A phase 2, randomized, double-blind, placebo- controlled study of chemo-immunotherapy combination using motolimod with pegylated liposomal doxorubicin in recurrent or persistent ovarian cancer: a Gynecologic Oncology Group partners study

B. J. Monk, M. F. Brady, C. Aghajanian, H. A. Lankes, T. Rizack, J. Leach, J. M. Fowler, R. Higgins, P. Hanjani, M. Morgan, R. Edwards, W. Bradley, T. Kolevska, P. Foukas, E. M. Swisher, Karen Anderson, R. Gottardo, J. K. Bryan, M. Newkirk, K. L. Manjarrez & 3 others R. S. Mannel, R. M. Hershberg, G. Coukos

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Background: A phase 2, randomized, placebo-controlled trial was conducted in women with recurrent epithelial ovarian carcinoma to evaluate the efficacy and safety of motolimod-a Toll-like receptor 8 (TLR8) agonist that stimulates robust innate immune responses-combined with pegylated liposomal doxorubicin (PLD), a chemotherapeutic that induces immunogenic cell death.

Patients and methods: Women with ovarian, fallopian tube, or primary peritoneal carcinoma were randomized 1 : 1 to receive PLD in combination with blinded motolimod or placebo. Randomization was stratified by platinum-free interval (≤6 versus >6-12 months) and Gynecologic Oncology Group (GOG) performance status (0 versus 1). Treatment cycles were repeated every 28 days until disease progression.

Results: The addition of motolimod to PLD did not significantly improve overall survival (OS; log rank one-sided P = 0.923, HR = 1.22) or progression-free survival (PFS; log rank one-sided P = 0.943, HR = 1.21). The combination was well tolerated, with no synergistic or unexpected serious toxicity. Most patients experienced adverse events of fatigue, anemia, nausea, decreased white blood cells, and constipation. In pre-specified subgroup analyses, motolimod-treated patients who experienced injection site reactions (ISR) had a lower risk of death compared with those who did not experience ISR. Additionally, pre-treatment in vitro responses of immune biomarkers to TLR8 stimulation predicted OS outcomes in patients receiving motolimod on study. Immune score (tumor infiltrating lymphocytes; TIL), TLR8 single-nucleotide polymorphisms, mutational status in BRCA and other DNA repair genes, and autoantibody biomarkers did not correlate with OS or PFS.

Conclusions: The addition of motolimod to PLD did not improve clinical outcomes compared with placebo. However, subset analyses identified statistically significant differences in the OS of motolimod-treated patients on the basis of ISR and in vitro immune responses. Collectively, these data may provide important clues for identifying patients for treatment with immunomodulatory agents in novel combinations and/or delivery approaches.

Trial registration: Clinicaltrials.gov, NCT 01666444.

Original languageEnglish (US)
Pages (from-to)996-1004
Number of pages9
JournalAnnals of oncology : official journal of the European Society for Medical Oncology
Volume28
Issue number5
DOIs
StatePublished - May 1 2017
Externally publishedYes

Fingerprint

Ovarian Neoplasms
Immunotherapy
Toll-Like Receptor 8
Placebos
Injections
Biomarkers
Carcinoma
Tumor-Infiltrating Lymphocytes
Fallopian Tubes
Constipation
Random Allocation
Platinum
Innate Immunity
DNA Repair
Autoantibodies
Nausea
Disease-Free Survival
Fatigue
Single Nucleotide Polymorphism
Disease Progression

Keywords

  • biomarkers
  • immunotherapy
  • motolimod
  • oncology
  • ovarian cancer
  • Toll-like receptor 8

ASJC Scopus subject areas

  • Hematology
  • Oncology

Cite this

A phase 2, randomized, double-blind, placebo- controlled study of chemo-immunotherapy combination using motolimod with pegylated liposomal doxorubicin in recurrent or persistent ovarian cancer : a Gynecologic Oncology Group partners study. / Monk, B. J.; Brady, M. F.; Aghajanian, C.; Lankes, H. A.; Rizack, T.; Leach, J.; Fowler, J. M.; Higgins, R.; Hanjani, P.; Morgan, M.; Edwards, R.; Bradley, W.; Kolevska, T.; Foukas, P.; Swisher, E. M.; Anderson, Karen; Gottardo, R.; Bryan, J. K.; Newkirk, M.; Manjarrez, K. L.; Mannel, R. S.; Hershberg, R. M.; Coukos, G.

In: Annals of oncology : official journal of the European Society for Medical Oncology, Vol. 28, No. 5, 01.05.2017, p. 996-1004.

Research output: Contribution to journalArticle

Monk, BJ, Brady, MF, Aghajanian, C, Lankes, HA, Rizack, T, Leach, J, Fowler, JM, Higgins, R, Hanjani, P, Morgan, M, Edwards, R, Bradley, W, Kolevska, T, Foukas, P, Swisher, EM, Anderson, K, Gottardo, R, Bryan, JK, Newkirk, M, Manjarrez, KL, Mannel, RS, Hershberg, RM & Coukos, G 2017, 'A phase 2, randomized, double-blind, placebo- controlled study of chemo-immunotherapy combination using motolimod with pegylated liposomal doxorubicin in recurrent or persistent ovarian cancer: a Gynecologic Oncology Group partners study' Annals of oncology : official journal of the European Society for Medical Oncology, vol. 28, no. 5, pp. 996-1004. https://doi.org/10.1093/annonc/mdx049
Monk, B. J. ; Brady, M. F. ; Aghajanian, C. ; Lankes, H. A. ; Rizack, T. ; Leach, J. ; Fowler, J. M. ; Higgins, R. ; Hanjani, P. ; Morgan, M. ; Edwards, R. ; Bradley, W. ; Kolevska, T. ; Foukas, P. ; Swisher, E. M. ; Anderson, Karen ; Gottardo, R. ; Bryan, J. K. ; Newkirk, M. ; Manjarrez, K. L. ; Mannel, R. S. ; Hershberg, R. M. ; Coukos, G. / A phase 2, randomized, double-blind, placebo- controlled study of chemo-immunotherapy combination using motolimod with pegylated liposomal doxorubicin in recurrent or persistent ovarian cancer : a Gynecologic Oncology Group partners study. In: Annals of oncology : official journal of the European Society for Medical Oncology. 2017 ; Vol. 28, No. 5. pp. 996-1004.
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abstract = "Background: A phase 2, randomized, placebo-controlled trial was conducted in women with recurrent epithelial ovarian carcinoma to evaluate the efficacy and safety of motolimod-a Toll-like receptor 8 (TLR8) agonist that stimulates robust innate immune responses-combined with pegylated liposomal doxorubicin (PLD), a chemotherapeutic that induces immunogenic cell death.Patients and methods: Women with ovarian, fallopian tube, or primary peritoneal carcinoma were randomized 1 : 1 to receive PLD in combination with blinded motolimod or placebo. Randomization was stratified by platinum-free interval (≤6 versus >6-12 months) and Gynecologic Oncology Group (GOG) performance status (0 versus 1). Treatment cycles were repeated every 28 days until disease progression.Results: The addition of motolimod to PLD did not significantly improve overall survival (OS; log rank one-sided P = 0.923, HR = 1.22) or progression-free survival (PFS; log rank one-sided P = 0.943, HR = 1.21). The combination was well tolerated, with no synergistic or unexpected serious toxicity. Most patients experienced adverse events of fatigue, anemia, nausea, decreased white blood cells, and constipation. In pre-specified subgroup analyses, motolimod-treated patients who experienced injection site reactions (ISR) had a lower risk of death compared with those who did not experience ISR. Additionally, pre-treatment in vitro responses of immune biomarkers to TLR8 stimulation predicted OS outcomes in patients receiving motolimod on study. Immune score (tumor infiltrating lymphocytes; TIL), TLR8 single-nucleotide polymorphisms, mutational status in BRCA and other DNA repair genes, and autoantibody biomarkers did not correlate with OS or PFS.Conclusions: The addition of motolimod to PLD did not improve clinical outcomes compared with placebo. However, subset analyses identified statistically significant differences in the OS of motolimod-treated patients on the basis of ISR and in vitro immune responses. Collectively, these data may provide important clues for identifying patients for treatment with immunomodulatory agents in novel combinations and/or delivery approaches.Trial registration: Clinicaltrials.gov, NCT 01666444.",
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author = "Monk, {B. J.} and Brady, {M. F.} and C. Aghajanian and Lankes, {H. A.} and T. Rizack and J. Leach and Fowler, {J. M.} and R. Higgins and P. Hanjani and M. Morgan and R. Edwards and W. Bradley and T. Kolevska and P. Foukas and Swisher, {E. M.} and Karen Anderson and R. Gottardo and Bryan, {J. K.} and M. Newkirk and Manjarrez, {K. L.} and Mannel, {R. S.} and Hershberg, {R. M.} and G. Coukos",
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TY - JOUR

T1 - A phase 2, randomized, double-blind, placebo- controlled study of chemo-immunotherapy combination using motolimod with pegylated liposomal doxorubicin in recurrent or persistent ovarian cancer

T2 - a Gynecologic Oncology Group partners study

AU - Monk, B. J.

AU - Brady, M. F.

AU - Aghajanian, C.

AU - Lankes, H. A.

AU - Rizack, T.

AU - Leach, J.

AU - Fowler, J. M.

AU - Higgins, R.

AU - Hanjani, P.

AU - Morgan, M.

AU - Edwards, R.

AU - Bradley, W.

AU - Kolevska, T.

AU - Foukas, P.

AU - Swisher, E. M.

AU - Anderson, Karen

AU - Gottardo, R.

AU - Bryan, J. K.

AU - Newkirk, M.

AU - Manjarrez, K. L.

AU - Mannel, R. S.

AU - Hershberg, R. M.

AU - Coukos, G.

PY - 2017/5/1

Y1 - 2017/5/1

N2 - Background: A phase 2, randomized, placebo-controlled trial was conducted in women with recurrent epithelial ovarian carcinoma to evaluate the efficacy and safety of motolimod-a Toll-like receptor 8 (TLR8) agonist that stimulates robust innate immune responses-combined with pegylated liposomal doxorubicin (PLD), a chemotherapeutic that induces immunogenic cell death.Patients and methods: Women with ovarian, fallopian tube, or primary peritoneal carcinoma were randomized 1 : 1 to receive PLD in combination with blinded motolimod or placebo. Randomization was stratified by platinum-free interval (≤6 versus >6-12 months) and Gynecologic Oncology Group (GOG) performance status (0 versus 1). Treatment cycles were repeated every 28 days until disease progression.Results: The addition of motolimod to PLD did not significantly improve overall survival (OS; log rank one-sided P = 0.923, HR = 1.22) or progression-free survival (PFS; log rank one-sided P = 0.943, HR = 1.21). The combination was well tolerated, with no synergistic or unexpected serious toxicity. Most patients experienced adverse events of fatigue, anemia, nausea, decreased white blood cells, and constipation. In pre-specified subgroup analyses, motolimod-treated patients who experienced injection site reactions (ISR) had a lower risk of death compared with those who did not experience ISR. Additionally, pre-treatment in vitro responses of immune biomarkers to TLR8 stimulation predicted OS outcomes in patients receiving motolimod on study. Immune score (tumor infiltrating lymphocytes; TIL), TLR8 single-nucleotide polymorphisms, mutational status in BRCA and other DNA repair genes, and autoantibody biomarkers did not correlate with OS or PFS.Conclusions: The addition of motolimod to PLD did not improve clinical outcomes compared with placebo. However, subset analyses identified statistically significant differences in the OS of motolimod-treated patients on the basis of ISR and in vitro immune responses. Collectively, these data may provide important clues for identifying patients for treatment with immunomodulatory agents in novel combinations and/or delivery approaches.Trial registration: Clinicaltrials.gov, NCT 01666444.

AB - Background: A phase 2, randomized, placebo-controlled trial was conducted in women with recurrent epithelial ovarian carcinoma to evaluate the efficacy and safety of motolimod-a Toll-like receptor 8 (TLR8) agonist that stimulates robust innate immune responses-combined with pegylated liposomal doxorubicin (PLD), a chemotherapeutic that induces immunogenic cell death.Patients and methods: Women with ovarian, fallopian tube, or primary peritoneal carcinoma were randomized 1 : 1 to receive PLD in combination with blinded motolimod or placebo. Randomization was stratified by platinum-free interval (≤6 versus >6-12 months) and Gynecologic Oncology Group (GOG) performance status (0 versus 1). Treatment cycles were repeated every 28 days until disease progression.Results: The addition of motolimod to PLD did not significantly improve overall survival (OS; log rank one-sided P = 0.923, HR = 1.22) or progression-free survival (PFS; log rank one-sided P = 0.943, HR = 1.21). The combination was well tolerated, with no synergistic or unexpected serious toxicity. Most patients experienced adverse events of fatigue, anemia, nausea, decreased white blood cells, and constipation. In pre-specified subgroup analyses, motolimod-treated patients who experienced injection site reactions (ISR) had a lower risk of death compared with those who did not experience ISR. Additionally, pre-treatment in vitro responses of immune biomarkers to TLR8 stimulation predicted OS outcomes in patients receiving motolimod on study. Immune score (tumor infiltrating lymphocytes; TIL), TLR8 single-nucleotide polymorphisms, mutational status in BRCA and other DNA repair genes, and autoantibody biomarkers did not correlate with OS or PFS.Conclusions: The addition of motolimod to PLD did not improve clinical outcomes compared with placebo. However, subset analyses identified statistically significant differences in the OS of motolimod-treated patients on the basis of ISR and in vitro immune responses. Collectively, these data may provide important clues for identifying patients for treatment with immunomodulatory agents in novel combinations and/or delivery approaches.Trial registration: Clinicaltrials.gov, NCT 01666444.

KW - biomarkers

KW - immunotherapy

KW - motolimod

KW - oncology

KW - ovarian cancer

KW - Toll-like receptor 8

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U2 - 10.1093/annonc/mdx049

DO - 10.1093/annonc/mdx049

M3 - Article

VL - 28

SP - 996

EP - 1004

JO - Annals of Oncology

JF - Annals of Oncology

SN - 0923-7534

IS - 5

ER -