Table 2.

Clinical trials using gamma secretase inhibitors (GSIs) organized by cancer type of participating patients. Specific GSI used, and potential combinatorial agents, are provided alongside trial phase, number of patients with indicated cancer type, and trial outcomes

Cancer and study cohort	GSI	Combination	Phase	Patients	n	Outcome	Reference
Ovarian
EOC: platinum resistant	RO4929097		II	Recurrent or metastatic	45	PFS: 1.3 mo	Diaz‐Padilla et al. 2015 [112]
Advanced solid tumors	RO4929097		I	Refractory to standard therapy	9	3 clinical benefit	Tolcher et al. 2012 [93]
Advanced solid tumors	RO4929097	Gemcitibine	I	Refractory to standard therapy	2	safe combination	Richter et al. 2014 [91]
Advanced solid tumors	RO4929097	Temsirolimus	Ib	Refractory to standard therapy	1	safe combination	Diaz‐Padilla et al. 2013 [110]
Advanced solid tumors	RO4929097	Cediranib	I	Refractory to standard therapy		safe combination	Sahebjam et al. 2013 [111]
Advanced solid tumors	LY900009		I	Refractory to standard therapy	11	MTD 30 mg 3×/wk	Pant et al. 2016 [109]
Advanced solid tumors	MK‐0752		I	Refractory to standard therapy	3	Inhibited Notch, minimal clinical activity as monotherapy	Krop et al. 2012 [84]
Colorectal
Advanced solid tumors	MK‐0752	Dalotuzumab	I	Refractory to standard therapy	9	Safe combination	Brana et al. 2014 [122]
Advanced solid tumors	RO4929097	Cediranib	I	Refractory to standard therapy	6	Safe combination	Sahebjam et al. 2013 [111]
Advanced solid tumors	PF‐03084014		I	Refractory to standard therapy	11	Safe, response in desmoid tumors, overall PFS 1.6 mo	Messersmith et al. 2015 [85]
Stage IV, metastatic	RO4929097		II	Refractory to standard therapy	37	Safe, PFS 1.8 mo, dose/schedule have minimal activity	Strosberg et al. 2012 [121]
Advanced solid tumors	RO4929097	Capecitabine	I	Refractory to standard therapy	18	Safe, promising activity in colon cancer	LoConte et al. 2015 [123]
Advanced solid tumors	RO4929097		I	Refractory to standard therapy	12	3 clinical benefit	Tolcher et al. 2012 [93]
Advanced solid tumors	LY900009		I	Refractory to standard therapy	5	MTD 30 mg 3×/wk	Pant et al. 2016 [109]
Advanced solid tumors	MK‐0752		I	Refractory to standard therapy	16	Inhibited Notch, minimal clinical activity as monotherapy	Krop et al. 2012 [88]
Advanced solid tumors	BMS‐986115		I	Refractory to standard therapy	5	Intermittent schedule likely preferable, better tolerated	Aung et al. 2018 [120]
Desmoid
Advanced solid tumors	BMS‐986115		I	Refractory to standard therapy	1	Intermittent schedule likely preferable/better tolerated	Aung et al. 2018 [120]
Advanced solid tumors	PF‐03084014		I	Refractory to standard therapy	9	Safe, response in desmoid tumors, overall PFS 1.6 mo	Messersmith et al. 2015 [85]
Unresectable	PF‐03084014		II	Progressive disease after more than one line	17	Promising strategy for desmoid tumors	Chen et al. 2016 [60]
Breast
Advanced breast tumors	MK‐0752	Docetaxel	I	Refractory to first‐line chemotherapy	30	Preliminary evidence of clinical efficacy	Schott et al. 2013 [107]
Advanced TNBC	PF‐03084014	Docetaxel	Ib	Refractory to standard therapy	29	Median PFS 4.1 mo, 6 mo PFS 17.1%	Locatelli et al. 2017 [106]
Metastatic ER+ breast cancer	RO4929097	Exemestane	Ib	Refractory to standard therapy	15	Safe combination, preliminary evidence of stable disease	Means‐Powell et al. 2012 [105]
Advanced solid tumors	MK‐0752		I	Refractory to standard therapy	24	Inhibited Notch, minimal clinical activity as monotherapy	Krop et al. 2012 [84]
Advanced solid tumors	PF‐03084014		I	Refractory to standard therapy	7	Safe combination, overall PFS 1.6 mo	Messersmith et al. 2015 [85]
Advanced solid tumors	RO4929097	Gemcitibine	I	Refractory to standard therapy	5	Safe combination	Richter et al. 2014 [91]
Advanced solid tumors	RO4929097		I	Refractory to standard therapy	10	Safe combination	Tolcher et al. 2012 [93]
Glioma
Advanced solid tumors	MK‐0752		I	Refractory to standard therapy	42	Modest level of clinical activity in gliomas	Krop et al. 2012 [84]
CNS malignancies	MK‐0752		I	Refractory pediatric tumors	4	Well tolerated, trial not completed	Hoffman et al. 2015 [99]
CNS malignancies	MK‐0752		I	Refractory pediatric tumors	9	Well tolerated	Fouladi et al. 2011 [98]
Malignant gliomas	RO4929097	Bevacizumab	I	Refractory to standard therapy	13	Well tolerated, PFS 3.7 mo	Pan et al. 2016 [100]
Glioblastoma, grade III AA	RO4929097	Temozolomide, RT	I	Newly diagnosed	21	Well tolerated, glioblastoma median PFS 13 mo	Xu et al. 2016 [101]
Melanoma
Advanced solid tumors	MK‐0752		I	Refractory to standard therapy	3	Inhibited Notch, minimal clinical activity as monotherapy	Krop et al. 2012 [84]
Advanced solid tumors	RO4929097		I	Refractory to standard therapy	24	Safe combination	Tolcher et al. 2012 [93]
Metastatic melanoma	RO4929097		II	Chemotherapy naïve	36	Safe combination, PFS: 1.5 mo	Lee et al. 2015 [69]
Pancreatic
Metastatic PDAC	RO4929097		II	Refractory to standard therapy	18	Well‐tolerated, PFS: 1.5 mo	De Jesus‐Acosta et al. 2014 [89]
Advanced solid tumors	RO4929097	Gemcitibine	I	Refractory to standard therapy	3	Safe combination	Richter et al. 2014 [91]
Advanced solid tumors	PF‐03084014		I	Refractory to standard therapy	3	Safe combination, overall PFS 1.6mo	Messersmith et al. 2015 [85]
Advanced solid tumors	MK‐0752		I	Refractory to standard therapy	2	Inhibited Notch, minimal clinical activity as monotherapy	Krop et al. 2012 [84]
Stage III/IV PDAC	MK‐0752	Gemcitibine	I	Prior therapy acceptable	44	Well tolerated, PFS: 5.6 mo	Cook et al. 2018 [92]
NSCLC
Advanced solid tumors	MK‐0752		I	Refractory to standard therapy	3	Inhibited Notch, minimal clinical activity as monotherapy	Krop et al. 2012 [84]
Advanced solid tumors	PF‐03084014		I	Refractory to standard therapy	5	Safe combination, overall PFS 1.6 mo	Messersmith et al. 2015 [85]
NSCLC	RO4929097	Erlotinib	I/II	Refractory to standard therapy	16	Safe combination, does not merit further eval	Gold et al. 2013 [86]

Abbreviations: AA, anaplastic astrocytoma; CNS, central nervous system; EOC, epithelial ovarian cancer; ER, estrogen receptor; MTD, maximum tolerated dose; NSCLC, non‐small cell lung cancer; PDAC, pancreatic adenocarcinoma; PFS, progression‐free survival; TNBC, triple‐negative breast cancer.