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

Developmental Therapeutics—Clinical Pharmacology and Immunotherapy
2545 General Poster Session (Board #2A), Mon, 8:00 AM-12:00 PM
Feasibility and safety of sequential research-related tumor core biopsies in
clinical trials with anti-angiogenic and targeted therapies. Presenting
Author: Jung-min Lee, Medical Oncology Branch, Center for Cancer
Research, National Cancer Institute, Bethesda, MD
Background: There has been increasing interest in serial/paired research
biopsies (bx) in studies of molecularly targeted therapies. Definition of
optimal target tissue and patient characteristics for safe and feasible
research tumor bx in the era of anti-angiogenic and targeted therapies is
needed. Methods: IRB-approved review of retrospective clinical data
including patient demographics, pre-and post-procedure and recovery
notes, and radiographic bx images. The cohort consisted of 142 pts
scheduled for serial bx enrolled in phase 1 (5) and phase 2 (1) studies.
Tumor core bx were obtained percutaneously under local anesthesia using a
16 or 18g needles under US or CT visualization by interventional radiologists.
Results: Paired tumor core bx were collected in 96 pts (68%) and
baseline only in 42 pts (32%). Bx were aborted in 4 pts due to cystic mass
(3) and safety (1). 132 pts were female and 10 pts were male, median age
56 yrs (27-78), median BMI 25.8 (14.4-46.2), ECOG PS 0-2, and normal
end-organ function. All pts had recurrent metastatic cancers (gynecologic
121, breast 6, sarcoma 5, melanoma 4, colon 2, adrenal 1, mesothelioma
1, RCC 1, papillary thyroid ca 1). 67 pts (51%) were on bevacizumab
(bev)-based therapy at the time of their 2nd /3rd bx (bev � sorafenib; bev �
dasatinib); others received gefitinib (27), imatinib (23), vandetinib (9), or
olaparib � carboplatin (16). Median tumor size was 2.7cm (1-14.5cm). Bx
sites were abd/pelvic masses 42, liver 40, lymph nodes 42, abd/chest wall
12, lung 4 (3 pleural, 1 parenchymal), and psoas muscle 1. Minor
complications were observed in four pts (3%; uncomplicated liver subcapsular
hematoma [1]; vasovagal syncope responding to fluids [2]; uncomplicated
pneumothorax without intervention [1]) and there were no major
complications. The median number of tumor cores was 3 (1-6) at the
baseline, 2nd (during or at the end of the first cycle) and 3rd time point
(during cycle 2). Conclusions: Core needle bx of deep internal lesions such
as intra-abdominal masses and retroperitoneal lymph nodes can be
obtained percutaneously under imaging guidance. Sequential tumor bx are
feasible and safe for pts on anti-angiogenic and chemotherapeutic agents.
2547 General Poster Session (Board #2C), Mon, 8:00 AM-12:00 PM
Predictive model for survival and toxicity in early-phase trials in hematology.
Presenting Author: Rahima Jamal, University of Montreal, Montreal,
QC, Canada
Background: Strict criteria are used to limit toxicity for patients (pts)
enrolled in phase I/II clinical trials, but the ability to survive beyond 12
weeks, a common inclusion criterion, is subjective and error-prone. A
prognostic score with 3 variables was designed and validated as an
independent predictor of OS in pts with solid tumors included in phase I
trials (Arkenau, JCO 2009). We examined the ability of objective measures
to predict OS and risk of grade �3 toxicity in pts with hematologic
malignancies enrolled in early-phase trials. Methods: A retrospective
analysis was conducted on 290 pts in Phase I (79 pts) and II (211 pts)
trials from the NCIC - Clinical Trials Group and our institution from 1995 to
2009. Only pts with survival data up to 90 days were included. Univariate
model (UVA) was used to identify factors significantly associated with OS. A
Cox proportional hazards model (MVA) included all factors identified from
the UVA. Six prognostic factors were identified in the MVA, and each
assigned a score of 0 or 1. Pts were categorized as high or low risk based on
the total scores that they received, �3 were assigned to the high risk group,
and a �2 to the low risk group. Kaplan-Meier method was used to generate
the survival distribution for the high and low risk groups. Multivariate
logistic regression was used to identify the risk factors for grade �3 toxicity.
Results: The overall median survival was 238 days (95% CI 237 to 331),
and 27% of pts had grade � 3 toxicity. In the MVA, albumin (alb), alkaline
phosphatase (ALP), lactate dehydrogenase (LDH), lymphocytes, platelets
(plts) and diagnosis were significantly associated with OS. Pts in the low
risk group had a median survival of 10.6 months, relative to 2.4 months
among pts in the high risk group. Survival at 90 days was 80% in lower risk
vs. 36% in the high risk group. In addition, the MVA for toxicity showed that
alb, ALP, LDH, plts and performance status were significantly associated
with grade �3 toxicity. Conclusions: Our model predicts OS, 90 day survival
and risk of grade � 3 toxicity among pts with hematologic malignancies
entered in Phase I/II trials. Future work will include a linear predictor score
based on MVA to refine the prediction model. The model will also be
validated using another dataset.
153s
2546 General Poster Session (Board #2B), Mon, 8:00 AM-12:00 PM
Phase I immunotherapy trial using glioblastoma apoptotic body-pulsed
dendritic cells. Presenting Author: Christopher L. Moertel, University of
Minnesota, Minneapolis, MN
Background: We recently reported that tumor cell vaccines cultured in 5%
oxygen (O2) had enhanced the immunogenicity relative to those grown in
standard atmospheric O2. In order to develop an “off-the-shelf” source of
whole cell antigen we screened a panel of primary glioblastoma (GBM) cell
lines, leading to identification of (GBM6) as an ideal candidate. GBM6 was
extensively characterized and shown to express glioma-associated antigens
(IL13Ra2, Sox2, Epha2, etc.). A Phase I clinical trial was initiated to
evaluate the safety and feasibility of a vaccine consisting of dendritic cells
(DC) pulsed with apoptotic bodies from GBM6 grown in 5% O2. Methods:
Patients ranging from 3 to 71 years with recurrent GBM (n�6) or
ependymoma (n�1) were enrolled. Monocytes were collected via apheresis,
matured into DC and pulsed with apoptotic bodies derived from GBM6.
The first three patients received escalating doses of DC (5x106 , 10x106 ,
and 15x106 ), the remainder received 15 x 106 DC. Pulsed dendritic
cellswere injectedsubcutaneously into the supra-scapular region. Imiquimod
cream was applied at the injection site just prior to vaccination and
24 hours later. The vaccine schedule dictated administration every 2 weeks
for 8 weeks (total of 5 doses) then monthly to progression or a total of 52
weeks. Prior to each vaccination, patients met eligibility parameters and
had no progression on MRI. Patients were imaged monthly and blood was
drawn to evaluate toxicity and immune response. Results: No vaccinerelated
toxicity has been reported. Time to progression ranges from 6.5
weeks for the patient treated at the first dose level to 35 weeks for one
patient receiving 15 x 106 DC. The latter patient experienced a partial
response at 20 weeks. Two patients have stable disease at 18.5 and 28
weeks, respectively. One patient was not evaluable. Flow cytometric
analysis demonstrated expansion of central memory T cells amidst declining
effector memory cells following vaccination in three patients at a dose
of 15x106 DC. Conclusions: Apoptotic body-pulsed DC vaccination was well
tolerated and preliminarily demonstrated clinical activity but a minimum of
15x106 DC was required for a modulation of central memory T cells.
2548 General Poster Session (Board #2D), Mon, 8:00 AM-12:00 PM
Difference between duration of treatment (DOT) and progression-free
survival (PFS) as a marker of unbalanced censoring. Presenting Author:
Laleh Amiri-Kordestani, National Cancer Institute, National Institutes of
Health, Bethesda, MD
Background: In the conduct of randomized trials Kaplan and Meier
envisioned rates of censoring as similar between arms, providing accurate
assessment of clinical trial results. Censoring is used when patients
withdraw consent, leave study due to toxicity, or reach data cut-off without
disease progression or death. Censoring can lead to erroneous conclusions
as it can be either beneficial or detrimental to the arm under study. Such
censoring can also explain how a statistically valid difference in PFS
“disappears” when overall survival (OS) is examined. We hypothesized that
censoring, especially that due to toxicity, would lead to a discrepancy
between DOT and PFS since two different patient populations would be
scored. Methods: We reviewed all phase III randomized studies of drugs
approved by FDA since 2005 for pts with metastatic solid tumors, looking
for DOT and PFS. We used standard statistical analyses using SAS. Results:
We identified 55 Phase III studies conducted with abiraterone, axitinib,
bevacizumab, cabazitaxel, cetuximab, eribulin, erlotinib, everolimus, ipilimumab,
ixabepilone, lapatinib, panitumumab, pazopanib, sorafenib,
sunitinib, temsirolimus and vandetinib. DOT was not provided in 27%.
Forty-four comparisons (88 arms) were included in the analysis. The
median PFS, DOT, delta PFS (difference in PFS between experimental and
control arms) and delta DOT were: 161, 126, 51 and 36 days, respectively.
The slopes of PFS vs DOT and delta PFS vs delta DOT were 1.16 and 1.03,
respectively close to the ideal of 1.0. Five trials fell above the 90% CI
boundary with delta PFS/delta DOT of 3 to 36, including two everolimus
studies (PNET and breast cancer) two sunitinb studies (RCC and PNET)
and one bevacizumab study (E2100, breast cancer). Conclusions: PFS and
DOT as well as delta PFS and delta DOT should be concordant. The most
likely explanation for a discordance between these values is toxicity-driven
censoring and its occurrence raises concerns regarding the degree of
efficacy. A greater utilization of “Time to Treatment Failure”, an endpoint
that includes toxicity in its definition would be valuable in oncology trials,
particularly those with high levels of toxicities.
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