Table 2.

Ongoing clinical trials of PI3K/Akt/mTOR pathway inhibitors accepting patients with breast cancer, which include a pre-screening component for pathway activation

Patient population	Study drug	Biomarker evaluations	Phase	NCT number
Postmenopausal women with HR+/HER2− locally advanced or mBC who are resistant to aromatase inhibitor	BKM120 (PI3K inhibitor) + fulvestrant	PFS measured in PI3K pathway activated, and total populations (primary objective), and non-activated population (secondary endpoint)	III	NCT01610284 (BELLE-2)
Postmenopausal women with HR+/HER2− locally advanced or mBC who are resistant to mTOR inhibitor	BKM120 (PI3K inhibitor) + fulvestrant	PFS measured in PI3K pathway activated, and total populations (primary objective), and non-activated population (secondary endpoint)	III	NCT01633060 (BELLE-3)
HER2− locally advanced or mBC	BKM120 (PI3K inhibitor) + paclitaxel	PFS measured in PI3K pathway activated and total population (primary objective)	II	NCT01572727
Metastatic triple-negative breast cancer	BKM120 (PI3K inhibitor)	Molecular alterations in tumor tissue and correlation with response (secondary objective)	II	NCT01629615
Postmenopausal ER+ locally advanced BC or mBC that is resistant to aromatase inhibitor	GDC-0941 (PI3K inhibitor) or GDC- 0980 (PI3K/mTOR inhibitor) + fulvestrant	Patients are stratified by PIK3CA mutations or PTEN loss. The second phase of the trial only will take patients with PIK3CA-mutant tumors	II	NCT01437566 (FERGI)
Advanced, metastatic, or recurrent BC	MK-2206 (Akt inhibitor)	PIK3CA mutation and/or PTEN loss is required for study enrollment	II	NCT01277757
Operable invasive BC	MK-2206 (Akt inhibitor)	Reverse-phase protein microarray analysis used to determine if tumors with PIK3CA mutations demonstrate different modulation of PI3K pathway signaling compared with tumors with PTEN loss (secondary endpoint)	II	NCT01319539
ER+/HER2− advanced BC previously treated with an aromatase inhibitor	PF-04691502 (PI3K/mTOR inhibitor) + exemestane	Biomarkers of PI3K/mTOR signal deregulation, proliferation, apoptosis (secondary objective)	II	NCT01658176
Postmenopausal women with ER+/HER2− BC	PF-4691502 (PI3K/mTOR inhibitor) + letrozole	Change from baseline Ki-67 (and positive tumor cells) (primary objective); change from baseline in pAkt and pS6 (secondary objectives)	I/II	NCT01430585
HR+/HER2− recurrent or mBC refractory to aromatase inhibitor	SAR245408 (PI3K inhibitor) or SAR245409 (PI3K/mTOR inhibitor) + letrozole	Pharmacodynamics of study drug (secondary objective)	I/II	NCT01082068
Relapsing HER2− overexpressing BC who have previously failed trastuzumab	BKM120 (PI3K inhibitor) + trastuzumab	Patients enrolled in the study are evaluated for PIK3CA mutation, which will be correlated with treatment response (exploratory endpoint)	I/II	NCT01132664
Patients with triple-negative mBC or HER2-amplified BC who have failed trastuzumab	Temsirolimus plus neratinib	Analysis of expression of PTEN and upstream molecular targets (IGF1-R, EGFR, and HER3) and the mutational activation of PI3K (secondary outcome measures)	I/II	NCT01111825
Postmenopausal women with HR+ mBC	BKM120 (PI3K inhibitor) or BEZ235 (PI3K/mTOR inhibitor) + letrozole	Correlation of response with PIK3CA mutations (exploratory objective)	I	NCT01300962
ER+ advanced or mBC (expansion part)	AZD5363 (Akt inhibitor) + paclitaxel	Patients are stratified by PIK3CA mutation status at study entry (expansion part). Correlation between PD biomarkers and response (secondary endpoint)	I	NCT01625286
Postmenopausal, estrogen receptor-positive Stage IV BC	BKM120 (PI3K inhibitor) + fulvestrant	Patients are evaluated for PIK3CA mutation, which will be correlated with treatment response (tertiary endpoint)	I	NCT01339442
mBC for whom treatment with capecitabine is a reasonable choice	BKM120 (PI3K inhibitor) or BEZ235 (PI3K/mTOR inhibitor) + capecitabine	Primary tissue is evaluated for predictive biomarkers of response (PI3K activating mutations, pAkt, mTOR) (exploratory objective)	I	NCT01300962
Postmenopausal, estrogen receptor-positive, locally advanced or mBC whose tumors have a PIK3CA alteration	BYL719 (PI3Kα inhibitor) + fulvestrant	PIK3CA mutation is required for study enrollment	I	NCT01219699
Estrogen receptor-positive/HER2− negative mBC, with histologic grade 2 or 3 and Ki67≥15%	Ridaforolimus ± dalotuzumab, or dalotuzumab alone	Patients are assessed for mean change from baseline in Growth Factor Signature* score (primary endpoint)	I	NCT01220570
In the dose-expansion phase, patients with mBC that have received a maximum of 3 lines of therapy	MK-2206 (Akt inhibitor) + paclitaxel	PIK3CA and PTEN status will be measured in the primary tumor and in metastases, and correlated with clinical response (secondary endpoint)	I	NCT01263145
In the dose-expansion phase, patients with HER2+ advanced BC	MK-2206 (Akt inhibitor) + lapatinib	Tumor tissue oncogenic status will be assessed and correlated with clinical response (exploratory endpoint)	I	NCT01245205
ER+/HER2− BC	BKM120 (PI3K inhibitor) or BEZ235 (PI3K/mTOR inhibitor)	Tumor status for PIK3CA mutation, PTEN mutation, Akt, pAkt, mTOR, p110, S6K, 4E-BP1, hormone receptors, and IGFR before and after treatment (primary objective). Correlation between tumor markers and response (secondary objective)	0	NCT01513356

Source: Clinicaltrials.gov (accessed October 2012).

BC, breast cancer; EGFR, epidermal growth factor receptor; ER, estrogen receptor; HER, human epidermal growth factor receptor; HR, hormone receptor; IGF1-R, insulin-like growth factor 1; mBC, metastatic breast cancer; mTOR, mammalian target of rapamycin; PD, pharmacodynamics; PTEN, phosphatase and tensin homolog.

^*Growth Factor Signature score represents a gene signature that is responsive to alterations in the PI3K/Akt/mTOR pathway⁵⁸.