache. The mean end of infusion CSA level (high-performance liquid chromatographic assay [HPLC]) was 1109 +/- 291 microg/mL (mean +/- SD). CBDCA pharmacokinetics revealed a measured AUC of 3.61 versus a targeted AUC of 3, suggesting a possible effect of IFN on CBDCA levels versus errors in the estimation of CBDCA clearance using measured creatinine clearance. Steady-state levels of >1 microg/mL CSA (HPLC assay) are achievable in vivo. Insufficient clinical resistance reversal was observed in this study to warrant further investigation of this combination.
TL;DR: In this paper, the indolent (follicular, marginal zone and mantle cell) lymphomas tend to recur with decreasing intervals of remission post standard chemotherapy using Vorinostat (SAHA, Zolinza).
Abstract: 18515 Background: The indolent (follicular, marginal zone and mantle cell) lymphomas tend to recur with decreasing intervals of remission post standard chemotherapy. Vorinostat (SAHA, Zolinza), an ...
Journal Article•
TL;DR: Vorinostat is a small molecule inhibitor of histone deacetylase that exerts its targeted action during post-translational acety... as discussed by the authors, with a median survival of 27 mo.
Abstract: 11502 Background: MBC patients (pts) have a median survival of 27 mo. Vorinostat is a small molecule inhibitor of histone deacetylase that exerts its targeted action during post-translational acety...
TL;DR: The overall response rate with the combination of gemcitabine and irinotecan was disappointing, and the median survival rate was lower than expected.
TL;DR: A phase I study of erlotinib and vinorelbine to establish the feasibility and safety of the combination and to determine the maximum tolerated dose (MTD) was associated with high rate of febrile neutropenia.
Abstract: Background Erlotinib is an oral epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI). Vinorelbine, a vinca alkaloid, interferes with microtubule assembly inhibiting mitosis during metaphase. Both drugs are commonly used as single agents in the treatment of advanced non small cell lung cancer (NSCLC). Given their efficacy in NSCLC and their non-overlapping toxicity profile, we conducted a phase I study of erlotinib and vinorelbine to establish the feasibility and safety of the combination and to determine the maximum tolerated dose (MTD). Patients and methods Patients with advanced solid tumors were treated with vinorelbine intravenously on day 1 and 8 and erlotinib orally daily on a 21 day schedule. The dose levels of vinorelbine/erlotinib were 25 mg/m2/100 mg, 25/150 and 30/150. Results Sixteen patients were enrolled. Five patients were chemo-naive; 11 had one prior therapy. The majority of patients had NSCLC (n = 7). Dose limiting toxicities included febrile neutropenia (4 patients) and grade 5 infection (1 patient). Non-hematologic grade 3/4 toxicities included diarrhea, hypokalemia, infection, dyspnea and mucositis. Of 12 patients assessable for radiologic response, there were no objective responses; eight had stable disease. Conclusions (1) The MTD was vinorelbine 25 mg/m2 day 1 and 8 with erlotinib 100 mg/day every 21 days. (2) The combination was associated with high rate of febrile neutropenia (25%). (3) Due to subsequent data demonstrating a lack of efficacy of erlotinib in combination with platinum doublets in advanced NSCLC, this combination has not been explored further.
TL;DR: Treatment with gemcitabine and oxaliplatin was well tolerated with primarily hematologic toxicity at the MTD, and decreased ribonucleotide reductase M2 expression correlated with response.
Abstract: Oxaliplatin has in vitro activity similar to or higher than other platinum agents. Preclinically, gemcitabine has demonstrated synergy when combined with platinum compounds. These facts formed the rationale for determining the maximum tolerated dose (MTD) of gemcitabine in combination with oxaliplatin. Eligible patients with advanced incurable solid tumors were given oxaliplatin 130 mg/m2 as a 2-h infusion on day 1 followed by escalating doses of gemcitabine given over 30 min on day 1 and 8 of a 21-day cycle. A total of 43 patients were enrolled, including 30 patients at the MTD in an expanded cohort. At a gemcitabine dose of 800 mg/m2, 1/6 patients had a dose limiting toxicity (DLT) (grade 3 blurred vision and memory loss). At 1,000 mg/m2, 1/6 patients had a DLT (grade 3 increase in AST). At 1,200 mg/m2, 2/3 patients had a DLT (grade 4 thrombocytopenia and grade 3 confusion). The MTD of gemcitabine with 130 mg/m2 of oxaliplatin was therefore 1,000 mg/m2. The clearances of gemcitabine and ultrafilterable platinum are within the ranges previously reported for single agents. A patient with colon cancer had a partial response, and 21 patients had a best response of stable disease. In patients with tumor biopsies treated at the MTD, decreased ribonucleotide reductase M2 expression correlated with response. Treatment with gemcitabine and oxaliplatin was well tolerated with primarily hematologic toxicity at the MTD. Study of biochemical correlates of response remain of interest althought current results remain exploratory.
TL;DR: The combination of gemcitabine and cisplatin is an active and reasonably well tolerated regimen for the treatment of ES-SCLC and does not appear to offer any compelling advantages over other commonly used two drug regimens in this disease.