Table 1.

Clinical data for IGF system targeted therapy (breast cancer studies in bold).

Agent	Agent description, company
	Phase	Tumor Type	Adverse Events (gr3/4-# or %)	Response	Ref.
CP-751,871	Fully human, monoclonal antibody (IgG2), Pfizer
	I/FIH	Multiple myeloma	Diarrhea, anemia (2.1%/−), thrombocytopenia, increase AST, hyperglycemia (2.1%/−), nausea, rash	47 patients were treated with single agent CP and 27 in combination with dexamethasone. 28 had SD with single agent. 9 of the 27 combo pts had a response	[59, 73]
	I	Solid tumors/ACC, sarcoma expansion cohorts	Hyperglycemia, anorexia, elevated GGT/AST (1/−), nausea, fatigue (1/−), arthralgia (1/−), hyperuricemia (−/1), DVT (1/−)	24 patients treated. Three long term SD (3> 10 months). At MFD, 7 of 12 had SD. -In Sarcoma cohort 1/22 PR, 6/22 SD	[18]
	I	Breast, neoadjuvant		Pending
	I/II	Sarcoma, Ewing’s family		Pending
	II	CRC		Pending
Paclitaxel/carboplatin +/− CP (TC vs TCI)	Ib/II	NSCLCA	Hyperglycemia (15%/5%), fatigue (10%, −), neutropenia (18%, 12%), anorexia (7%/−). thrombocytopenia (6%/1%), neuropathy (5%/1%)	97 patients treated with TCI and 53 patients TC. Response rate: TCI-54%; TC-41%. Subset of squamous cell carcinoma on TCI-78% RR (18/23)	[39]
+Sunitinib	I	Soslid tumors		Pending
+Gemcitabine/cisplatin	I	NSCLCA—non-adeno		Pending
+PF-299804	I	Solid tumors/NSCLCA cohort		Pending
+Paclitaxel/carboplatin/erlotinib	I/II	Expansion cohort, NSCLCA		Pending
+Docetaxel	II	Breast		Pending
+Docetaxel/prednisone	II	Prostate		Pending
+Exemestane	II	Breast		Pending
Paclitaxel/carboplatin +/− CP	III	NSCLCA—non-adeno		Pending
Erlotinib+/− CP	III	NSCLCA—non-adeno		Pending
IMC-A12	Fully human, monoclonal antibody (IgG1), ImClone
	I	Solid Tumor	Hyperglycemia- DLT (#?/−), pruritis, rash, discolored feces, anemia, psoriasis, infusion reaction.	15 patients treated. 4/11 had SD. 2 had SD >9 months. 1 had >25% PSA reduction.	[62]
	II	HRPC		Pending
	II	Sarcoma, Ewing’s, PNET		Pending
	II	Hepatocellular		Pending
+Cetuximab	II	CRC, H&N		Pending
+Temsirolimus	II	Solid tumors, breast		Pending
+Adriamycin	II	Sarcoma, Soft tissue, MFH		Pending
+/− Antiestrogens	II	Breast		Pending
Lapatinib/capecitabine +/−A12	II	Breast		Pending
Gemcitabine/erlotinib +/− A12	II	Pancreatic		Pending
Mitoxantrone/prednisone/A12 or 1121B (VEGFR2 mab)	II	Prostate		Pending
AMG-479	Fully human, monoclonal antibody (IgG1), Amgen
	I	Solid tumors, NHL	Thrombocytopenia-DLT (9%/3%), arthralgia (3%/−), diarrhea (3%/−), transaminitis (2%/−), hyperglycemia, autoantibody production, infusion reaction	33 patients treated. 1 CR (Ewing’s sarcoma), 1 PR and 1 MR (both neuroendocrine), 5 SD, 1 mixed response (breast). 17/26 patients had evidence of decreased metabolic activity by PET	[72]
	II	Sarcoma, Ewing’s		Pending
	II	Ovarian, platinum sensitive		Pending
+Gemcitabine (G) or panitumumab (P)	1b	Solid tumors	+ P: hyperglycemia-DLT (10%), rash (20%), hypomagnesemia (30%), anemia, nausea, vomiting, anorexia, fatigue, diarrhea, dizziness, thrombocytopenia. +G: neutropenia-DLT (50%), thrombocytopenia, fatigue, anemia, nausea, vomiting, anorexia, rash, hypomagnesemia	18 patients treated (10 with P): 1 PR in P arm (Colon). 9/18 SD (5 in P arm, 4 in G arm)	[64]
+gemcitabine	I/II	Pancreatic		Pending
+exemestane or fulvestrant	II	Breast		Pending
paclitaxel/carboplatin +/− AMG	II	Ovarian		Pending
MK-0646	Humanized monoclonal antibody, Merck
	I	Solid tumors, multiple myeloma, breast	Q2w schedule: Thrombocytopenia (−/1), GI bleeding (1/−), pneumonitis (1/−), transaminitis (1/−), fatigue, vomiting, nausea, constipation, diarrhea, weight loss, abdominal pain.	Q2w: 36 patients. 5 pts with SD>4 months, 2 greater than 1 year.	[65, 66]
			QW schedule: Tumor pain-DLT (2%/−), purpura-DLT(2%/−), hyperglycemia (6%/−), chills (4%/−), nausea (2%/−), rash (2%/−), asthenia (2%/−), pyrexia (2%/−), infusion reaction	QW: 53 patients. Decrease IGF-1R expression and signaling (e.g. AKT) identified in paired biopsies. 3 PET/metabolic responses. One mixed radiologic response (Ewing’s sarcoma), 3 patients SD>3 months
	II	Neuroendocrine		Pending
+MK8669 (deforolimus)	I	Solid tumors		Pending
+erlotinib	I/II	NSCLCA		Pending
+Cetuximab/irinotecan	II	CRC		Pending
R1507	Fully human, monoclonal antibody (IgG1), Roche
	I	Solid tumors—adult, children	Adults: Infection, fatigue, rash, fever, arthralgia, cough, diarrhea, abdominal and back pain	26 patients. 11 SD>15 weeks.	[67]
	II	Sarcomas		Pending
+Erlotinib	II	NSCLCA		Pending
AVE-1642	Humanized monoclonal antibody, Sanofi-Aventis
	I	Solid tumors (combined with docetaxel after cycle 1), multiple myeloma	Hyperglycemia, hypersensitivity reactions, asthenia, anemia, nail disorders, paresthesia, pruritis	14 patients (solid tumors). 1 reduction in skin nodules (breast), 4 SD confirmed at cycle 4 -14 patients (multiple myeloma). 1 decrease bone pain/proteinuria	[68, 69]
OSI-906	Tyrosine kinase inhibitor-reversible ATP competitive inhibitor, OSI
	I	Solid tumors— continuous, intermittent dosing		Pending
+/−Erlotinib	I	Solid tumors		Pending
SCH-717454	Fully human, monoclonal antibody, Schering-Plough
	II	Sarcomas, Osteosarcoma, Ewing’s		Pending
Chemo +/− SCH	II	Recurrent CRC		Pending
XL-228	Tyrosine kinase inhibitor of IGF-1R, abl and src, Exelixis
	I	CML/ALL, Solid tumors, lymphoma, multiple myeloma		Pending
INSM-18 (NDGA)	Tyrosine kinase inhibitor of IGF-1R, HER2/neu, Insmed
	I	Prostate cancer	Transaminitis	15 patients. 1 had >50% PSA decline. 1 had reduction in PSA doubling time.	[70]
BIIB022	Fully human, monoclonal antibody (IgG4.P), Biogen Idec
	I	Solid tumors		Pending
BMS-754807	Tyrosine kinase inhibitor-reversible ATP competitive inhibitor, Bristol-Myers Squibb
	I/FIH	Solid tumors		Pending