Showing papers by "David R. Gandara published in 2009"
Loyola University Chicago1, Radiation Therapy Oncology Group2, Memorial Sloan Kettering Cancer Center3, Wayne State University4, University of Toronto5, Tom Baker Cancer Centre6, University of Rochester7, University of Arizona8, University of North Carolina at Chapel Hill9, University of California, Davis10, NorthShore University HealthSystem11, University Health Network12, Vanderbilt University13, Medical University of South Carolina14, Mayo Clinic15, Primary Children's Hospital16, University of Texas MD Anderson Cancer Center17
TL;DR: The primary endpoint was overall survival (OS) and an exploratory analysis, OS was improved for patients who underwent lobectomy, but not pneumonectomy, versus chemotherapy plus radiotherapy, compared with standard concurrent chemotherapy and definitive radiotherapy without resection.
1,202 citations
TL;DR: This large North American trial failed to confirm the previously reported survival benefit observed with IP in Japanese patients, and both regimens produced comparable efficacy, with less hematologic and greater gastrointestinal toxicity with IP.
Abstract: Purpose Irinotecan plus cisplatin (IP) improved survival over etoposide plus cisplatin (EP) in Japanese patients with extensive-stage small-cell lung cancer (E-SCLC). To confirm those results and discern the potential role of population-related pharmacogenomics (PG) in outcomes, we conducted a large randomized trial of identical design to the Japanese trial in North American patients with E-SCLC. Patients and Methods Patients were randomly assigned to IP (irinotecan 60 mg/m2 on days 1, 8, and 15; cisplatin 60 mg/m2 day 1, every 4 weeks) or EP (etoposide 100 mg/m2 on days 1 through 3; cisplatin 80 mg/m2 day 1, every 3 weeks). Blood specimens for genomic DNA analysis were collected before random assignment in 169 patients. Results Of 671 patients, 651 were eligible (324 and 327 patients in the IP and EP arms, respectively). Response rates with IP and EP were 60% and 57%, respectively (P = .56). Median progression-free survival for IP and EP was 5.8 and 5.2 months, respectively (P = .07). Median overall surv...
453 citations
TL;DR: There was evidence of activity in HCC, but therapy with lapatinib did not meet the predefined efficacy rate.
Abstract: To evaluate the response to lapatinib, an inhibitor of epidermal growth factor receptors 1 and 2, in patients with advanced bilary tree cancer (BTC) and hepatocellular cancer (HCC). Lapatinib was dosed at 1,500 mg/day orally continuously. Fifty-seven patients were accrued (BTC 17, HCC 40). Therapy was well tolerated. The response in BTC was 0% and in HCC was 5%. The progression free survival (PFS) for BTC and HCC patients was 1.8 (95% CI: 1.7–5.2) months and 2.3 (95% CI: 1.7–5.6) months. The median survival for BTC and HCC patients was 5.2 (95% CI 3.3–∞) months and 6.2 (95% CI: 5.1–∞) months. EGFR genotyping indicated HCC patients with <20 repeats have the lowest PFS. The occurrence of any skin rash significantly prolonged PFS and survival. Lapatinib was well-tolerated. There was evidence of activity in HCC, but therapy with lapatinib did not meet the predefined efficacy rate.
266 citations
TL;DR: Differences in allelic distribution for genes involved in paclitaxel disposition or DNA repair were observed between Japanese and US patients.
Abstract: Purpose To explore whether population-related pharmacogenomics contribute to differences in patient outcomes between clinical trials performed in Japan and the United States, given similar study designs, eligibility criteria, staging, and treatment regimens. Methods We prospectively designed and conducted three phase III trials (Four-Arm Cooperative Study, LC00-03, and S0003) in advanced-stage, non–small-cell lung cancer, each with a common arm of paclitaxel plus carboplatin. Genomic DNA was collected from patients in LC00-03 and S0003 who received paclitaxel (225 mg/m 2 ) and carboplatin (area under the concentration-time curve, 6). Genotypic variants of CYP3A4, CYP3A5, CYP2C8, NR1I2-206, ABCB1, ERCC1, and ERCC2 were analyzed by pyrosequencing or by PCR restriction fragment length polymorphism. Results were assessed by Cox model for survival and by logistic regression for response and toxicity. Results Clinical results were similar in the two Japanese trials, and were significantly different from the US trial, for survival, neutropenia, febrile neutropenia, and anemia. There was a significant difference between Japanese and US patients in genotypic distribution for CYP3A4*1B (P .01), CYP3A5*3C (P .03), ERCC1 118 (P .0001), ERCC2 K751Q (P .001), and CYP2C8 R139K (P .01). Genotypic associations were observed between CYP3A4*1B for progression-free survival (hazard ratio [HR], 0.36; 95% CI, 0.14 to 0.94; P .04) and ERCC2 K751Q for response (HR, 0.33; 95% CI, 0.13 to 0.83; P .02). For grade 4 neutropenia, the HR for ABCB1 3425C3 T was 1.84 (95% CI, 0.77 to 4.48; P .19).
187 citations
TL;DR: A phase II study of belinostat in patients with relapsed malignant pleural mesothelioma found that this novel inhibitor of class I and II histone deacetylases is not active as monotherapy against recurrent malignant psoriasis.
153 citations
TL;DR: AZD0530, a potent oral Src kinase inhibitor, is feasible and tolerable in this pretreated patient population but possessed little clinical efficacy as monotherapy, and strong preclinical evidence warrants further investigation of AZD 190530 in earlier-stage prostate cancer or as combination therapy.
Abstract: Prostate cancer cells undergo neuroendocrine differentiation during androgen deprivation and secrete neuropeptides, hence activating androgen receptor-regulated genes. Src-family protein kinases are involved in neuropeptide-induced prostate cancer growth and migration. A phase II trial of AZD0530, an oral Src-family kinase inhibitor, in patients with advanced castration resistant prostate cancer was conducted. The primary endpoint was prostate cancer-specific antigen (PSA) response rate, defined as a 30% or greater decrease. A two-stage Simon design was used. Eligibility criteria included documentation of castration resistance (including antiandrogen withdrawal), adequate end-organ function, and performance status, and not more than one prior taxane-based chemotherapy regimen. AZD0530 was given at 175 mg orally once daily continuously. Rapid accrual led to 28 patients registering in the first stage. Median age was 67 years. Sixteen patients had performance status (PS) 0, eight patients had PS 1, and four patients had PS 2. Nine patients (32%) had prior docetaxel-based chemotherapy. Five patients had transient PSA reductions not meeting PSA response criteria. Median progression-free survival time was 8 weeks. Treatment was generally well tolerated. AZD0530, a potent oral Src kinase inhibitor, is feasible and tolerable in this pretreated patient population but possessed little clinical efficacy as monotherapy. Strong preclinical evidence warrants further investigation of AZD0530 in earlier-stage prostate cancer or as combination therapy.
97 citations
TL;DR: Bortezomib plus gemcitabine/carboplatin resulted in a notable survival benefit in patients with advanced NSCLC, with the anticipated primary toxicity of myelosuppression.
71 citations
TL;DR: Activating EGFR mutations detected in shed DNA in plasma are significantly associated with favorable outcomes in patients with advanced NSCLC receiving docetaxel plus intercalated erlotinib.
68 citations
TL;DR: Combination cisplatin and gemcitabine is active in metastatic breast cancer regardless of prior therapy, and genetic polymorphisms may tailor which patients benefit from this regimen.
Abstract: Purpose Cisplatin and gemcitabine have single-agent activity in metastatic breast cancer, and preclinical data support synergy of the combination. Two parallel, phase II trials were conducted to evaluate the response rate, response duration, and toxicities of the combination. Genetic polymorphisms were analyzed for correlation with outcomes. Patients and Methods Eligible women had measurable disease and heavily or minimally pretreated metastatic breast cancer. The heavily pretreated protocol required prior anthracycline and taxane therapy; cisplatin as part of high-dose therapy was allowed. All patients received cisplatin 25 mg/m2 on days 1 through 4 and gemcitabine 1,000 mg/m2 on days 2 and 8 of a 21-day cycle with prophylactic granulocyte colony-stimulating factor in the heavily pretreated group. Sera from a subset of patients were evaluated by polymerase chain reaction restriction fragment length polymorphism for polymorphisms in 10 genes of interest. Results Of 136 women enrolled, 74 were heavily pret...
62 citations
TL;DR: Results of the phase II study S0222 showed acceptable levels of toxicity and similar promising median survival as S0004, and further study of hypoxia-targeted therapy is warranted in LSCLC.
Abstract: Purpose A SWOG pilot study (S0004) showed that tirapazamine (TPZ) when combined with concurrent chemoradiotherapy yielded a promising median survival of 22 months in limited-stage small-cell lung cancer (LSCLC). We report results of the phase II study designed to confirm this result. Patients and Methods The concurrent phase consisted of two cycles of cisplatin, etoposide, and once-daily radiation to 61 Gy. TPZ was given at 260 mg/m2 on days 1, 29, and at 160 mg/m2 on days 8, 10, 12, 36, 38, and 40. Consolidation consisted of two cycles of cisplatin and etoposide. Complete responders received prophylactic cranial irradiation. Results were considered promising if the median survival time was at least 21 months and of no further interest if ≤ 14 months. Results S0222 was closed early due to a report of excess toxicity for TPZ in a head and neck cancer trial elsewhere. Of planned 85 patients, 69 were accrued. In 68 assessable patients, 17 (25%) had grade 3 to 4 esophagitis and eight (12%) had grade 3 febrile...
54 citations
TL;DR: AZD0530, aside from being a potent inhibitor of tumor cell invasion which could translate to inhibition of disease progression in the clinic, may also lower resistance of lung cancer cells to pro-apoptotic signals.
TL;DR: This is the first clinical trial to test intermittent erlotinib plus pemetrexed and it is reported that this approach is feasible and well tolerated and arm B efficacy is being examined in a randomized phase II trial for second-line NSCLC.
TL;DR: This 21-day regimen of irinotecan and carboplatin seems promising for the treatment of relapsed SCLC.
Abstract: Purpose The regimens of weekly irinotecan with platinum have been used for treatment of metastatic small-cell lung cancer (SCLC). We conducted a multi-institution phase II trial to evaluate a novel 21-day schedule of irinotecan and carboplatin in patients with relapsed or extensive SCLC. Patients and Methods Eighty patients were enrolled with the following characteristics: 39 male patients, 41 female patients; median age, 65 years; and Zubrod performance status, 0 to 1 in 85% and 2 in 15% of patients. Dosing schemas were based on the maximum-tolerated dose derived in a previous phase I study. Chemotherapy-naive patients with extensive SCLC were treated with irinotecan 200 mg/m2 and carboplatin area under the curve (AUC) of 5 (arm A). Patients, who had previously been treated with chemotherapy and had relapsed disease received irinotecan 150 mg/m2 and carboplatin AUC of 5 (arm B). In each study arm, the treatment was given every 21 days for up to six cycles. Results The most common grade 3 to 4 toxicities ...
TL;DR: Although well-tolerated, oral fenretinide did not meet prespecified PSA criteria for response in biochemically recurrent prostate cancer; however, 30% of patients had SD, which suggests modest single-agent clinical activity.
TL;DR: This study found that response and progression-free survival were highly associated with EGFR mutation status, and patients with tumors harboring EGFR TK domain mutations did much better with gefitinib, whereas those with wild-type EGFR tumors fared better with chemotherapy, despite near uniformity in clinical factors that would have suggested superior outcomes with gEFITinib.
TL;DR: Evolving Treatment Algorithms for Advanced Non–Small-Cell Lung Cancer: 2009 Looking Toward 2012 David R. GANDARA, Philip C. MACK, Tianhong LI, Primo N. LARA, JR, Roy S. Lara, JR.
TL;DR: The potential roles for IGF-1R and HDAC inhibitors in NSCLC management, and the need for optimizing treatment by seeking a more personalized approach to care are discussed.
Abstract: Purpose of reviewIntegrating targeted therapies against the epidermal growth factor receptor (EGFR) and angiogenesis pathways into standard treatment paradigms for advanced nonsmall cell lung cancer (NSCLC) have been successful, but not yet curative. Two treatment strategies, in development, seem pa
TL;DR: A combination of GTI-2040, capecitabine and oxaliplatin is feasible in patients with advanced solid tumors and two of six patients had stable disease at the maximum tolerated dose and one patient had a partial response at a higher dose level.
Abstract: Background
GTI-2040 is a 20-mer antisense oligonucleotide targeting the mRNA of ribonucleotide reductase M2. It was combined with oxaliplatin and capecitabine in a phase I trial in patients with advance solid tumors based on previous studies demonstrating potentiation of chemotherapy with ribonucleotide reductase inhibitors.
TL;DR: Aflibercept was well tolerated with toxicities similar to those seen with other VEGF pathway inhibitors, however it has limited single agent activity in platinum-pretreated TCC pts.
Abstract: e16030 Background: The role and efficacy of subsequent systemic therapies for advanced TCC following failure of frontline platinum-based chemotherapy is unclear. There is evidence that vascular end...
TL;DR: ABT-869 demonstrates an acceptable safety profile and appears to be active in NSCLC patients and overall survival (OS) is demonstrated.
Abstract: 8074 Background: ABT-869 is a novel orally active, potent and specific inhibitor of vascular endothelial growth factor and platelet derived growth factor receptor tyrosine kinases. Methods: This ongoing, open-label, randomized, multicenter phase 2 trial of ABT-869 at 0.10 mg/kg daily (Arm A) and 0.25 mg/kg daily (Arm B) until progressive disease (PD) or intolerable toxicity, was initiated to assess antitumor activity and toxicity of ABT-869 in patients (pts) with NSCLC. Eligibility criteria included locally advanced or metastatic NSCLC; ≥ 1 prior systemic treatment, and ≥1 measurable lesion by RECIST criteria. The primary endpoint was the progression free (PF) rate at 16 wks. Secondary endpoints were objective response rate (ORR), time to progression (TTP), progression free survival (PFS) and overall survival (OS). CT scans were assessed by the investigator and centrally; central assessment results are provided. Results: 138 patients (pts) were enrolled from 08/07–10/08 from 27 centers with interim data a...
Stanford University1, City of Hope National Medical Center2, Vanderbilt University3, University of Maryland, Baltimore4, University of Chicago5, University of Texas Southwestern Medical Center6, Netherlands Cancer Institute7, Roswell Park Cancer Institute8, Ottawa Hospital Research Institute9, University of California, Davis10
TL;DR: A major focus of the groups at this time is a push toward more personalized medicine, as reflected in the selection criteria for many of the trials, along with planned correlates to better define populations most likely to benefit.
TL;DR: This phase I study is being conducted to determine the maximum tolerated dose (MTD) and pharmacokinetics (PK) of the combination of lapatinib and everolimus and observed diarrhea, stomatitis and fatigue.
Abstract: 3553 Background: Anti-tumor activity of Her inhibitors including lapatinib, an oral inhibitor of Her1 and Her 2, appears to correlate with their ability to down regulate PI3/Akt pathway. Everolimus...
TL;DR: Significant strides in lung cancer treatment often originate from investigations designed within the cooperative group system, and highlights include an ongoing Intergroup phase III study exploring differing radiation therapy schemes for limited-stage SCLC and a Southwest Oncology Group 0124 trial establishing platinum/etoposide as the standard of care for untreated extensive-stageSCLC in North America.