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

3096 General Poster Session (Board #19F), Mon, 8:00 AM-12:00 PM
Phase I study of sirolimus plus gemcitabine in patients with advanced solid
tumors: A Spanish Group for Research on Sarcomas (GEIS) study. Presenting
Author: Juan Martin Liberal, Instituto Catalan Oncologia, Barcelona,
Spain
Background: In preclinical studies, combination of sirolimus with gemcitabine
enhances apoptosis in vitro and increases anti-tumor efficacy in vivo.
Methods: Patients with advanced solid tumors, age 18-70 years, no prior
mTOR inhibitor or gemcitabine, ECOG PS 0-1, and adequate hematological,
renal and hepatic function, were enrolled in this phase I study to assess
safety, tolerability, pharmacokinetics (PK), and to identify the dose limiting
toxicity (DLT), maximum tolerated dose (MTD) and recommended dose
(RD) of the combination of sirolimus and gemcitabine. A 3�3 dose
escalation design with cohorts of 3-6 patients was used. Sirolimus was
given po continuously. Gemcitabine was given iv 10mg/m2 /minute on days
1 and 8 every 3 weeks. Dose levels 1, 2 and 3 corresponded to sirolimus 2,
2 and 5mg/24h plus gemcitabine 800, 1000 and 1000mg/m2 respectively.
After observing DLTs at higher dose level and poorer mTOR signaling
inhibition at lower doses, a new cohort of sirolimus 5mg/24h plus
gemcitabine 800 mg/m2 was added. Skin biopsies pre and post treatment
were performed to assess the inhibition of mTOR pathway. Results: 19
patients were enrolled: median age 51 years (36-70); gender 12M, 7F.
Median number of cycles was 4. Patients were treated at 4 dose levels, the
MTD was reached at level 3 and the RD was: sirolimus 5mg/24h and
gemcitabine 800mg/m2 . 3 DLTs were observed, 1 at dose level 2 and 2 at
dose level 3: transaminitis grade 3, thrombocytopenia grade 3 and
thrombocytopenia grade 4. Other toxicities grade 1-2 included anemia,
neutropenia, asthenia, mucositis and high cholesterol levels. 2 patients
achieved partial response (1 uterine cervix cancer and 1 colon cancer).
Immunohistochemistry of pS6 in skin biopsies showed significative inhibition
of mTOR pathway at RD. PK parameters estimated were in agreement
with those previously reported in the literature. No influence of sirolimus
administration on gemcitabine clearance was found. Conclusions: Combination
of sirolimus and gemcitabine is feasible and safe, allowing administration
of active doses of both agents and achieving mTOR signaling
inhibition. A phase II study to assess the activity of this combination in
sarcomas is ongoing.
3098 General Poster Session (Board #19H), Mon, 8:00 AM-12:00 PM
A phase Ib proof-of-concept study of LBH589 (LBH) and everolimus (EVE)
in advanced solid tumors enriched for Epstein-Barr virus (EBV)-related
cancers. Presenting Author: Daniel Shao-Weng Tan, National Cancer
Centre, Singapore, Singapore
Background: Histone deacetylase and mTOR inhibition circumvent critical
EBV-oncogenic pathways with preclinical studies demonstrating lytic
induction in EBV infected cells, as well as immunomodulatory and
antiangiogenic effects. Methods: Patients (Pt) with advanced solid tumors
enriched for EBV–related cancers were enrolled to determine safety,
tolerability, maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics
and preliminary antitumor activity. LBH was instituted
7-days prior to combination treatment. NPC pt received antiviral prophylaxis
of either acyclovir (Ac) or valaciclovir (Vc). Serum EBV DNA levels
(EBNA-1) were measured weekly and plasma cytokines profiled using a
31-plex Luminex panel. Results: 15 pt have been treated (M:F 13:2,
median age 50, R: 38-63) 10 NPC, 5 non-NPC (colon, RCC, breast,
gastric, sarcoma) at 3 dose levels – LBH (3x/wk)-EVE (daily):10-2.5, 10-5,
15-5. Two dose limiting toxicities of G4 (grade) thrombocytopenia were
observed at LBH15-RAD5. Significant adverse events (AE) (G�3) were
dysphagia (1) and thrombocytopenia (3). Common AEs (G1/2) included
fatigue (80%), anorexia (60%), mucositis (53%), xerostomia (26%),
dysphagia (26%). Two minor responses were seen (1 NPC, 1 breast) and 2
pt (1 NPC, 1 RCC) had prolonged stable disease (�16 weeks). Modulation
of EBV DNA titres was seen only in NPC pt, with median fold-change from
baseline of 10.9 (0.05-174). Pt on Ac prophylaxis (n�5) had significant
increases in DNA titres (9-174 fold), while those on Vc (n�4) were less
pronounced (0.05-11 fold, p�0.03), with one pt (with minor response)
having persistent decline in EBV titres. In a limited pt subset (n�9, 30
timepoints), plasma cytokine profiles were consistent with a T-cell response,
specifically, elevated levels of FLT3L, IFN-gamma, IL-13 and
IL-17. PK and PBMC target modulation studies are being analysed.
Conclusions: LBH-EVE results in induction of EBV DNA titres with an
associated host T cell response. MTD is LBH10-EVE5 in Asian pt, majority
of whom had NPC. A pre-planned expansion cohort that incorporates
multi-parametric functional imaging exploring two schedules of LBH in
combination with EVE5 is ongoing.
Developmental Therapeutics—Experimental Therapeutics
197s
3097 General Poster Session (Board #19G), Mon, 8:00 AM-12:00 PM
The PI3K/mTOR inhibitor BEZ235 given twice daily for the treatment of
patients (pts) with advanced solid tumors. Presenting Author: Hendrik-
Tobias Arkenau, Sarah Cannon Research Institute, London, United Kingdom
Background: The PI3 kinase (PI3K) pathway is the most deregulated
pathway in cancers and is an attractive target for antitumor therapy.
BEZ235 is an oral highly specific and selective inhibitor of the PI3K and
TORC1/2. The MTD (1200 mg) and toxicity profile of BEZ235 once daily
dosing has been established. This study was designed to evaluate twice
daily dosing of BEZ235 and its effect on treatment tolerability, PK, PD, and
preliminary efficacy. Methods: Pts with advanced disease were enrolled in a
3�3 dose escalation schedule starting at 200 mg PO BID in 28 day cycles.
For intrapatient PK comparison the first week pts received the total dose in
a QD schedule. DLT assessment was in Cycle 1. Efficacy evaluations were
every 2 cycles, and PK and PD were assessed. Results: 12 pts were enrolled
at the following dose levels: 200 mg (n�3), 400 mg (n�3), 600 mg (n�3),
and 600 mg (BID only, no QD lead-in) (n�3). No G4 AEs were reported. G3
related AEs were mucositis (n�2), AST/ALT elevation (n�2), anorexia
(n�1) and diarrhea (n�1). The most common related G1/2 adverse events
(AEs) were anorexia (n�6), diarrhea (n�3), fatigue (n�2), and headache
(n�2). DLTs of G3 mucositis were observed in 2 patients at the 600 mg
BID dose level with 1 week 1200 mg QD lead-in, which were attributed to
the QD lead-in dosing during the first week. 3 pts then enrolled at 600 mg
BID without lead in and had no further DLT. PK shows consistent increase
in PK parameters with dose level. Of 10 evaluable, 3 pts had stable disease
(13� to 21� weeks, 2 colorectal, 1 endometrial). Of 9 evaluable, 4 pts at
various dose levels had decreased PET SUV uptake by greater than 25%.
Conclusions: BEZ235 is tolerable at a dose of 600 mg BID, with less toxicity
than has been seen with equivalent QD dosing. Preliminary signs of clinical
and PD activity are noted.
3099 General Poster Session (Board #20A), Mon, 8:00 AM-12:00 PM
Meta-analysis on the relationship between everolimus exposure and safety
and efficacy. Presenting Author: Dalila B. Sellami, Oncology Clinical
Development, Novartis Pharmaceuticals Corporation, Florham Park, NJ
Background: Data on everolimus exposure–safety and response relationships
are available from individual studies. We performed a meta-analysis
to assess these relationships using everolimus predose minimum blood
concentration (Cmin). Methods: Individual patient data from 5 phase 2 or 3
oncology studies in which steady-state predose pharmacokinetic samples
were taken from patients administered everolimus monotherapy 10 mg/day
were pooled. In a Cox regression, the times to first grade �3 select adverse
events (AEs) associated with everolimus and first progression-free survival
(PFS) event were related to log-transformed instant or time-averaged Cmin as time-varying covariates stratified by study. Probability of tumor size
reduction according to RECIST (yes vs no) was assessed using a generalized
linear mixed model fitted with GEE method with log-transformed instant or
time-averaged Cmin as covariates and treatment arm as fixed effect. Results:
945 patients were evaluable for efficacy, 938 for safety. Patient characteristics
were relatively well balanced across studies. Regardless of whether
instant or time-averaged Cmin was used, a 2-fold increase in everolimus
exposure increased the risk of grade �3 pulmonary, metabolic, and
stomatitis events (Table); no increased risk of other grade �3 AEs was
observed. A 2-fold increase in everolimus exposure increased the likelihood
of tumor size reduction; there was a trend of reduced risk of a PFS event
(Table). Conclusions: A 2-fold increase in everolimus exposure is associated
with a higher probability of tumor size reduction and increased risk of
high-grade pulmonary, metabolic, and stomatitis AEs associated with
everolimus.
Risk and odds ratios associated with 2-fold everolimus exposure increase.
Tumor size
Grade >3 AEs, risk ratio (95% CI)
PFS event,
risk ratio
reduction,
odds ratio
Cmin Pulmonary Metabolic Stomatitis (95% CI) (95% CI)
Time-averaged 1.93 1.30 1.49 0.90 1.40
(1.12-3.34) (1.02-1.65) (1.05-2.10) (0.69-1.18) (1.23-1.60)
Instant 2.15 1.37 1.44 0.88 1.43
(1.17-3.92) (1.06-1.77) (1.01-2.05) (0.68-1.14) (1.25-1.63)
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