title: phase i safety, pharmacokinetic and pharmacodynamic · 2/28/2014 · author manuscript...

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Title: Phase I safety, pharmacokinetic and pharmacodynamic

study of SAR245409 (XL765), a novel, orally

administered PI3K/mTOR inhibitor in patients with

advanced solid tumors

Authors: Kyriakos P Papadopoulos1, Josep Tabernero2, Ben

Markman2,3, Amita Patnaik1, Anthony W Tolcher1, José

Baselga4, Weiliang Shi5, Coumaran Egile6, Rodrigo Ruiz-

Soto5, A Douglas Laird7, Dale Miles7, Patricia M.

LoRusso8

1South Texas Accelerated Research Therapeutics, San

Antonio, TX, USA; 2Vall d’Hebron University Hospital and

Institute of Oncology (VHIO), Universitat Autònoma de

Barcelona, Barcelona, Spain; 3Monash Institute of

Medical Research, Monash University, Melbourne,

Victoria, Australia; 4Memorial Sloan-Kettering Cancer

Center, Memorial Hospital, New York, NY, USA; 5Sanofi,

Cambridge, MA, USA; 6Sanofi, Vitry-sur-Seine, France;

7Exelixis Inc., South San Francisco, CA, USA; 8Karmanos

Cancer Institute, Wayne State University School of

Medicine, Detroit, MI, USA

Running head: Phase I study of SAR245409 in pts with advanced solid

tumors

Research. on August 28, 2021. © 2014 American Association for Cancerclincancerres.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 28, 2014; DOI: 10.1158/1078-0432.CCR-13-2403

http://clincancerres.aacrjournals.org/

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Keywords: PI3K, mTOR, pharmacokinetics,

pharmacodynamics, advanced solid tumor

Financial support: This study was funded by Sanofi and Exelixis.

Corresponding author: Kyriakos P Papadopoulos

South Texas Accelerated Research Therapeutics

4383 Medical Drive

San Antonio, TX 78229, USA

[email protected]

Tel: 210 593 5250

Fax: 210 615 1121

Conflicts of interest:

ADL and DM are employees of Exelixis Inc.; ADL and DM

hold stocks and shares in Exelixis Inc. CE, RRS and WS

are employees of Sanofi; RRS holds stocks and shares in

Sanofi. AP declares research funding from Sanofi. JT

declares honoraria from speaker bureaus from Amgen,

Merck, KGaA, Novartis, Roche and Sanofi. JT declares a

consultant/advisory board role with Amgen, Boehringer,

Bristol-Myers Squibb, Genetech, Imclone, Lilly and

Merck. KPP, AWT, PL, JB and BM have no conflicts

relating to this manuscript to declare.

Note: Presented in part at the annual meeting of the American

Society of Clinical Oncology (ASCO) June 2009 and




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2010, Chicago, IL, USA and at the AACR-NCI-EORTC

International Conference on Molecular Targets and

Cancer Therapeutics: Discovery, Biology, and Clinical

Applications, October 21–24, 2008, Geneva, Switzerland.

Word count (excluding references): 3,263

Tables and figures: 6

Supplementary files: 8




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Translational relevance

Molecular alterations in the PI3K pathway are frequently observed in human

cancer and have been implicated in resistance to anticancer therapies. In this

regard PI3K has been established as a valid target for anticancer therapy and

several PI3K inhibitors are under clinical evaluation. However, agents that

inhibit both PI3K and mTOR are able to suppress mTORC1 and mTORC2

downstream of PI3K, which may result in more complete pathway inhibition

and attenuation of PI3K activation triggered by inhibition of mTOR-dependent

negative-feedback mechanisms.

This paper reports the results of a first-in-human study of SAR245409

(XL765), a specific pan-Class I PI3K inhibitor and mTORC1/mTORC2

inhibitor, in patients with advanced tumors. PI3K and mTORC1/mTORC2

pathway inhibition by SAR245409 was observed in serial hair sheath cells,

skin and tumor tissue. Preliminary evidence of antitumor activity and a

manageable toxicity profile supports further development of SAR245409 as

monotherapy or in combination with other agents.




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Abstract

Purpose

This phase I, first-in-human study evaluated the safety, maximum tolerated

dose (MTD), pharmacokinetics (PK), pharmacodynamics and preliminary

efficacy of SAR245409, an inhibitor of pan-Class I PI3K and mTOR,

administered orally once or twice daily in patients with advanced solid tumors.

Patients and Methods

Eighty-three patients received SAR245409. Doses ranged from 15–120 mg

twice daily, and 70–100 mg once daily. A 3+3 dose-escalation design was

used to determine the MTD. Patients were evaluated for adverse events (AEs)

and response. Assessments included PK, pharmacodynamic impact of

SAR245409 on PI3K pathway signaling in hair sheath cells, skin and tumor,

and characterization of tumor molecular alterations.

Results

The MTDs were 50 mg twice daily and 90 mg once daily. The most frequent

treatment-related AEs were nausea (36.1%), diarrhea (21.7%), vomiting

(19.3%) and decreased appetite (16.9%). The most frequent treatment-related

grade 3/4 AEs were increases in alanine aminotransferase (6.0%) and

aspartate aminotransferase (4.8%). SAR245409 had a relatively short plasma

half-life (2.96–7.52 hours). At MTDs, once- and twice-daily regimens yielded

similar mean steady-state plasma exposure. A reduction in PI3K and

mTORC1/mTORC2 pathway signaling was observed in serial hair sheath

cells, skin and tumor samples. Best response was stable disease (SD) in 48%

of evaluable patients; seven patients had minor tumor regression. Twelve




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patients with SD were treated for ≥16 weeks. No trend was observed

correlating tumor molecular alteration with antitumor activity.

Conclusion

SAR245409 had a manageable safety profile, demonstrated reduced PI3K

and mTORC1/mTORC2 pathway signaling and was associated with clinically

relevant SD.




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Introduction

Phosphatidylinositol-3-kinase (PI3K) signaling is involved in essential cellular

functions including cell metabolism, growth, survival and motility (1). Molecular

alterations in components of the PI3K pathway are frequently observed in

human cancers. These include gain-of-function mutations or amplifications of

oncogenes and loss or downregulation of negative regulators of the pathway

(2–4). Alterations in the PI3K pathway are implicated in resistance to receptor

tyrosine kinase antagonists/inhibitors (5) and a number of cytotoxic anticancer

therapies (6, 7). Therefore, treatment with PI3K inhibitors as single agents

may reduce tumor cell proliferation and possibly promote tumor cell death,

while their use in combination with other anticancer therapies may sensitize

cancer cells to such therapies (6–8).

Inhibitors of the PI3K pathway in clinical development include agents targeting

PI3K (either pan-Class I or isoform-specific inhibitors), AKT, mammalian

target of rapamycin (mTOR), and molecules with multiple targets such as dual

PI3K/mTOR inhibitors (9, 10). Dual PI3K/mTOR inhibitors are able to

suppress the mTORC1 and mTORC2 protein complexes downstream of PI3K,

resulting in more complete pathway inhibition, and should attenuate PI3K

activation triggered by inhibition of mTOR-dependent negative-feedback

mechanisms (1, 11).

SAR245409 (XL765; Sanofi, Bridgewater, NJ, USA) is a pyridopyrimidinone-

derivative, highly selective, potent ATP-competitive, reversible pan-Class I

PI3K inhibitor and mTORC1/mTORC2 inhibitor (Yu, P et al. Manuscript




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submitted for publication) (9, 12). SAR245409 inhibits the phosphorylation of

multiple PI3K/phosphatase and tensin homolog (PTEN) pathway proteins

(AKT, p70S6K and S6) in cell lines in vitro and in human xenograft tumor

tissue (13). The pharmacodynamic activity of SAR245409 is associated with

inhibition of tumor cell proliferation, inhibition of tumor angiogenesis and

induction of apoptosis in xenograft tumors, which results in substantial tumor

growth inhibition in multiple human tumor models (9, 13).

In preclinical toxicology studies for up to 6 months in rats and dogs, findings of

potential clinical relevance included reversible toxicity to the hematopoietic

tissues, gastrointestinal tract and liver. In a 6-month study in rats, possible

SAR245409-related ophthalmologic findings included focal cataracts in both

eyes of two rats (2%), with a correlative microscopic finding of unilateral

lenticular degeneration in one animal (data on file). Based on preclinical data,

the potential for SAR245409 to affect the QTc interval and cause torsade de

pointes appeared to be low. In vivo results from rat and dog demonstrated that

the major circulating metabolite was a glucuronide of a hydroxylated

SAR245409.

The primary objective of this phase I, first-in-human study (NCT00485719)

was to evaluate the safety and tolerability and to determine the maximum

tolerated dose (MTD) of SAR245409 administered orally once or twice daily in

fasting patients with solid tumors. Secondary objectives included evaluation of

pharmacokinetics (PK), pharmacodynamic impact and preliminary efficacy




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data. Pharmacodynamic impact on the PI3K pathway was explored using

plasma biomarkers, hair sheath cells, skin and tumor tissue.




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Patients and Methods

Study population

Eligible patients were aged ≥18 years, with histologically confirmed metastatic

or unresectable solid tumors, Eastern Cooperative Oncology Group (ECOG)

performance status ≤2 and adequate hematologic and organ function.

Additional requirements were fasting plasma glucose <160 mg/dL and

glycosylated hemoglobin <8%. Patients were excluded if they had received

prior treatment with a PI3K inhibitor. Patients with brain metastases were

considered eligible if they had not received radiation therapy within 2 weeks of

enrollment and had been on a stable dose of steroids for ≥2 weeks.

The protocol was approved by all relevant Independent Ethics Committees

and Institutional Review Boards, and complied with the recommendations of

the Helsinki Declaration. Informed consent was obtained from each patient

prior to any study-related procedure.

Study design

This multicenter, phase I, non-randomized, open-label, first-in-human study

evaluated SAR245409 as a single agent in patients with solid tumors. Two

oral dosing regimens, continuous once- and twice-daily administration of

SAR245409 capsules for 28-day cycles, were investigated sequentially.

Patients fasted for 2 hours before and 1 hour after each dose of SAR245409.

A standard 3+3 dose-escalation design was employed to determine the MTD

for each dose schedule, with starting doses of 15 mg twice daily, based on




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preclinical in vivo studies, and 100 mg once daily. The starting dose for the

once-daily dosing schedule was based on the preliminary MTD determined for

the preceding twice-daily dosing schedule. The preliminary MTD for each

dose schedule was defined as the highest dose level in which ≤1 in 6 patients

experienced a dose-limiting toxicity (DLT), based on drug-related toxicities

that occurred during cycle 1; at subsequent cycles, cumulative toxicity

observed at lower doses and adverse events (AEs) in all patients enrolled

were taken into consideration in assigning the final MTD and recommended

phase II dose. A DLT was defined as any National Cancer Institute Common

Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0 (14) grade

≥3 hematologic or non-hematologic toxicity, or any toxicity requiring dose

reduction/discontinuation, including grade ≥3 hyperglycemia despite treatment

with an oral hypoglycemic at standard doses and grade ≥3 nausea, vomiting

and diarrhea despite adequate management.

Once the preliminary MTD was determined for each schedule, an additional

9–15 patients with selected solid tumors considered likely to harbor PI3K

pathway alterations, or patients with tumors with documented molecular

alterations affecting the PI3K pathway, were enrolled into the expanded MTD

cohorts.

Safety assessments

Safety evaluations were performed at baseline, days 1, 8, 15, 22, 27 and

28/29 of cycle 1, days 1, 8, 15, 22 and 23 of cycle 2, weekly in cycle 3 and bi-

weekly thereafter. Variables included clinical findings, AEs, electrocardiogram




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(ECG), vital signs and laboratory assessments. Ophthalmic evaluation was

performed at baseline and at day 1 of cycles 2 and 4, and every three

subsequent cycles.

Pharmacokinetic assessments

Blood samples for PK analyses were collected pre-dose and 0.25, 0.5, 1, 2, 3,

4, 6, 8, approximately 10–12 hours, and 24 hours post-morning dose on day 1

and 27 of cycle 1, and on day 22 of cycle 2. Single pre-dose and 2-hour post-

morning dose samples were taken on additional days (see Supplementary

Material). To investigate drug washout, no doses were given following the

morning dose on day 27 of cycle 1 and PK samples were taken at 24 and 48

hours post-dose prior to cycle 2. Plasma concentrations of SAR245409 were

measured using a validated liquid chromatography/tandem mass

spectrometry (LC-MS/MS) method. Non-compartmental PK analysis and

calculation of descriptive statistics were performed using WinNonlin

Professional 5.2 (Pharsight Corp., Mountain View, CA, USA). PK plasma

concentrations and PK parameters were based on measured free-base

SAR245409 whereas doses were expressed as the amount of SAR245409

HCl salt for this capsule formulation (e.g. a 50 mg dose contains 44 mg of

SAR245409 free-base). The amount and percentage of SAR245409 excreted

unchanged in urine were also determined (see Supplementary Methods).

Pharmacodynamic assessments

The pharmacodynamic effects of SAR245409 were explored using plasma

biomarkers, hair sheath cells, skin and tumor tissue collected at pre-specified

time points. In addition, archival and/or freshly collected tumor tissues from




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patients were subjected to molecular profiling for alterations in genes

encoding PI3K pathway components and/or modulators. Additional tumor

molecular alteration data were provided by the trial sites (See Supplementary

Materials for pharmacodynamic methods).

Efficacy measurements

Tumor response was assessed using the Response Evaluation Criteria in

Solid Tumors (RECIST v1.0) (15). Patients with measurable lesions were

assessed using computed tomography scan at baseline and approximately

every 8 weeks.

Statistical analysis

Continuous and categorical data were summarized with descriptive statistics

or frequencies and percentages, respectively. The safety population included

all patients who received at least one dose of study drug; the .efficacy

population included all patients in the safety population with a baseline

assessment and at least one post-baseline tumor assessment.




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Results

Patient population

A total of 83 patients were enrolled between June 6, 2007 and July 15, 2010.

Of these, 52 patients received SAR245409 orally twice daily (15 mg, 30 mg,

50 mg, 60 mg and 120 mg twice-daily cohorts) and 31 received treatment

once daily (70 mg, 90 mg and 100 mg once-daily cohorts). Patient

demographics are summarized in Table 1. All patients discontinued treatment;

61 (73.5%) had disease progression, 11 (13.3%) had an AE requiring

discontinuation, 9 (10.8%) withdrew consent, one (1.2%) discontinued due to

investigator decision and one (1.2%) died. The median duration of exposure

for all patients was 41.0 days (range: 4–371 days).

Dose-limiting toxicities and maximum tolerated dose

DLTs occurred in six patients. With twice-daily dosing, dose escalation from

15 mg (n=3) to 30 mg (n=3), 60 mg (n=3) and 120 mg (n=4) proceeded

without DLT. One patient receiving 120 mg developed grade 3 liver enzyme

elevation during cycle 2, prompting expansion to three additional patients at

this dose level. One of these patients experienced a DLT of grade 3

decreased appetite and hypophosphatemia, and two patients developed

grade 3 liver enzyme elevation during cycle 2. Consequently, the 60 mg dose

level was expanded, with no DLT in three additional patients. With further

safety expansion at this dose level in four patients, there was one DLT of

intolerable grade 2 pruritic rash and one patient developed grade 2 liver

enzyme elevation in cycle 2 requiring dose interruption. An intermediate dose

of 50 mg was tested in eight patients, without occurrence of DLT. A further 17




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patients were treated at 50 mg, two of whom developed grade ≥2 liver

enzyme elevation in cycle 2. Four additional patients with tumor genetic

alterations of the PI3K pathway were permitted to enroll at a dose level one

lower than the MTD (30 mg); none experienced DLT or grade >2 AEs.

Although most cases of treatment-related liver function abnormalities did not

meet DLT criteria and often occurred after cycle 1, concerns existed that liver

toxicity would be cumulative and therefore limit dosing at and above the 60

mg twice-daily dose level. Thus 50 mg was declared the MTD for twice-daily

dosing.

With once-daily dosing, 2 of 7 patients treated at 100 mg had DLTs of grade 3

rash and grade 2 dyskinesia. Dose de-escalation to 70 mg in five patients

showed no DLTs. A dose of 90 mg once daily was next explored: no DLTs

occurred in six patients and the cohort was expanded to include an additional

13 patients. There was one DLT each of grade 3 rash and grade 3 ECG

abnormalities (asymptomatic T-wave inversion without cardiac sequelae). The

90 mg dose was declared the MTD for the once-daily dosing schedule.

Dose delays or reductions related to AEs occurred in 7 of 25 patients in the 50

mg twice-daily cohort and 7 of 19 patients in the 90 mg once-daily cohort.

Safety and tolerability

All 83 patients were evaluable for safety and all experienced ≥1 AE; the most

frequently reported AEs regardless of causality are shown in Supplementary

Tables 1 and 2. Sixty-one (73.5%) patients had ≥1 AE considered related or




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possibly related to study treatment; the most frequently reported treatment-

related AEs were nausea (36.1%), diarrhea (21.7%), vomiting (19.3%) and

decreased appetite (16.9%) (Table 2). Gastrointestinal events occurred less

frequently in the 50 mg twice-daily cohort than in the 90 mg once-daily cohort

(nausea 16.0% vs 47.4%; diarrhea 12.0% vs 31.6%; vomiting 12.0% vs

31.6%), but differences were not clinically meaningful overall.

The most common treatment-related grade 3/4 AEs, occurring in five patients,

were reversible increases in alanine aminotransferase (ALT; 6.0%) and

aspartate aminotransferase (AST; 4.8%) (Table 2). A total of 16 (19.3%)

patients experienced at least one incidence of elevated liver enzymes due to

SAR245409.

Treatment-related skin events, most commonly rash and dry skin, were

experienced by 10 (12.0%) patients, of which two (2.4%) had a grade 3/4

event. Rashes were most commonly pruritic and/or maculopapular.

Treatment-related ocular AEs were experienced by four (4.8%) patients;

cataracts occurred in three (3.6%) patients and grade 1 reversible decreased

visual acuity in one patient. Drug attribution for cataracts was based on

preclinical findings of focal cataracts following prolonged exposure to

SAR245409. Consistent with preclinical data, no patients experienced QTcF

prolongation.




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Grade 1/2 hyperglycemia was reported as an AE in 11 (13.3%) patients with

no apparent dose effect; only one of these events was treatment-related. No

patient had grade ≥3 hyperglycemia.

A total of 11 (13.3%) patients discontinued treatment due to an AE, most

commonly due to increases in the liver enzymes AST and ALT, each in three

(3.6%) patients. Two (2.4%) patients discontinued due to rash.

Six treatment-related serious AEs (diarrhea [grade 2], oral mucosa erythema

[grade 3], rash generalized [grade 3], ALT increased [grade 4], AST increased

[grade 4] and ECG abnormal T-wave inversion [grade 3]) occurred in four

(4.8%) patients. Ten patients died during the study, nine due to disease

progression and one of stroke; no deaths were attributed to SAR245409.

Pharmacokinetic analysis

The median time to maximum plasma concentration (tmax) of SAR245409

ranged from 1–4 hours, and the geometric mean terminal half-lives ranged

from 2.96 to 7.52 hours (Table 3; Supplementary Figure 1). Neither parameter

showed a clear dependence on dosing regimen or dose level. Steady state

was achieved by day 8. At day 27, the 90 mg once-daily and 50 mg twice-

daily regimens showed approximately 1.1-fold and 2.6-fold accumulation of

SAR245409 in plasma, respectively. The majority of SAR245409 was cleared

from plasma over the dosing interval (12 or 24 hours); geometric mean values

of the minimum observed plasma concentration (Cmin) on day 27 were 3.3%




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and 5.4% of the maximum observed plasma concentration (Cmax) for the 90

mg once-daily and 50 mg twice-daily regimens, respectively.

Exposure following single and repeated doses of SAR245409 was variable

between patients; the CV% for the 50 mg twice-daily and 90 mg once-daily

dose groups ranged from 76% to 91% for the area under the plasma

concentration–time curve (AUC). Because of this interpatient variability, dose

proportionality could not be definitively established, although a non-statistically

significant trend toward a less than dose-proportional increase in plasma

exposure was observed. Likewise, a non-statistically significant trend toward a

higher steady-state plasma Cmin (~1.8-fold) was seen for the twice-daily

regimen. The percentage of the SAR245409 dose excreted unchanged in

urine was low and independent of dose (<1%; data not shown).

Pharmacodynamic analysis

A significant augmentation in plasma insulin was observed at 4 hours post-

dose on days 1, 8 and 27/28, coinciding with the end of fasting. In contrast

with day 1, at the 2-hour time point on days 8 and 27/28, insulin levels were

modestly but significantly elevated over baseline, suggesting hyperinsulinemia

(Supplementary Figure 2A). A minimal increase in plasma glucose was

observed, which was transient and reversible with no evidence of

hyperglycemia (Supplementary Figure 2B). No consistent modulation of

vascular endothelial growth factor-A (VEGF-A), insulin-like growth factor

binding protein-2 (IGFBP-2) or regulated and normal T-cell expressed and

secreted (RANTES) levels was observed (data not shown).




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During dose escalation, limited surrogate tissue analyses were performed to

confirm pharmacodynamic activity, with a focus on tumor pharmacodynamics

at MTD. Four sets of serial hair sheath cells and 12 sets of serial skin biopsies

were analyzed (see Supplementary Materials) and time-dependent inhibition

of PI3K and mTORC1/mTORC2 pathways was evident (Figure 1). Pathway

inhibition on day 27–29 reached 53–90% in hair sheath cells (in four patients

receiving SAR245409 15, 60 and 120 mg twice daily) and 42–92% in skin

biopsies (in 12 patients receiving SAR245409 50, 60 and 120 mg twice daily

and 70 and 100 mg once daily).

Paired baseline and day 27/28 tumor biopsies were collected from 12 patients

receiving either the twice-daily MTD of 50 mg (n=6), the once-daily MTD of 90

mg (n=5), or 60 mg twice daily (n=1). Inhibition of PI3K and

mTORC1/mTORC2 pathways in tumor was evident in 11 patients, with

reductions of 45–88% for pAKTT308, 45–94% for pAKTS473 and 55–89% for

p4EBP1T70 at day 27/28 compared with baseline (Figure 2 and Supplementary

Table 3). A moderate (20–53%) post-dose reduction in the proliferation

marker Ki67 in tumor was evident for nine patients. However, a more

pronounced reduction in tumor Ki67 was observed for a patient with PTEN-

deficient chondrosarcoma and a patient with breast cancer with an AKT1

mutation (96% and 68% reduction, respectively). Changes in the apoptotic

marker TUNEL were minimal, suggesting that the effect of SAR245409 as

monotherapy in patients with solid tumors is primarily anti-proliferative, not

pro-apoptotic. In addition, SAR245409 had an impact on tumor extracellular-

signal-regulated kinase (ERK) with reductions in pERKT202/Y204 (42–88%) and




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phosphorylated mitogen-activated protein kinase kinase (pMEK)S217/S221 (45–

62%) (Figure 2, Supplementary Figure 3 and Supplementary Table 3). As

surrogate tissue analyses were generally limited to the dose-escalation phase,

tumor/surrogate tissue comparisons were not possible.

Of the 12 tumors assessed, six had no detectable molecular abnormalities

leading to PI3K/mTOR pathway activation, whereas one patient with

chondrosarcoma, one patient with colorectal mucinous tumor and three

patients with breast cancer exhibited either PI3K catalytic subunit alpha

(PIK3CA) mutation, AKT1 mutation, PTEN deficiency or HER2 amplification.

Hence, pharmacodynamic modulation and impact on cell proliferation was not

confined to tumors with molecular alterations predicted to result in PI3K

pathway activation (Supplementary Table 3). The lack of pathway inhibition

observed in the patient with BRAF-mutant/PTEN-deficient colorectal cancer

may reflect constitutive activation of both the PI3K and ERK pathways.

Efficacy

The best overall response was stable disease (SD), occurring in 24 out of 50

evaluable patients (48%), with seven patients showing some evidence of

tumor regression (Figure 3). Of these 24 patients, 15 received the twice-daily

schedule and nine received the once-daily schedule. Twelve patients (24%)

had documented SD and were treated for ≥16 weeks. Three patients with

KRAS-mutant tumors remained on study for 24–33 weeks. Overall, no

correlation between molecular alterations and clinical outcomes was

observed. However, consistent with observed pathway inhibition and




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decreased tumor cell proliferation, improvement in skin lesions was noted in a

patient with AKT1-mutant ductal breast carcinoma following initiation of

SAR245409 (Supplementary Figure 4).




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Discussion

This phase I, first-in-human, dose-escalation study of the orally administered

pan-Class I PI3K and mTOR inhibitor SAR245409 in patients with advanced

solid tumors determined the MTD, and recommended doses for phase II

development, to be 50 mg for the twice-daily and 90 mg for the once-daily

dosing schedules.

The safety profile of SAR245409, with the exception of hyperglycemia, was

comparable to other PI3K inhibitors in clinical development, for which fatigue,

gastrointestinal and cutaneous AEs, and biochemical changes such as liver

enzyme abnormalities and hyperglycemia have been commonly reported (16–

20). Overall, the incidence of AEs did not differ markedly between once-daily

and twice-daily dose cohorts at the MTDs. Drug-related increases in liver

enzymes were frequently observed, but were reversible with dose reduction or

discontinuation. Efficacy was an exploratory objective in the study; best

overall response of SD was achieved in 48% of patients, which is consistent

with responses in phase I studies of other oral PI3K and PI3K/mTOR

inhibitors in solid tumors (16–18, 20). Interestingly, prolonged objective

responses with SAR245409 50 mg twice daily were observed in patients with

relapsed lymphoma (ongoing complete response of over 125 weeks in a

patient with transformed lymphoma, and partial responses in a patient with

diffuse large B-cell lymphoma and a patient with mantle cell lymphoma of 15

weeks and 111 weeks respectively) (21).




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SAR245409 had a relatively short plasma terminal half-life with no clear dose

dependence. At the MTD, once-daily and twice-daily regimens appeared to

yield similar average plasma exposures at steady state within the context of

interpatient variability. Due to interpatient variability in exposure, a definitive

assessment of dose proportionality could not be conducted.

Novel immunofluorescence staining protocols with pixel- and intensity-based

quantitative readouts were developed to investigate pathway modulation by

SAR245409. PI3K and mTORC1/mTORC2 pathway inhibition was observed

in serial hair sheath cells and skin (below MTD), and in tumor tissue (at MTD).

In skin and tumor tissue, similar degrees of pathway inhibition were observed

with once-daily and twice-daily regimens. Whether more complete pathway

inhibition might translate into improved single-agent efficacy in solid tumor

patients is conjectural. Of note, comparable depth of PI3K/mTOR pathway

inhibition (−60% to −88%) in tumor samples from a mantle cell lymphoma

patient treated with the twice-daily MTD of 50 mg was sufficient to block cell

proliferation and demonstrate a partial response following two cycles of

treatment (21). Similar levels of pathway inhibition were observed in

glioblastoma tumor tissue using quantitative immunochemistry (22).

Although SAR245409 has no direct inhibitory activity on ERK pathway

enzymes (Yu P, et al. Manuscript submitted for publication), a reduction in

ERK signaling in tumor tissues was observed at tolerated doses. The

mechanism underlying this modulation of the RAS/ERK pathway in tumor

tissue is unclear, but may reflect diminished cross-talk between the PI3K and




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RAS/ERK pathways, or changes in tumor biology secondary to PI3K pathway

inhibition. The reduction in tumor pERK associated with SAR245409

administration contrasts with the increase in tumor pERK associated with

administration of the rapamycin analog everolimus (23). Prolonged SD

observed in three patients with KRAS-mutant colorectal cancer suggests

attenuation of the effect of upstream hyperactivated RAS (24).

Importantly, effects on PI3K pathway signaling and on proliferation were not

confined to tumors exhibiting molecular alterations in the PI3K pathway.

Based on the limited characterization performed, no correlation between

molecular alterations and clinical outcome was identified, perhaps reflecting

the diverse phase I population, the multiple doses administered, and the

modest degree of clinical benefit evident in solid tumor patients. Similar

results were reported in a phase I trial of the PI3K inhibitor BKM120 (Novartis

Pharma AG, Basel, Switzerland) (17). Identification of predictive biomarkers

for patient selection, elucidation of optimal depth and duration of target

inhibition, and rational drug combinations will help maximize the antitumor

potential of this class of agents. Exploration of predictive biomarkers of

response to SAR245409 in archival tumor tissue and in circulating tumor DNA

is ongoing in phase II studies in solid tumors and in relapsed or refractory

lymphoma. In addition, the relationship of SAR245409 exposure to glucose

homeostasis is being further explored in ongoing phase II studies.

In summary, this phase I, first-in-human study demonstrated a favorable

safety profile, promising pharmacodynamic effects and preliminary antitumor




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activity of SAR245409 in patients with advanced solid tumors, supporting its

further development. Rational combination studies of SAR245409 with other

targeted and cytotoxic agents are ongoing or completed, including with the

MEK inhibitor pimasertib in solid tumors (NCT01390818) and ovarian cancer

(NCT01936363), erlotinib (NCT00777699) and temozolomide (in anaplastic

gliomas/glioblastomas; NCT00704080). Both once-daily and twice-daily MTDs

of SAR245409 are being explored in phase II combination- and single-agent

studies. Encouraging objective partial and complete responses in patients with

lymphomas (21) have prompted studies of twice-daily SAR245409 in

combination with rituximab and/or bendamustine (NCT01410513) and as

monotherapy in a phase II trial in lymphoma and leukemia (NCT01403636).

Acknowledgments

The authors would like to thank Art DeCillis, Steven Gendreau, Bih Hsu,

Valentina Vysotskaia, Belinda Cancilla and Frauke Bentzien (all from

Exelixis), and Celine Lefranc and Kevin Rockich (both from Sanofi) for their

contributions to the study. This study was funded by Sanofi and Exelixis. The

authors received editorial support from Simone Blagg and Ben Caldwell of

MediTech Media Ltd, funded by Sanofi.




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Figure legends

Figure 1. Reduction of phosphatidylinositol-3-kinase (PI3K) and

mTORC1/mTORC2 pathway signaling by SAR245409 in serial hair and

skin samples

A) Effect of SAR245409 on the PI3K/mTOR signaling pathway and

proliferation in hair sheath cells documented by immunofluorescence

staining of phosphorylated eIF4E-binding protein-1 (p4EBP1)T70, pAKTS473,

phosphorylated proline-rich AKT1 substrate (pPRAS40)T246, and pS6S240/244

in cross-sections of baseline and day 85 post-dose hair collected from a

patient administered SAR245409 at 15 mg twice daily (bid). Representative

fields from each time point were captured per readout at 400x

magnification.

B) Progressive reduction in immunofluorescence staining of pAKTT308,

pAKTS473, pPRAS40T246, p4EBP1T70 and pS6S240/244 in hair sheath cells

from four patients administered SAR245409 15 mg (n=2), 60 mg (n=1) and

120 mg (n=1) bid.

C) Effect of SAR245409 on the PI3K/mTOR signaling pathway and on

proliferation in skin biopsies documented by immunofluorescence staining.

Quantification at baseline and post-dose (on cycle 1, days 27/28/29, 4–8h

post-dosing) of individual patient samples (each line representing an

individual patient) and box plot representations (inset plot) for pAKTT308,

pAKTS473, pPRAS40T246, p4EBP1T70 and pS6S240/244 and Ki67 in skin

biopsies for 12 patients administered SAR245409 at 50 mg bid (n=3), at 60

mg bid (n=3), 120 mg bid (n=2), 70 mg qd (once daily; n=2) and 100 mg qd

(n=2).




31

Figure 2. Reduction in phosphatidylinositol-3-kinase (PI3K) and

mTORC1/mTORC2 signaling by SAR245409 in paired tumor biopsies

A) Effect of SAR245409 on the PI3K/mTOR signaling pathway and tumor

proliferation. Inhibition of PI3K/mTOR pathway signaling was documented

by immunofluorescence staining of cryopreserved biopsy samples

collected from a patient with ductal breast carcinoma at baseline and cycle

1, day 27 post-dose. Representative fields from each time point were

captured per readout (red for pAKTT308, pAKTS473 or phosphorylated

eIF4E-binding protein-1 [p4EBP1]T70, blue for 4',6-diamidino-2-

phenylindole [DAPI] and magenta for Ki67) at 400x magnification.

Reductions in immunofluorescence of 64% (pAKTT308), 53% (pAKTS473),

55% (p4EBP1T70) and 68% (Ki67) were observed at cycle1 day 27

compared with baseline.

B) Quantification of immunofluorescence staining at baseline and on cycle 1

day 27 or 28 of individual patient samples (each line representing an

individual patient) and box plot representations (inset plot) for pAKTT308,

pAKTS473, p4EBP1T70 and phosphorylated extracellular-signal-regulated

kinase (pERK)T202/Y204 levels in tumor biopsies for 12 patients receiving

twice-daily and once-daily MTD of SAR245409.

Figure 3. Radiologic response to SAR245409 with corresponding status

of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit

alpha (PIK3CA), phosphatase and tensin homolog (PTEN), KRAS and

AKT1 alterations




32

Blue indicates gene alteration or altered protein expression, yellow indicates

no detected alteration, gray indicates status unknown. Best percentage

change from baseline in the sum of the longest target lesions diameter for 48

patients with pre- and post-baseline tumor assessments. Solid lines indicate

RECIST threshold for response (-30% for partial response and +20% for

progressive disease).

*Indicates patient had 153% increase.




33

Figures for inclusion in online supplementary material

Supplementary Figure 1. Mean (±SE) SAR245409 plasma concentration–

time profiles on days 1 and 27 of cycle 1.

N = number of patients on day 1 for each group. Error bars represent the

standard error of the mean. Lower limit of quantification = 1 ng/mL.

bid, twice daily; qd, once daily

Supplementary Figure 2. Effects of SAR245409 on plasma fasting insulin

and fasting glucose

A) Plasma fasting insulin on days 1, 8 and 27/28 in patients administered

SAR245409. * P<0.05, ** P<0.01, *** P<0.0001 vs pre-dose by Student’s t-

test.

B) Comparison of individual patient glucose level (mg/dL) on days 1, 8 and

27/28 in patients administered SAR245409 by dose cohort.

bid, twice daily; qd, once daily.

Supplementary Figure 3. Reduction in extracellular signal-regulated

kinase (ERK) pathway signaling by SAR245409 in paired tumor biopsies

Effects on A) ERK pathway signaling (pERK and total ERK) and B) mitogen-

activated protein kinase kinase (MEK) in paired tumor biopsies from two

patients with breast ductal carcinoma administered SAR245409 at the daily

MTD of 90 mg, assessed by immunofluorescence staining. Representative

fields were captured at 400x magnification to document staining in panel A of

pERKT202/Y204 (green) and total ERK (red) and in panel B for pMEKS217/S221

(red) and 4',6-diamidino-2-phenylindole [DAPI] (blue). Significant impact on




34

pERKT202/Y204 (61–62% reduction) was observed in both patient samples.

Likewise, pMEKS217/S221 was reduced by 52–62%.

Supplementary Figure 4. Effect of SAR245409 on skin lesions of a ductal

breast carcinoma patient

Photographs of mastectomy region in a patient with AKT1-mutant ductal

breast carcinoma showing improvement in skin lesions following initiation of

SAR245409.

C, cycle; D, day.




35

Table 1. Patient demographics and baseline characteristics for entire

cohort (N=83)

Characteristic

Age, years

Median 60.0

Min, Max 23, 80

Sex, n (%)

Male 33 (39.8)

Female 50 (60.2)

Race, n (%)

Asian 1 (1.2)

Black or African-American 6 (7.2)

White 75 (90.4)

Other 1 (1.2)

Ethnicity, n (%)

Hispanic or Latino 29 (34.9)

Not Hispanic or Latino 54 (65.1)

ECOG performance status, n (%)

0–1 76 (91.6)

2 7 (8.4)

Number of prior anti-cancer regimens

Median

Min, Max

4.0

1, 12

Tumor types, n (%)

Breast

Colon

Lung

Rectal

Endometrial/uterine

Kidney

Pancreas

Ovary

Other*

21 (25.3)

18 (21.7)

8 (9.6)

5 (6.0)

5 (6.0)

3 (3.6)

3 (3.6)

3 (3.6)

17 (20.5)

*Other tumor types included: adrenal, neuroendocrine, gastric, prostate, testicular, esophageal, mesothelioma, cervical, bladder, sarcoma, small bowel, melanoma, basal cell cancer. ECOG, Eastern Cooperative Oncology Group




36

Table 2. Treatment-related adverse events that occurred in ≥5.0% of patients (all grades) and ≥2.0% of patients (grade 3/4)

15 mg bid

N=3 n (%)

30 mg bidN=7

n (%)

60 mg bidN=10 n (%)

120 mg bidN=7

n (%)

50 mg bid N=25 n (%)

100 mg qdN=7

n (%)

70 mg qdN=5

n (%)

90 mg qd N=19 n (%)

Total

N=83 n (%)

Number of cycles of study treatment administered per patient, median (range)

4.0 (2, 8) 2.0 (1, 6) 2.0 (1, 10) 2.0 (1, 2) 2.0 (1, 12) 1.0 (1, 6) 1.0 (1, 2) 2.0 (1, 13) 2.0 (1, 13)

Number of patients who received

≤80% of SAR245409 doses 0 0 1 (10.0) 1 (14.3) 2 (8.0) 1 (14.3) 0 0 5 (6.0)

81%–90% of SAR245409 doses 0 0 2 (20.0) 0 0 0 0 1 (5.3) 3 (3.6)

91%–100% of SAR245409 doses 3 (100.0) 7 (100.0) 7 (70.0) 6 (85.7) 23 (92.0) 6 (85.7) 5 (100.0) 18 (94.7) 75 (90.4)

Treatment-related AEs, all grades

Number of patients with at least 1 AE related to study treatment 3 (100.0) 6 (85.7) 7 (70.0) 6 (85.7) 15 (60.0) 7 (100.0) 1 (20.0) 16 (84.2) 61 (73.5)

Nausea 1 (33.3) 1 (14.3) 3 (30.0) 4 (57.1) 4 (16.0) 7 (100.0) 1 (20.0) 9 (47.4) 30 (36.1)

Diarrhea 0 2 (28.6) 0 5 (71.4) 3 (12.0) 1 (14.3) 1 (20.0) 6 (31.6) 18 (21.7)

Vomiting 0 0 2 (20.0) 3 (42.9) 3 (12.0) 2 (28.6) 0 6 (31.6) 16 (19.3)

Decreased appetite 1 (33.3) 2 (28.6) 0 4 (57.1) 3 (12.0) 2 (28.6) 1 (20.0) 1 (5.3) 14 (16.9)

Aspartate aminotransferase increased 0 0 2 (20.0) 5 (71.4) 3 (12.0) 0 0 1 (5.3) 11 (13.3)

Alanine aminotransferase increased 0 0 1 (10.0) 5 (71.4) 4 (16.0) 0 0 1 (5.3) 11 (13.3)

Gamma-glutamyltransferase increased 0 0 1 (10.0) 2 (28.6) 3 (12.0) 0 0 2 (10.5) 8 (9.6)

Fatigue 0 0 1 (10.0) 1 (14.3) 0 3 (42.9) 1 (20.0) 1 (5.3) 7 (8.4)

Asthenia 0 1 (14.3) 1 (10.0) 2 (28.6) 0 0 0 2 (10.5) 6 (7.2)

Rash 0 1 (14.3) 0 1 (14.3) 1 (4.0) 1 (14.3) 1 (20.0) 0 5 (6.0)

Dysgeusia 1 (33.3) 0 0 1 (14.3) 1 (4.0) 1 (14.3) 1 (20.0) 0 5 (6.0)

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15 mg bid

N=3 n (%)

30 mg bidN=7

n (%)

60 mg bidN=10 n (%)

120 mg bidN=7

n (%)

50 mg bid N=25 n (%)

100 mg qdN=7

n (%)

70 mg qdN=5

n (%)

90 mg qd N=19 n (%)

Total

N=83 n (%)

Treatment-related AEs, grade 3/4

Number of patients with at least 1 grade 3/4 AE related to study treatment

0 0 1 (10.0) 5 (71.4) 2 (8.0) 1 (14.3) 0 5 (26.3) 14 (16.9)

Alanine aminotransferase increased 0 0 0 3 (42.9) 1 (4.0) 0 0 1 (5.3) 5 (6.0)

Aspartate aminotransferase increased 0 0 0 3 (42.9) 1 (4.0) 0 0 0 4 (4.8)

Gamma-glutamyltransferase increased 0 0 0 0 2 (8.0) 0 0 0 2 (2.4)

Decreased appetite 0 0 0 2 (28.6) 0 0 0 0 2 (2.4)

Fatigue 0 0 0 0 0 1 (14.3) 0 1 (5.3) 2 (2.4)

AE, adverse event; bid, twice daily; qd, once daily.

Reported event terms were coded using MedDRA dictionary version 15.0. AEs were defined according to National Cancer Institute

Common Terminology Criteria for Adverse Events version 3.0. Treatment-related AEs were defined as judged possibly or probably

related by the investigator.

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Table 3. Summary of pharmacokinetic parameters of SAR245409

15 mg bid

30 mg bid

50 mg bid

60 mg bid

120 mg bid

70 mg qd

90 mg qd

100 mg qd

Day 1 n 3 7 25a 10 7b 5 19 6

tmax, hr, median (range)

1.92 (1.00, 2.00)

2.00 (1.00, 3.00)

1.03 (0.250, 8.00)

2.04 (1.00, 4.00)

2.08 (0.583, 3.08)

2.00 (2.00, 6.00)

3.00 (0.500, 6.08)

1.50 (0.500, 4.00)

Cmax, ng/mL, geometric mean, mean (CV%)

43.5, 53.5 (62.7)

105, 121 (56.6)

148, 197 (72.1)

142, 235 (92.5)

277, 379 (85.5)

241, 275 (42.7)

302, 432 (70.6)

269, 349 (62.8)

AUC0–t, hr*ng/mL, geometric mean, mean (CV%)

155, 197 (82.2)

387, 446 (59.5)

556, 818 (86.0)

675, 1250 (114.0)

1180, 2100 (110.0)

1240, 1330 (37.6)

2110, 3560 (90.8)

1340, 1750 (50.0)

Day 27 n 2 4c 16d 5 3e 3 14f 2

tmax, hr, median (range)

1.50 (1.00, 2.00)

2.50 (1.02, 3.07)

1.00 (1.00, 3.00)

2.00 (1.00, 6.00)

2.00 (1.00, 2.07)

2.00 (2.00, 2.00)

2.50 (1.00, 24.0)

4.00 (2.00, 6.00)

Cmax, ng/mL, geometric mean, mean (CV%)

126, 133 (44.0)

151, 176 (59.1)

319, 407 (63.1)

126, 162 (60.6)

437, 524 (77.6)

410, 434 (39.5)

285, 361 (68.3)

270, 276 (28.5)

Cmin, ng/mL, geometric mean, mean (CV%)

5.40, 10.7 (122.2)

4.43, 7.49 (122.3)

17.2, 37.9 (146.1)

8.40, 12.5 (90.1)

33.5, 36.3 (43.3)

4.39, 5.71 (70.3)

9.43g, 15.9 (160.3)

12.8, 14.2 (61.7)

AUC0–t, hr*ng/mL, geometric mean, mean (CV%)

472, 504 (49.4)

490, 616 (87.1)

1400, 1890 (76.0)

601, 813 (60.9)

2210, 2390 (50.3)

1720, 1790 (31.0)

1830, 2530 (79.1)

2360, 2460 (38.7)

t1/2z, hr, geometric mean, mean (CV%)

2.96, 3.15

(48.7) 4.09, 5.19

(87.8) 5.92, 7.53

(75.2) 7.52, 8.50

(61.7) 5.82, 6.39

(55.3) 7.34, 8.43

(54.8) 7.10, 9.43

(79.1) 6.51, 6.58

(19.8)

AUC0–t day 27/day 1 ratio geometric mean, mean (CV%)

2.03, 2.05 (17.7)

0.932, 1.01 (44.2)

2.58, 3.62 (88.2)

1.03, 1.52 (118.9)

2.10, 2.18 (39.1)

1.28, 1.29 (20.6)

1.10, 1.66 (117.6)

3.41, 5.68 (113.2)

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AUC0–t , the area under the plasma concentration–time curve, integrated from time 0 to end of dosing interval (>9 and ≤14 hours for

bid; >20 and ≤28 hours for qd) on day 1 and integrated from time 0 to exactly 12 hours (bid) or to exactly 24 hours (qd) on day 27;

bid, twice daily; Cmax, observed maximum plasma concentration over dosing interval; Cmin, observed minimum plasma

concentration over dosing interval; CV, coefficient of variation; qd, once daily; t1/2z, terminal phase half-life; tmax, time to reach the

maximum plasma concentration. a Except for AUC0–t (n=22); b except for AUC0–t (n=6); c except for t1/2z (n=3); d except for t1/2z (n=15), and for AUC0–t day 27/day 1

ratio (n=14); e except for AUC0–t day 27/day 1 ratio (n=2); f except for t1/2z (n=13); g the geometric mean value for this parameter

could not be calculated using all available data because two patients had concentrations below the lower limit of quantitation (set to

zero) over the dosing interval. When these two patients were excluded, the geometric mean Cmin value was 9.43 ng/mL (n=12).

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Published OnlineFirst February 28, 2014.Clin Cancer Res Kyriakos Papadopoulos, Josep Tabernero, Ben Markman, et al. inhibitor in patients with advanced solid tumorsSAR245409 (XL765), a novel, orally administered PI3K/mTOR Phase I safety, pharmacokinetic and pharmacodynamic study of

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