Randomized, double-blind, placebo-controlled phase II study of AMG 386 combined with weekly paclitaxel in patients with recurrent ovarian cancer

Beth Y. Karlan, Amit M. Oza, Gary E. Richardson, Diane M. Provencher, Vincent L. Hansen, Martin Buck, Setsuko K Chambers, Prafull Ghatage, Charles H. Pippitt, John V. Brown, Allan Covens, Raj V. Nagarkar, Margaret Davy, Charles A. Leath, Hoa Nguyen, Daniel E. Stepan, David M. Weinreich, Marjan Tassoudji, Yu Nien Sun, Ignace B. Vergote

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Abstract

Purpose: To estimate the efficacy and toxicity of AMG 386, an investigational peptide-Fc fusion protein that neutralizes the interaction between the Tie2 receptor and angiopoietin-1/2, plus weekly paclitaxel in patients with recurrent ovarian cancer. Patients and Methods: Patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer were randomly assigned 1:1:1 to receive paclitaxel (80 mg/m 2 once weekly [QW], 3 weeks on/1 week off) plus intravenous AMG 386 10 mg/kg QW (arm A), AMG 386 3 mg/kg QW (arm B), or placebo QW (arm C). The primary end point was progression-free survival (PFS). Secondary end points included overall survival, objective response, CA-125 response, safety, and pharmacokinetics. Results: One hundred sixty-one patients were randomly assigned. Median PFS was 7.2 months (95% CI, 5.3 to 8.1 months) in arm A, 5.7 months (95% CI, 4.6 to 8.0 months) in arm B, and 4.6 months (95% CI, 1.9 to 6.7 months) in arm C. The hazard ratio for arms A and B combined versus arm C was 0.76 (95% CI, 0.52 to 1.12; P = .165). Further analyses suggested an exploratory dose-response effect for PFS across arms (Tarone's test, P = .037). Objective response rates for arms A, B, and C were 37%, 19%, and 27%, respectively. The incidence of grade ≥ 3 adverse events (AEs) in arms A, B, and C was 65%, 55%, and 64%, respectively. Frequent AEs included hypertension (8%, 6%, and 5% in arms A, B, and C, respectively), peripheral edema (71%, 51%, and 22% in arms A, B, and C, respectively), and hypokalemia (21%, 15%, and 5% in arms A, B, and C, respectively). AMG 386 exhibited linear pharmacokinetic properties at the tested doses. Conclusion: AMG 386 combined with weekly paclitaxel was tolerable, with a manageable and distinct toxicity profile. The data suggest evidence of antitumor activity and a dose-response effect, warranting further studies in ovarian cancer.

Original languageEnglish (US)
Pages (from-to)362-371
Number of pages10
JournalJournal of Clinical Oncology
Volume30
Issue number4
DOIs
StatePublished - Feb 1 2012

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Paclitaxel
Ovarian Neoplasms
Placebos
Disease-Free Survival
TIE-2 Receptor
Pharmacokinetics
Angiopoietin-2
Angiopoietin-1
Hypokalemia
Fallopian Tubes
Edema
trebananib
Hypertension
Safety
Peptides
Survival
Incidence
Neoplasms
Proteins

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Randomized, double-blind, placebo-controlled phase II study of AMG 386 combined with weekly paclitaxel in patients with recurrent ovarian cancer. / Karlan, Beth Y.; Oza, Amit M.; Richardson, Gary E.; Provencher, Diane M.; Hansen, Vincent L.; Buck, Martin; Chambers, Setsuko K; Ghatage, Prafull; Pippitt, Charles H.; Brown, John V.; Covens, Allan; Nagarkar, Raj V.; Davy, Margaret; Leath, Charles A.; Nguyen, Hoa; Stepan, Daniel E.; Weinreich, David M.; Tassoudji, Marjan; Sun, Yu Nien; Vergote, Ignace B.

In: Journal of Clinical Oncology, Vol. 30, No. 4, 01.02.2012, p. 362-371.

Research output: Contribution to journalArticle

Karlan, BY, Oza, AM, Richardson, GE, Provencher, DM, Hansen, VL, Buck, M, Chambers, SK, Ghatage, P, Pippitt, CH, Brown, JV, Covens, A, Nagarkar, RV, Davy, M, Leath, CA, Nguyen, H, Stepan, DE, Weinreich, DM, Tassoudji, M, Sun, YN & Vergote, IB 2012, 'Randomized, double-blind, placebo-controlled phase II study of AMG 386 combined with weekly paclitaxel in patients with recurrent ovarian cancer', Journal of Clinical Oncology, vol. 30, no. 4, pp. 362-371. https://doi.org/10.1200/JCO.2010.34.3178
Karlan, Beth Y. ; Oza, Amit M. ; Richardson, Gary E. ; Provencher, Diane M. ; Hansen, Vincent L. ; Buck, Martin ; Chambers, Setsuko K ; Ghatage, Prafull ; Pippitt, Charles H. ; Brown, John V. ; Covens, Allan ; Nagarkar, Raj V. ; Davy, Margaret ; Leath, Charles A. ; Nguyen, Hoa ; Stepan, Daniel E. ; Weinreich, David M. ; Tassoudji, Marjan ; Sun, Yu Nien ; Vergote, Ignace B. / Randomized, double-blind, placebo-controlled phase II study of AMG 386 combined with weekly paclitaxel in patients with recurrent ovarian cancer. In: Journal of Clinical Oncology. 2012 ; Vol. 30, No. 4. pp. 362-371.
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abstract = "Purpose: To estimate the efficacy and toxicity of AMG 386, an investigational peptide-Fc fusion protein that neutralizes the interaction between the Tie2 receptor and angiopoietin-1/2, plus weekly paclitaxel in patients with recurrent ovarian cancer. Patients and Methods: Patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer were randomly assigned 1:1:1 to receive paclitaxel (80 mg/m 2 once weekly [QW], 3 weeks on/1 week off) plus intravenous AMG 386 10 mg/kg QW (arm A), AMG 386 3 mg/kg QW (arm B), or placebo QW (arm C). The primary end point was progression-free survival (PFS). Secondary end points included overall survival, objective response, CA-125 response, safety, and pharmacokinetics. Results: One hundred sixty-one patients were randomly assigned. Median PFS was 7.2 months (95{\%} CI, 5.3 to 8.1 months) in arm A, 5.7 months (95{\%} CI, 4.6 to 8.0 months) in arm B, and 4.6 months (95{\%} CI, 1.9 to 6.7 months) in arm C. The hazard ratio for arms A and B combined versus arm C was 0.76 (95{\%} CI, 0.52 to 1.12; P = .165). Further analyses suggested an exploratory dose-response effect for PFS across arms (Tarone's test, P = .037). Objective response rates for arms A, B, and C were 37{\%}, 19{\%}, and 27{\%}, respectively. The incidence of grade ≥ 3 adverse events (AEs) in arms A, B, and C was 65{\%}, 55{\%}, and 64{\%}, respectively. Frequent AEs included hypertension (8{\%}, 6{\%}, and 5{\%} in arms A, B, and C, respectively), peripheral edema (71{\%}, 51{\%}, and 22{\%} in arms A, B, and C, respectively), and hypokalemia (21{\%}, 15{\%}, and 5{\%} in arms A, B, and C, respectively). AMG 386 exhibited linear pharmacokinetic properties at the tested doses. Conclusion: AMG 386 combined with weekly paclitaxel was tolerable, with a manageable and distinct toxicity profile. The data suggest evidence of antitumor activity and a dose-response effect, warranting further studies in ovarian cancer.",
author = "Karlan, {Beth Y.} and Oza, {Amit M.} and Richardson, {Gary E.} and Provencher, {Diane M.} and Hansen, {Vincent L.} and Martin Buck and Chambers, {Setsuko K} and Prafull Ghatage and Pippitt, {Charles H.} and Brown, {John V.} and Allan Covens and Nagarkar, {Raj V.} and Margaret Davy and Leath, {Charles A.} and Hoa Nguyen and Stepan, {Daniel E.} and Weinreich, {David M.} and Marjan Tassoudji and Sun, {Yu Nien} and Vergote, {Ignace B.}",
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TY - JOUR

T1 - Randomized, double-blind, placebo-controlled phase II study of AMG 386 combined with weekly paclitaxel in patients with recurrent ovarian cancer

AU - Karlan, Beth Y.

AU - Oza, Amit M.

AU - Richardson, Gary E.

AU - Provencher, Diane M.

AU - Hansen, Vincent L.

AU - Buck, Martin

AU - Chambers, Setsuko K

AU - Ghatage, Prafull

AU - Pippitt, Charles H.

AU - Brown, John V.

AU - Covens, Allan

AU - Nagarkar, Raj V.

AU - Davy, Margaret

AU - Leath, Charles A.

AU - Nguyen, Hoa

AU - Stepan, Daniel E.

AU - Weinreich, David M.

AU - Tassoudji, Marjan

AU - Sun, Yu Nien

AU - Vergote, Ignace B.

PY - 2012/2/1

Y1 - 2012/2/1

N2 - Purpose: To estimate the efficacy and toxicity of AMG 386, an investigational peptide-Fc fusion protein that neutralizes the interaction between the Tie2 receptor and angiopoietin-1/2, plus weekly paclitaxel in patients with recurrent ovarian cancer. Patients and Methods: Patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer were randomly assigned 1:1:1 to receive paclitaxel (80 mg/m 2 once weekly [QW], 3 weeks on/1 week off) plus intravenous AMG 386 10 mg/kg QW (arm A), AMG 386 3 mg/kg QW (arm B), or placebo QW (arm C). The primary end point was progression-free survival (PFS). Secondary end points included overall survival, objective response, CA-125 response, safety, and pharmacokinetics. Results: One hundred sixty-one patients were randomly assigned. Median PFS was 7.2 months (95% CI, 5.3 to 8.1 months) in arm A, 5.7 months (95% CI, 4.6 to 8.0 months) in arm B, and 4.6 months (95% CI, 1.9 to 6.7 months) in arm C. The hazard ratio for arms A and B combined versus arm C was 0.76 (95% CI, 0.52 to 1.12; P = .165). Further analyses suggested an exploratory dose-response effect for PFS across arms (Tarone's test, P = .037). Objective response rates for arms A, B, and C were 37%, 19%, and 27%, respectively. The incidence of grade ≥ 3 adverse events (AEs) in arms A, B, and C was 65%, 55%, and 64%, respectively. Frequent AEs included hypertension (8%, 6%, and 5% in arms A, B, and C, respectively), peripheral edema (71%, 51%, and 22% in arms A, B, and C, respectively), and hypokalemia (21%, 15%, and 5% in arms A, B, and C, respectively). AMG 386 exhibited linear pharmacokinetic properties at the tested doses. Conclusion: AMG 386 combined with weekly paclitaxel was tolerable, with a manageable and distinct toxicity profile. The data suggest evidence of antitumor activity and a dose-response effect, warranting further studies in ovarian cancer.

AB - Purpose: To estimate the efficacy and toxicity of AMG 386, an investigational peptide-Fc fusion protein that neutralizes the interaction between the Tie2 receptor and angiopoietin-1/2, plus weekly paclitaxel in patients with recurrent ovarian cancer. Patients and Methods: Patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer were randomly assigned 1:1:1 to receive paclitaxel (80 mg/m 2 once weekly [QW], 3 weeks on/1 week off) plus intravenous AMG 386 10 mg/kg QW (arm A), AMG 386 3 mg/kg QW (arm B), or placebo QW (arm C). The primary end point was progression-free survival (PFS). Secondary end points included overall survival, objective response, CA-125 response, safety, and pharmacokinetics. Results: One hundred sixty-one patients were randomly assigned. Median PFS was 7.2 months (95% CI, 5.3 to 8.1 months) in arm A, 5.7 months (95% CI, 4.6 to 8.0 months) in arm B, and 4.6 months (95% CI, 1.9 to 6.7 months) in arm C. The hazard ratio for arms A and B combined versus arm C was 0.76 (95% CI, 0.52 to 1.12; P = .165). Further analyses suggested an exploratory dose-response effect for PFS across arms (Tarone's test, P = .037). Objective response rates for arms A, B, and C were 37%, 19%, and 27%, respectively. The incidence of grade ≥ 3 adverse events (AEs) in arms A, B, and C was 65%, 55%, and 64%, respectively. Frequent AEs included hypertension (8%, 6%, and 5% in arms A, B, and C, respectively), peripheral edema (71%, 51%, and 22% in arms A, B, and C, respectively), and hypokalemia (21%, 15%, and 5% in arms A, B, and C, respectively). AMG 386 exhibited linear pharmacokinetic properties at the tested doses. Conclusion: AMG 386 combined with weekly paclitaxel was tolerable, with a manageable and distinct toxicity profile. The data suggest evidence of antitumor activity and a dose-response effect, warranting further studies in ovarian cancer.

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