A randomized phase III trial of gemcitabine (G) in combination with carboplatin (C) or paclitaxel (P) versus paclitaxel plus carboplatin in advanced (Stage IIIB, IV) non-small cell lung cancer (NSCLC): Update of the Alpha Oncology trial (A1–99002L)

Treat, Joseph; Belani, Chandra P.; Edelman, Martin J.; Socinski, Mark A.; Ansari, Rafat; Obasaju, Coleman K.; Bloss, Jeffrey D.; Marinucci, D. M.; Catalano, Robert B.; Comis, Robert L.

doi:10.1200/jco.2005.23.16_suppl.lba7025

Cited by 37 publications

(33 citation statements)

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“…In that regard, a more fair comparison would be with the Alpha Oncology trial (f15% brain metastasis; ref. 39). Here, our results compare substantially better with a median survival of 2.7 months higher (10% higher 1-year survival).…”

Section: Discussionsupporting

confidence: 57%

Phase I/II Study of Atrasentan, an Endothelin A Receptor Antagonist, in Combination with Paclitaxel and Carboplatin as First-Line Therapy in Advanced Non–Small Cell Lung Cancer

Chiappori

Haura

Rodriguez³

et al. 2008

Clinical Cancer Research

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Purpose: Endothelins and their cell membrane receptors (ET A R and ET B R) are implicated in neoplastic pathogenesis. Atrasentan, a potent, selective ET A R antagonist, has a direct effect on tumor proliferation, apoptosis, and angiogenesis.This study was designed to assess the influence of atrasentan on paclitaxel pharmacokinetics and to determine the safety and efficacy of atrasentan in combination with paclitaxel-carboplatin. Experimental Design: Chemonaive patients with stage IIIB (malignant pleural effusion) and IV non^small cell lung cancer were enrolled. Toxicity and response were determined using the National Cancer Institute CommonToxicity Criteria version 2.0 and Response Evaluation Criteria in Solid Tumors criteria, respectively. Treatment consisted of paclitaxel (225 mg/m 2 ) and carboplatin (area under the curve, 6) administered on day 1every 3 weeks. A fixed 10 mg daily oral dose of atrasentan was administered continuously, starting on day 4 of cycle 1. Paclitaxel clearance was calculated during the first two cycles (pre-and post-atrasentan) in the first 10 patients. Results: All 44 patients were evaluable for survival, toxicity, and response. No significant change in mean paclitaxel clearance was detected (mean F SD, 21.2 F 4.5 L/h versus 21.3 F 4.9 L/h) for pre-and post-atrasentan values, respectively (P = 0.434). Grade 3/4 toxicities z10% were lymphopenia (22.7%), neutropenia (20.5%), dyspnea (11.4%), and hyperglycemia (11.4%). Response rate was 18.2%, with progression-free survival of 4.2 months, median survival of 10.6 months, and 1-year survival of 43%. Conclusion: Atrasentan plus paclitaxel-carboplatin was safe and well tolerated, with no apparent paclitaxel-atrasentan pharmacokinetic interaction. Efficacy and survival in advanced non^small cell lung cancer were comparable with studies of chemotherapy alone.In 2006, lung cancer remains the most frequent cause of cancer mortality in the United States (1). More than 80% of patients have non -small cell lung cancer (NSCLC) and half of them have advanced disease at diagnosis (2). In these cases, treatment mostly consists of chemotherapy with a platinumbased doublet (3). Chemotherapy, however, has reached an efficacy plateau, and newer therapies are needed (4,5). Improved understanding of the molecular biology of NSCLC (signaling pathways, etc.) has opened a whole new field of therapeutic options, where development of many new agents targets these pathways (6, 7), such as the endothelin axis pathway (8).The endothelins include three 21 -amino acid isopeptides (ET-1, ET-2, and ET-3) characterized by a single a-helix and two disulfide bridges. They exert their effects by binding to two cell surface receptors (ET A R and ET B R), which belong to the G protein -linked family of receptors (8,9). The binding of ET-1 to ET A R exerts pleiotropic biological effects that influence cell survival and proliferation (through activation of various kinases, namely, protein kinase C, epidermal growth factor, and insulin-like growth factor), apoptosis (b...

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Section: Discussionsupporting

confidence: 57%

Phase I/II Study of Atrasentan, an Endothelin A Receptor Antagonist, in Combination with Paclitaxel and Carboplatin as First-Line Therapy in Advanced Non–Small Cell Lung Cancer

Chiappori

Haura

Rodriguez³

et al. 2008

Clinical Cancer Research

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“…Combination chemotherapy is considered the standard of care for patients with advanced NSCLC and a PS score of 0 or 1 [9]. Both platinum-based two-drug regimens and nonplatinum combinations have been shown to be efficacious in the first-line treatment of advanced NSCLC [10][11][12][13][14].…”

Section: Treatment Of Advanced-stage Nsclcmentioning

confidence: 99%

“…The advantage of excluding platinum compounds is that they are associated with considerable toxicity. Randomized trials that have directly compared platinum-based regimens with nonplatinum combinations have demonstrated comparable results [13,14]. A recent randomized study compared carboplatin plus paclitaxel with carboplatin plus gemcitabine The Oncologist ® and the nonplatinum regimen of gemcitabine plus paclitaxel for advanced NSCLC [14].…”

Section: Platinum Versus Nonplatinum Regimensmentioning

confidence: 99%

Systemic Chemotherapy for Advanced Non-Small Cell Lung Cancer: Recent Advances and Future Directions

2008

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Systemic therapy improves the survival and quality of life of patients with advanced stage non-small cell lung cancer (NSCLC). Several new therapeutic options have emerged for advanced NSCLC, incorporating novel cytotoxic agents (taxanes, gemcitabine, pemetrexed) and molecular-targeted agents (erlotinib, bevacizumab). Efforts to improve the outcome of firstline therapy for advanced and metastatic NSCLC have primarily focused on the addition of targeted agents to platinum-based two-drug regimens. Bevacizumab, an antibody against vascular endothelial growth factor, is the first drug to demonstrate superior outcomes when added to systemic chemotherapy in advanced disease. Evaluation of the role of maintenance therapy following four to six cycles of first-line combination chemotherapy is ongoing. Both cytotoxic agents and targeted agents are suitable for evaluation in the maintenance setting. Promising results have been noted with single-agent paclitaxel as maintenance therapy following four cycles of combination therapy with carboplatin and paclitaxel. Phase III studies are now under way to evaluate the roles of gemcitabine, pemetrexed, and erlotinib as maintenance therapies for patients who experience a response or disease stabilization after four cycles of combination chemotherapy. Whether this approach will be successful in extending the survival of a select group of patients remains to be seen. The Oncologist 2008;13(suppl 1):5-13

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“…On a recent North American trial of advanced NSCLC, 17% of patients presented with brain metastases, and there is evidence that the prevalence of brain metastases is increasing on cooperative group trials (Treat et al, 2005;Wakelee et al, 2006a). Previously, brain imaging was only performed in patients with advanced disease if there was a clinical suspicion of brain metastases (Pfister et al, 2004).…”

Section: Patient Populations Excluded From the Ecog 4599 Trialmentioning

confidence: 99%

Bevacizumab in the treatment of non-small-cell lung cancer

Stinchcombe

Socinski

2007

Oncogene

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A randomized phase III trial of gemcitabine (G) in combination with carboplatin (C) or paclitaxel (P) versus paclitaxel plus carboplatin in advanced (Stage IIIB, IV) non-small cell lung cancer (NSCLC): Update of the Alpha Oncology trial (A1–99002L)

Cited by 37 publications

References 0 publications

Phase I/II Study of Atrasentan, an Endothelin A Receptor Antagonist, in Combination with Paclitaxel and Carboplatin as First-Line Therapy in Advanced Non–Small Cell Lung Cancer

Phase I/II Study of Atrasentan, an Endothelin A Receptor Antagonist, in Combination with Paclitaxel and Carboplatin as First-Line Therapy in Advanced Non–Small Cell Lung Cancer

Systemic Chemotherapy for Advanced Non-Small Cell Lung Cancer: Recent Advances and Future Directions

Bevacizumab in the treatment of non-small-cell lung cancer

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