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

4099 General Poster Session (Board #48B), Mon, 8:00 AM-12:00 PM
A phase II trial of temsirolimus (TEM) and bevacizumab (BEV) in patients
with advanced hepatocellular carcinoma (HCC). Presenting Author: Jennifer
J. Knox, Princess Margaret Hospital, Toronto, ON, Canada
Background: There is strong rationale to combine an m-TOR inhibitor (TEM)
with a VEGF inhibitor (BEV) as a potentially active and well tolerated
treatment for HCC. Both agents have shown modest single agent activity in
HCC and so evaluated here in a phase II trial. Methods: A modified 2-stage
Simon design planned 25 or 50 patients (pts) to test the null hypothesis
that true tumor response rate is at most 10% andtrue 6-mo progressionfree
survival rate (PFS) (by RECIST) is at most 65%, or no better than single
agent BEV (6 mo PR �2 pts or PFS 6 mo �18 out of 25.) Toxicity, TTP,
PFS and survival were 2nd endpoints. Eligible pts had confirmed HCC with
disease unresectable or amenable to other localised therapies, Child Pugh
A liver status and no prior systemic therapy involving the VEGF or m-TOR
class of agents. TEM was administered at starting dose 25 mg IV
d1,8,15,22 with BEV at 10mg/kg IV d 1, 15, all q 28 days (1 cycle).
Imaging was q 8 wks. Results: From 09/09 to 09/11, 27 eligible pts were
enrolled with 25 evaluable for toxicity and efficacy. Med age 59 yrs, 85%
male, PS 0/1: 35/65, 58% metastatic, �85% BCLC stage C. With med 6
cycles (range 1-14) delivered, most pts (88%) experienced a grade 3�
adverse event (a/e.) Common grade 3 a/es related to treatment included
thrombocytopenia (40%), neutropenia (20%), leucopenia (12%), fatigue
(8%), anemia, mucositis, dyspnea, diarrhea, bleeds, fistula, infections (4%
each). There was one possible treatment related death. Per protocol dose
reductions/discontinuation for TEM-related a/es were most common. There
were 2 confirmed PRs and 16 pts progression-free by 6 mos. A third pt
developed a late PR at cycle 13. Median TTP on study was 6 mos, median
PFS was 7.4 mos and median survival was 8.3 mos, with 13 pts still alive.
Accrual closed at end of stage 1 as neither the number of responses nor the
PFS at 6 mos passed the futility stopping rule set for this combination.
Conclusions: This multicenter study is the first HCC trial evaluating the
BEV/TEM doublet. Despite manageable toxicity, the ORR and 6 mo PFS did
not surpass assumptions based on single agent BEV in HCC. Further study
of BEV/TEM combination in this advanced HCC population is not recommended.
4101 General Poster Session (Board #48D), Mon, 8:00 AM-12:00 PM
Serum folate, LINE-1 hypomethylation, and overall survival in a prospective
cohort of hepatocellular carcinoma patients. Presenting Author: Abby
B. Siegel, Columbia University, New York, NY
Background: Folate plays a central role in DNA methylation reactions, but
the relationship between folate and methylation status has not been
studied in HCC patients. We hypothesized that low folate levels would
correlate with global hypomethylation, and worsened survival in HCC
patients. Methods: 72 newly-diagnosed HCC patients were enrolled in a
prospective study, beginning 10/08, and followed until 9/11. We excluded
those with previous malignancy, and uncompensated Child Pugh (CP) B or
C disease. We used pyrosequencing to evaluate quartiles of LINE-1
methylation in plasma as a surrogate for global tumor hypomethylation. We
evaluated the relationship between folate deficiency (serum folate levels �
6ng/mL), DNA hypomethylation (LINE-1 methylation � 25th percentile
i.e., � 69.4%), and overall survival in our cohort. Results: Median age was
60; 82% were men and 67% had hepatitis C. Mean serum folate levels
were 12.1 ng/mL (SD � 5.3 ng/mL), while mean % LINE-1 methylation
was 69.9 (SD � 4.6). In a univariate analysis, folate deficiency and LINE-1
hypomethylation were significant predictors of poor overall survival (HR �
3.77; 95% CI: 1.37, 10.41, and HR�3.50; 95% CI: 1.51, 8.13,
respectively). These markers remained independent predictors of survival
in a multivariate model including age, CP class, AJCC stage and AFP. HR
for folate deficiency in this model was 3.52 (95% CI: 1.16, 10.70), and HR
for LINE-1 hypomethylation was 2.74 (95% CI: 1.10, 6.85). We also found
a significant association between folate deficiency and LINE-1 hypomethylation
(p � 0.04). Conclusions: We provide novel data that folate deficiency
is an independent predictor of worsened overall survival in patients with
HCC in a multivariate model. Further, we show that global changes in DNA
methylation assesed in plasma correlate with folate levels, supporting a
possible mechanistic link between the two. Folate supplementation, and
the use of other agents which modulate methylation, deserve further study
in HCC.
Gastrointestinal (Noncolorectal) Cancer
263s
4100^ General Poster Session (Board #48C), Mon, 8:00 AM-12:00 PM
A phase I/II study of AZD6244 in combination with sorafenib in advanced
hepatocellular carcinoma. Presenting Author: Su Pin Choo, National
Cancer Center Singapore, Singapore
Background: Preclinical studies have shown that pharmacological inhibition
of the MEK/ERK pathway by AZD6244 enhanced the anti-tumor effect
of sorafenib in both orthotopic and ectopic models of HCC. We conducted
this study to determine tolerability, pharmacokinetics, and pharmacodynamics
of AZD6244 when combined with sorafenib in advanced HCC. Methods:
Patients with biopsy-proven unresectable BCLC B/C hepatocellular carcinoma
were recruited. Only those with Childs-Pugh A or B (7) liver cirrhosis
and without prior systemic therapy were included. Sorafenib at 400mg bd
was given 1 week before initiation of AZD6244 which was escalated in
subsequent cohorts from 75mg om based on 3�3 design. PK and PD
studies and QOL assessments were performed. DCE-MRI imaging was
performed to assess tumor vascularity in response to treatment. Results:
Fourteen patients were recruited (including 2 replaced). 11 had evaluable
disease. Characteristics: all male, all Chinese, 12 were BCLC C stage. Two
DLTs were seen out of 6 patients at dose level 1 (AZD6244 at 50mg bd)
which were grade 3 fatigue and grade 3 abdominal pain with elevated
transaminases. When an additional dose level 1A was added (ADZ6244 at
100mg om), 2 out of 3 patients had DLTs of grade 3 raised aspartate
transaminase and grade 3 diarrhea. Thus, the MTD was determined to be
AZD6244 at 75mg om when combined with sorafenib 400mg bd. Common
toxicities were diarrhea (83%), rash (58%), fatigue (50%), hypertension
(42%), anorexia/vomiting/thrombocytopenia (25%). Two patients had reversible
LVEF dysfunction and there were no eye toxicities. PK of AZD6244
showed oral clearance of 11.2 � 6.8 L/h and terminal half-life of 6.0 �2.0
h.Objective responses were 3 PR, 6 SD and 2 PD.DCE-MRI measurements
demonstrated significant reductions in permeability surface area product
(PS, ml/100ml/min) and fractional intravascular blood volume (v1, ml/
100ml) seven days after starting sorafenib. No additional antivascular
activity was observed when AZD6244 was added to sorafenib. Conclusions:
The recommended phase II dose for AZD6244 is 75mg om when combined
with sorafenib 400mg bd for advanced HCC patients. This combination is
feasible, shows activity and warrants further investigation.
4102 General Poster Session (Board #48E), Mon, 8:00 AM-12:00 PM
Phase I trial of temsirolimus (TEM) plus sorafenib (SOR) in advanced
hepatocellular carcinoma (HCC) with pharmacokinetic (PK) and biomarker
correlates. Presenting Author: Robin Katie Kelley, Helen Diller Family
Comprehensive Cancer Center, University of California, San Francisco, San
Francisco, CA
Background: Mammalian target of rapamycin inhibitors added to SOR
augment antitumor effect in HCC models. We developed a phase 1 trial to
determine maximum tolerated dose (MTD) and recommended phase 2 dose
(RP2D) of TEM plus SOR in HCC patients (pts). The study was approved
and funded by the National Comprehensive Cancer Network (NCCN) from
general research support from Pfizer, Inc., and conducted at 2 NCCN
centers. Methods: Eligibility: �1 measurable site. No prior systemic therapy
(Tx). ECOG �2, Child Pugh �7, bilirubin �2 mg/dL, platelets (PLT)
�75,000/mcL. Design: 3�3 escalation. Dose-limiting toxicity (DLT) window
28 days. MTD expansion cohort of 9 pts for PK and biomarkers.
Endpoints: 1°: MTD, RP2D. 2°: Safety, toxicity, PK for TEM. Exploratory:
Tumor necrosis, alpha fetoprotein (AFP)-L3, des-�-carboxyprothrombin,
and circulating tumor cells (CTC) by slide-based assay. Results: 21 pts
enrolled. Median age: 60 (47-77). Male/Female: 15/6. Etiology: HCV 9
(43%), HBV 4 (19%), HBV�HCV 2 (10%), ETOH 2 (10%), unknown 4
(19%). Toxicity: DL1: 1 DLT Grade (Gr) 3 PLT. All pts required reductions
for adverse events (AE); de-escalated to DL-1 for intolerability. DL-1: 1 DLT
Gr3 hand-foot syndrome (HFS). Most common related �Gr 3 AE: HypoPO4
(52%); PLT (24%); transaminitis (19%); diarrhea, fatigue, HFS (10%
each). Possibly related serious AE (SAE): Gr4 tumor rupture, Gr4 urosepsis,
Gr3 dental infection with Gr2 ANC, Gr2 pneumonia (1 pt, 5% each). Best
response: Confirmed partial response (PR) 2/21 (10%), stable disease (SD)
11/21 (52%), progression 1/21 (5%), 7/21 (33%) not evaluable. Time on
study: Range �1 to 19�months; median 3� months for pts who
completed �1 cycle (16/21). 16/21 (76%) had baseline elevated AFP
�20; 8/16 (50%) had �50% decline. CTC were detected in 5/5 of tested
samples. Decreased tumor enhancement on Tx was seen. Conclusions:
DL-1 is MTD and RP2D, lower than a prior trial in pts without HCC;
tolerability may be impacted by cirrhosis. Encouraging durable radiographic
and AFP responses occurred.
Dose level (DL) TEM (mg IV/week) SOR (mg PO) Accrual to date
-2 10 200 QD 0
-1 (RP2D) 10 200 BID 9 � 5 expansion
1 (starting) 15 200 BID 7
2 15 400 BID 0
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