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

3000 Oral Abstract Session, Sun, 9:45 AM-12:45 PM
Phase I clinical and pharmacologic study of the focal adhesion kinase
(FAK) inhibitor GSK2256098 in pts with advanced solid tumors. Presenting
Author: Jean-Charles Soria, Institut Gustave Roussy, INSERM U981,
Villejuif, France
Background: FAK has an important role in cancer invasion and metastasis.
FAK and phospho-FAK (pFAK) are increased in advanced cancer and are
correlated with poor prognosis. GSK2256098 is a potent and specific small
molecule inhibitor of FAK. Methods: This is a first-time in cancer pts, dose
escalation study (NCT01138033) to identify the maximum tolerated dose
(MTD), safety, pharmacokinetics (PK), pharmacodynamics (PD), and
clinical activity. Part 1 used a modified accelerated titration procedure
switching to standard 3�3 design based on toxicity during the first 21 days
of treatment. Pts were treated with GSK2256098 orally twice daily (BID)
with food. Safety was established in cohorts of 1-6 pts. After MTD
determination, Parts 2 and 3 were opened to further evaluate safety, PK
and PD. Serial PK samples were obtained over 24 h on Days 1 and 15. Preand
post-dose skin, hair and tumor tissue biopsies were analyzed for pFAK.
Results: 57 pts with advanced solid tumors have been treated at escalating
doses ranging from 80 mg to 1500 mg BID: median age�58.8 (range
21-84). The most common tumor types include: mesothelioma (23), ovary
(7), colon (3), kidney (3), and pancreas (3). MTD was determined to be
1000 mg BID. DLTs were Gr 2 proteinuria (1000 mg), Gr 2 nausea,
vomiting, fatigue (1250 mg) and Gr 3 asthenia (1500 mg). Most frequent
toxicities were nausea (32 pts, 56%), diarrhea (31 pts, 54%), vomiting (25
pts, 44%), decreased appetite (18 pts 32%) and asthenia (11 pts, 19%).
The majority of toxicities were Gr 1-2; Gr 3 drug-related events included
hypertriglyceridemia (n�2), hyperlipasemia (2), asthenia (1), increased
amylase (1), and loss of consciousness (1). Few dose reductions and
interruptions have occurred. Minor responses/stable disease (SD) were
observed in pts with mesothelioma (-12%, 27 wks), melanoma (-26%, 54
wks), and naso/pharyngeal cancer (-31% target lesion, 30 wks) and SD in
renal cell (48� wks). In preliminary analysis of single-dose PK, exposure
generally increased in a dose-proportional manner, and the geometric mean
t½ was 4.2 h. Accumulation was not observed with repeat dosing.
Conclusions: GSK2256098 is well tolerated with evidence of clinical
activity. PK supports BID dosing.
3002 Oral Abstract Session, Sun, 9:45 AM-12:45 PM
Phase I study of OPB51602, a small molecule inhibitor of STAT3
phosphorylation, in patients with refractory solid malignancies. Presenting
Author: Boon C. Goh, Cancer Science Institute of Singapore, Singapore
Background: STAT3 is constitutively activated by growth signaling pathways
in many malignancies; in many cell lines inhibition of STAT3 leads to cell
death. OPB51602 is a small molecule inhibitor of STAT3 phosphorylation
(Tyr705) and activation. Methods: A phase I study of OPB51602 administered
for 2 weeks every 3 weeks was initiated to determine the maximum
tolerable dose (MTD), evaluate pharmacokinetics (PK), and assess pharmacodynamics
effects on STAT3 in peripheral blood mononuclear cells
(PBMCs). The starting dose was 2mg/day, and dose escalations to 5mg/d,
10mg/d, 20mg/d, were planned. Single dose PK was done on the first day of
administration for 4 days. Dose escalation was based on the “3�3” design,
MTD was defined as the dose with at least 2/6 dose limiting toxicities
(DLTs) in the first cycle and toxicities were graded by NCICTCv4.0. Results:
32 patients (pt) were treated at doses of 2mg/d (n�7), 4mg/d (n�18),
5mg/d (n�7). The main toxicities observed included nausea/vomiting,
diarrhea, peripheral neuropathy and fatigue. 5 mg/d was the MTD, where
cycle 1 DLTs of grade 3 diarrhea/dehydration and hyponatremia occurred in
1 patient respectively. One pt developed grade 3 peripheral neuropathy at
4mg/d cohort. PK showed maximal drug levels 2-3 hours after administration,
bi-exponential decay, with mean oral clearance of 316.5 �/- 638.9
L/h and long terminal mean half-life of 61.8 �/- 15.9 h on day 17. STAT3
phosphorylation in PBMCs assessed in 6 pts receiving 4mg/d was reduced
from 67.4 �/- 17.4% at baseline to 53.0 �/- 18.1% (p�0.001) after
administration on day 1. Interestingly, reduction in tumor metabolism by
PET CT on day 15 was observed in 4/8 pts receiving 4mg/d. A pt with
heavily pretreated adenocarcinoma of lung at 5mg/d dose had partial
response; another pt with metastatic endometrial cancer at 4mg/d dose
experienced stable disease for 6 cycles. Conclusions: OPB51602 has an
MTD of 5mg/d on this schedule, demonstrates inhibition of STAT3
phosphorylation, and evidence of clinical activity. Further proof of concept
studies of OPB51602 are warranted.
Developmental Therapeutics—Experimental Therapeutics
173s
3001 Oral Abstract Session, Sun, 9:45 AM-12:45 PM
A first-in-human phase I study of the oral p38 MAPK inhibitor LY2228820
dimesylate in patients with advanced cancer. Presenting Author: Matthew
P. Goetz, Mayo Clinic , Rochester, MN
Background: p38 MAPK regulates production of cytokines by the tumor
microenvironment and its activation enables cancer cells to survive in the
presence of oncogenic stress, radiation, chemotherapy, and targeted
therapies. LY2228820 is a selective small-molecule inhibitor of p38
MAPK and preclinical studies demonstrate antitumor activity as a single
agent and in combination with standard agents. We performed a phase I
study to determine the maximum tolerated dose (MTD) and dose-limiting
toxicity (DLT) of LY2228820 and to characterize its pharmacokinetics and
pharmacodynamics. Methods: Dose escalation was performed in a 3�3
design. LY2228820 was taken orally every 12 hours on days 1-14 of a
28-day cycle. Results: 54 patients received either capsules at 8 dose levels
(10, 20, 40, 65, 90, 120, 160, and 200mg) or tablets at 5 dose levels
(160, 200, 300, 420, and 560mg). For both formulations, Cmax and AUC
increased in a dose-dependent manner. LY2228820 inhibited p38 MAPK
induced phosphorylation of MAPKAP-K2 in peripheral blood with dosedependent
maximum inhibition from 10 to 70% across the dose range
10-200mg. The most common drug-related adverse events included
fatigue, nausea, rash, constipation, vomiting, and pruritus. 1 patient
(200mg) had DLT of erythema multiforme (Gr3) and 2 patients (560mg)
had DLT of ataxia (Gr3) and dizziness (Gr2), respectively. Although the
MTD was 420mg, the frequency of Gr1/2 adverse events (mainly rash,
dizziness, and tremor) and observation of clinical activity at lower dose
levels led to a recommended dose of 300mg (mean AUC0-24 � 11.7ughr/ml
at steady state). Early clinical activity has been observed in ovary,
breast, and kidney cancers. One patient with metastatic clear cell carcinoma
of the kidney refractory to sorafenib, sunitinib, and temsirolimus had
confirmed near partial response (29% decrease) after 8 cycles and remains
on therapy. 15 patients (28%) achieved best overall response of stable
disease, which in 12 patients (22%) was prolonged (�4 cycles). Conclusions:
LY2228820 demonstrates acceptable pharmacokinetics, safety, and early
clinical activity as a single agent in advanced cancer. A phase II study for
patients with ovary cancer is planned.
3003 Oral Abstract Session, Sun, 9:45 AM-12:45 PM
A phase lb, open-label, multicenter, dose-escalation study of the oral
pan-PI3K inhibitor BKM120 in combination with the oral MEK1/2 inhibitor
GSK1120212 in patients (pts) with selected advanced solid tumors.
Presenting Author: Philippe Bedard, Division of Medical Oncology &
Hematology, Princess Margaret Hospital, Department of Medicine, University
of Toronto, Toronto, ON, Canada
Background: MAPK and PI3K/AKT signaling pathways regulate proliferation,
differentiation and cell death in human cancers. Known interaction
between the 2 pathways provides the rationale for combining both
inhibitors in a phase I study. Methods: The objective is to determine the
maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D)
for oral, daily administered, BKM120 � GSK1120212, mainly in pts with
tumors with RAS/RAF mutations (mt). A Bayesian logistic regression model
with overdose control guides the dose escalation of the treatment. Secondary
objectives include safety, tolerability, PK and efficacy. Results: As of
22.09.11, 49 pts were treated with BKM120 � GSK1120212 as follows:
30mg � 0.5mg, 60mg � 0.5mg, 60mg � 1.0mg, 60mg � 1.5mg, 60mg
� 2.0mg, 70mg � 1.5mg, 80mg � 1.0mg, 80mg � 1.5mg. 6 pts had
dose-limiting toxicities (DLTs); all were reversible. Grade 3 DLTs were: 3 x
stomatitis, 1 x dysphagia, 1 x LVEF decrease, 1xCKincrease, 1 x nausea,
1 x anorexia, 1 x decreased oral intake. MTD and/or RP2D for the
combination have not been reached. Most common adverse events (AEs)
(�25%), all grades and causality, were dermatitis acneiform, diarrhea
(51% each); nausea (41%); vomiting (37%); rash (33%); asthenia (31%);
CK increase, decreased appetite, pyrexia or stomatitis (29% each) and
hyperglycemia (27%). There were 4 on-treatment deaths unrelated to
treatment. AEs led to treatment discontinuation, 17 pts (35%) and
interruptions/dose reductions, 25 pts (51%). Apparent steady-states of
BKM120 and GSK1120212 were reached by day 28. Plasma concentrations
of BKM120 in combination with GSK1120212 were lower than for
monotherapy. Exposure to GSK1120212 with BKM120 was similar to that
observed in monotherapy studies. 3 confirmed partial responses have been
observed in pts with KRAS mt ovarian cancer; 2 lasting �9 months. 2
patients with BRAF mt melanoma, who had previously progressed on BRAF
inhibitors, had stable disease, for 1 of whom treatment is still ongoing in
cycle 6. Conclusions: BKM120 and GSK1120212 can be safely combined.
Signs of clinical activity have been seen in pts with RAS/RAF mt tumors.
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