A phase I multi-institutional study of systemic sorafenib in conjunction with regional melphalan for in-transit melanoma of the extremity

G. M. Beasley, A. P. Coleman, A. Raymond, G. Sanders, M. A. Selim, B. L. Peterson, M. S. Brady, M. A. Davies, C. Augustine, Douglas Tyler

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Background. Isolated limb infusion with melphalan (ILIM) corrected for ideal body weight (IBW) is a well-tolerated treatment for patients with in-transit extremity melanoma with an approximate 29 % complete response (CR) rate. Sorafenib, a multi-kinase inhibitor, has been shown to augment tumor response to chemotherapy in preclinical studies. Methods. A multi-institutional, dose-escalation, phase I study was performed to evaluate the safety and antitumor activity of sorafenib in combination with ILI-M. Patients with AJCC stage IIIB/IIIC/IV melanoma were treated with sorafenib starting at 400 mg daily for 7 days before and 7 days after ILI-M corrected for IBW. Toxicity, drug pharmacokinetics, and tumor protein expression changes were measured and correlated with clinical response at 3 months. Results. A total of 20 patients were enrolled at two institutions. The maximum tolerated dose (MTD) of sorafenib in combination with ILI-M was 400 mg. Four dose-limiting toxicities occurred, including soft tissue ulcerations and compartment syndrome. There were three CRs (15 %) and four partial responses (20 %). Of patients with the Braf mutation, 83 % (n = 6) progressed compared with only 33 % without (n = 12). Short-term sorafenib treatment did alter protein expression as measured with reverse phase protein array (RPPA) analysis, but did not inhibit protein expression in the MAP kinase pathway. Sorafenib did not alter melphalan pharmacokinetics. Conclusion. This trial defined the MTD of systemically administered sorafenib in combination with ILI-M. Although some responses were seen, the addition of sorafenib to ILI-M did not appear to augment the effects of melphalan but did increase regional toxicity.

Original languageEnglish (US)
Pages (from-to)3896-3905
Number of pages10
JournalAnnals of Surgical Oncology
Volume19
Issue number12
DOIs
StatePublished - Nov 2012
Externally publishedYes

Fingerprint

Melphalan
Melanoma
Extremities
Ideal Body Weight
Maximum Tolerated Dose
Phosphotransferases
Pharmacokinetics
Compartment Syndromes
Protein Array Analysis
Proteins
sorafenib
Drug-Related Side Effects and Adverse Reactions
Neoplasms
Safety
Drug Therapy
Mutation
Therapeutics

ASJC Scopus subject areas

  • Surgery
  • Oncology

Cite this

A phase I multi-institutional study of systemic sorafenib in conjunction with regional melphalan for in-transit melanoma of the extremity. / Beasley, G. M.; Coleman, A. P.; Raymond, A.; Sanders, G.; Selim, M. A.; Peterson, B. L.; Brady, M. S.; Davies, M. A.; Augustine, C.; Tyler, Douglas.

In: Annals of Surgical Oncology, Vol. 19, No. 12, 11.2012, p. 3896-3905.

Research output: Contribution to journalArticle

Beasley, GM, Coleman, AP, Raymond, A, Sanders, G, Selim, MA, Peterson, BL, Brady, MS, Davies, MA, Augustine, C & Tyler, D 2012, 'A phase I multi-institutional study of systemic sorafenib in conjunction with regional melphalan for in-transit melanoma of the extremity', Annals of Surgical Oncology, vol. 19, no. 12, pp. 3896-3905. https://doi.org/10.1245/s10434-012-2373-8
Beasley, G. M. ; Coleman, A. P. ; Raymond, A. ; Sanders, G. ; Selim, M. A. ; Peterson, B. L. ; Brady, M. S. ; Davies, M. A. ; Augustine, C. ; Tyler, Douglas. / A phase I multi-institutional study of systemic sorafenib in conjunction with regional melphalan for in-transit melanoma of the extremity. In: Annals of Surgical Oncology. 2012 ; Vol. 19, No. 12. pp. 3896-3905.
@article{da76d86107cf4488896234e15f149893,
title = "A phase I multi-institutional study of systemic sorafenib in conjunction with regional melphalan for in-transit melanoma of the extremity",
abstract = "Background. Isolated limb infusion with melphalan (ILIM) corrected for ideal body weight (IBW) is a well-tolerated treatment for patients with in-transit extremity melanoma with an approximate 29 {\%} complete response (CR) rate. Sorafenib, a multi-kinase inhibitor, has been shown to augment tumor response to chemotherapy in preclinical studies. Methods. A multi-institutional, dose-escalation, phase I study was performed to evaluate the safety and antitumor activity of sorafenib in combination with ILI-M. Patients with AJCC stage IIIB/IIIC/IV melanoma were treated with sorafenib starting at 400 mg daily for 7 days before and 7 days after ILI-M corrected for IBW. Toxicity, drug pharmacokinetics, and tumor protein expression changes were measured and correlated with clinical response at 3 months. Results. A total of 20 patients were enrolled at two institutions. The maximum tolerated dose (MTD) of sorafenib in combination with ILI-M was 400 mg. Four dose-limiting toxicities occurred, including soft tissue ulcerations and compartment syndrome. There were three CRs (15 {\%}) and four partial responses (20 {\%}). Of patients with the Braf mutation, 83 {\%} (n = 6) progressed compared with only 33 {\%} without (n = 12). Short-term sorafenib treatment did alter protein expression as measured with reverse phase protein array (RPPA) analysis, but did not inhibit protein expression in the MAP kinase pathway. Sorafenib did not alter melphalan pharmacokinetics. Conclusion. This trial defined the MTD of systemically administered sorafenib in combination with ILI-M. Although some responses were seen, the addition of sorafenib to ILI-M did not appear to augment the effects of melphalan but did increase regional toxicity.",
author = "Beasley, {G. M.} and Coleman, {A. P.} and A. Raymond and G. Sanders and Selim, {M. A.} and Peterson, {B. L.} and Brady, {M. S.} and Davies, {M. A.} and C. Augustine and Douglas Tyler",
year = "2012",
month = "11",
doi = "10.1245/s10434-012-2373-8",
language = "English (US)",
volume = "19",
pages = "3896--3905",
journal = "Annals of Surgical Oncology",
issn = "1068-9265",
publisher = "Springer New York",
number = "12",

}

TY - JOUR

T1 - A phase I multi-institutional study of systemic sorafenib in conjunction with regional melphalan for in-transit melanoma of the extremity

AU - Beasley, G. M.

AU - Coleman, A. P.

AU - Raymond, A.

AU - Sanders, G.

AU - Selim, M. A.

AU - Peterson, B. L.

AU - Brady, M. S.

AU - Davies, M. A.

AU - Augustine, C.

AU - Tyler, Douglas

PY - 2012/11

Y1 - 2012/11

N2 - Background. Isolated limb infusion with melphalan (ILIM) corrected for ideal body weight (IBW) is a well-tolerated treatment for patients with in-transit extremity melanoma with an approximate 29 % complete response (CR) rate. Sorafenib, a multi-kinase inhibitor, has been shown to augment tumor response to chemotherapy in preclinical studies. Methods. A multi-institutional, dose-escalation, phase I study was performed to evaluate the safety and antitumor activity of sorafenib in combination with ILI-M. Patients with AJCC stage IIIB/IIIC/IV melanoma were treated with sorafenib starting at 400 mg daily for 7 days before and 7 days after ILI-M corrected for IBW. Toxicity, drug pharmacokinetics, and tumor protein expression changes were measured and correlated with clinical response at 3 months. Results. A total of 20 patients were enrolled at two institutions. The maximum tolerated dose (MTD) of sorafenib in combination with ILI-M was 400 mg. Four dose-limiting toxicities occurred, including soft tissue ulcerations and compartment syndrome. There were three CRs (15 %) and four partial responses (20 %). Of patients with the Braf mutation, 83 % (n = 6) progressed compared with only 33 % without (n = 12). Short-term sorafenib treatment did alter protein expression as measured with reverse phase protein array (RPPA) analysis, but did not inhibit protein expression in the MAP kinase pathway. Sorafenib did not alter melphalan pharmacokinetics. Conclusion. This trial defined the MTD of systemically administered sorafenib in combination with ILI-M. Although some responses were seen, the addition of sorafenib to ILI-M did not appear to augment the effects of melphalan but did increase regional toxicity.

AB - Background. Isolated limb infusion with melphalan (ILIM) corrected for ideal body weight (IBW) is a well-tolerated treatment for patients with in-transit extremity melanoma with an approximate 29 % complete response (CR) rate. Sorafenib, a multi-kinase inhibitor, has been shown to augment tumor response to chemotherapy in preclinical studies. Methods. A multi-institutional, dose-escalation, phase I study was performed to evaluate the safety and antitumor activity of sorafenib in combination with ILI-M. Patients with AJCC stage IIIB/IIIC/IV melanoma were treated with sorafenib starting at 400 mg daily for 7 days before and 7 days after ILI-M corrected for IBW. Toxicity, drug pharmacokinetics, and tumor protein expression changes were measured and correlated with clinical response at 3 months. Results. A total of 20 patients were enrolled at two institutions. The maximum tolerated dose (MTD) of sorafenib in combination with ILI-M was 400 mg. Four dose-limiting toxicities occurred, including soft tissue ulcerations and compartment syndrome. There were three CRs (15 %) and four partial responses (20 %). Of patients with the Braf mutation, 83 % (n = 6) progressed compared with only 33 % without (n = 12). Short-term sorafenib treatment did alter protein expression as measured with reverse phase protein array (RPPA) analysis, but did not inhibit protein expression in the MAP kinase pathway. Sorafenib did not alter melphalan pharmacokinetics. Conclusion. This trial defined the MTD of systemically administered sorafenib in combination with ILI-M. Although some responses were seen, the addition of sorafenib to ILI-M did not appear to augment the effects of melphalan but did increase regional toxicity.

UR - http://www.scopus.com/inward/record.url?scp=84868138961&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84868138961&partnerID=8YFLogxK

U2 - 10.1245/s10434-012-2373-8

DO - 10.1245/s10434-012-2373-8

M3 - Article

VL - 19

SP - 3896

EP - 3905

JO - Annals of Surgical Oncology

JF - Annals of Surgical Oncology

SN - 1068-9265

IS - 12

ER -