Results of phase I pharmacokinetic and pharmacodynamic studies of the Raf kinase inhibitor BAY 43-9006 in patients with solid tumors

Strumberg, Dirk; Voliotis, D.; Moeller, J; Hilger, Ralf A.; Richly, Heike; Kredtke, S; Beling, Carl G.; Scheulen, M. E.; Seeber, S

doi:10.5414/cpp40580

Cited by 106 publications

(74 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Sorafenib monotherapy has been shown to have a manageable side effect profile in Phase I/II/III studies (Strumberg et al, 2003Ratain et al, 2004Ratain et al, , 2006Awada et al, 2005;Escudier et al, 2005). The most common toxicities associated with sorafenib are hand-foot skin reaction (HFS), rash and diarrhoea (Strumberg et al, 2003Ratain et al, 2004Ratain et al, , 2006Awada et al, 2005;Escudier et al, 2005).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis

et al. 2006

View full text Add to dashboard Cite

The effects of sorafenib -an oral multikinase inhibitor targeting the tumour and tumour vasculature -were evaluated in patients with advanced melanoma enrolled in a large multidisease Phase II randomised discontinuation trial (RDT). Enrolled patients received a 12-week run-in of sorafenib 400 mg twice daily (b.i.d.). Patients with changes in bi-dimensional tumour measurements o25% from baseline were then randomised to sorafenib or placebo for a further 12 weeks (ie to week 24). Patients with X25% tumour shrinkage after the run-in continued on open-label sorafenib, whereas those with X25% tumour growth discontinued treatment. This analysis focussed on secondary RDT end points: changes in bi-dimensional tumour measurements from baseline after 12 weeks and overall tumour responses (WHO criteria) at week 24, progression-free survival (PFS), safety and biomarkers (BRAF, KRAS and NRAS mutational status). Of 37 melanoma patients treated during the run-in phase, 34 were evaluable for response: one had X25% tumour shrinkage and remained on open-label sorafenib; six (16%) had o25% tumour growth and were randomised (placebo, n ¼ 3; sorafenib, n ¼ 3); and 27 had X25% tumour growth and discontinued. All three randomised sorafenib patients progressed by week 24; one remained on sorafenib for symptomatic relief. All three placebo patients progressed by week-24 and were re-started on sorafenib; one experienced disease re-stabilisation. Overall, the confirmed best responses for each of the 37 melanoma patients who received sorafenib were 19% stable disease (SD) (ie n ¼ 1 open-label; n ¼ 6 randomised), 62% (n ¼ 23) progressive disease (PD) and 19% (n ¼ 7) unevaluable. The overall median PFS was 11 weeks. The six randomised patients with SD had overall PFS values ranging from 16 to 34 weeks. The most common drug-related adverse events were dermatological (eg rash/desquamation, 51%; hand-foot skin reaction, 35%). There was no relationship between V600E BRAF status and disease stability. DNA was extracted from the biopsies of 17/22 patients. Six had V600E-positive tumours (n ¼ 4 had PD; n ¼ 1 had SD; n ¼ 1 unevaluable for response), and 11 had tumours containing wild-type BRAF (n ¼ 9 PD; n ¼ 1 SD; n ¼ 1 unevaluable for response). In conclusion, sorafenib is well tolerated but has little or no antitumour activity in advanced melanoma patients as a single agent at the dose evaluated (400 mg b.i.d.). Ongoing trials in advanced melanoma are evaluating sorafenib combination therapies.

show abstract

mentioning

confidence: 99%

“…The most common toxicities associated with sorafenib are hand-foot skin reaction (HFS), rash and diarrhoea (Strumberg et al, 2003Ratain et al, 2004Ratain et al, , 2006Awada et al, 2005;Escudier et al, 2005). However, these adverse events are predominantly mild to moderate in severity and easily manageable.…”

mentioning

confidence: 99%

Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis

et al. 2006

View full text Add to dashboard Cite

show abstract

“…Preclinical studies have shown inhibition of tumor growth, and clinical benefit in patients with liver or colon cancer has been reported. 124 Another approach to inhibit Raf is using the ASO ISIS 5132, which blocks translation of c-Raf mRNA. In a Phase I trial of ISIS 5132, disease stability was reported for two patients with NSCLC.…”

Section: Kinase Pathways That Mediate the Effects Of Activated Receptmentioning

confidence: 99%

“…In a Phase I trial of ISIS 5132, disease stability was reported for two patients with NSCLC. 125 In two Phase I trials with LErafAON, a liposome encapsulated Raf ASO, the maximum tolerated dose was determined to be 4.0 mg/kg/week, 126,127 and disease stability was reported in patients with SCLC. 128 In a phase II trial that included patients with both SCLC and NSCLC, mild toxicity was observed but response rates were inconclusive.…”

Section: Kinase Pathways That Mediate the Effects Of Activated Receptmentioning

confidence: 99%

Targeting Aberrant Signal Transduction Pathways in Lung Cancer

Gills

Granville

Dennis

2004

Cancer Biology & Therapy

View full text Add to dashboard Cite

Lung cancer is the deadliest form of cancer in the world and is most commonly associated with smoking. Current treatment strategies are largely ineffective due to advanced stage at diagnosis and the inherent therapeutic resistance of lung cancer cells. To improve patient outcomes, many studies have been designed to identify molecular alterations in lung cancer in order to develop new therapeutic strategies. Molecular alterations in lung cancer include genetic changes, epigenetic changes, and changes in the expression or activity of kinases that comprise signaling pathways within cells. Signaling pathways are attractive targets for lung cancer therapy because activation of signaling pathways contributes to tumor growth and therapeutic resistance, and constitutively active signaling commonly occurs in lung cancer. This review will discuss signaling pathways that are relevant to lung cancer. We will discuss specific signaling aberrations found in lung cancers, review the status of signaling inhibitors being developed for lung cancer, identify emerging targets, and provide recommendations for the development of agents designed to inhibit signal transduction.

show abstract

“…Strategies for Raf-1 suppression that we and others have explored include the use of small molecule inhibitors of the Raf-1 protein and the use of antisense oligonucleotides (AON) directed against the c-raf-1 mRNA (13)(14)(15). Preclinical models have shown that AON can inhibit translation and accelerate degradation of c-raf-1 mRNA, leading to a decrease in Raf-1 intracellular concentration (16).…”

Section: Introductionmentioning

confidence: 99%

Delivery of a Liposomal c-raf-1 Antisense Oligonucleotide by Weekly Bolus Dosing in Patients with Advanced Solid Tumors

Rudin

Marshall

Huang

et al. 2004

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: Rapid cleavage in vivo and inefficient cellular uptake limit the clinical utility of antisense oligonucleotides (AON). Liposomal formulation may promote better intratumoral AON delivery and inhibit degradation in vivo. We conducted the first clinical evaluation of this concept using a liposomal AON complementary to the c-raf-1 protooncogene (LErafAON).Experimental Design: A dose escalation study was done to determine the maximum tolerated dose and to characterize the toxicities of LErafAON given as weekly intravenous infusion for 8 weeks to adults with advanced solid tumors. Pharmacokinetic analysis and evaluation of c-raf-1 target suppression in peripheral blood mononuclear cells were included.Results: Twenty-two patients received LErafAON (median 7 infusions; range 1-27) at doses of 1, 2, 4, and 6 mg/kg/week. Across all dose cohorts patients experienced infusion-related hypersensitivity reactions including flushing, dyspnea, hypoxia, rigors, back pain, and hypotension. Prolonged infusion duration and pretreatment with acetaminophen, H1-and H2-antagonists, and corticosteroids reduced the frequency and severity of these reactions. Progressive thrombocytopenia was dose-limiting at 6 mg/kg/ week. No objective responses were observed. Two patients treated at the maximum tolerated dose of 4 mg/kg/week had evidence of stable disease, with dosing extended beyond 8 weeks. Pharmacokinetic analysis revealed persistence of detectable circulating rafAON at 24 hours in 7 of 10 patients in the highest 2 dose cohorts. Suppression of c-raf-1 mRNA was noted in two of five patients analyzed.Conclusions: Dose-independent hypersensitivity reactions and dose-dependent thrombocytopenia limited tolerance of LErafAON. Future clinical evaluation of this approach will depend on modification of the liposome composition.

show abstract

Results of phase I pharmacokinetic and pharmacodynamic studies of the Raf kinase inhibitor BAY 43-9006 in patients with solid tumors

Cited by 106 publications

References 0 publications

Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis

Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis

Targeting Aberrant Signal Transduction Pathways in Lung Cancer

Delivery of a Liposomal c-raf-1 Antisense Oligonucleotide by Weekly Bolus Dosing in Patients with Advanced Solid Tumors

Contact Info

Product

Resources

About