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

Developmental Therapeutics—Clinical Pharmacology and Immunotherapy
2529 Poster Discussion Session (Board #17), Sat, 8:00 AM-12:00 PM and
12:00 PM-1:00 PM
Safety and long-term maintenance of anti-HER2 immunity following
booster inoculations of the E75 breast cancer vaccine. Presenting Author:
Raetasha Sheavette Dabney, Brooke Army Medical Center, San Antonio, TX
Background: We have completed accrual and are in the follow up portion of
phase I/II clinical trials evaluating the E75 HER2 peptide vaccine. E75 has
been proven safe, capable of stimulating HER2 immunity, and effective in
decreasing breast cancer recurrence rates. During the conduct of this trial,
it was noted that E75-specific immunity waned after the Primary Vaccine
Series (PVS) which corresponded with late recurrences. To maintain
long-term immunity, a voluntary booster program was started. Here we
present analysis of the booster inoculations. Methods: The trial enrolled
node-positive or high-risk, node-negative breast cancer patients (pts) with
tumors expressing any level of HER2 (IHC 1-3�). HLA-A2/A3� pts
comprised the vaccine group (VG), HLA-A2/A3- pts were followed as the
control group (CG). The VG received 4-6 monthly inoculations of E75�GM-
CSF. Volunteer booster program pts (BG) received inoculations every 6
months after the PVS. Pts were monitored for toxicities, in vivo responses by
local reactions (LR) and DTH, and in vitro responses measured by
enumeration of E75 specific cytotoxic T lymphocytes. Results: 53 pts
received at least 1 booster, 34 received 2, 24 three, 20 four, 12 five, and 8
at least 6. 24% of pts had no local toxicity, 73% Grade 1 (G1), 3% G2.
74% had no systemic toxicity, 35% G1, 1% G2. LRs increased significantly
from the initial vaccine (R1) during PVS to each booster (B) (R1: 59.5�3.1
v B1: 89.2�3.3, p�0.001; v B2: 95.15�5, p�0.001; v B3: 86.63�5.5,
p�0.001; v B4: 83.26�4.6, p��0.001; v B5: 80.67�6.7, p�0.006; v
B6: 78.75�9.4, p�0.04). Dimer values increased from the end of PVS to
each post-booster value (pre B1:1.29�0.25 v post B1: 1.46�0.38; post
B2: 1.41�0.4; post B3: 1.84�0.35; post B4: 2.23�0.4; post B5:
1.94�0.31; post B6: 2.73�0.09, p�0.02). At median 60 months, the
recurrence rate for BG was 3.8% vs 18.9% in the CG (p�0.01).
Conclusions: Booster inoculations are well-tolerated and appear to assist in
the maintenance of long term peptide-specific immunity. Boosted pts have
improved recurrence rates. Based on the success of this program, we have
incorporated the practice of booster inoculations in our current cancer
vaccine trials.
2531 Poster Discussion Session (Board #19), Sat, 8:00 AM-12:00 PM and
12:00 PM-1:00 PM
Response to epidermal growth factor vaccine in patients with metastatic
non-small cell lung cancer (NSCLC) after progressing to first-line therapy.
Presenting Author: Diego Venegas, Universidad Peruana Cayetano Heredia,
Lima, Peru
Background: A direct correlation between anti–epidermal growth factor
(EGF)antibody titers and survival was demonstrated in vaccinated patients
with novel NSCLC advanced in Phase II studies. We show the results of
treatment with anti-EGF vaccine in a cohort of patients with metastatic
NSCLC after progressing to first line therapy. We evaluated immunogenicity,
safety, treatment response and effect on survival. Methods: 12 patients
with metastatic NSCLC after progressing to first-line therapy received anti
EGF-vaccine alone or in combination with chemotherapy. Results: From
October 2009 until August 2011, 12 patients started treatment with anti
EGF vaccine; mean age 56.5 (42-79 y); 66.7% male; ECOG 0 and 1:
41.7% and 58,3% respectively. Adenocarcinoma (50%), bronchioloalveolar
(33.3%), adenosquamous (16.7%). Metastatic sites: lung (41.7%),
pleura (25%), CNS (16.7%), Kidney (8.3%). In addition to chemotherapy
previous used: radiotherapy (50%), surgery (41.7%), erlotinib (41.7%),
bevacizumab (25%). The 50% patients received vaccine alone. The 83.3%
of patients had titers 1/4000 sera dilutions or more (good responders).
According to RECIST 1.1: CR: 8.3%, PR: 16.7%, SD: 41.7%, PD 25%.
Median overall survival was 18.8 months (95% CI: 13.3- 24.4 m). Median
progression-free survival was 7.3 months (95% CI: 6.4 -8.2 m). We found
no statistically significant differences in OS and PFS when comparing
vaccine alone or combined (p � 0.181 and p � 0.801). 75% of patients
had adverse effect: more frequently were: 42.4% application site pain,
15.1% fever and 10.38% chills, none of them serious. Conclusions:
Vaccination anti EGF in patients with metastatic NSCLC after progressing
to first line, alone or in combination, was safe and provoked an increase in
anti-EGF antibody titers, produced clinical benefit, improved overall
survival and progression free survival.
2530 Poster Discussion Session (Board #18), Sat, 8:00 AM-12:00 PM and
12:00 PM-1:00 PM
Phase I clinical trial of a genetically modified and oncolytic vaccinia virus
GL-ONC1 with green fluorescent protein imaging. Presenting Author: Jesus
Corral Jaime, Royal Marsden Hospital and Institute of Cancer Research,
Sutton, United Kingdom
Background: GL-ONC1 is a genetically engineered vaccinia virus attenuated
by insertion of the RUC-GFP (Renilla luciferase and Aequorea green
fluorescent protein fusion gene), beta-galactosidase (lacZ) and betaglucuronidase
(gusA) reporter genes into the F14.5L, J2R (thymidine
kinase) and A56R (hemaglutinin) loci. A phase I clinical trial of iv GL-ONC1
was pursued to evaluate safety, tolerability, tumour delivery, neutralizing
antibody development and anti-tumour activity. Methods: GL-ONC1 was
administered to patients with advanced solid tumours at escalating doses
(1�105 ,1�106 ,1�107 ,1�108 ,1�109 ,3�109 plaque-forming units
(pfu) on day 1; 1.667�107 and 1.667�108 pfu on day 1-3 of a 28-day
cycle) using a 3�3 dose escalation design. Green fluorescent protein (GFP)
imaging was performed on skin rash and mucosal tumour lesions at
baseline and after each cycle. Optional tumour biopsies were obtained for
pharmacodynamic and viral delivery evaluation. Results: 27 patients (21
males, median age 60 years) were treated. One of six patients at the 1x109 pfu dose level developed a dose-limiting, grade 3 rise in aspartate
transaminase levels after a single infusion. Other reported adverse events
(grade 1/2) included pyrexia (21), musculoskeletal pain (9), fatigue (8),
nausea (7), and vomiting (4). Two patients developed skin rash during the
first week of treatment, which appeared green by GFP and were positive to
viral plaque assay (VPA). VPA of blood, urine, stool and sputum were
negative for viral shedding in all but one patient who had positive shedding
for 11 days. Increased neutralizing antibody titres were detected in all
tested patients apart from one. Best response by RECIST was stable
disease at 48 weeks (1), 24 weeks (3) and 8-12 weeks (5). A patient with
squamous cell carcinoma of the tongue had a biopsy after 4 cycles which
showed positive IHC staining of vaccinia virus. This is the first time that a
virus is shown to be delivered to solid tumour after iv delivery. Conclusions:
GL-ONC1 administered iv is well tolerated, with documented colonisation
in patient tumour, and preliminary evidence of anti-tumour activity.
2532 Poster Discussion Session (Board #20), Sat, 8:00 AM-12:00 PM and
12:00 PM-1:00 PM
Association of breast cancer in men with exposure to 5-� reductase inhibitors: A
RADAR report. Presenting Author: Steven M. Belknap, Department of Dermatology,
Northwestern University Feinberg School of Medicine, Chicago, IL
Background: Breast cancers in men (BCM) account for �1% of all breast
cancers. Dihydrotestosterone (DHT) inhibits proliferation of normal and neoplastic
mammary tissue and constrains the effect of estrogens. Finasteride (F) and
dutasteride (D) are 5-� reductase inhibitors (5-�RIs) that reduce systemic and
local dihydrotestosterone and cause gynecomastia in 1–3% of men. The package
inserts for F and D state, “the relationship between long-term use of (finasteride/
dutasteride) and male breast neoplasia is currently unknown.” F and D are
marketed for treatment of symptomatic benign-prostatic hyperplasia. F is
marketed for treatment of androgenetic alopecia. Methods: To detect disproportionality
in the FDA MedWatch dataset, we calculated the empiric Bayes
geometric mean (EBGM) for association of BCM with F or D. We also calculated
the attributable risk of BCM exposed to F or D among men at an urban academic
hospital (Northwestern Memorial Hospital) and at a rural healthcare system
(Marshfield Clinic). Results: In the MedWatch dataset, we identified 33 reports of
F-associated BCM and 5 reports of D-associated BCM. For F–associated BCM,
the EBGM was 58.95 (95% CI 24.47-81.76; p�0.0001). For D-associated
BCM, the EBGM was 15.79 (95% CI 4.57-35.49; p�0.0001). The mean age
for BCM after 5-�RI exposure was 70�11 years; 11/38 (29%) had gynecomastia.
There were 38 cases of BCM associated with 5-�RI in the combined
Northwestern and Marshfield cohort (see table below). Conclusions: We found a
highly significant association between BCM and 5-�RI exposure in each of 6
separate analyses (3 sources X 2 drugs), with an estimated 1 extra BCM per 564
men exposed to 5-�RIs. We now plan to assess BRCA status and other risk
factors. Given that 5-�RIs are marketed for control of lower urinary tract
symptoms or for cosmetic purposes, it is not immediately obvious that use of
finasteride or dutasteride for their labeled indications would provide any net
benefit.
Risk of breast cancer in men with 5-�RI exposure.
Breast cancer
Risk/
Yes No Total 1,000
5-�RI exposure 38 17,161 17,199 2.21
No 5-�RI exposure 576 1,319,183 1,319,759 0.436
Total 614 1,336,344
95% CI
1,336,958
Attributable risk per 1.77 (1.07–2.48)
1,000 men
Risk ratio 5.1 (3.6–7.0)
Number needed to harm 564
Chi-square 116.3
p value p � 0.00001
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