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

2609 General Poster Session (Board #10B), Mon, 8:00 AM-12:00 PM
Should patients with extrapulmonary small cell carcinoma receive prophylactic
cranial irradiation? An Irish experience. Presenting Author: Jarushka
Naidoo, Waterford Regional Hospital, Waterford, Ireland
Background: Extrapulmonary small cell carcinoma (EPSCC) is a rare
disease. Management is based on small cell lung carcinoma, and experience
of disease biology on single institution studies. Prophylactic cranial
irradiation (PCI) is not routinely administered in EPSCC. This study
investigates the role of PCI in EPSCC, by analyzing the incidence,
treatment and survival of patients with brain metastases in a national
cohort. Secondary aims were to investigate disease biology and epidemiology.
Methods: An audit was undertaken of patients diagnosed with primary
EPSCC from the National Cancer Registry of Ireland, between 1995-2007.
The number of patients who developed brain metastases, received cranial
radiotherapy, and their survival data, were documented. Patient and
disease characteristics, treatment, and survival data stratified by stage and
primary site, were tabulated. Results: 280 patients were found. 141
(50.4%) patients were male, and 139 (49.6%) were female. 186 (66.4%)
patients had extensive stage disease, 65 (23.2%) had limited stage
disease, and in 29 (10.3%) patients the stage was not known. 17 patients
(5.4%) developed brain metastases, 11 of which (64.7%) received cranial
irradiation. These patients had a median progression-free survival (PFS) of
5.2 months, and a median overall survival (OS) of 10.2 months. The
commonest primary sites were the oesophagus (n�43, 15.4%), cervix uteri
(n�17, 6.0%), bladder (n�13, 4.6%) and prostate (n�10, 3.6%). There
were 315 events of distant metastasis, and 21 local recurrence events. The
commonest metastatic sites were the liver, 110 (34.9%), lymph nodes 58
(20.7%), lung 38 (12.1%), and bone 36 (12.8%). The median PFS and OS
for limited stage EPSCC was 8.8 months and 14.9 months, and 1.5 months
and 2.3 months for extensive stage EPSCC. Conclusions: Brain metastases
were uncommon in this cohort (5.4%), and patients lived longer, suggesting
a low rate of mortality from brain metastases. PCI is thus probably not
warranted in EPSCC. Prospective data are necessary to support PCI in
EPSCC. This is one of the largest datasets on EPSCC, providing insights
into disease biology.
2611 General Poster Session (Board #10D), Mon, 8:00 AM-12:00 PM
Evaluation of utility of pharmacokinetic studies in phase I combination
trials. Presenting Author: Kehua Wu, The University of Chicago, Chicago, IL
Background: There are many phase I clinical combination trials including
drug-drug interaction (DDI) studies, but very few of them report positive
results. We hypothesized that the utility of DDI studies is low in the absence
of a mechanistic hypothesis. Methods: We retrospectively reviewed 119
phase I (2 drug) combination studies published in 2007-2011. Results:
Only 23 (19%) studies had a positive rationale, either inhibition/induction
of a drug metabolizing enzyme or transporter, co-substrates for the same
enzyme or transporter, potential for end-organ toxicity, or protein- binding.
Only 9 (8%) studies demonstrated a statistically significant effect DDI,
based on AUC of parent drug or active metabolite. There was a strong
association between lack of rationale and a lack of interaction, as only 2%
of studies without a rationale demonstrated a DDI, compared to 30% of
studies with a rationale (Fisher’s exact test, p�0.0004) (Table). Conclusions:
DDI studies should not be routinely performed as part of phase I clinical
trials.
Preclinical
rationale
Developmental Therapeutics—Clinical Pharmacology and Immunotherapy
Number of
papers with (�) DDI
Number of
papers with (�) DDI
(�) 94 2
(�) 16 7
169s
2610 General Poster Session (Board #10C), Mon, 8:00 AM-12:00 PM
Phase I/II dose-finding study of crizotinib (CRIZ) in combination with
erlotinib (E) in patients (pts) with advanced non-small cell lung cancer
(NSCLC). Presenting Author: Sai-Hong Ignatius Ou, Chao Family Comprehensive
Cancer Center, Orange, CA
Background: c Met expression is common in NSCLC tumors and has been
implicated in the development of resistance to EGFR inhibitors. CRIZ is an
ALK and MET/HGF receptor tyrosine kinase inhibitor (TKI). In pre-clinical
studies, combining CRIZ with an EGFR inhibitor enhanced anti-tumor
activity in NSCLC cell lines that were either sensitive or resistant to EGFR
inhibition. The phase I portion of a phase I/II study (A8081002;
NCT00965731) investigated the combination of E (EGFR TKI) and CRIZ in
pts with advanced NSCLC. Methods: Pts had advanced NSCLC, 1 or 2 prior
chemotherapy regimens, and no previous MET-directed therapy. Endpoints
included maximum tolerated dose (MTD) determination, safety, and
pharmacokinetics (PK). Pts received CRIZ 150 or 200 mg BID combined
with E 100 mg QD (150/100 and 200/100, respectively). Results:
Twenty-five pts have been treated to date. Median duration of combination
therapy in 150/100 (n�18) was 6.6 weeks (0.1–25.3); for 200/100 (n�7)
was 6.9 weeks (3.0–64.7). Five pts had dose-limiting toxicities (grade [G]
2 and unable to receive at least 80% of the planned dose or �G3), all of
which resolved: 3 pts at 150/100, G2 vomiting, G2 esophagitis and
dysphagia, G3 diarrhea and dehydration; and at 200/100, G3 dry eye (1 pt)
and G3 esophagitis (1 pt). Most pts (92%) experienced treatment-related
adverse events (TRAEs), mainly of G1 or 2 severity. Common TRAEs were
diarrhea (72%), rash (56%) and fatigue (44%). Six pts discontinued
therapy due to TRAEs (150/100: G3 diarrhea, G3 dehydration, and G2 rash
in 1 pt, G2 asthenia, G2 vomiting, G2 esophagitis, n�1 each; 200/100: G3
dry eyes, G1 esophagitis, n�1 each). One partial response (200/100;
duration 61 weeks) and 9 stable diseases (n�7 150/100, n�2 200/100;
duration 7–54 weeks) were observed overall. Co-administration of both
doses of CRIZ with E increased E AUC by 1.8 fold, while CRIZ PK
parameters appeared to be unaffected. Plasma exposure to E 100 mg QD
with CRIZ was comparable to that of 150 mg QD from historical data.
Conclusions: E plus CRIZ at the MTD was well tolerated, with no unexpected
AEs, and showed signs of activity in a pre-treated population. E 100 mg QD
plus CRIZ 150 mg BID was defined as MTD.
2612 General Poster Session (Board #10E), Mon, 8:00 AM-12:00 PM
Effect of baseline QTc interval prolongation on oncology clinical trial
enrollment. Presenting Author: Carolina Moreno, H. Lee Moffitt Cancer
Center & Research Institute, Tampa, FL
Background: An increasing number of clinical trials in oncology require
normal or near-normal intervals of electrocardiographic corrected QT (QTc)
as an eligibility criterion. However the normal QTc reference range
(conventionally defined as �450ms) has been developed in broad populations
of patients, and it is unclear whether average QTc intervals are higher
in adult cancer patients. Methods: All electrocardiograms (ECGs) performed
for any indication at the Moffitt Cancer Center during a one-week period
were reviewed. The QTc interval for each patient was calculated according
to the Bazett and Fridericia formulas. Mean and median QTc intervals were
calculated along with standard deviations. The percentage of QTc intervals
above 450ms, 470ms, and 500ms were calculated and graded accordingly
to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE v4.0).
The effects of gender on the QTc interval were also evaluated. Results: 257
patients underwent ECGs over a one-week period. A total of 90 patients
(35%) had abnormally prolonged QTc. 50 patients (20%) had QTc
prolongation �450 (� grade 1), 32 (12%) had QTc prolongation � 470
(�grade 2) and 8 patients (3%) had QTc prolongation �500ms (�grade 3)
using the Bazett formula. The corresponding numbers according to the
Fridericia formula were 23 (9%), 13 (5%) and 2 (1%) . The median QTc
interval was 441 (Bazett) and 422 (Fridericia) with a standard deviation of
30 and 28 respectively. Women had a mean QTc of 438 (Bazett) versus
443 for men. Conclusions: A very large percentage of patients seen at a
comprehensive cancer center have QTc intervals above the normal reference
range on routine ECGs. The growth in number of trials requiring a
normal QTc interval as an eligibility criteria suggests that an ever-larger
number of patients are excluded from trial participation. Regulatory
agencies may need to reconsider eligibility criteria that substantially
restrict trial enrollment and that accrue patients who are not reflective of
the general patient population.
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