Annual Meeting Proceedings Part 1 - American Society of Clinical ...

174s Developmental Therapeutics—Experimental Therapeutics
3004 Oral Abstract Session, Sun, 9:45 AM-12:45 PM
First-in-human phase I trial of the dual mTORC1 and mTORC2 inhibitor
AZD2014 in solid tumors. Presenting Author: Udai Banerji, Drug Development
Unit, The Institute of Cancer Research/The Royal Marsden Hospital,
Sutton, United Kingdom
Background: AZD2014 is a potent, dual mTORC1/mTORC2 inhibitor with
clear activity in in vivo and in vitro experimental models. Methods: This
2-part study consisted of �rolling six� dose escalation (Part A) and
expansion (Part B) phases. Part A: 3–6 pts per cohort received an oral
solution of AZD2014 BD starting at 50 mg. A further 6 pts were treated in
Part A below the MTD to study changes in pharmacodynamic (PD)
biomarkers. Part B: additional pts were dosed at the MTD, including a
group of ER�/PR� or HER2� patients with breast cancer. Primary
endpoint: safety and tolerability; secondary endpoints: pharmacokinetics
(PK), PD and efficacy. Biomarkers assessed: mTORC1: pS6 (S235/236)
and p4EBP1 (T37/46); mTORC2: pAKT (S473). Results: 50 pts have been
enroled in this ongoing study and interim data are reported: Part A, n�23
(25 mg, n�6; 50 mg, n�8; 70 mg, n�5; 100 mg, n�4; all BD); Part B,
n�27. The MTD was 50 mg BD. DLTs were seen at both 100 mg (Gr 2 and
3 lethargy/fatigue, n�4/4) and 70 mg (Gr 3 mucositis, Gr 2 lethargy,
n�2/4); no DLTs were seen at 25 mg or 50 mg. The most common AEs in
order of incidence were fatigue, stomatitis, decreased appetite, nausea and
diarrhea. Seven SAEs (nausea, vomiting, lethargy, abdominal pain, mucositis)
reported by 3 pts were considered ‘possibly related’ to the study drug by
investigators. AZD2014 is rapidly absorbed following single and BD
multiple doses with a short t1/2 of ~3 h. At 50 mg (n�32), preliminary data
show geometric mean AUCss�7.4 �g.h/ml and Cmax ss�1.7 �g/ml. One pt
with acinar pancreatic cancer had a RECIST partial response. pAKT and
p4EBP1 reductions were observed between 2–8 h in platelet-rich plasma
and peripheral blood mononuclear cells respectively. Target modulation in
paired tumor biopsies was seen at the MTD. Reduction in the phosphorylation
of S6 and 4EBP1 was evident in 8/10 and 3/9 paired biopsies
respectively. pAKT was reduced in 3/6 evaluable paired biopsies. As
opposed to rapalogs, pAKT was not upregulated in any of the evaluable
post-treatment biopsies. Conclusions: The MTD for AZD2014 is 50 mg BD.
Further clinical evaluation of AZD2014 is now warranted based on the
safety, PK and proof-of-mechanism PD data, as well as its preliminary
clinical activity. Updated results will be presented.
3006^ Oral Abstract Session, Sun, 9:45 AM-12:45 PM
Phase I trial of an oral TORC1/TORC2 inhibitor (CC-223) in advanced solid
and hematologic cancers. Presenting Author: Kent C. Shih, Sarah Cannon
Research Institute, Nashville, TN
Background: The mammalian target of rapamycin (mTOR) signaling pathway
is frequently activated in cancer. The mTOR kinase exists in two
multi-protein complexes, TORC1 and TORC2, which drive key cellular
metabolic and proliferative functions. TORC1-selective inhibitors can
induce feedback upregulation of TORC2 and treatment resistance. CC-223
is an oral, potent, selective, ATP-competitive inhibitor of both TORC1 and
TORC2, selected to address this escape mechanism. Methods: Subjects
with advanced solid and hematologic cancers were enrolled using an
accelerated (1�5) dose escalation design. CC-223 was administered
orally once daily (QD) in 28 day cycles until disease progression. Safety,
pharmacokinetic, pharmacodynamic and clinical endpoints were evaluated.
Results: 28 subjects were treated across 5 dose levels: 7.5 (n�1), 15
(n�2), 30 (n�9), 45 (n�7) and 60 mg (n�8). The most common
(� 20%) related adverse events (all grades) were fatigue (64%), nausea
(50%), hyperglycemia and diarrhea (43% each), mucositis (39%), anorexia
and vomiting (32% each) and rash (29%). Dose-limiting toxicity (all
grade 3) occurred in 4 subjects: hyperglycemia (30 mg), rash (45 mg),
fatigue (60mg), and mucositis (60 mg). The maximum tolerated dose
(MTD) was 45 mg QD. Dose proportional exposure was observed with a
terminal half life of 4 to 8 hrs (mean steady state Cmax 485 ng/mL, AUC0-24 2371 ngxhr/mL at 45 mg). Inhibition of TORC1 (pS6, p4EBP1) and
TORC2 (pAKT) biomarkers in blood cells was characterized to be exposuredependent
and described by an Emax model. Near maximal inhibition of
both TORC1 and TORC2 biomarkers was achieved at the peak concentrations
of 30 or 45mg QD. Target inhibition was predicted to last 8 to 20
hours at 45mg QD. Tumor responses included: 1 partial response lasting 9
months (ER� breast) and 7 subjects with stable disease (SD) lasting 8�
weeks (range 8 to 23.3). Conclusions: CC-223 was well tolerated with
toxicities comparable to other drugs in this class. Evidence of TORC1/
TORC2 pathway inhibition was observed as well as preliminary signals of
anti-tumor activity, including one durable PR. Expansion cohorts in
selected hematologic and solid tumors will evaluate CC-223 at the MTD of
45 mg QD.
3005 Oral Abstract Session, Sun, 9:45 AM-12:45 PM
First-in-human phase I study of LY2780301, an oral P70S6K/AKT
inhibitor, in patients with refractory solid tumors. Presenting Author:
Emiliano Calvo, START Madrid, Centro Integral Oncológico Clara Campal,
Madrid, Spain
Background: LY2780301is an oral potent, highly selective ATP competitive
inhibitor against p70S6 kinase and AKT. We report on safety, pharmacokinetics
(PK), pharmacodynamics (PD), and anti-tumor activity from the
first-in-men study of LY2780301 in solid tumors. Methods: Eligible pts
(ECOG�1) had relapsed solid tumors, adequate hematologic, renal, and
hepatic functions. Using a predictive pre-clinical PK/PD model and
non-clinical toxicology data, a total daily dose of 100-1000 mg, was
selected. LY2780301 was given either once or twice daily for 28-day cycle
until disease progression. Dose escalation (3�3 design) was based on
CTCAE V4 toxicities. The primary objective was to define the recommended
phase 2 dose of LY2780301. Secondary objectives were PK, PD (pS6 in
skin), and preliminary antitumor activity. Results: 32 patients were treated
at dose levels from 100mg – 500mg total daily dose. LY2780301 was well
tolerated at all dose levels No dose-limiting toxicities were observed in
cycle 1. Common toxicities potentially related to study therapy included:
constipation (7pts), fatigue (5pts), nausea (4pts), diarrhea (3pts), and
vomiting (3pts). Grade 3/4 toxicities potentially related to study therapy
were: anemia (3pts), increased ALT/AST (1pt), and increased GGT (1pt).
Average number of cycles received across all dose levels was 2. There were
no partial or complete responses; best response observed was prolonged
stable disease for 6.5 cycles. Plasma exposures of LY278030 exceeded
predicted efficacious dose in all pts (AUC 0-24H �25000 ng*hr/mL).
Increase in exposure with dose was observed (QD or BID) with significant
inter-pt variability. The exposure increase was less than linear with dose.
Preliminary PK parameters are CL/F 4.5L/h and t1/2 of 24 hours. pS6
assessment in skin showed inhibition in � 50% of pts receiving 400-500
mg per day. Positive correlation with the exposure of the didesmethyl
metabolite was observed. Conclusions: LY2780301displayed favorable
safety profile, and high PK exposures in the range of efficacious dose. The
recommended dose will be defined in the range between 300 and 500 mg.
Further exploration of PK/PD effect in mesothelioma is ongoing.
3007 Oral Abstract Session, Sun, 9:45 AM-12:45 PM
First-in-human phase I study of the ALK inhibitor LDK378 in advanced
solid tumors. Presenting Author: Ranee Mehra, Fox Chase Cancer Center,
Philadelphia, PA
Background: LDK378 is a novel, potent and selective small molecule
anaplastic lymphoma kinase (ALK) inhibitor (IC50 0.00015 �M), that does
not inhibit c-MET (IC50 3.2 �M). Tumor regression has been observed in
ALK-driven NSCLC xenografts. A first-in-human, Phase I study is being
conducted to determine the MTD and safety profile in patients (pts) with
tumors with ALK rearrangement, amplification or mutation. Other objectives
were safety, PK and antitumor activity in pts with ALK-driven NSCLC,
both naïve to ALK inhibitors and relapsed following previous ALK inhibitor
treatment, and other ALK-positive cancers. Methods: Adult pts with
advanced malignancies harboring a genetic alteration in ALK who progressed
on standard therapy or for whom there was no effective therapy,
were given once daily oral LDK378 on a continuous 21-day schedule. Dose
escalation, starting at 50 mg/day, was guided by a Bayesian logistic
regression model (BLRM) to determine the MTD. Results: At a January 5th 2012 cutoff,31 pts (primary site: lung 26 pts; breast 3 pts; other 2 pts;
median age 52 years; 87% ECOG PS 0/1) were enrolled and received
LDK378 at doses of 50–750 mg/day. Two dose limiting toxicities, Grade
(Gr) 3 alanine aminotransferase elevation (1 pt), and Gr 3 hypophosphatemia
(1 pt) occurred in 8 pts at a 400 mg dose level. BLRM allowed
dose escalation, and there were no DLTs in 4 pts at 500 mg. Median
duration of treatment with LDK378 was 7 weeks (range �1–22�). At the
cutoff date, 13 (42%) pts discontinued treatment: 1 (3%) due to adverse
events (AEs), and 12 (39%) due to disease progression; 18 (58%) pts were
still on treatment. The most frequent AEs (all Gr) were nausea (45%),
vomiting (36%), and diarrhea (29%). The most frequent Gr 3/4 AEs were
diarrhea and dyspnea (2 pts [7%] each). At doses �400 mg steady state
exposures exceeded efficacious exposures in xenograft models. Of 16 pts
with available response data (RECIST, per investigator) there were 4/6
responses in crizotinib (CRZ)-treated pts, and 2/10 responses in CRZ-naïve
pts, of whom 7 were treated below 400 mg. All responses were in NSCLC.
Conclusions: Daily oral LDK378 is well tolerated up to 500 mg/day, and
escalation continues at 750 mg/day. Preliminary responses have been seen
in both CRZ-naïve and CRZ-relapsed pts.
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