Clinical activity and safety of combination therapy with temsirolimus and bevacizumab for advanced melanoma

A phase II trial (CTEP 7190/Mel47)

Craig L. Slingluff, Gina R. Petroni, Kerrington R. Molhoek, David L. Brautigan, Kimberly A. Chianese-Bullock, Amber L. Shada, Mark E. Smolkin, Walter C. Olson, Alison Gaucher, Cheryl Murphy Chase, William W. Grosh, Geoffrey R. Weiss, Aubrey G. Wagenseller, Anthony J. Olszanski, Lainie Martin, Sofia M. Shea, Gulsun Erdag, Prahlad Ram, Jeffrey E. Gershenwald, Michael J. Weber

Research output: Contribution to journalArticle

Abstract

Purpose: A CTEP-sponsored phase II trial was conducted to evaluate safety and clinical activity of combination therapy with CCI-779 (temsirolimus) and bevacizumab in patients with advanced melanoma. Experimental Design: Patients with unresectable stage III to IV melanoma were treated intravenously with temsirolimus 25 mgweekly and bevacizumab 10mgevery 2 weeks. Adverse events were recorded using CTCAE v3.0. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors and overall survival was recorded. Correlative studies measured protein kinases and histology of tumor biopsies and immune function in peripheral blood. Results: Seventeen patients were treated. Most patients tolerated treatment well, but 2 had grade 4 lymphopenia and 1 developed reversible grade 2 leukoencephalopathy. Best clinical response was partial response (PR) in 3 patients [17.7%, 90% confidence interval (CI) 5, 0-39.6], stable disease at 8 weeks (SD) in 9 patients, progressive disease (PD) in 4 patients, and not evaluable in 1 patient. Maximal response duration for PR was 35 months. Ten evaluable patients had BRAFWT tumors, among whom 3 had PRs, 5 had SD, and 2 had PD. Correlative studies of tumor biopsies revealed decreased phospho-S6K (d2 and d23 vs. d1, P <0.001), and decreased mitotic rate (Ki67+) among melanoma cells by d23 (P = 0.007). Effects on immune functions were mixed, with decreased alloreactive T-cell responses and decreased circulating CD4+ FoxP3+ cells. Conclusion: These data provide preliminary evidence for clinical activity of combination therapy with temsirolimus and bevacizumab, which may be greater in patients with BRAFwt melanoma. Mixed effects on immunologic function also support combination with immune therapies.

Original languageEnglish (US)
Pages (from-to)3611-3620
Number of pages10
JournalClinical Cancer Research
Volume19
Issue number13
DOIs
StatePublished - Jul 1 2013

Fingerprint

Melanoma
Safety
Therapeutics
Neoplasms
temsirolimus
Bevacizumab
Biopsy
Leukoencephalopathies
Lymphopenia
Protein Kinases
Histology
Research Design
Confidence Intervals
T-Lymphocytes
Survival

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Slingluff, C. L., Petroni, G. R., Molhoek, K. R., Brautigan, D. L., Chianese-Bullock, K. A., Shada, A. L., ... Weber, M. J. (2013). Clinical activity and safety of combination therapy with temsirolimus and bevacizumab for advanced melanoma: A phase II trial (CTEP 7190/Mel47). Clinical Cancer Research, 19(13), 3611-3620. https://doi.org/10.1158/1078-0432.CCR-12-3919

Clinical activity and safety of combination therapy with temsirolimus and bevacizumab for advanced melanoma : A phase II trial (CTEP 7190/Mel47). / Slingluff, Craig L.; Petroni, Gina R.; Molhoek, Kerrington R.; Brautigan, David L.; Chianese-Bullock, Kimberly A.; Shada, Amber L.; Smolkin, Mark E.; Olson, Walter C.; Gaucher, Alison; Chase, Cheryl Murphy; Grosh, William W.; Weiss, Geoffrey R.; Wagenseller, Aubrey G.; Olszanski, Anthony J.; Martin, Lainie; Shea, Sofia M.; Erdag, Gulsun; Ram, Prahlad; Gershenwald, Jeffrey E.; Weber, Michael J.

In: Clinical Cancer Research, Vol. 19, No. 13, 01.07.2013, p. 3611-3620.

Research output: Contribution to journalArticle

Slingluff, CL, Petroni, GR, Molhoek, KR, Brautigan, DL, Chianese-Bullock, KA, Shada, AL, Smolkin, ME, Olson, WC, Gaucher, A, Chase, CM, Grosh, WW, Weiss, GR, Wagenseller, AG, Olszanski, AJ, Martin, L, Shea, SM, Erdag, G, Ram, P, Gershenwald, JE & Weber, MJ 2013, 'Clinical activity and safety of combination therapy with temsirolimus and bevacizumab for advanced melanoma: A phase II trial (CTEP 7190/Mel47)', Clinical Cancer Research, vol. 19, no. 13, pp. 3611-3620. https://doi.org/10.1158/1078-0432.CCR-12-3919
Slingluff, Craig L. ; Petroni, Gina R. ; Molhoek, Kerrington R. ; Brautigan, David L. ; Chianese-Bullock, Kimberly A. ; Shada, Amber L. ; Smolkin, Mark E. ; Olson, Walter C. ; Gaucher, Alison ; Chase, Cheryl Murphy ; Grosh, William W. ; Weiss, Geoffrey R. ; Wagenseller, Aubrey G. ; Olszanski, Anthony J. ; Martin, Lainie ; Shea, Sofia M. ; Erdag, Gulsun ; Ram, Prahlad ; Gershenwald, Jeffrey E. ; Weber, Michael J. / Clinical activity and safety of combination therapy with temsirolimus and bevacizumab for advanced melanoma : A phase II trial (CTEP 7190/Mel47). In: Clinical Cancer Research. 2013 ; Vol. 19, No. 13. pp. 3611-3620.
@article{aa864d1fb8d142a096859b7dfdcb4592,
title = "Clinical activity and safety of combination therapy with temsirolimus and bevacizumab for advanced melanoma: A phase II trial (CTEP 7190/Mel47)",
abstract = "Purpose: A CTEP-sponsored phase II trial was conducted to evaluate safety and clinical activity of combination therapy with CCI-779 (temsirolimus) and bevacizumab in patients with advanced melanoma. Experimental Design: Patients with unresectable stage III to IV melanoma were treated intravenously with temsirolimus 25 mgweekly and bevacizumab 10mgevery 2 weeks. Adverse events were recorded using CTCAE v3.0. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors and overall survival was recorded. Correlative studies measured protein kinases and histology of tumor biopsies and immune function in peripheral blood. Results: Seventeen patients were treated. Most patients tolerated treatment well, but 2 had grade 4 lymphopenia and 1 developed reversible grade 2 leukoencephalopathy. Best clinical response was partial response (PR) in 3 patients [17.7{\%}, 90{\%} confidence interval (CI) 5, 0-39.6], stable disease at 8 weeks (SD) in 9 patients, progressive disease (PD) in 4 patients, and not evaluable in 1 patient. Maximal response duration for PR was 35 months. Ten evaluable patients had BRAFWT tumors, among whom 3 had PRs, 5 had SD, and 2 had PD. Correlative studies of tumor biopsies revealed decreased phospho-S6K (d2 and d23 vs. d1, P <0.001), and decreased mitotic rate (Ki67+) among melanoma cells by d23 (P = 0.007). Effects on immune functions were mixed, with decreased alloreactive T-cell responses and decreased circulating CD4+ FoxP3+ cells. Conclusion: These data provide preliminary evidence for clinical activity of combination therapy with temsirolimus and bevacizumab, which may be greater in patients with BRAFwt melanoma. Mixed effects on immunologic function also support combination with immune therapies.",
author = "Slingluff, {Craig L.} and Petroni, {Gina R.} and Molhoek, {Kerrington R.} and Brautigan, {David L.} and Chianese-Bullock, {Kimberly A.} and Shada, {Amber L.} and Smolkin, {Mark E.} and Olson, {Walter C.} and Alison Gaucher and Chase, {Cheryl Murphy} and Grosh, {William W.} and Weiss, {Geoffrey R.} and Wagenseller, {Aubrey G.} and Olszanski, {Anthony J.} and Lainie Martin and Shea, {Sofia M.} and Gulsun Erdag and Prahlad Ram and Gershenwald, {Jeffrey E.} and Weber, {Michael J.}",
year = "2013",
month = "7",
day = "1",
doi = "10.1158/1078-0432.CCR-12-3919",
language = "English (US)",
volume = "19",
pages = "3611--3620",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "13",

}

TY - JOUR

T1 - Clinical activity and safety of combination therapy with temsirolimus and bevacizumab for advanced melanoma

T2 - A phase II trial (CTEP 7190/Mel47)

AU - Slingluff, Craig L.

AU - Petroni, Gina R.

AU - Molhoek, Kerrington R.

AU - Brautigan, David L.

AU - Chianese-Bullock, Kimberly A.

AU - Shada, Amber L.

AU - Smolkin, Mark E.

AU - Olson, Walter C.

AU - Gaucher, Alison

AU - Chase, Cheryl Murphy

AU - Grosh, William W.

AU - Weiss, Geoffrey R.

AU - Wagenseller, Aubrey G.

AU - Olszanski, Anthony J.

AU - Martin, Lainie

AU - Shea, Sofia M.

AU - Erdag, Gulsun

AU - Ram, Prahlad

AU - Gershenwald, Jeffrey E.

AU - Weber, Michael J.

PY - 2013/7/1

Y1 - 2013/7/1

N2 - Purpose: A CTEP-sponsored phase II trial was conducted to evaluate safety and clinical activity of combination therapy with CCI-779 (temsirolimus) and bevacizumab in patients with advanced melanoma. Experimental Design: Patients with unresectable stage III to IV melanoma were treated intravenously with temsirolimus 25 mgweekly and bevacizumab 10mgevery 2 weeks. Adverse events were recorded using CTCAE v3.0. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors and overall survival was recorded. Correlative studies measured protein kinases and histology of tumor biopsies and immune function in peripheral blood. Results: Seventeen patients were treated. Most patients tolerated treatment well, but 2 had grade 4 lymphopenia and 1 developed reversible grade 2 leukoencephalopathy. Best clinical response was partial response (PR) in 3 patients [17.7%, 90% confidence interval (CI) 5, 0-39.6], stable disease at 8 weeks (SD) in 9 patients, progressive disease (PD) in 4 patients, and not evaluable in 1 patient. Maximal response duration for PR was 35 months. Ten evaluable patients had BRAFWT tumors, among whom 3 had PRs, 5 had SD, and 2 had PD. Correlative studies of tumor biopsies revealed decreased phospho-S6K (d2 and d23 vs. d1, P <0.001), and decreased mitotic rate (Ki67+) among melanoma cells by d23 (P = 0.007). Effects on immune functions were mixed, with decreased alloreactive T-cell responses and decreased circulating CD4+ FoxP3+ cells. Conclusion: These data provide preliminary evidence for clinical activity of combination therapy with temsirolimus and bevacizumab, which may be greater in patients with BRAFwt melanoma. Mixed effects on immunologic function also support combination with immune therapies.

AB - Purpose: A CTEP-sponsored phase II trial was conducted to evaluate safety and clinical activity of combination therapy with CCI-779 (temsirolimus) and bevacizumab in patients with advanced melanoma. Experimental Design: Patients with unresectable stage III to IV melanoma were treated intravenously with temsirolimus 25 mgweekly and bevacizumab 10mgevery 2 weeks. Adverse events were recorded using CTCAE v3.0. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors and overall survival was recorded. Correlative studies measured protein kinases and histology of tumor biopsies and immune function in peripheral blood. Results: Seventeen patients were treated. Most patients tolerated treatment well, but 2 had grade 4 lymphopenia and 1 developed reversible grade 2 leukoencephalopathy. Best clinical response was partial response (PR) in 3 patients [17.7%, 90% confidence interval (CI) 5, 0-39.6], stable disease at 8 weeks (SD) in 9 patients, progressive disease (PD) in 4 patients, and not evaluable in 1 patient. Maximal response duration for PR was 35 months. Ten evaluable patients had BRAFWT tumors, among whom 3 had PRs, 5 had SD, and 2 had PD. Correlative studies of tumor biopsies revealed decreased phospho-S6K (d2 and d23 vs. d1, P <0.001), and decreased mitotic rate (Ki67+) among melanoma cells by d23 (P = 0.007). Effects on immune functions were mixed, with decreased alloreactive T-cell responses and decreased circulating CD4+ FoxP3+ cells. Conclusion: These data provide preliminary evidence for clinical activity of combination therapy with temsirolimus and bevacizumab, which may be greater in patients with BRAFwt melanoma. Mixed effects on immunologic function also support combination with immune therapies.

UR - http://www.scopus.com/inward/record.url?scp=84879847151&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84879847151&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-12-3919

DO - 10.1158/1078-0432.CCR-12-3919

M3 - Article

VL - 19

SP - 3611

EP - 3620

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 13

ER -