Combination of the mTOR inhibitor ridaforolimus and the anti-IGF1R monoclonal antibody dalotuzumab: Preclinical characterization and phase I clinical trial

Serena Di Cosimo, Sriram Sathyanarayanan, Johanna C. Bendell, Andrés Cervantes, Mark Stein, Irene Braña, Desamparados Roda, Brian B. Haines, Theresa Zhang, Christopher G. Winter, Sharda Jha, Youyuan Xu, Jason Frazier, Richard A. Klinghoffer, Ann Leighton-Swayze, Yang Song, Scot Ebbinghaus, José Baselga

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Abstract

Purpose: Mammalian target of rapamycin (mTOR) inhibition activates compensatory insulin-like growth factor receptor (IGFR) signaling. We evaluated the ridaforolimus (mTOR inhibitor) and dalotuzumab (anti-IGF1R antibody) combination. Experimental Design: In vitro and in vivo models, and a phase I study in which patients with advanced cancer received ridaforolimus (10-40 mg/day every day x 5/week) and dalotuzumab (10 mg/kg/week or 7.5 mg/kg/every other week) were explored. Results: Preclinical studies demonstrated enhanced pathway inhibition with ridaforolimus and dalotuzumab. With 87 patients treated in the phase I study, main dose-limiting toxicities (DLT) of the combination were primarily mTOR-related stomatitis and asthenia at doses of ridaforolimus lower than expected, suggesting blockade of compensatory pathways in normal tissues. Six confirmed partial responses were reported (3 patients with breast cancer); 10 of 23 patients with breast cancer and 6 of 11 patients with ER+/high-proliferative breast cancer showed antitumor activity. Conclusions: Our study provides proof-of-concept that inhibiting the IGF1R compensatory response to mTOR inhibition is feasible with promising clinical activity in heavily pretreated advanced cancer, particularly in ER+/high-proliferative breast cancer (ClinicalTrials.gov identifier: NCT00730379).

Original languageEnglish (US)
Pages (from-to)49-59
Number of pages11
JournalClinical Cancer Research
Volume21
Issue number1
DOIs
StatePublished - Jan 1 2015

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Clinical Trials, Phase I
Sirolimus
Monoclonal Antibodies
Breast Neoplasms
Somatomedin Receptors
Asthenia
Stomatitis
Anti-Idiotypic Antibodies
Neoplasms
Research Design
dalotuzumab
ridaforolimus

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Di Cosimo, Serena ; Sathyanarayanan, Sriram ; Bendell, Johanna C. ; Cervantes, Andrés ; Stein, Mark ; Braña, Irene ; Roda, Desamparados ; Haines, Brian B. ; Zhang, Theresa ; Winter, Christopher G. ; Jha, Sharda ; Xu, Youyuan ; Frazier, Jason ; Klinghoffer, Richard A. ; Leighton-Swayze, Ann ; Song, Yang ; Ebbinghaus, Scot ; Baselga, José. / Combination of the mTOR inhibitor ridaforolimus and the anti-IGF1R monoclonal antibody dalotuzumab : Preclinical characterization and phase I clinical trial. In: Clinical Cancer Research. 2015 ; Vol. 21, No. 1. pp. 49-59.
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abstract = "Purpose: Mammalian target of rapamycin (mTOR) inhibition activates compensatory insulin-like growth factor receptor (IGFR) signaling. We evaluated the ridaforolimus (mTOR inhibitor) and dalotuzumab (anti-IGF1R antibody) combination. Experimental Design: In vitro and in vivo models, and a phase I study in which patients with advanced cancer received ridaforolimus (10-40 mg/day every day x 5/week) and dalotuzumab (10 mg/kg/week or 7.5 mg/kg/every other week) were explored. Results: Preclinical studies demonstrated enhanced pathway inhibition with ridaforolimus and dalotuzumab. With 87 patients treated in the phase I study, main dose-limiting toxicities (DLT) of the combination were primarily mTOR-related stomatitis and asthenia at doses of ridaforolimus lower than expected, suggesting blockade of compensatory pathways in normal tissues. Six confirmed partial responses were reported (3 patients with breast cancer); 10 of 23 patients with breast cancer and 6 of 11 patients with ER+/high-proliferative breast cancer showed antitumor activity. Conclusions: Our study provides proof-of-concept that inhibiting the IGF1R compensatory response to mTOR inhibition is feasible with promising clinical activity in heavily pretreated advanced cancer, particularly in ER+/high-proliferative breast cancer (ClinicalTrials.gov identifier: NCT00730379).",
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Di Cosimo, S, Sathyanarayanan, S, Bendell, JC, Cervantes, A, Stein, M, Braña, I, Roda, D, Haines, BB, Zhang, T, Winter, CG, Jha, S, Xu, Y, Frazier, J, Klinghoffer, RA, Leighton-Swayze, A, Song, Y, Ebbinghaus, S & Baselga, J 2015, 'Combination of the mTOR inhibitor ridaforolimus and the anti-IGF1R monoclonal antibody dalotuzumab: Preclinical characterization and phase I clinical trial', Clinical Cancer Research, vol. 21, no. 1, pp. 49-59. https://doi.org/10.1158/1078-0432.CCR-14-0940

Combination of the mTOR inhibitor ridaforolimus and the anti-IGF1R monoclonal antibody dalotuzumab : Preclinical characterization and phase I clinical trial. / Di Cosimo, Serena; Sathyanarayanan, Sriram; Bendell, Johanna C.; Cervantes, Andrés; Stein, Mark; Braña, Irene; Roda, Desamparados; Haines, Brian B.; Zhang, Theresa; Winter, Christopher G.; Jha, Sharda; Xu, Youyuan; Frazier, Jason; Klinghoffer, Richard A.; Leighton-Swayze, Ann; Song, Yang; Ebbinghaus, Scot; Baselga, José.

In: Clinical Cancer Research, Vol. 21, No. 1, 01.01.2015, p. 49-59.

Research output: Contribution to journalArticle

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T1 - Combination of the mTOR inhibitor ridaforolimus and the anti-IGF1R monoclonal antibody dalotuzumab

T2 - Preclinical characterization and phase I clinical trial

AU - Di Cosimo, Serena

AU - Sathyanarayanan, Sriram

AU - Bendell, Johanna C.

AU - Cervantes, Andrés

AU - Stein, Mark

AU - Braña, Irene

AU - Roda, Desamparados

AU - Haines, Brian B.

AU - Zhang, Theresa

AU - Winter, Christopher G.

AU - Jha, Sharda

AU - Xu, Youyuan

AU - Frazier, Jason

AU - Klinghoffer, Richard A.

AU - Leighton-Swayze, Ann

AU - Song, Yang

AU - Ebbinghaus, Scot

AU - Baselga, José

PY - 2015/1/1

Y1 - 2015/1/1

N2 - Purpose: Mammalian target of rapamycin (mTOR) inhibition activates compensatory insulin-like growth factor receptor (IGFR) signaling. We evaluated the ridaforolimus (mTOR inhibitor) and dalotuzumab (anti-IGF1R antibody) combination. Experimental Design: In vitro and in vivo models, and a phase I study in which patients with advanced cancer received ridaforolimus (10-40 mg/day every day x 5/week) and dalotuzumab (10 mg/kg/week or 7.5 mg/kg/every other week) were explored. Results: Preclinical studies demonstrated enhanced pathway inhibition with ridaforolimus and dalotuzumab. With 87 patients treated in the phase I study, main dose-limiting toxicities (DLT) of the combination were primarily mTOR-related stomatitis and asthenia at doses of ridaforolimus lower than expected, suggesting blockade of compensatory pathways in normal tissues. Six confirmed partial responses were reported (3 patients with breast cancer); 10 of 23 patients with breast cancer and 6 of 11 patients with ER+/high-proliferative breast cancer showed antitumor activity. Conclusions: Our study provides proof-of-concept that inhibiting the IGF1R compensatory response to mTOR inhibition is feasible with promising clinical activity in heavily pretreated advanced cancer, particularly in ER+/high-proliferative breast cancer (ClinicalTrials.gov identifier: NCT00730379).

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