A parallel-arm phase I trial of the humanised anti-IGF-1R antibody dalotuzumab in combination with the AKT inhibitor MK-2206, the mTOR inhibitor ridaforolimus, or the NOTCH inhibitor MK-0752, in patients with advanced solid tumours

I. Brana, R. Berger, T. Golan, P. Haluska, J. Edenfield, J. Fiorica, J. Stephenson, L. P. Martin, S. Westin, P. Hanjani, M. B. Jones, K. Almhanna, R. M. Wenham, D. M. Sullivan, W. S. Dalton, A. Gunchenko, J. D. Cheng, L. L. Siu, J. E. Gray

Research output: Contribution to journalArticle

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Abstract

Background:Two strategies to interrogate the insulin growth factor 1 receptor (IGF-1R) pathway were investigated: vertical inhibition with dalotuzumab and MK-2206 or ridaforolimus to potentiate PI3K pathway targeting and horizontal cross-talk inhibition with dalotuzumab and MK-0752 to exert effects against cellular proliferation, angiogenesis, and stem cell propagation.Methods:A phase I, multi-cohort dose escalation study was conducted in patients with advanced solid tumours. Patients received dalotuzumab (10 mg kg -1) and escalating doses of MK-2206 (90-200 mg) or escalating doses of dalotuzumab (7.5-10 mg kg -1) and MK-0752 (1800 mg) weekly. Upon maximum tolerated dose determination, patients with low-RAS signature, high-IGF1 expression ovarian cancer were randomised to dalotuzumab/MK-2206 versus dalotuzumab/ridaforolimus, whereas patients with high IGF1/low IGF2 expression colorectal cancer received dalotuzumab/MK-0752.Results:A total of 47 patients were enrolled: 29 in part A (18 in the dalotuzumab/MK-2206 arm and 11 in the dalotuzumab/MK-0752 arm) and 18 in part B (6 in each arm). Dose-limiting toxicities (DLTs) for dalotuzumab/MK-2206 included grade 4 neutropenia and grade 3 serum sickness-like reaction, maculopapular rash, and gastrointestinal inflammation. For dalotuzumab/MK-0752, DLTs included grade 3 dehydration, rash, and diarrhoea. Seven patients remained on study for >4 cycles.Conclusions:Dalotuzumab/MK-2206 and dalotuzumab/MK-0752 combinations were tolerable. Further developments of prospectively validated predictive biomarkers to aid in patient selection for anti-IGF-1R therapies are needed.

Original languageEnglish (US)
Pages (from-to)1932-1944
Number of pages13
JournalBritish Journal of Cancer
Volume111
Issue number10
DOIs
StatePublished - Nov 11 2014

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Growth Factor Receptors
Insulin
Antibodies
Neoplasms
Exanthema
3-(4-((4-chlorophenyl)sulfonyl)-4-(2,5-difluorophenyl)cyclohexyl)propanoic acid
dalotuzumab
ridaforolimus
MK 2206
Serum Sickness
Maximum Tolerated Dose
Neutropenia
Phosphatidylinositol 3-Kinases
Dehydration
Ovarian Neoplasms
Patient Selection
Colorectal Neoplasms
Diarrhea
Stem Cells
Biomarkers

Keywords

  • colorectal cancer
  • dalotuzumab
  • MK-0752
  • MK-2206
  • ovarian cancer
  • ridaforolimus

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

A parallel-arm phase I trial of the humanised anti-IGF-1R antibody dalotuzumab in combination with the AKT inhibitor MK-2206, the mTOR inhibitor ridaforolimus, or the NOTCH inhibitor MK-0752, in patients with advanced solid tumours. / Brana, I.; Berger, R.; Golan, T.; Haluska, P.; Edenfield, J.; Fiorica, J.; Stephenson, J.; Martin, L. P.; Westin, S.; Hanjani, P.; Jones, M. B.; Almhanna, K.; Wenham, R. M.; Sullivan, D. M.; Dalton, W. S.; Gunchenko, A.; Cheng, J. D.; Siu, L. L.; Gray, J. E.

In: British Journal of Cancer, Vol. 111, No. 10, 11.11.2014, p. 1932-1944.

Research output: Contribution to journalArticle

Brana, I, Berger, R, Golan, T, Haluska, P, Edenfield, J, Fiorica, J, Stephenson, J, Martin, LP, Westin, S, Hanjani, P, Jones, MB, Almhanna, K, Wenham, RM, Sullivan, DM, Dalton, WS, Gunchenko, A, Cheng, JD, Siu, LL & Gray, JE 2014, 'A parallel-arm phase I trial of the humanised anti-IGF-1R antibody dalotuzumab in combination with the AKT inhibitor MK-2206, the mTOR inhibitor ridaforolimus, or the NOTCH inhibitor MK-0752, in patients with advanced solid tumours', British Journal of Cancer, vol. 111, no. 10, pp. 1932-1944. https://doi.org/10.1038/bjc.2014.497
Brana, I. ; Berger, R. ; Golan, T. ; Haluska, P. ; Edenfield, J. ; Fiorica, J. ; Stephenson, J. ; Martin, L. P. ; Westin, S. ; Hanjani, P. ; Jones, M. B. ; Almhanna, K. ; Wenham, R. M. ; Sullivan, D. M. ; Dalton, W. S. ; Gunchenko, A. ; Cheng, J. D. ; Siu, L. L. ; Gray, J. E. / A parallel-arm phase I trial of the humanised anti-IGF-1R antibody dalotuzumab in combination with the AKT inhibitor MK-2206, the mTOR inhibitor ridaforolimus, or the NOTCH inhibitor MK-0752, in patients with advanced solid tumours. In: British Journal of Cancer. 2014 ; Vol. 111, No. 10. pp. 1932-1944.
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abstract = "Background:Two strategies to interrogate the insulin growth factor 1 receptor (IGF-1R) pathway were investigated: vertical inhibition with dalotuzumab and MK-2206 or ridaforolimus to potentiate PI3K pathway targeting and horizontal cross-talk inhibition with dalotuzumab and MK-0752 to exert effects against cellular proliferation, angiogenesis, and stem cell propagation.Methods:A phase I, multi-cohort dose escalation study was conducted in patients with advanced solid tumours. Patients received dalotuzumab (10 mg kg -1) and escalating doses of MK-2206 (90-200 mg) or escalating doses of dalotuzumab (7.5-10 mg kg -1) and MK-0752 (1800 mg) weekly. Upon maximum tolerated dose determination, patients with low-RAS signature, high-IGF1 expression ovarian cancer were randomised to dalotuzumab/MK-2206 versus dalotuzumab/ridaforolimus, whereas patients with high IGF1/low IGF2 expression colorectal cancer received dalotuzumab/MK-0752.Results:A total of 47 patients were enrolled: 29 in part A (18 in the dalotuzumab/MK-2206 arm and 11 in the dalotuzumab/MK-0752 arm) and 18 in part B (6 in each arm). Dose-limiting toxicities (DLTs) for dalotuzumab/MK-2206 included grade 4 neutropenia and grade 3 serum sickness-like reaction, maculopapular rash, and gastrointestinal inflammation. For dalotuzumab/MK-0752, DLTs included grade 3 dehydration, rash, and diarrhoea. Seven patients remained on study for >4 cycles.Conclusions:Dalotuzumab/MK-2206 and dalotuzumab/MK-0752 combinations were tolerable. Further developments of prospectively validated predictive biomarkers to aid in patient selection for anti-IGF-1R therapies are needed.",
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T1 - A parallel-arm phase I trial of the humanised anti-IGF-1R antibody dalotuzumab in combination with the AKT inhibitor MK-2206, the mTOR inhibitor ridaforolimus, or the NOTCH inhibitor MK-0752, in patients with advanced solid tumours

AU - Brana, I.

AU - Berger, R.

AU - Golan, T.

AU - Haluska, P.

AU - Edenfield, J.

AU - Fiorica, J.

AU - Stephenson, J.

AU - Martin, L. P.

AU - Westin, S.

AU - Hanjani, P.

AU - Jones, M. B.

AU - Almhanna, K.

AU - Wenham, R. M.

AU - Sullivan, D. M.

AU - Dalton, W. S.

AU - Gunchenko, A.

AU - Cheng, J. D.

AU - Siu, L. L.

AU - Gray, J. E.

PY - 2014/11/11

Y1 - 2014/11/11

N2 - Background:Two strategies to interrogate the insulin growth factor 1 receptor (IGF-1R) pathway were investigated: vertical inhibition with dalotuzumab and MK-2206 or ridaforolimus to potentiate PI3K pathway targeting and horizontal cross-talk inhibition with dalotuzumab and MK-0752 to exert effects against cellular proliferation, angiogenesis, and stem cell propagation.Methods:A phase I, multi-cohort dose escalation study was conducted in patients with advanced solid tumours. Patients received dalotuzumab (10 mg kg -1) and escalating doses of MK-2206 (90-200 mg) or escalating doses of dalotuzumab (7.5-10 mg kg -1) and MK-0752 (1800 mg) weekly. Upon maximum tolerated dose determination, patients with low-RAS signature, high-IGF1 expression ovarian cancer were randomised to dalotuzumab/MK-2206 versus dalotuzumab/ridaforolimus, whereas patients with high IGF1/low IGF2 expression colorectal cancer received dalotuzumab/MK-0752.Results:A total of 47 patients were enrolled: 29 in part A (18 in the dalotuzumab/MK-2206 arm and 11 in the dalotuzumab/MK-0752 arm) and 18 in part B (6 in each arm). Dose-limiting toxicities (DLTs) for dalotuzumab/MK-2206 included grade 4 neutropenia and grade 3 serum sickness-like reaction, maculopapular rash, and gastrointestinal inflammation. For dalotuzumab/MK-0752, DLTs included grade 3 dehydration, rash, and diarrhoea. Seven patients remained on study for >4 cycles.Conclusions:Dalotuzumab/MK-2206 and dalotuzumab/MK-0752 combinations were tolerable. Further developments of prospectively validated predictive biomarkers to aid in patient selection for anti-IGF-1R therapies are needed.

AB - Background:Two strategies to interrogate the insulin growth factor 1 receptor (IGF-1R) pathway were investigated: vertical inhibition with dalotuzumab and MK-2206 or ridaforolimus to potentiate PI3K pathway targeting and horizontal cross-talk inhibition with dalotuzumab and MK-0752 to exert effects against cellular proliferation, angiogenesis, and stem cell propagation.Methods:A phase I, multi-cohort dose escalation study was conducted in patients with advanced solid tumours. Patients received dalotuzumab (10 mg kg -1) and escalating doses of MK-2206 (90-200 mg) or escalating doses of dalotuzumab (7.5-10 mg kg -1) and MK-0752 (1800 mg) weekly. Upon maximum tolerated dose determination, patients with low-RAS signature, high-IGF1 expression ovarian cancer were randomised to dalotuzumab/MK-2206 versus dalotuzumab/ridaforolimus, whereas patients with high IGF1/low IGF2 expression colorectal cancer received dalotuzumab/MK-0752.Results:A total of 47 patients were enrolled: 29 in part A (18 in the dalotuzumab/MK-2206 arm and 11 in the dalotuzumab/MK-0752 arm) and 18 in part B (6 in each arm). Dose-limiting toxicities (DLTs) for dalotuzumab/MK-2206 included grade 4 neutropenia and grade 3 serum sickness-like reaction, maculopapular rash, and gastrointestinal inflammation. For dalotuzumab/MK-0752, DLTs included grade 3 dehydration, rash, and diarrhoea. Seven patients remained on study for >4 cycles.Conclusions:Dalotuzumab/MK-2206 and dalotuzumab/MK-0752 combinations were tolerable. Further developments of prospectively validated predictive biomarkers to aid in patient selection for anti-IGF-1R therapies are needed.

KW - colorectal cancer

KW - dalotuzumab

KW - MK-0752

KW - MK-2206

KW - ovarian cancer

KW - ridaforolimus

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