Phase I/II, pharmacokinetic and pharmacodynamic trial of BAY 43–9006 alone in patients with metastatic melanoma

Flaherty, K. T.; Redlinger, Maryann; Schuchter, Lynn M.; Lathia, Chetan; Weber, Benjamin; O’Dwyer, Peter J.

doi:10.1200/jco.2005.23.16_suppl.3037

Cited by 45 publications

(30 citation statements)

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“…Clinical coadministration of the CYP3A4 inhibitor itraconazole with gefitinib resulted in a 78% increase in gefitinib AUC, whereas the CYP3A4 inducer rifampicin decreased gefitinib AUC by 83% (32). However, the decrease in gefitinib exposure with concurrent sorafenib does not seem to be due to CYP3A4 induction (33). In a probe substrate clinical trial, sorafenib in combination with the CYP3A4 substrate midazolam showed no significant changes in midazolam exposure, indicating that sorafenib was neither an inhibitor nor an inducer of CYP3A4 (33).…”

Section: Discussionmentioning

confidence: 94%

Phase I Trial of Sorafenib in Combination with Gefitinib in Patients with Refractory or Recurrent Non–Small Cell Lung Cancer

Adjei

Molina

Mandrekar

et al. 2007

Clinical Cancer Research

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Purpose: To evaluate the combination of sorafenib and gefitinib in patients with advanced nonŝ mall cell lung cancer. Experimental Design: In this dose-escalation trial, patients received oral sorafenib (200-400 mg) twice daily with gefitinib (250 mg orally) once daily to identify the recommended dose for phase II trials (RDP; part A). The pharmacokinetics of the RDP were characterized further in additional patients (part B) receiving single-agent gefitinib or sorafenib for 21days followed by a 7-day washout with crossover to the other agent for an additional 21days. Patients then received the combination of sorafenib plus gefitinib in 28-day cycles. Safety, pharmacokinetics, and antitumor efficacy were evaluated. Potential drug-drug interactions and the relationship between pharmacokinetics and toxicity were also assessed. Results: Thirty-one patients were treated (n = 12, part A; n = 19, part B). Most adverse events were grade 1/2. The most frequent grade 3/4 events included diarrhea and elevated alanine aminotransferase (both 9.7%). One dose-limiting toxicity occurred (part A: elevated alanine aminotransferase at 400 mg twice daily). Gefitinib had no effect on sorafenib pharmacokinetics. However, gefitinib C max (26%) and area under the curve (38%) were reduced by concomitant sorafenib. One patient had a partial response; 20 (65%; n = 8, part A; n = 12, part B) had stable disease z4 months.The RDP was sorafenib 400 mg twice daily with gefitinib 250 mg once daily. Conclusions: Sorafenib combined with gefitinib is well tolerated, with promising efficacy in patients with advanced non^small cell lung cancer. Studies to further investigate the significance of the reduction in gefitinib exposure by sorafenib are warranted.

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Section: Discussionmentioning

confidence: 94%

Phase I Trial of Sorafenib in Combination with Gefitinib in Patients with Refractory or Recurrent Non–Small Cell Lung Cancer

Adjei

Molina

Mandrekar

et al. 2007

Clinical Cancer Research

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“…The likely antiangiogenic effect of vascular endothelial growth factor receptor inhibition is one obvious consideration. We have thus studied the effect of single-agent sorafenib on MAPK pathway activity and tumor perfusion as a surrogate for antiangiogenic effect (22,23). Among a subset of patients who underwent serial tumor biopsies or dynamic contrast-enhanced magnetic resonance imaging, we found evidence that the MAPK pathway is inhibited and tumor perfusion is significantly decreased.…”

Section: Targeting Oncogenes and Downstream Signaling Pathwaysmentioning

confidence: 99%

Chemotherapy and Targeted Therapy Combinations in Advanced Melanoma

Flaherty

2006

Clinical Cancer Research

142

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For three decades, clinical trials with chemotherapy in melanoma have failed to show superiority of any one regimen over another. Dacarbazine remains the only ''standard''agent.With response rates of <10% and median progression-free survival of 2 months or less in contemporary trials, there is a need to improve systemic therapy. Combination chemotherapy is associated with higher response rates than single-agent therapy but this has not translated into improved survival. An increasing number of potential therapeutic targets have been identified. For some, pharmacologic inhibitors are available, including sorafenib for BRAF, farnesyltransferase inhibitors for NRAS, PD-0325901 for mitogen-activated protein kinase/extracellular signal-regulated kinase kinase, rapamycin analogues for mammalian target of rapamycin, and agents that inhibit either vascular endothelial growth factor or its receptors. Several multitargeted kinase inhibitors have potency against the fibroblast growth factor receptor, c-kit, and platelet-derived growth factor receptor. Small-molecule inhibitors of c-met and Akt are in preclinical development. Another class of agents indirectly affect aberrant signaling, including inhibitors of chaperones and proteasomes. Several targeted agents seem to enhance the cytotoxicity of chemotherapy in preclinical models. The mechanism by which signaling inhibition might synergize with chemotherapy requires more study so that rational combinations move forward. Very few targeted agents have been studied rigorously in this fashion.

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“…57,58 Mechanistic investigations have been limited but suggest that sorafenib does not effectively inhibit BRAF in human tumors (as measured by ERK activation before and during treatment), whereas significant changes were noted in tumor vascular permeability (an established surrogate for VEGF signaling). 59 On the basis of this evidence, it appeared that sorafenib was unable to exert a sufficient effect on BRAF to test the value of BRAF as a therapeutic target in melanoma. Even taking into account the other signaling effects of sorafenib, this agent was unable to augment the activity of chemotherapy in randomized trials in melanoma.…”

Section: Braf Inhibitorsmentioning

confidence: 99%

BRAF, a target in melanoma

Flaherty

McArthur

2010

Cancer

113

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The successful translation of therapies targeting signal-transduction pathways that are activated by oncogenes has provided a model for molecularly targeted therapy, and the identification of mutations in v-raf murine sarcoma viral oncogene homolog B1 (BRAF), a serine/threonine kinase, has turned the attention of the melanoma field toward this concept. The current review indicated that BRAF represents an important target in cancer, in part because it is present in 7% of all cancers and also because it represents the first intracellular signaling molecule that is activated by point mutations for which single-agent therapy appears to have efficacy. Therapy for advanced melanoma has progressed slowly over the past 3 decades, although significant advances have been made in other cancers with the application of cytotoxic chemotherapy and targeted therapies. However, in melanoma, cytotoxic chemotherapies have severe limits, chemotherapy does not convincingly improve on the natural history of metastatic disease and has no role in the adjuvant setting, and cytokine therapy may have a niche in both the adjuvant and metastatic settings but confers only a modest benefit to a small proportion of patients at the cost of severe toxicity. Thus, there are few other cancers in which completely novel therapies are so highly prioritized in clinical research. Understanding network of signal-transduction pathways and how that network may adapt to BRAF inhibition or mitogen-activated protein kinase kinase inhibition will point to the next generation of clinical trials investigating rational combination regimens. The current investigations in melanoma will create a set of hypotheses to be tested in each cancer that harbors BRAF mutations. Cancer 2010;116:4902-13. V C 2010 American Cancer Society.KEYWORDS: BRAF, melanoma, oncogene, kinase inhibitor, mutation.Therapy for advanced melanoma has progressed slowly over the past 3 decades, whereas significant advances have been made with the application of cytotoxic chemotherapy and, more recently, targeted therapies in other cancers. The application of cytotoxic chemotherapies that have disease-altering ability in other cancers has severe limits in melanoma. Chemotherapy does not convincingly improve upon the natural history of metastatic disease and has no role in the adjuvant setting. Cytokine therapy has a niche in both the adjuvant and metastatic settings but confers a modest benefit to a small proportion of patients at the cost of severe toxicity. Thus, there are few other cancers in which completely novel therapies are so highly prioritized in clinical research. The successful translation of therapies targeting signal-transduction pathways that are activated by oncogenes has provided a model for molecularly targeted therapy. The identification of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations in 2002 was the watershed event that turned the attention of the melanoma field to this concept. 1 BRAF BiologyRaf kinases are components of the mitogen-activated protein (MAP) k...

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Phase I/II, pharmacokinetic and pharmacodynamic trial of BAY 43–9006 alone in patients with metastatic melanoma

Cited by 45 publications

References 0 publications

Phase I Trial of Sorafenib in Combination with Gefitinib in Patients with Refractory or Recurrent Non–Small Cell Lung Cancer

Phase I Trial of Sorafenib in Combination with Gefitinib in Patients with Refractory or Recurrent Non–Small Cell Lung Cancer

Chemotherapy and Targeted Therapy Combinations in Advanced Melanoma

BRAF, a target in melanoma

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