Purpose: This first-in-human dose-escalation trial evaluated the safety, tolerability, maximal-tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, pharmacodynamics, and preliminary clinical activity of pictilisib (GDC-0941), an oral, potent, and selective inhibitor of the class I phosphatidylinositol-3-kinases (PI3K).

Patients and Methods: Sixty patients with solid tumors received pictilisib at 14 dose levels from 15 to 450 mg once-daily, initially on days 1 to 21 every 28 days and later, using continuous dosing for selected dose levels. Pharmacodynamic studies incorporated 18F-FDG-PET, and assessment of phosphorylated AKT and S6 ribosomal protein in platelet-rich plasma (PRP) and tumor tissue.

Results: Pictilisib was well tolerated. The most common toxicities were grade 1–2 nausea, rash, and fatigue, whereas the DLT was grade 3 maculopapular rash (450 mg, 2 of 3 patients; 330 mg, 1 of 7 patients). The pharmacokinetic profile was dose-proportional and supported once-daily dosing. Levels of phosphorylated serine-473 AKT were suppressed >90% in PRP at 3 hours after dose at the MTD and in tumor at pictilisib doses associated with AUC >20 h·μmol/L. Significant increase in plasma insulin and glucose levels, and >25% decrease in 18F-FDG uptake by PET in 7 of 32 evaluable patients confirmed target modulation. A patient with V600E BRAF–mutant melanoma and another with platinum-refractory epithelial ovarian cancer exhibiting PTEN loss and PIK3CA amplification demonstrated partial response by RECIST and GCIG-CA125 criteria, respectively.

Conclusion: Pictilisib was safely administered with a dose-proportional pharmacokinetic profile, on-target pharmacodynamic activity at dose levels ≥100 mg and signs of antitumor activity. The recommended phase II dose was continuous dosing at 330 mg once-daily. Clin Cancer Res; 21(1); 77–86. ©2014 AACR.

Translational Relevance

The phosphatidylinositol-3-kinase (PI3K) pathway is one of the most commonly deregulated in cancer and is currently a major focus for anticancer drug development. This article describes the first-in-human phase I trial of pictilisib (GDC-0941), one of the very first pan-class I selective PI3K inhibitors evaluated in patients with advanced cancer. Pictilisib demonstrated a favorable pharmacokinetic profile and was well tolerated at biologically active doses. Comprehensive pharmacodynamic biomarker evaluation showed suppression of AKT and S6 phosphorylation in platelet-rich plasma (PRP) and tumor, together with significant changes in plasma insulin and glucose levels, and decreases in 18F-FDG uptake by PET. In addition, there was preliminary evidence of antitumor activity. These results provide the basis for further evaluation of pictilisib in rationally designed monotherapy or combination trials. In addition, this phase I trial of pictilisib exemplifies the use of “Pharmacological Audit Trail” guidelines for molecularly targeted therapy in cancer.

Phosphatidylinositol-3-kinase (PI3K) regulates processes involved in the hallmark traits of cancer, such as cell growth, survival, metabolism, invasion, and metastases (1). Multiple isoforms of PI3K exist in mammalian cells and these isoforms are subdivided into three classes based on structural features and lipid substrate preferences (1). The class IA isoforms (p110α, β, and δ) are responsible for the production of the second messenger phosphatidyl-inositol-3,4,5 triphosphate (PIP3; refs. 2, 3). PI3K activation initiates a signal transduction cascade, of which the major effectors are the kinases AKT and mTORC1 (4). PTEN is a tumor-suppressor gene that functions as a phosphatase, and is the primary negative regulator of PI3K, through hydrolysis of PIP3 (5). Deregulation of the PI3K pathway has been frequently implicated in a wide range of malignancies, including glioma, prostate, breast, ovarian, and endometrial cancer (6). Alteration of the pathway commonly occurs through mutation or amplification of PIK3CA that encodes the p110α catalytic subunit, loss of function of PTEN (through deletion, mutation, or reduced expression), alterations in the INPP4B and PHLPP phosphatases, mutations of the PI3K regulatory subunits encoded by PIK3R1 and PIK3R3, or through activation of upstream receptor tyrosine kinases or cross-talk with the RAS pathway (3, 6, 7).

Pictilisib (GDC-0941; Genentech Inc.) is an oral, potent, selective pan-inhibitor of class I PI3K (IC50 against purified recombinant human PI3K isoforms: p110α = 3 nmol/L, p110β = 33 nmol/L, p110δ = 3 nmol/L, and p110γ = 75 nmol/L) with 193-fold less activity against mTOR compared to p110α (8). Antitumor activity was demonstrated in human tumor xenograft murine models; at an oral dose of 150 mg/kg, pictilisib achieved 98% and 80% growth inhibition in PI3K pathway–activated U87MG glioblastoma and IGROV1 ovarian cancer xenografts, respectively (9). At this dose level, pictilisib achieved plasma concentrations in tumor tissue >GI50-antiproliferative concentrations for >8 hours and demonstrated downstream PI3K pathway biomarker changes such as time- and dose-dependent inhibition of phosphorylation of AKT (Ser473) and P70S6 kinase (Thr421/Ser424; ref. 9). These data led us to conduct a first-in-human phase I dose-escalation study of pictilisib in patients with advanced solid tumors to evaluate safety and tolerability, define dose-limiting toxicities (DLT) and the maximum-tolerated dose (MTD) of pictilisib administered orally. Secondary objectives included characterization of pharmacokinetics, assessment of pharmacodynamics including changes in tumor 18F-fluorodeoxyglucose (18F-FDG) uptake [by positron emission tomography (PET) studies], tumor expression of phosphorylated (Ser235/Ser236) S6 ribosomal protein (phospho-S6) in mandatory pre- and on-treatment biopsies and phosphorylated (Ser473) AKT (phospho-AKT) in PRP, and preliminary evaluation of antitumor activity.

This single-center trial was conducted in accordance with the Declaration of Helsinki at The Royal Marsden NHS Foundation Trust (London, United Kingdom) after approval by local Institutional Review Boards. Informed consent from all patients was obtained.

Eligibility

Patients of ages ≥18 years with histologically confirmed solid tumors and no conventional treatment option were eligible. Other inclusion criteria included fasting serum glucose ≤120 mg/dL, HbA1c ≤upper limit of normality, prior chemotherapy or radiotherapy completed ≥4 weeks previously, toxicity from prior therapy resolved to grade ≤1, an Eastern Cooperative Oncology Group (ECOG) performance status ≤1, expected life expectancy ≥12 weeks, and adequate organ functions. Significant exclusion criteria included diabetes mellitus requiring medication, significant respiratory disease [requiring supplemental oxygen or predicted diffusion capacity of carbon monoxide (DLCO) ≤50%], and use of anticoagulation or chronic corticosteroid.

Study design

This was an open-label, single-center, phase I study using a modified 3+3 dose-escalation design. During dose escalation, the dose of pictilisib was doubled until drug-related toxicity of grade ≥2 was observed. Dose escalations from this point were limited to ≤50% of the previous dose (if grade ≤2) or 33% in the event of grade ≥3 toxicities.

Pictilisib was administered on day 1, followed by a 1-week washout to evaluate single-dose pharmcokinetics and pharmacodynamics. Dosing was once-daily for 21 or 28 days every 28 days (21/28 or 28/28 schedule, respectively). The recommended starting dose in humans of 15 mg once-daily was chosen on the basis of the no observed adverse effect level and MTD in 28-day rodent and dog species studies. The 21/28 starting schedule was chosen to implement a drug-free period to allow recovery from acute toxicities and limit cumulative toxicities to maximize the administered dose of pictilisib. A continuous dosing schedule (28/28) was implemented to further explore safety and pharmacodynamics of dose levels of 330 to 400 mg.

Definitions of DLT and MTD

DLTs were based on toxicities observed in the first cycle and assessed by the investigator as possibly related to pictilisib. A DLT was defined as grade 4 neutropenia for >5 days or accompanied by fever >38.5°C, grade 4 thrombocytopenia, or grade 3 nonhematologic toxicity of any duration with the exception of alopecia. Grade 3–4 nausea, vomiting, and diarrhea were only considered DLTs if they occurred despite optimal medical management. Grade ≥3 total bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were considered DLTs except when preexisting grade 1 values and were <7.5x ULN due to known liver metastases. Decreases in DLco ≥20% were also considered DLTs. The MTD was defined as the highest dose at which ≤1 of 6 DLTs (<33%) patients experienced DLT at that dose level.

Safety and efficacy

Clinical and laboratory assessments were conducted at baseline and weekly thereafter. Safety assessments included medical history, physical examination, electrocardiogram, hematology, biochemistry (including fasting glucose and HbA1C,), and assessment of pulmonary toxicity with pulse oximetry, DLCO, and high-resolution CT (HRCT) of the chest. Adverse events (AE) were graded using Common Toxicity Criteria for Adverse Events (CTCAE) version 3.0. Tumor assessments were performed at the end of cycles 1 and 2, and then every two cycles using RECIST guidelines (10).

Pharmacokinetics

Plasma levels of pictilisib were determined from samples collected on day 1: pre-dose, and 0.5, 1, 2, 3, 4, 8, 24, 48, and 72 hours after dose; and on day 15: pre-dose, and 0.5, 1, 2, 3, 4, 8, and 24 hours after dose. Pharmacokinetic samples for pictilisib were analyzed using a validated HPLC/MS/MS method. Standard pharmacokinetic parameters were determined using a noncompartmental method (WinNonlin version 5.2.1; Pharsight Corporation).

Pharmacodynamics

PRP was obtained from patients pre-dose, and at 1, 3, 8, and 24 hours after dose on days 1 and 15 of cycle 1 for analysis of phospho-AKT (Ser473) using an electrochemiluminescense assay (Luminex xMAP; Luminex Corp.). Wherever feasible, patients underwent tumor biopsies pretreatment and 1 to 4 hours after dose on day 15; samples were fixed, sectioned, and stained with hematoxylin and eosin, and for phospho-S6 using anti-phospho-S6 (Ser235/236; Cell Signaling Technology Inc.), or anti-phospho-AKT (Serine 473) clone D9E (Cell Signaling Technology). Plasma was obtained pre-dose and at 1 hour after dose on cycle 1 day 1 for analysis of glucose and insulin levels at dose levels ≥100 mg. Whole-body 18F-FDG-PET scans were performed at baseline, 1 to 4 hours after dose between day 22 and the end of cycle 1 as well as between day 50 and the end of cycle 2.

PI3K pathway alteration biomarkers

PIK3CA mutations were identified in circulating tumor plasma DNA (ctDNA) using a site-specific molecular characterization protocol (11). Archival and fresh tumor samples were analyzed using the SEQUENOM OncoCarta Panel (Sequenom Inc.). PIK3CA amplification was assessed by fluorescence in-situ hybridization (FISH) and PTEN status by immunohistochemistry (12).

Patient characteristics

Sixty patients with confirmed progressive cancer at study entry were enrolled, most of whom were heavily pretreated [median of 3 prior systemic therapies (range, 0–16); Table 1]. All patients were included in the safety analysis.

Table 1.

Demographics and clinical characteristics of all treated patients

All patients
CharacteristicPatients, n (%)
Sex 
 Male 30 (50) 
 Female 30 (50) 
Age, y 
 Median 59 
 Range 27–77 
ECOG performance status at screening 
 0 28 (47) 
 1 32 (53) 
Primary cancer diagnosis 
 Colorectal 16 (27) 
 Breast 9 (15) 
 Soft tissue sarcoma 7 (12) 
 Melanoma 5 (8) 
 Ovarian 3 (5) 
 Gastric 2 (3) 
 Prostate 2 (3) 
 Others 16 (27) 
Prior lines of systemic therapies (n
 Median 
 Range 0–16 
All patients
CharacteristicPatients, n (%)
Sex 
 Male 30 (50) 
 Female 30 (50) 
Age, y 
 Median 59 
 Range 27–77 
ECOG performance status at screening 
 0 28 (47) 
 1 32 (53) 
Primary cancer diagnosis 
 Colorectal 16 (27) 
 Breast 9 (15) 
 Soft tissue sarcoma 7 (12) 
 Melanoma 5 (8) 
 Ovarian 3 (5) 
 Gastric 2 (3) 
 Prostate 2 (3) 
 Others 16 (27) 
Prior lines of systemic therapies (n
 Median 
 Range 0–16 

Treatment and dose escalation

Sixty patients were treated in 14 dose schedules (Table 2). Dose escalation on the 21/28 schedule proceeded through 11 dose levels from 15 mg. At 450 mg, 2 of 3 patients experienced DLTs. The dose level of 330 mg was then evaluated with 1 DLT observed in 7 patients treated at this dose level on a 21/28 schedule. Subsequently, the dose levels of 330, 340, and 400 mg on the 28/28 schedule were assessed.

Table 2.

Summary of AEs

Dose level (mg)1530456080100130180245330450330340400All
Schedule21/2821/2821/2821/2821/2821/2821/2821/2821/2821/2821/2828/2828/2828/2821 or 28/28
No. of patients43443533373107160
Toxicity gradeAllAllAllAllAllAll≥3AllAllAll≥3All≥3All≥3All≥3AllAll≥3All
Any AE 10 46 
Gastrointestinal 
 Nausea 28 
 Diarrhea 19 
 Vomiting 15 
 Decreased appetite 14 
 Dysgeusia 13 
Skin and mucosa 
 Rasha 14 
 Stomatitisb 
 Xeroderma 
Constitutional 
 Fatigue 21 
Dose level (mg)1530456080100130180245330450330340400All
Schedule21/2821/2821/2821/2821/2821/2821/2821/2821/2821/2821/2828/2828/2828/2821 or 28/28
No. of patients43443533373107160
Toxicity gradeAllAllAllAllAllAll≥3AllAllAll≥3All≥3All≥3All≥3AllAll≥3All
Any AE 10 46 
Gastrointestinal 
 Nausea 28 
 Diarrhea 19 
 Vomiting 15 
 Decreased appetite 14 
 Dysgeusia 13 
Skin and mucosa 
 Rasha 14 
 Stomatitisb 
 Xeroderma 
Constitutional 
 Fatigue 21 

NOTE: AEs possibly or likely treatment-related that occurred in ≥10% of patients according to maximum grade for each patient by dose level and grade. AEs grades ≥3 are presented in separate columns for each dose-schedule only when observed.

aIncluding preferred terms of rash, rash maculo-papular, rash macular, rash pruritic, rash erythematous, and rash papular.

bIncluding preferred terms of stomatitis, mucosal inflammation, mouth ulceration.

DLTs and MTD

The MTD was exceeded at 450 mg once-daily (21/28 schedule) with a DLT of grade 3 rash in 2 patients. This was a maculopapular rash covering 70% to 80% of the body surface area that presented approximately 2 weeks after commencement of daily pictilisib dosing and resolved spontaneously 2 weeks after treatment discontinuation. At 330 mg once-daily (21/28 schedule), the grade 3 maculopapular rash observed in 1 of 7 patients had a similar temporal pattern of onset and resolution; this was also declared as a DLT. On the 28/28 schedule, no DLT was observed.

Safety and tolerability

Pictilisib was well tolerated up to 330 mg (21/28 schedule); most AEs were mild to moderate in severity with no treatment-related deaths (Table 2). At the assessed dose levels, there did not appear to be a significant difference in the toxicity profile between the 21/28 and 28/28 schedules. Treatment-related AEs that occurred in ≥10% of patients included: nausea, diarrhea, vomiting, fatigue, dysgeusia, decreased appetite, and rash. In addition to the two DLTs of grade 3 rash at the 450-mg dose level, the third patient at this dose level experienced grade 2 rash; nonetheless, this patient received 8 months of pictilisib with concomitant use of oral antihistamines and skin emollients. Of 10 patients treated with 330 mg once-daily (28/28 schedule), grade 1 or 2 rash was observed in 2 patients, and grade 3 rash (occurring after the DLT-defining window) in 2 patients; these similarly resolved with the introduction of drug holidays and supportive medications including emollients and corticosteroids.

Other clinically relevant drug-related AEs ≥grade 3 were grade 4 hyperglycemia (n = 1; 130 mg) and grade 3 pneumonitis (n = 1; 340 mg). The grade 4 hyperglycemia was transient, unaccompanied by clinically significant symptoms, signs or acidosis, and occurred in a patient with cholangiocarcinoma and previous pancreatico-duodenectomy who started low-dose prednisolone 2 days before the event. Grade 3 pneumonitis was observed at the end of cycle 1 in a patient with breast cancer previously treated with chest radiotherapy who developed grade 1 dyspnea, reduced DLCO and a ground glass appearance on HRCT; these resolved following 2 weeks of drug interruption and concomitant use of prednisolone. When pictilisib was reintroduced at 240 mg, the dyspnea and HRCT changes recurred; these subsequently resolved following permanent discontinuation of pictilisib due to disease progression.

Pharmacokinetics

Pharmacokinetic parameters of pictilisib were estimated for all dose cohorts and are summarized in Table 3 and Supplementary Table S1. Under fasting conditions, pictilisib was rapidly absorbed after oral administration [median Tmax of 2 hours (range, 0.5–8)]; this was independent of dose and was unchanged after multiple doses. Terminal plasma elimination half-life (T1/2) on day 1 ranged between 13.1 and 24.1 hours. Dose-proportional increases in exposure (Cmax and AUC0–24) was observed across the dose levels studied (Fig. 1). Similar pharmacokinetic characteristics were seen on day 15. The accumulation index (AUCDay15/AUCDay1) ranged from 1.2 to 2.2, suggesting modest accumulation following multiple doses.

Figure 1.

Pharmacokinetic profile of pictilisib. A, plasma concentration versus time profile for all dose levels. B, maximum plasma concentration (Cmax) versus dose. C, area under the curve (AUC) versus dose. Solid and dashed lines represent the fitted regression lines for days 1 and 15, respectively.

Figure 1.

Pharmacokinetic profile of pictilisib. A, plasma concentration versus time profile for all dose levels. B, maximum plasma concentration (Cmax) versus dose. C, area under the curve (AUC) versus dose. Solid and dashed lines represent the fitted regression lines for days 1 and 15, respectively.

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Table 3.

Key pharmacokinetic parameters of pictilisib on days 1 and 15

Elimination half-life, hTmax, hCmax, μmol/LAUC 0–24, h· μmol/L
Patients (n)Geometric meanMedianRangeGeometric meanGeometric mean
Day 1 
 15 mg QD 19.2 1–2 0.112 0.978 
 30 mg QD 24.1 1–2 0.144 1.18 
 45 mg QD 19.5 0.362 2.77 
 60 mg QD 18.8 1–2 0.242 2.02 
 80 mg QD 20.1 1–2 0.632 5.45 
 100 mg QD 14.6 1–8 0.362 3.19 
 130 mg QD 13.1 1–2.5 0.359 2.99 
 180 mg QD 17.1 2–3 0.611 5.95 
 245 mg QD 16.8 1–2 0.994 8.18 
 330 mg QD 17 15.7 0.5–8 1.52 14.4 
 340 mg QD 20.9 1–4 1.68 14.9 
 400 mg QD 14.8 1.65 15.6 
 450 mg QD 15.0 1–2 1.95 13.9 
Day 15 
 15 mg QD  1.5 1–4 0.116 1.35 
 30 mg QD  0.5–4 0.179 1.90 
 45 mg QD  0.436 4.09 
 60 mg QD  2–4 0.27 2.78 
 80 mg QD  3–4 0.779 9.86 
 100 mg QD  1–3 0.751 5.64 
 130 mg QD  1–2 0.457 5.03 
 180 mg QD  1–3 0.783 8.25 
 245 mg QD  1–3 1.37 11.3 
 330 mg QD 17  0–8 2.07 22.8 
 340 mg QD  1–4 1.95 16.5 
 450 mg QD  1–3 2.64 23.5 
Elimination half-life, hTmax, hCmax, μmol/LAUC 0–24, h· μmol/L
Patients (n)Geometric meanMedianRangeGeometric meanGeometric mean
Day 1 
 15 mg QD 19.2 1–2 0.112 0.978 
 30 mg QD 24.1 1–2 0.144 1.18 
 45 mg QD 19.5 0.362 2.77 
 60 mg QD 18.8 1–2 0.242 2.02 
 80 mg QD 20.1 1–2 0.632 5.45 
 100 mg QD 14.6 1–8 0.362 3.19 
 130 mg QD 13.1 1–2.5 0.359 2.99 
 180 mg QD 17.1 2–3 0.611 5.95 
 245 mg QD 16.8 1–2 0.994 8.18 
 330 mg QD 17 15.7 0.5–8 1.52 14.4 
 340 mg QD 20.9 1–4 1.68 14.9 
 400 mg QD 14.8 1.65 15.6 
 450 mg QD 15.0 1–2 1.95 13.9 
Day 15 
 15 mg QD  1.5 1–4 0.116 1.35 
 30 mg QD  0.5–4 0.179 1.90 
 45 mg QD  0.436 4.09 
 60 mg QD  2–4 0.27 2.78 
 80 mg QD  3–4 0.779 9.86 
 100 mg QD  1–3 0.751 5.64 
 130 mg QD  1–2 0.457 5.03 
 180 mg QD  1–3 0.783 8.25 
 245 mg QD  1–3 1.37 11.3 
 330 mg QD 17  0–8 2.07 22.8 
 340 mg QD  1–4 1.95 16.5 
 450 mg QD  1–3 2.64 23.5 

Pharmacodynamics

We observed a dose- and concentration-dependent decrease in phospho-AKT in PRP on days 1 and 15 (Fig. 2). Inhibition up to 90% of phospho-AKT level in PRP was demonstrated 1 to 3 hours after dose at the recommended phase II dose (RP2D); this effect was sustained (50% of baseline) at 24 hours after dose. Reductions in S6 and AKT phosphorylation in tumor biopsies were greatest at the highest exposure level of pictilisib (AUC >20 μmol/L·h on day 15), with all 3 patients in this cohort showing ≥75% decrease in S6 phosphorylation and 2 patients also exhibiting a 100% decrease in AKT phosphorylation (Fig. 3). Following pictilisib treatment at 330 mg on cycle 1 day 1, there was a statistically significant increase in plasma insulin and glucose levels at 1 hour from baseline with mean fold change (i.e., ratio of post- over pretreatment level) in plasma insulin and glucose levels of 3.58 [95% confidence interval (CI), 2.33–5.49] and 1.18 (95% CI, 1.10–1.26), respectively (Supplementary Fig. S1). 18F-FDG-PET imaging showed a reduction from baseline of 18F-FDG-tracer uptake at dose levels ≥45 mg with an overall median change in maximum standardized uptake value (SUVmax) of −13% (range, −47 to 22; Supplementary Fig. S2). Seven of 32 evaluable patients (22%) achieved a metabolic partial response by EORTC-PET criteria (>25% reduction in mean SUVmax without new lesions) on 18F-FDG-PET (10).

Figure 2.

A, percentage change in levels of phosphorylated AKT (pAKT) in PRP and plasma level of pictilisib up to 24 hours following administration of pictilisib (at RP2D of 330 mg) on days 1 and 15 of cycle 1 (n = 8). B, pictilisib concentration-dependent inhibition of phosphorylated AKT (pAKT) in PRP following systemic exposure to pictilisib. Data represent available concentration-matched PRP pAKT inhibition from duration of phase I investigation.

Figure 2.

A, percentage change in levels of phosphorylated AKT (pAKT) in PRP and plasma level of pictilisib up to 24 hours following administration of pictilisib (at RP2D of 330 mg) on days 1 and 15 of cycle 1 (n = 8). B, pictilisib concentration-dependent inhibition of phosphorylated AKT (pAKT) in PRP following systemic exposure to pictilisib. Data represent available concentration-matched PRP pAKT inhibition from duration of phase I investigation.

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Figure 3.

Pharmacodynamic analysis in tumor biopsies. A, phospho-S6 (pS6) and phospho-AKT (pAKT) levels in baseline and on-treatment paired tumor biopsies grouped according to AUC0–24 [h· (μmol/L)] on day 15. pS6 staining levels were measured using a standard H-Score method, and pAKT staining levels were measured using a validated, qualitative scoring method (represented on y-axis). Pre- and on-treatment samples from the same patient were stained in the same experiment and examined blind. Arrows indicate patient 50036. B, immunohistochemistry images of pS6 and pAKT from patient 50036. C, percentage change from baseline of pS6 and pAKT levels. Tumor biopsies for three patients were not evaluable for phospho-AKT and are indicated with an “x.” All patients received doses of >60 mg of pictilisib with the exception of patient 50008 who received 45 mg.

Figure 3.

Pharmacodynamic analysis in tumor biopsies. A, phospho-S6 (pS6) and phospho-AKT (pAKT) levels in baseline and on-treatment paired tumor biopsies grouped according to AUC0–24 [h· (μmol/L)] on day 15. pS6 staining levels were measured using a standard H-Score method, and pAKT staining levels were measured using a validated, qualitative scoring method (represented on y-axis). Pre- and on-treatment samples from the same patient were stained in the same experiment and examined blind. Arrows indicate patient 50036. B, immunohistochemistry images of pS6 and pAKT from patient 50036. C, percentage change from baseline of pS6 and pAKT levels. Tumor biopsies for three patients were not evaluable for phospho-AKT and are indicated with an “x.” All patients received doses of >60 mg of pictilisib with the exception of patient 50008 who received 45 mg.

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Antitumor activity

One patient with BRAF V600E–mutated metastatic melanoma, but no detected PI3K pathway deregulation, achieved a confirmed RECIST-partial response; she received pictilisib at 330 mg once-daily (21/28 schedule) for 9.5 months. She had previously been treated sequentially with paclitaxel and dacarbazine, but had not received a BRAF or MEK inhibitor. A heavily pretreated, platinum-refractory advanced epithelial ovarian cancer patient with PIK3CA amplification (with high polysomy and >60% of tumor cells harboring four copies of PIK3CA) and loss of PTEN achieved radiologic stable disease for 4 months with GCIG-CA125 partial response (Supplementary Fig. S3; ref. 13) associated with 36% reduction in SUVmax on 18F-FDG-PET and 56% reduction in tumor phospho-S6 expression. A patient with cKIT exon 9 mutant gastrointestinal stromal tumor but no evidence of PI3K pathway deregulation achieved stable disease for 7.5 months on pictilisib 450 mg once-daily, and this was associated with pharmacodynamic changes of 47% reduction in SUVmax on 18F-FDG-PET and 75% reduction in tumor phospho-S6 expression.

Of 60 patients, 12 (20%) remained on study for >3 months and 2 (3%) for >6 months. Supplementary Table S2 shows the pharmacokinetic–pharmacodynamic–clinical relationship of patients who demonstrated a partial response by RECIST, GCIG-CA125, or 18F-FDG-PET EORTC criteria.

In this first-in-human dose-escalation phase I study, we confirm the feasibility of safely inhibiting class I PI3K in patients with solid tumors. Pictilisib was well tolerated at doses shown here to modulate PI3K signaling in normal and tumor tissues, and demonstrated dose-proportional pharmacokinetics. The most common drug-related toxicities included grade 1–2 nausea, fatigue, diarrhea, vomiting, dysgeusia, and reduced appetite. The RP2D of oral pictilisib was 330 mg continuous once-daily dosing. DLT was grade 3 maculopapular rash occurring in 2 of 3 patients treated at 450 mg/day and 1 of 7 patients at 330 mg/day. Our data indicate that the severity of the rash was not clearly related to higher exposures of pictilisib (Supplementary Fig. S4) and resolved with discontinuation of pictilisib. The rash was maculopapular but not acneiform or blistering, did not show a predilection for sun-exposed areas, and was similar to the rash observed with other PI3K, AKT, and mTOR inhibitors, thereby pointing to a mechanism-based toxicity (14–16). Although this toxicity could be a potential pharmacodynamic biomarker of pictilisib, its underlying pathophysiology remains unclear and warrants further evaluation.

Our study design incorporated the use of the “Pharmacological Audit Trail” guidelines using appropriate pharmacokinetic–pharmacodynamic biomarkers (17, 18). The audit trail has been used by both academia (19) and industry (20) as a guideline to help answer critical “go/ no-go” decisions based on scientifically measurable and rigorous endpoints. This audit trail has utility in providing broad guidance for drug development, even though the same precise effects in preclinical models may not be exactly reproduced in patients, as demonstrated in this trial. The favorable preclinical PK properties of pictilisib were reproduced in this phase I trial (9). Preclinical pharmacokinetic–pharmacodynamic modeling based on MDA-MB-361, a human breast cancer xenograft with HER2 amplification and PIK3CA 1633G>A mutation, predicted the minimal target plasma AUC to be 6 μmol/L·h (3000 ng·h/mL) to achieve ≥90% tumor growth inhibition; this target AUC was achieved in most patients treated at doses >80 mg following 1 week of consecutive dosing and support the view that pictilisib is associated with biologically meaningful activity at these dose levels and exposures, especially at the RP2D. On the basis of these preclinical data, we additionally postulated that ≥90% inhibition of AKT phosphorylation is needed to inhibit cancer cell proliferation (9, 21). We demonstrate here a dose–response relationship between drug exposure and target modulation in normal tissue, with up to 90% decrease in AKT phosphorylation in PRP at up to 3 hours after dose at the RP2D. Although a direct correlation between pictilisib exposure and decrease in S6 and AKT phosphorylation in tumor is less clear, at the highest level of drug exposure [AUC >20 h·(μmol/L)] there was clear evidence of pharmacodynamic effect, with >75% decrease in S6 phosphorylation and 100% reduction in AKT phosphorylation in 2 of 3 patients. The lack of consistent target modulation in tumor at lower drug exposures contrasts with the consistent dose–response relationship in PRP and is possibly related to different assay conditions that likely favor greater inhibition in the latter, together with disparities in drug concentrations between normal and tumor tissues due to probable differences in tissue architecture and hemodynamics. Such differences highlight the complexity of accurately defining the pharmacokinetic–pharmacodynamic relationship of molecularly targeted drugs, along with additional important issues including extrapolation of preclinical models to predict effects in patients, interpatient variation due to host pharmacogenomic variation, intra- and interpatient tumor heterogeneity, and differences in analytic sensitivity/methodology in PRP versus tumor biopsies. All of these are likely to be important, highlighting the importance of evaluating different pharmacodynamic biomarkers to increase confidence in the overall pharmacologic effects of a drug within the audit trail framework, as we have done here.

To this end, at the RP2D of 330 mg, we demonstrate multimodal pharmacodynamic evidence of target modulation including the reduction of 18F-FDG-PET tracer uptake, inhibition of phospho-AKT in PRP and phospho-S6 in tumor tissue as well as increase in plasma glucose and insulin levels. These pharmacodynamic changes were observed regardless of molecular genetic status and from dose levels ≥100 mg.

PI3K signaling regulates insulin sensitivity, and hyperglycemia has been predicted to be a hallmark toxicity of PI3K inhibition (6, 22, 23). However, pictilisib-related hyperglycemia was limited to grade 1–2 elevations in this study with grade ≥3 hyperglycemia being observed in only 1 patient with an extrahepatic cholangiocarcinoma who had undergone a previous pancreatic resection and was commenced on a corticosteroid 2 days before the AE. We confirmed target and pathway modulation at the RP2D with observations of convincing pharmacodynamic changes in phospho-S6 and 18FDG-PET in tumor, and phospho-AKT, glucose and insulin in plasma. Nonetheless, it is possible that homeostatic mechanisms via negative feedback loops may cause drug resistance and account for the lack of more significant hyperglycemia.

The toxicity profile of pictilisib is in contrast to BKM120 (another pan-class I PI3K inhibitor) where rash, hyperglycemia, and mood alterations were the observed DLTs (15). Apart from rash, the latter two were not significant toxicities of pictilisib. One would not have expected such differences if these DLTs are mechanism-based toxicities, especially when the observed in vitro potency of pictilisib is higher than that of BKM120 (24). Pictilisib has a lower central nervous system (CNS) penetration than BKM120 while the targeted disruption of insulin signaling in the brain has been shown to lead to a diabetes mellitus phenotype (15, 25–28). It is likely that the marked hyperglycemia observed with BKM120 is due to the synergistic inhibition of PI3K signaling in peripheral tissues (e.g., muscle and adipose tissues) with noncanonical insulin-targeted tissues (including the brain), and the lack of CNS penetration may have enhanced the clinical therapeutic index of pictilisib relative to BKM120. The other pan-class I PI3K inhibitors that have undergone phase I clinical evaluation include SAR245408 and the irreversible wortmanin derivative PX-866 (29, 30). Both drugs were associated with minimal hyperglycemia but differences were observed in the frequency of rash, which occurred in 26% of patients treated with SAR245048 (all grades) and in none of the patients treated with PX-866. The importance of the therapeutic window of the pan-class I inhibitors with regards to their pharmacodynamic effect is critical, and in this respect our hypothesis that ≥90% inhibition of AKT phosphorylation is needed to inhibit cancer cell proliferation reveals potentially important differences between pictilisb and the other drugs in this class, with SAR245048 reporting a 40% to 80% reduction in tumor AKT phosphorylation, in comparison to pictilisib achieving 100% AKT inhibition in two patients at the MTD.

There is currently no validated predictive biomarker for PI3K pathway inhibitors. Somatic mutational sequencing and assessment of PTEN expression status were therefore undertaken. Our results highlight ongoing difficulties in the attempt to identify predictive biomarkers for pan-class I PI3K inhibitors, with no clear relationship between PI3K mutation/amplification or PTEN expression status and response to pictilisib (3). In this trial, PI3K pathway alterations were identified in 9 of 60 patients (15%), comprising 3 PTEN negative; 1 PTEN negative and PIK3CA amplification by FISH; and 5 PIK3CA mutations. Of these, none achieved a RECIST-based response and only 1 achieved a response by GCIG-CA125 criteria. This suggests the prediction of sensitivity may require more complex biomarker signatures rather than single mutational events (3, 21). In addition, an association between 18F-FDG-PET changes and RECIST response was not detected, in keeping with results from an earlier study of mTOR inhibitors (31).

We note the modest response rates in this trial and therefore, while we postulate that approximately 90% inhibition of AKT phosphorylation for several hours is needed to inhibit cancer cell proliferation based on our preclinical tumor phosphorylation data (9), the exact duration and magnitude to which the pathway should be inhibited remains unclear and more work is required to relate the extent of downstream phosphoprotein biomarker modulation to efficacy in patients. We also believe that important distinctions should be made between the utility of reduction in AKT phosphorylation as a pharmacodynamic and predictive biomarker of response. The best RECIST-responder in this study bore a BRAF V600E–mutant melanoma with no demonstrable PI3K mutation; she achieved a radiologic partial response by RECIST and remained on pictilisib for 9.5 months (she was not previously treated with a BRAF inhibitor and this was not therefore a withdrawal response). Responses to PI3K pathway inhibitors have been reported in BRAF-mutated cancer cell lines, including those without any known PI3K pathway aberration (32). Although these cancer cell lines are primarily dependent on RAS–RAF–MEK–ERK signaling for their proliferation, they are likely to have a degree of codependence on the PI3K–AKT pathway for their proliferation and survival, possibly explaining the response to pictilisib in this patient. In addition, there may be other activating effects in the PI3K pathway that we have been unable to assess that predispose to sensitivity including potential immunomodulatory effects given that T-cell receptor signaling involves the PI3K pathway (33).

An increasing understanding of potential resistance mechanisms (21) and promising preclinical data from combinatorial use of pictilisib (34–36) has led to clinical trials of pictilisib in combination with drugs including erlotinib, fulvestrant, trastuzumab emtansine (Kadcyla), GDC-0973 (a MEK inhibitor), paclitaxel, and chemotherapy regimens comprising paclitaxel/bevacizumab, carboplatin/paclitaxel/bevacizumab, and cisplatin/pemetrexed. Results from these ongoing studies are awaited.

In summary, pictilisib was safely tolerated at doses up to the RP2D which is 330 mg once-daily administered continuously. Displaying favorable pharmacokinetic properties, the plasma exposure levels achieved with ≥80 mg once-daily dosing were consistent with those associated with effective target modulation and antitumor activity predicted by preclinical in vivo pharmacokinetic-pharmacodynamic modeling. Analysis of pharmacodynamic biomarkers in peripheral blood and tumor tissue crucially provided evidence of significant PI3K pathway modulation at the RP2D. There is also evidence of clinical antitumor activity. Overall, these data provide strong support for the continued clinical evaluation of pictilisib.

J. de Bono is a consultant/advisory board member for AstraZeneca, Chugai, Genentech, Merck and Millennium, and Pfizer, and reports receiving a commercial research grant from Genentech. R. Baird is a consultant/advisory board member for, and reports receiving speakers' bureau honoraria and commercial research grants from Genentech. P. Clarke reports receiving commercial research grants from Astellas Pharma and Piramed Pharma. M.K. Derynck, J. Fredrickson, L. Friedman, M. Lackner, and J. Spoerke are employees of and have ownership interests (including patents) in Genentech. K. Mazina has ownership interests (including patents) in Genentech. J. Ware has ownership interests in Roche. P. Workman reports receiving a commercial research grant from Astellas Pharma and Piramed Pharma; has ownership interest in Chroma Therapeutics and Piramed Pharma; and is a consultant/advisory board member for Chroma Therapeutics, Nextech Invest, NuEvolution, Piramed Pharma, and Wilex. Note: P. Workman, P. Clarke, F. Raynaud, and J. de Bono are current employees of The Institute of Cancer Research, which has a commercial interest in the development of PI3K inhibitors, including pictilisib (GDC-0941), and operates a rewards-to-inventors scheme. D. Sarker, J.E. Ang, R. Baird, R. Kristeleit, K. Shah, V. Moreno and S. Kaye are previous employees of The Institute of Cancer Research and are not part of the rewards-to-inventors scheme for pictilisib. No other potential conflicts of interest were disclosed.

Conception and design: J.E. Ang, P.A. Clarke, G. Levy, K. Mazina, R. Lin, M.R. Lackner, S.B. Kaye, M.K. Derynck, P. Workman, J.S. de Bono

Development of methodology: J.E. Ang, P.A. Clarke, F.I. Raynaud, J.A. Ware, R. Lin, J. Wu, J.M. Spoerke, M.R. Lackner, Y. Yan, M.K. Derynck, P. Workman, J.S. de Bono

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): D. Sarker, J.E. Ang, R. Baird, R. Kristeleit, V. Moreno, G. Levy, J. Wu, Y. Yan, S.B. Kaye, M.K. Derynck, J.S. de Bono

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): D. Sarker, J.E. Ang, R. Kristeleit, V. Moreno, F.I. Raynaud, G. Levy, J.A. Ware, K. Mazina, R. Lin, J. Wu, J. Fredrickson, J.M. Spoerke, M.R. Lackner, Y. Yan, L.S. Friedman, M.K. Derynck, P. Workman, J.S. de Bono

Writing, review, and/or revision of the manuscript: D. Sarker, J.E. Ang, R. Baird, R. Kristeleit, K. Shah, V. Moreno, P.A. Clarke, F.I. Raynaud, G. Levy, J.A. Ware, K. Mazina, R. Lin, J. Fredrickson, J.M. Spoerke, M.R. Lackner, Y. Yan, L.S. Friedman, S.B. Kaye, M.K. Derynck, P. Workman, J.S. de Bono

Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): J.E. Ang, R. Baird, K. Shah, G. Levy, J.M. Spoerke, S.B. Kaye, M.K. Derynck, P. Workman, J.S. de Bono

Study supervision: D. Sarker, J.E. Ang, R. Baird, R. Kristeleit, G. Levy, K. Mazina, S.B. Kaye, M.K. Derynck, J.S. de Bono

Other (pharmacokinetic assessment of pictilisib (GDC-0941)): J.A. Ware

The authors thank the patients who participated in this study and their families.

This study was supported by Genentech Inc. The Drug Development Unit, The Royal Marsden NHS Foundation Trust, and The Institute of Cancer Research (London) are supported, in part, by program grants from Cancer Research UK. Support was also provided by Experimental Cancer Medicine Center grants (to The Institute of Cancer Research and the Cancer Research UK Center), the National Institute for Health Research Biomedical Research Center (jointly to The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research), and the Wellcome Trust (grant 090952/Z/09/Z to J.E. Ang).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1.
Vanhaesebroeck
B
,
Guillermet-Guibert
J
,
Graupera
M
,
Bilanges
M
. 
The emerging mechanisms of isoform-specific PI3K signalling
.
Nat Rev Mol Cell Biol
2010
;
11
:
329
41
.
2.
Engelman
JA
. 
Targeting PI3K signalling in cancer: opportunities, challenges and limitations
.
Nat Rev Cancer
2009
;
9
:
550
62
.
3.
Clarke
PA
,
Workman
P
. 
Phosphatidylinositide-3-kinase inhibitors: addressing questions of isoform selectivity and pharmacodynamic/predictive biomarkers in early clinical trials
.
J Clin Oncol
2012
;
30
:
331
3
.
4.
Huang
J
,
Manning
BD
. 
A complex interplay between Akt, TSC2 and the two mTOR complexes
.
Biochem Soc Trans
2009
;
37
:
217
22
.
5.
Sansal
I
,
Sellers
WR
. 
The biology and clinical relevance of the PTEN tumor suppressor pathway
.
J Clin Oncol
2004
;
22
:
2954
63
.
6.
Courtney
KD
,
Corcoran
RB
,
Engelman
JA
. 
The PI3K pathway as drug target in human cancer
.
J Clin Oncol
2010
;
28
:
1075
83
.
7.
Liu
P
,
Cheng
H
,
Roberts
TM
,
Zhao
JJ
. 
Targeting the phosphoinositide 3-kinase pathway in cancer
.
Nat Rev Drug Discov
2009
;
8
:
627
44
.
8.
Folkes
AJ
,
Ahmadi
K
,
Alderton
WK
,
Alix
S
,
Baker
SJ
,
Box
G
, et al
The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-t hieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer
.
J Med Chem
2008
;
51
:
5522
32
.
9.
Raynaud
FI
,
Eccles
SA
,
Patel
S
,
Alix
S
,
Baker
SJ
,
Box
G
, et al
Biological properties of potent inhibitors of class I phosphatidylinositide 3-kinases: from PI-103 through PI-540, PI-620 to the oral agent GDC-0941
.
Mol Cancer Ther
2009
;
8
:
1725
38
.
10.
Therasse
P
,
Arbuck
SG
,
Eisenhauer
EA
,
Wanders
J
,
Kaplan
RS
,
Rubinstein
L
, et al
New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada
.
J Natl Cancer Inst
2000
;
92
:
205
16
.
11.
Chanock
SJ
,
Burdett
L
,
Yeager
M
,
Llaca
V
,
Langerod
A
,
Presswalla
S
, et al
Somatic sequence alterations in twenty-one genes selected by expression profile analysis of breast carcinomas
.
Breast Cancer Res
2007
;
9
:
R5
.
12.
Reid
AH
,
Attard
G
,
Brewer
D
,
Miranda
S
,
Riisnaes
R
,
Clark
J
, et al
Novel, gross chromosomal alterations involving PTEN cooperate with allelic loss in prostate cancer
.
Mod Pathol
2012
;
25
:
902
10
.
13.
Rustin
GJ
,
Vergote
I
,
Eisenhauer
E
,
Pujade-Lauraine
E
,
Quinn
M
,
Thigpen
T
, et al
Definitions for response and progression in ovarian cancer clinical trials incorporating RECIST 1.1 and CA 125 agreed by the Gynecological Cancer Intergroup (GCIG)
.
Int J Gynecol Cancer
2011
;
21
:
419
23
.
14.
Rodon
J
,
Dienstmann
R
,
Serra
V
,
Tabernero
J
. 
Development of PI3K inhibitors: lessons learned from early clinical trials
.
Nat Rev Clin Oncol
2013
;
10
:
143
53
.
15.
Bendell
JC
,
Rodon
J
,
Burris
HA
,
de Jonge
M
,
Verweij
J
,
Birle
D
, et al
Phase I, dose-escalation study of BKM120, an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors
.
J Clin Oncol
2012
;
30
:
282
90
.
16.
Yap
TA
,
Yan
L
,
Patnaik
A
,
Fearen
I
,
Olmos
D
,
Papadopoulos
K
, et al
First-in-man clinical trial of the oral pan-AKT inhibitor MK-2206 in patients with advanced solid tumors
.
J Clin Oncol
2011
;
29
:
4688
95
.
17.
Workman
P
. 
How much gets there and what does it do?: the need for better pharmacokinetic and pharmacodynamic endpoints in contemporary drug discovery and development
.
Curr Pharm Des
2003
;
9
:
891
902
.
18.
Yap
TA
,
Sandhu
SK
,
Workman
P
,
de Bono
JS
. 
Envisioning the future of early anticancer drug development
.
Nat Rev Cancer
2010
;
10
:
514
23
.
19.
Dean
E
,
Greystoke
A
,
Ranson
M
,
Dive
C
. 
Biomarkers of cell death applicable to early clinical trials
.
Exp Cell Res
2012
;
318
:
1252
9
.
20.
Hait
WN
. 
Forty years of Translational Cancer Research
.
Cancer Discov
2011
;
1
:
383
390
.
21.
Workman
P
,
Clarke
PA
,
Raynaud
FI
,
van Montfort
RL
. 
Drugging the PI3 kinome: from chemical tools to drugs in the clinic
.
Cancer Res
2010
;
70
:
2146
57
.
22.
Powis
G
,
Ihle
N
,
Kirkpatrick
DL
. 
Practicalities of drugging the phosphatidylinositol-3-kinase/Akt cell survival signaling pathway
.
Clin Cancer Res
2006
;
12
:
2964
6
.
23.
Foukas
LC
,
Claret
M
,
Pearce
W
,
Okkenhaug
K
,
Meek
S
,
Peskett
E
, et al
Critical role for the p110alpha phosphoinositide-3-OH kinase in growth and metabolic regulation
.
Nature
2006
;
441
:
366
70
.
24.
Brachmann
SM
,
Kleylein-Sohn
J
,
Gaulis
S
,
Kauffmann
A
,
Blommers
MJ
,
Kazic-Legeux
M
, et al
Characterization of the mechanism of action of the pan class I PI3K inhibitor NVP-BKM120 across a broad range of concentrations
.
Mol Cancer Ther
2012
;
11
:
1747
57
.
25.
Salphati
L
,
Lee
LB
,
Pang
J
,
Plise
EG
,
Zhang
X
. 
Role of P-glycoprotein and breast cancer resistance protein-1 in the brain penetration and brain pharmacodynamic activity of the novel phosphatidylinositol 3-kinase inhibitor GDC-0941
.
Drug Metab Dispos
2010
;
38
:
1422
6
.
26.
Bruning
JC
,
Gautam
D
,
Burks
DJ
,
Gilette
J
,
Schubert
M
,
Orban
PC
, et al
Role of brain insulin receptor in control of body weight and reproduction
.
Science
2000
;
289
:
2122
5
.
27.
Okamoto
H
,
Nakae
J
,
Kitamura
T
,
Park
BC
,
Dragastis
I
,
Accili
D
. 
Transgenic rescue of insulin receptor-deficient mice
.
J Clin Invest
2004
;
114
:
214
23
.
28.
Obici
S
,
Zhang
BB
,
Karkanias
G
,
Rossetti
L
. 
Hypothalamic insulin signaling is required for inhibition of glucose production
.
Nat Med
2002
;
8
:
1376
82
.
29.
Shapiro
GI
,
Rodon
J
,
Bedell
C
,
Kwak
EL
,
Baselga
J
,
Brana
I
, et al
Phase I safety, pharmacokinetic, and pharmacodynamic study of SAR245408 (XL147), an oral pan-class I PI3K inhibitor, in patients with advanced solid tumors
.
Clin Cancer Res
2014
20
:
233
45
.
30.
Hong
DS
,
Bowles
DW
,
Falchook
GS
,
Messersmith
WA
,
George
GC
,
O'Bryant
CL
, et al
A multicenter phase I trial of PX-866, an oral irreversible phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors
.
Clin Cancer Res
2012
;
18
:
4173
82
.
31.
Ma
WW
,
Jacene
H
,
Song
D
,
Vilardelli
F
,
Messersmith
WA
,
Laheru
D
, et al
[18F]fluorodeoxyglucose positron emission tomography correlates with Akt pathway activity but is not predictive of clinical outcome during mTOR inhibitor therapy
.
J Clin Oncol
2009
;
27
:
2697
704
.
32.
Lassen
A
,
Atefi
M
,
Robert
L
,
Wong
DJ
,
Cerniglia
M
,
Comin-Anduix
B
, et al
Effects of AKT inhibitor therapy in response and resistance to BRAF inhibition in melanoma
.
Mol Cancer
2014
;
13
:
83
.
33.
Ali
K
,
Soond
DR
,
Piñeiro
R
,
Hagemann
T
,
Pearce
W
,
Lim
EL
,
Bouabe
H
, et al
Inactivation of PI(3)K p110δ breaks regulatory T-cell-mediated immune tolerance to cancer
.
Nature
2014
;
510
:
407
11
.
34.
Junttila
TT
,
Akita
RW
,
Parsons
K
,
Fields
C
,
Lewis Phillips
GD
,
Friedman
LS
, et al
Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941
.
Cancer Cell
2009
;
15
:
429
40
.
35.
Hoeflich
KP
,
O'Brien
C
,
Boyd
Z
,
Cavet
G
,
Guerroero
S
,
Jung
K
, et al
In vivo antitumor activity of MEK and phosphatidylinositol 3-kinase inhibitors in basal-like breast cancer models
.
Clin Cancer Res
2009
;
15
:
4649
64
.
36.
Yao
E
,
Zhou
W
,
Lee-Hoeflich
ST
,
Truong
T
,
Haverty
PM
,
Eastham-Anderson
J
, et al
Suppression of HER2/HER3-mediated growth of breast cancer cells with combinations of GDC-0941 PI3K inhibitor, trastuzumab, and pertuzumab
.
Clin Cancer Res
2009
;
15
:
4147
56
.