Cancer Therapy: Clinical
A Phase I Trial to Determine the Optimal Biological Dose of
Celecoxib when Combined with Erlotinib in Advanced
Non ^ Small Cell Lung Cancer
Karen L. Reckamp,1,5 Kostyantyn Krysan,1 Jason D. Morrow,6 Ginger L. Milne,6 Robert A. Newman,7
Christopher Tucker,8 Robert M. Elashoff,2 Steven M. Dubinett,3,4,5 and Robert A. Figlin1
Abstract
Purpose: Overexpression of cyclooxygenase-2 (COX-2) activates extracellular signal-regulated
kinase/mitogen-activated protein kinase signaling in an epidermal growth factor receptor (EGFR)
tyrosine kinase inhibition (TKI) ^ resistant manner. Because preclinical data indicated that tumor
COX-2 expression caused resistance to EGFR TKI, a phase I trial to establish the optimal biological
dose (OBD), defined as the maximal decrease in urinary prostaglandin E-M (PGE-M), and toxicity
profileof the combinationofcelecoxibanderlotinibinadvancednon ^ smallcelllungcancer was done.
Experimental Design: Twenty-two subjects with stage IIIB and/or IV non ^ small cell lung
cancer received increasing doses of celecoxib from 200 to 800 mg twice daily (bid) and a fixed
dose of erlotinib. Primary end points included evaluation of toxicity and determination of the
OBD of celecoxib when combined with erlotinib. Secondary end points investigate exploratory
biological markers and clinical response.
Results: Twenty-two subjects were enrolled, and 21were evaluable for the determination of the
OBD, toxicity, and response. Rash and skin-related effects were the most commonly reported
toxicities and occurred in 86%. There were no dose-limiting toxicities and no cardiovascular
toxicities related to study treatment. All subjects were evaluated on intent to treat. Seven patients
showed partial responses (33%), and five patients developed stable disease (24%). Responses
were seen in patients both with and without EGFR-activating mutations. A significant decline in
urinary PGE-M was shown after 8 weeks of treatment, with an OBD of celecoxib of 600 mg bid.
Conclusions: This study defines the OBD of celecoxib when combined with a fixed dose of
EGFR TKI.These results show objective responses with an acceptable toxicity profile. Future trials
using COX-2 inhibition strategies should use the OBD of celecoxib at 600 mg bid.
Lung cancer is the leading cause of cancer death in the United
States and is responsible for more deaths each year than colon,
breast, and prostate cancers combined (1). For all stages, the
5-year survival for non – small cell lung cancer (NSCLC) is
f14%. In advanced disease, 1-year survival is f33% in treated
patients (2). New therapeutic strategies are needed, and the
search for improved therapies has led to the investigation
of agents that target novel pathways involved in tumor
proliferation, invasion, and survival. Activation of kinases,
transcription factors, and cytokines involve multiple mechanisms, and targeting common signaling pathways may lead to
better therapeutic outcomes.
Epidermal growth factor receptor (EGFR) is a 170-kDa
glycoprotein with an extracellular ligand binding domain, a
transmembrane lipophilic segment, and an intracellular tyrosine kinase (TK) domain that acts as a receptor tyrosine kinase
(3). EGFR signaling activates a pathway that promotes tumor
proliferation, migration, stromal invasion, neovascularization,
and resistance to apoptosis (4). Overexpression of EGFR and its
ligands have been shown in multiple tumors, including NSCLC
(5, 6). Erlotinib is a highly specific EGFR-TK inhibitor that has
been shown to inhibit the growth of human cancer cells in vitro
and has been associated with G1 cell cycle arrest and enhanced
apoptosis (7). Recently, Shepherd et al. reported a phase III trial
Authors’Affiliations: 1Departmentof Medicine, DivisionofHematology/Oncology;
2
Department of Biomathematics; Departments of 3Pathology and Laboratory
Medicine and 4Medicine, Division of Pulmonary and Critical Care Medicine, David
Geffen School of Medicine at University of California at Los Angeles; 5Greater Los
Angeles Veterans Affairs Healthcare System, Los Angeles, California; 6Department of
Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee;
7
Pharmaceutical Development Center, The University of Texas M.D. Anderson
Cancer Center, Houston,Texas; and 8OSIPharmaceuticals, Inc., Boulder, Colorado
Received 1/17/06; revised 3/9/06; accepted 3/23/06.
Grant support: NIH grants P50CA90388 (K.L. Reckamp, K. Krysan, R.M.
Elashoff, S.M. Dubinett, and R.A. Figlin), GM15431 (J.D. Morrow and G.L. Milne),
CA77839 (J.D. Morrow and G.L. Milne), DK48831 (J.D. Morrow and G.L. Milne),
and ES13125 (J.D. Morrow and G.L. Milne); GLAVAHS Career Development Award
(K.L. Reckamp); University of California at Los Angeles STOP Cancer Memorial
Award (K.L. Reckamp); and American Society of Clinical Oncology Young
Investigator Award (K.L. Reckamp).
The costs of publication of this article were defrayed in part by the payment of page
charges. This article must therefore be hereby marked advertisement in accordance
with 18 U.S.C. Section 1734 solely to indicate this fact.
Note: S.M. Dubinett and R.A. Figlin share senior authorship of this study.
Requests for reprints: Karen L. Reckamp, David Geffen School of Medicine at
University of California at Los Angeles, 10945 LeConte Avenue, Suite 2333,
Los Angeles, CA 90095. Phone: 310-825-5788; Fax: 310-267-1491; E-mail:
kreckamp@ mednet.ucla.edu.
F 2006 American Association for Cancer Research.
doi:10.1158/1078-0432.CCR-06-0112
www.aacrjournals.org
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Cancer Therapy: Clinical
of erlotinib alone versus placebo in patients with advanced
NSCLC following failure of first or second line chemotherapy,
which showed a significant increase in overall survival in
erlotinib-treated patients (8). Molecular evaluation of EGFR in
a subset of patients showed that EGFR expression and
polysomy or amplification of EGFR predicted an improvement
in overall survival in those who received erlotinib by univariate
analysis, whereas mutational status alone did not (9).
Cyclooxygenase (COX) is the rate-limiting enzyme in the
conversion of arachidonic acid to prostaglandins and thromboxanes. Two isoforms of COX have been identified: COX-1,
which is a constitutive enzyme produced in most cells, and
an inducible enzyme COX-2. COX-2 can be up-regulated in
response to growth factors, cytokines, tumor promoters, and
other stimuli (10). Multiple studies have suggested that
overexpression of COX-2 plays a significant role in tumor
development, angiogenesis, tumor invasion, resistance to
apoptosis, and suppression of host immunity (11 – 15). It has
been reported to be constitutively overexpressed in a variety of
malignancies, including NSCLC (16). In murine lung cancer
models, inhibition of COX-2 resulted in reduction in tumor
growth and prolonged survival (12). Importantly, recent
studies suggest that tumor COX-2 expression promotes EGFR
TK inhibition (TKI) resistance (17). Previous trials using the
COX-2 inhibitor celecoxib for chemoprevention and treatment
of cancer have used an oral dose of 400 mg twice daily (bid).
This is based on the published studies of celecoxib in familial
adenomatous polyposis, in which the 400 mg bid dose led to a
significant reduction in the number of polyps compared with
100 mg bid (18). This dose has been approved by the Food and
Drug Administration for chemoprevention of colorectal carcinoma in familial adenomatous polyposis subjects and has been
the choice in subsequent trials. The optimal biological dose
(OBD) for celecoxib in cancer therapy has not been defined.
Evidence that EGFR and COX-2 have related signaling
pathways that can interact to regulate cellular proliferation,
migration, and invasion (17, 19 – 21) has triggered interest in
evaluating the combination of COX-2 inhibition and EGFR
inhibition in NSCLC. Recently, the combination of celecoxib
and the EGFR TKI gefitinib was evaluated in a phase I study in
head and neck carcinoma, and the combination was well
tolerated with a 22% response rate (22). The overexpression of
COX-2 and EGFR in NSCLC and the interaction of their
signaling pathways provide a unique method for inhibiting
tumor angiogenesis, invasion, and growth. The preclinical
documentation that the COX-2 metabolite prostaglandin E2
(PGE2) could promote EGFR TKI resistance strongly suggested
the potential for COX-2 inhibition to augment the efficacy of
EGFR inhibition (17). Thus, these findings provided the
rationale for investigating the OBD and toxicity and the activity
of erlotinib and celecoxib in a phase I clinical trial in advanced
NSCLC.
Materials and Methods
Study design
A phase I, nonrandomized, multicohort, dose escalation trial was
conducted at the University of California at Los Angeles Medical Center
between August 2003 and June 2005. The University of California at
Los Angeles institutional review board approved this study protocol,
and all patients provided written informed consent.
Clin Cancer Res 2006;12(11) June 1, 2006
Patient selection
Adults over the age of 21 capable of giving informed consent, with
pathologically proven stage IIIb or IV NSCLC measurable by Response
Evaluation Criteria in Solid Tumors Guidelines, were eligible for this
study. Further inclusion criteria were an Eastern Cooperative
Oncology Group performance status of 0, 1, or 2 and progressive
disease despite z2 prior chemotherapy regimens as standard of care
or subject’s refusal to receive standard chemotherapy. Subjects were
also required to have normal renal function (defined as serum
creatinine V2 mg/dL), normal liver function (defined as serum total
bilirubin V1.5, or serum transaminases V2.5 the upper limits of
normal), no evidence of coagulopathy (defined as prothrombin time
and/or partial thromboplastin time V1.5 upper limits of normal or
platelets z100,000), no evidence of leukopenia (defined as absolute
neutrophil count z1,500/mm3), and a negative pregnancy test before
initiation of treatment and adequate contraception throughout
treatment.
Exclusion criteria included a history of radiation therapy, chemotherapy, noncytotoxic investigational agents, or corticosteroids within
4 weeks of initiating treatment; evidence of New York Heart Association
class III or greater cardiac disease; history of myocardial infarction
within the last 12 months, symptomatic ventricular arrhythmia, or
symptomatic conduction abnormality; comorbid disease or a medical
condition that would impair the ability of the subject to receive or
comply with the study protocol; hypersensitivity of celecoxib, sulfonamides, aspirin, or other nonsteroidal anti-inflammatory drugs or to any
reagents used in the study; previous history of gastrointestinal
ulceration, bleeding, or perforation; concurrent use of COX-2 inhibitors
or other nonsteroidal anti-inflammatory drugs or treatment with
fluconazole or lithium; prior history of EGFR inhibitor or COX-2
inhibitor for the treatment of metastatic NSCLC; lactating females; and
active central nervous system metastasis regarded as untreated or
previously treated and growing. Following the notification from Pfizer,
Inc. (New York, NY) regarding new cardiovascular safety issues for
celecoxib on December 17, 2004, the exclusion criteria were modified
to exclude any patient with a prior history of myocardial infarction or
stroke.
Treatment and dose escalation
Erlotinib was supplied by OSI Pharmaceuticals, Inc. (Melville, NY)
and Genentech Inc. (South San Francisco, CA). Three subjects were
assigned to each cohort and received erlotinib at a fixed dose of 150 mg
p.o. daily for two 4-week cycles. In addition, they received celecoxib in
escalating doses per cohort, starting with 200 mg p.o. bid and
increasing by 100 mg doses to 400 mg p.o. bid, and then increasing
by 200 mg doses to 800 mg p.o. bid. Following the notification of new
cardiovascular safety issues for celecoxib, the study protocol was
amended to add cohort 6. Subjects in this cohort 6 received celecoxib at
800 mg p.o. bid for 4 weeks followed by 400 mg p.o. bid. Dose
escalation was considered when three subjects in a cohort were
evaluated for 28 days without experiencing any dose-limiting toxicity
(DLT); the next dose cohort was opened. A DLT was defined as two or
more grade 3 or a single grade 4 toxicity, as assessed by the National
Cancer Institute Common Toxicity Criteria. In the presence of a toxicity
grade z3 within the first 28-day safety period, three additional subjects
would be added at that dose level. If grade 3 or 4 toxicity occurred in
cohort one, a dose reduction of celecoxib to observe for toxicity at the
lower dose was planned. If a DLT was observed in cohort 1, the dose of
celecoxib would have been reduced to 100 mg p.o. bid in cohort 1. The
OBD was determined at the lowest dose level showing optimal
biological activity, defined as a maximal decrease in the level of urinary
PGE-M, where no DLT occurred. All subjects were monitored for
clinical and biological responses for 8 weeks, and the duration of
treatment continued until subjects developed progressive disease or
unacceptable toxicity. Subjects continued celecoxib up to 12 months
only, after that time, they continued erlotinib alone while they
remained on study.
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Combined Celecoxib and Erlotinib in Advanced NSCLC
Biomarker evaluation
Urinary PGE-M measurement. Urine samples were analyzed in a
blinded manner by J.M. (Vanderbilt University, Nashville, TN).
Twenty-four-hour urine samples were collected at baseline, at week
4, and at week 8 of the study. Collection containers were refrigerated
during the collection. Each specimen was aliquoted into 25-mL
cryovials and stored at 80jC. Urinary PGE-M levels were measured
by mass spectrometry as previously described (23, 24). Briefly, 1 mL
of urine was acidified to pH 3 with 1 mol/L HCl, and endogenous
PGE-M was then converted to the O-methyloxime derivative by
treatment with 0.5 mL of 16% (w/v) methyloxime HCl in 1.5 mol/L
sodium acetate buffer (pH 5). Following a 1-hour incubation, the
methoximated PGE-M was extracted with 10 mL water adjusted to pH
3, and the aqueous sample was applied to a C-18 Sep-Pak (Waters,
Milford, MA) that had been preconditioned with 5 mL methanol and
5 mL water (pH 3). The Sep-Pak was washed with 20 mL water (pH 3)
and 10 mL heptane. PGE-M was then eluted from the Sep-Pak with
5 mL ethyl acetate, and any residual aqueous material was removed
from the eluate by aspiration. The [2H6]O-methyloxime PGE-M
internal standard (6.2 ng in 10 AL ethanol) was then added, and the
eluate was evaporated under a continuous stream of nitrogen at 37jC.
The dried residue was resuspended in 50 AL mobile phase A and was
filtered through a 0.2-Am Spin-X filter (Corning, Corning, NY). This
was followed by liquid chromatography-tandem mass spectrometry as
described (23, 24). Liquid chromatography was done on a 2.1 50mm, 5-Am particle Zorbax Eclipse XDB-C18 column (Aligent, Palo
Alto, CA) attached to a Surveyor MS Pump (ThermoFinnigan, San Jose,
CA). For endogenous PGE-M, the predominant product ion m/z 336
representing [M(OCH3 + H2O)] and the analogous ion m/z 339
[M(OC[2H3] + H2O)] for the deuterated internal standard were
monitored in SRM mode. Quantification of endogenous PGE-M used
the ratio of the mass chromatogram peak areas of the m/z 336 and
339 ions. Urinary 2,3-dinor-6-keto-PGF1a was determined as described
previously (25).
Plasma celecoxib assay. Plasma was collected at baseline, at week 4,
and at week 8 of combination, celecoxib, and erlotinib administration.
The samples were centrifuged at 3,000 rpm for 15 minutes immediately
after collection and stored at 80jC. Celecoxib levels were measured in
plasma by liquid chromatography-tandem mass spectrometry by R.N.
(M.D. Anderson, Houston, TX) as previously described (26). Briefly,
100 AL of plasma were diluted with an equal volume of 10 mmol/L
ammonium acetate (pH 8.5). To this solution, 4 mL hexane/ethyl
acetate (1:1, v/v) were added; the mixture was vortex mixed for
5 minutes and then centrifuged at 4,000 rpm at 5jC for 5 minutes.
The extraction was repeated twice, and the upper organic layer was
collected, pooled, and evaporated to dryness under a stream of nitrogen
at room temperature under reduced room light conditions to limit the
possibility of photooxidation. The sample was then reconstituted in
200 AL of methanol/10 mmol/L ammonium acetate (pH 8.5, 1:1, v/v).
The celecoxib level in the samples was determined by liquid
chromatography-tandem mass spectrometry. Ten microliters of the
sample were injected on a Luna 3-Am phenyl-hexyl 2 150 mm
analytic column (Phenomenex, Torrance, CA). Celecoxib was detected
and quantified by operating the mass spectrometer in electrospraynegative ion mode and monitoring the transition m/z 380.2 > 316.1.
Quantification was done by comparing the sample peak areas to a
standard curve constructed from peak areas of extracted plasma sample
added to known amounts of celecoxib.
Plasma erlotinib assay. Plasma was collected at baseline, at week 4,
and at week 8 of combination, celecoxib, and erlotinib (OSI-774)
administration. The samples were centrifuged at 3,000 rpm for
15 minutes immediately after collection and stored at 80jC. Erlotinib
concentrations were determined by a high-performance liquid chromatography-tandem mass spectrometry assay modified from the
method of Hildalgo et al. (27). Briefly, plasma samples were thawed
and mixed, and 100 AL of internal standard were added (methylated
OSI-774 at 50 ng/mL in 100 mmol/L ammonium formate, pH 4.8).
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After mixing, the sample was loaded on a diatomaceous earth extraction
cartridge (Argonaut, Redwood City, CA). The loaded cartridge was
allowed to incubate 30 minutes, and the sample was eluted with t-butyl
methyl ether. The organic fraction was evaporated to dryness under
nitrogen at 35jC. Extracts were reconstituted in 150 AL of mobile phase,
and 20 AL were injected. The high-performance liquid chromatography
system consisted of a Leap CTC Pal autosampler and an Agilent 1100
series binary pump. Chromatographic separation of extracted plasma
samples was done using a Waters, Symmetry C18 column (4.6 50
mm inner diameter, 3.5-Am particle size) in isocratic mode at ambient
temperature. The mobile phase consisted of 70% methanol, 30%
20 mmol/L ammonium formate (pH 4.8), and was delivered at a flow
rate of 1.0 mL/min. Mass spectrometric detection was carried out using
an Applied Biosystems/MDS Sciex API 3000 triple quadrupole mass
spectrometer (Concord, Ontario, Canada), equipped with an atmospheric pressure chemical ionization source operating in positive ion
mode under multiple reaction monitoring. The following transitions
were monitored: m/z 394.3 > 278.0 for OSI-774 and m/z 408.4 > 292.0
for internal standard. Peak area ratios (erlotinib peak area/internal
standard) versus concentration were fitted to a linear regression
equation, with 1/x 2 weighting. The regression equation was used to
calculate concentrations of OSI-774 in the samples. The range of the
assay was from 1.00 to 600 ng/mL.
EGFR mutation analysis. EGFR mutational analysis was done at
the CLIA certified laboratory at the City of Hope Medical Center
(Duarte, CA). The laboratory routinely performs mutational analysis
for a number of cancer predisposition syndromes. For this assay,
tumor blocks or slides were submitted. Slides were reviewed by a
board-certified pathologist who demarcated areas of tumor for
dissection. Needle microdissection was done under a microscope,
taking two representative areas from the region demarcated by the
pathologist. These areas were digested overnight. Each dissected area
was analyzed independently. Exons 18 to 21 of the EGFR gene
were amplified from the digested products by PCR. Negative controls
were included to rule out contamination. The amplified products were
directly sequenced using ABI’s automated fluorescent sequencing kit
and sequencer. The chromatogram data were then reviewed for
changes and reported.
Statistical analysis
The primary end points of this trial were safety and OBD; therefore,
no formal sample size estimation was done. Patients who received at
least one dose of both celecoxib and erlotinib were evaluated for safety.
Descriptive statistics on patient characteristics and outcomes have been
done. Patients who received at least 4 weeks of the combination were
evaluated for both safety and response. Exploratory analyses were done
to characterize the relationship between urinary PGE-M and baseline
clinical characteristics and outcomes Fisher’s exact test or Wilcoxon
rank-sum test. Mixed logistic regression models were used to correlate
change in urinary PGE-M and response to baseline factors.
Results
Patient characteristics. Twenty-two patients were enrolled at
the University of California at Los Angeles Medical Center.
Twenty-two patients were evaluable for toxicity, and 21 were
evaluable for response; the remaining patient received an
interruption of celecoxib at week 2 of treatment secondary to
the Food and Drug Administration warning regarding cardiovascular safety and remained on erlotinib alone. The median
number of prior regimens in this study was one (range, 0-4).
Ten subjects received one prior systemic therapy; five patients
had received z2 prior therapies; and seven refused standard
chemotherapy and had received no prior treatments. Demographics are listed in Table 1. The average age was 64 years
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Cancer Therapy: Clinical
Table 1. Patient characteristics
Gender
Female
Male
Age
Mean F SD
Min-max, median
Stage
IIIb
IV
ECOG performance status
0
1
Histology
AD
SQ
NS
Tobacco
0
1-20
>20
No. prior treatments
0
1
z2
7
15
64.1 F15.7
35-94, 66
2
20
13
9
14
5
3
9
4
9
7
10
5
Abbreviations: AD, adenocarcinoma, SQ, squamous cell carcinoma, NS,
NSCLC subtype not specified; ECOG, Eastern Cooperative Oncology Group.
(range, 35-94 years), and the most patients were male and had
some prior smoking history (range, 0-90 pack-years: one
current smoker). Nine patients had an Eastern Cooperative
Oncology Group performance status of 1, whereas 13 had a
performance status of 0 at baseline. Twenty patients had stage
IV disease, and two had stage IIIB with pleural effusion.
Toxicity. Dose escalation proceeded through cohort 5
(celecoxib, 800 mg bid) without any DLT. The final cohort
(cohort 6) received celecoxib at 800 mg bid for 4 weeks
followed by 400 mg bid, and no DLTs were observed. The most
common adverse events were skin toxicity and diarrhea as
commonly seen with erlotinib alone. Skin toxicity occurred in
86% of patients at any grade, and one patient developed a
grade 3 event as shown in Table 2. Fifty-five percent of patients
experienced grade 1 diarrhea, and 5% experienced grade 2
diarrhea. One subject in cohort 6 developed a grade 3
gastrointestinal bleed requiring blood transfusion and was
discontinued from study. Three subjects developed asymptomatic elevations in amylase: one grade 1, one grade 2, and one
grade 3 was seen. Four subjects experienced grade 1 elevations
of serum glutamic-oxaloacetic transaminase. Two subjects
developed allergic reactions in the form of urticaria within
several hours of taking the first dose of celecoxib and erlotinib.
The reactions resolved with diphenhydramine and did not
recur. Grade 1 alopecia and grade 1 keratitis were seen in one
subject each. One patient developed a cardiovascular toxicity
in the form of myocardial infarction, which occurred 11 days
following discontinuation of celecoxib and erlotinib and was
due to prior cardiac history and not drug related. This occurred
Clin Cancer Res 2006;12(11) June 1, 2006
before the Food and Drug Administration notification and
change in exclusion criteria. The patient had been on a drug
interruption secondary to grade 3 skin toxicity at the time of the
event. Two subjects required drug interruptions during treatment: one in cohort 1 (celecoxib, 200 mg bid) secondary to
grade 3 skin toxicity and another in cohort 3 (celecoxib, 400 mg
bid) secondary to grade 2 stomatitis. The first patient developed
progressive disease and went off study, whereas the second
recovered and required a dose reduction to 100 mg four times
daily of erlotinib and had a partial response. There were no
treatment-related deaths.
Biologically active dose. We investigated urinary 11ahydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid
(PGE-M, the major urinary metabolite of PGE2) to determine
the OBD of celecoxib. Urinary PGE-M was measured by mass
spectrometry. Baseline values were compared with levels after
4 and 8 weeks of treatment. There was a trend toward lower
baseline urinary PGE-M levels in subjects who experienced
a partial response or stable disease, but this result was not
significant. Urinary PGE-M levels at weeks 4 and 8 were
significantly lower than baseline (P = 0.0034 and P = 0.0537,
respectively), but there was no significant difference between
week 4 and 8 urinary PGE-M levels (Fig. 1). The percentage
change in urinary PGE-M from baseline at week 4 was
significantly correlated with celecoxib dose (Spearman correlation coefficient = 0.88, P < 0.0001). Other clinical factors
(gender, age, Eastern Cooperative Oncology Group performance status, histology, and mutation status) were not
significantly correlated with the percentage change in PGE-M
level. A 65% decline in PGE-M was shown after 8 weeks of
treatment at a celecoxib dose of 400 mg bid compared with
<10% at doses of 200 and 300 mg bid. Furthermore, we saw
an additional decline at celecoxib doses of 600 mg bid
(87%) and 800 mg bid (84%; Fig. 2). A mixed model was
developed to correlate urinary PGE-M levels at both weeks
4 and 8 with baseline levels, celecoxib dose, and time. We
found that subjects in cohort 4 (celecoxib, 600 mg bid) and
cohort 5 (celecoxib, 800 mg bid) had significantly lower
urinary PGE-M levels than cohort 3 (celecoxib, 400 mg bid),
with a P = 0.0480 (Fig. 2). Moreover, subjects in cohorts
4 and 5 had significantly lower urinary PGE-M levels than
cohorts 1 to 3 (P = 0.0014). Therefore, 600 mg bid is the
OBD of celecoxib when combined with erlotinib in advanced
NSCLC.
Response to therapy. Target lesions were measured according
to Response Evaluation Criteria in Solid Tumors. Of the 21
evaluable subjects, 7 experienced partial responses (33%), and
5 patients maintained stable disease (24%) for a disease control
rate of 57% (Table 3). Nineteen of 21 patients have had disease
progression with a median time to progression of 17 weeks
(range, 5-95 weeks; Table 3). The duration of response was 69
weeks in one patient and 24 weeks in four patients with partial
responses. Two patients continue with a partial response at
32 weeks. Five of seven subjects with partial responses have
progressed at 27 to 95 weeks, and five subjects with stable
disease have progressed at 16 to 84 weeks (Table 3). Younger
age and positive mutation status correlated with partial
response (P = 0.0247 and P = 0.0034, respectively). Gender,
stage, Eastern Cooperative Oncology Group performance
status, number of prior treatments, histology, and smoking
history were not correlated with response. At the time of
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Combined Celecoxib and Erlotinib in Advanced NSCLC
analysis, eight patients had died secondary to progressive
disease.
Plasma celecoxib and erlotinib measurement. Increasing
doses of celecoxib resulted in variable elevations in plasma
concentration and doses at z400 mg bid produced more
consistent levels above the known steady state of 705 ng/mL
(celecoxib PI). Celecoxib at these doses did not have a
significant effect on erlotinib concentration in the plasma at
any doses level. Smoking status has been noted to be the most
significant prognostic factor for predicting response to erlotinib
(8). When plasma concentration of erlotinib was studied in
never/former smokers compared with current smokers, erlotinib levels were found to be 50% lower in subjects who smoked
(28). One subject in this study supports this observation. This
study enrolled only one current smoker who continued
smoking for the first 4 weeks of treatment and had no
detectable level of OSI-774 in the plasma at week 4. The
subject quickly progressed despite smoking cessation during the
second 4 weeks on study.
EGFR mutation status. Clinical responses have been
observed in subjects with and without activating mutations.
Seventeen of 21 subjects had tumor specimen available for
EGFR mutation analysis. Five of 17 (29%) had mutations in
the EGFR gene, all of whom experienced partial responses.
Three male patients had a previously described deletion in
exon 19, and two had point mutations in exon 18, one of
which has been described (29 – 31). Patient 3, a 50-year-old
male, nonsmoker with stage IV NSCLC had a partial response
to erlotinib/celecoxib by Response Evaluation Criteria in
Solid Tumors. Analysis of EGFR status in this patient revealed
a mutation that has not previously been described: a
heterozygous 2105C for T substitution in the juxtamembrane
region outside of EGFR TK domain. This mutation resulted in
substitution of Ala702 for valine (A702V) in the protein
sequence. Thus far, only mutations in the TK domain of
EGFR and particularly in the ATP-binding pocket, responsible
for inhibitor binding, have been implicated in significant
clinical responses with EGFR TK inhibitor therapy. Although
investigations have concentrated on the receptor’s TK
domain, structural studies of EGFR/erlotinib binding have
shown that Ala702 may be important for the protein-drug
interaction (32).
Discussion
The overexpression of COX-2 and EGFR in NSCLC and the
interaction of their signaling pathways provide a strong
rationale to evaluate the opportunity for inhibiting tumor
growth, angiogenesis, and invasion via combination therapy
(17, 19 – 21, 33, 34). EGFR and COX-2 are overexpressed in a
variety of malignancies, including NSCLC (refs. 5, 11 – 16). In
addition, the coexpression of EGFR and COX-2 in human
cervical cancer specimens portended a poor prognosis with
increased recurrences (35). In laboratory-based studies,
Krysan et al. reported novel mechanisms of resistance to EGFR
TKI in NSCLC; this resistance is mediated through an EGFRindependent activation of the mitogen-activated protein
kinase/extracellular signal-regulated kinase signaling pathway
by the COX-2 metabolite PGE2 (17). This resistance pathway
is distinct from that described previously in colon cancer cells
Table 2. Adverse events by cohort (seen in z10% of subjects)
Adverse event
Skin toxicity
Total
Diarrhea
Total
Anemia
Total
Elevated amylase
Total
Nausea
Total
Paronychia
Total
Elevated serum glutamicoxaloacetic transaminase
Total
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Maximum
grade
Cohort 1
(n = 3)
Cohort 2
(n = 3)
Cohort 3
(n = 4)
Cohort 4
(n = 3)
Cohort 5
(n = 3)
Cohort 6
(n = 6)
Total (n = 22),
n (%)
1
2
3
2
0
1
3
0
0
3
0
0
2
1
0
3
0
0
6
0
0
1
2
2
0
3
0
3
0
2
0
1
0
1
1
1
2
0
1
1
0
0
1
2
0
0
1
2
1
1
2
3
0
0
0
0
0
0
0
0
1
0
1
0
0
0
0
1
0
0
1
2
0
0
0
0
0
0
1
0
1
1
0
0
0
0
0
0
0
1
1
2
1
2
0
0
0
0
0
1
0
0
0
0
1
1
1
0
1
0
1
0
0
0
19 (86.3)
1 (4.5)
1 (4.5)
21 (95.5)
12 (54.5)
1 (4.5)
13 (59.1)
5 (22.7)
4 (18.2)
9 (40.9)
1 (4.5)
1 (4.5)
1 (4.5)
3 (13.6)
2 (9.1)
2 (9.1)
4 (18.2)
2 (9.1)
2 (9.1)
4 (18.2)
4 (18.2)
1
0
1
1
1
0
4 (18.2)
1
2
1
3385
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Cancer Therapy: Clinical
Fig. 1. Urinary PGE-M levels during treatment. Urinary PGE-M was measured by
mass spectrometry at baseline, at week 4, and at week 8 in cohorts 1to 5.
5, baseline urinary PGE-M by celecoxib dose cohort. o, week 4 urinary PGE-M by
celecoxib dose cohort. ., week 8 urinary PGE-M by celecoxib dose cohort. Dot,
subject’s value; line, connect the means of celecoxib dose cohorts. Levels at
weeks 4 and 8 were significantly lower than baseline. *, P = 0.05, compared with
baseline; **, P = 0.034, compared with baseline.
(19 – 21) and involves PGE2-mediated, protein kinase C –
dependent extracellular signal-regulated kinase activation that
is not inhibited by otherwise effective doses of the EGFR
inhibitor erlotinib (17). These findings provide evidence for the
possible link between tumor COX-2 overexpression and lung
cancer cell proliferation and migration mediated by elevated
extracellular signal-regulated kinase activity. Thus, more effective therapy may require blocking both the EGFR-dependent
and EGFR-independent pathways to mitogen-activated
protein kinase/extracellular signal-regulated kinase activation
in NSCLC. An additional mechanism whereby COX-2 overexpression can mediate resistance to EGFR TK inhibition relates
to the PGE2-dependent promotion of epithelial to mesenchymal transition (36). Thomson et al. recently reported that
the suppression of epithelial markers, such as E-cadherin, led to
resistance to erlotinib (37). In addition, PGE2 down-regulates
E-cadherin expression by up-regulating transcriptional repressors, including ZEB1 and Snail (36). Importantly, these findings
suggest that COX-2 inhibition may enhance the efficacy of
EGFR TKI therapy in NSCLC and provide a specific biological
rationale to assess this combination in clinical lung cancer
trials.
The potential for added benefits when combining EGFR
and COX-2 inhibition stimulated interest for investigating the
biologically active dose and toxicity of celecoxib when
combined with erlotinib in this phase I clinical trial in
advanced NSCLC. The optimal dose of celecoxib of 600 mg
bid in this combination has been defined without significant
toxicity. In addition, 33% of patients displayed a partial
response, including both patients with and without activating
mutations. Tsao et al. evaluated EGFR by immunohistochemistry, fluorescence in situ hybridization, and mutation status in
a subset of subjects who received erlotinib or placebo and did
not find a significant correlation with survival on multivariate
analysis (9). In this study, sufficient tumor specimens were
not available for evaluating EGFR by immunohistochemistry or
fluorescence in situ hybridization.
Investigation of COX-2 inhibitors with conventional
anticancer therapy in human lung cancer cell lines and in
Clin Cancer Res 2006;12(11) June 1, 2006
murine models showed an inhibition tumor growth both
in vitro and in vivo (38). Several groups have investigated the
therapeutic effects of COX-2 inhibitors in clinical trials. Some
have included the use of conventional chemotherapy
concurrently with celecoxib, both in resectable NSCLC as
neoadjuvant therapy and in advanced NSCLC. The results
using concurrent paclitaxel and carboplatin with celecoxib in
the neoadjuvant setting in stage IB to IIIA NSCLC showed an
increased pathologic and clinical response compared with
historical controls (39). A recent study using COX-2
inhibition in combination with docetaxel in recurrent NSCLC
examined the pretreatment and posttreatment levels of i.t.
PGE2 and urinary PGE-M in a subset of patients. They found
a decline in i.t. and urinary level pre-celecoxib and postcelecoxib (40). These data indicate that celecoxib in
combination with chemotherapy can significantly decrease
PGE2 within tumor tissues and urinary PGE-M, suggesting
that COX-2-dependent expression of genes that are deleterious to the antitumor response may also be decreased.
Furthermore, those patients who experienced a decline in
urinary PGE-M of z72% had an improvement in overall
survival compared with other groups (40). The role of
celecoxib in reducing urinary PGE-M levels is highlighted by
the results presented here, which indicate that doses of
celecoxib below 400 mg bid do not result in a significant
decrease in urinary PGE-M. At doses of z400 mg bid, a dosedependent decline in urinary PGE-M occurred. An OBD of
600 mg bid was established. These data complement the
prior study in which the decline in urinary PGE-M correlated
with survival when celecoxib was used in combination with
chemotherapy (40). These results suggest that urinary PGE-M
measurement may be a valuable tool when developing
clinical trials with targeted celecoxib therapy.
The results of this study must be viewed with regards to the
potential toxicities of this combination. The combination of
celecoxib and erlotinib did not result in added toxicities. When
Fig. 2. Increasing celecoxib doses result in a dose-dependent decrease in urinary
PGE-M. Urinary PGE-M was measured by mass spectrometry at baseline, at
week 4, and at week 8 in cohorts 1to 5. Cohorts 4 and 5 had significantly lower
urinary PGE-M levels than cohorts 1to 3. *, P = 0.0014. Cohorts 4 and 5 had
significantly lower urinary PGE-M levels than cohort 3. **, P = 0.048.
3386
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Combined Celecoxib and Erlotinib in Advanced NSCLC
Table 3. Patient responses
Cohort
Celecoxib
dose
Gender
Age
1
1
1
2
2
2
3
3
3
3
4
4
4
5
5
5
6
6
6
6
6
6
200 bid
200 bid
200 bid
300 bid
300 bid
300 bid
400 bid
400 bid
400 bid
400 bid
600 bid
600 bid
600 bid
800 bid
800 bid
800 bid
800 ! 400
800 ! 400
800 ! 400
800 ! 400
800 ! 400
800 ! 400
M
M
M
M
M
F
F
F
M
F
M
M
M
M
M
M
F
F
M
M
M
F
94
68
68
50
66
72
81
75
35
63
84
40
68
65
66
59
54
85
42
50
47
79
Smoking
status
Never
Former
Former
Never
Former
Former
Former
Former
Never
Never
Never
Never
Former
Former
Never
Former
Current
Former
Never
Never
Former
Former
Tumor
histology
No. prior
treatments
AD
SQ
NS
AD
SQ
AD
AD
AD
AD
AD
AD
AD
AD
AD
AD
NS
SQ
SQ
NS
AD
AD
AD
0
3
1
4
1
2
1
0
2
1
1
0
0
1
1
0
1
0
1
1
2
0
Time to
progression (wk)
19
84
10
95
7
6
36
13
27
NS
9
34
47
9
9
33
7
16
9
z32
z32
5
Mutation
analysis
Response
NA
wt
wt
Exon 18 2105C ! T
wt
NA
Exon 18 2156G ! C
wt
wt
NA
wt
wt
wt
NA
wt
del exon 19
wt
wt
NA
del exon 19
del exon 19
wt
SD
SD
PD
PR
PD
PD
PR
PD
PR
NE
PD
PR
SD
PD
SD
PR
PD
SD
PD
PR
PR
PD
Abbreviations: SD, stable disease; PD, progressive disease; PR, partial response; wt, wild type; NA, not available; del, deletion; M, male; F, female.
the combination of celecoxib and gefitinib was evaluated in
head and neck cancer, doses of gefitinib were escalated from
250 to 500 mg daily, and celecoxib was increased from 200 to
400 mg bid. This combination was well tolerated (22). The
selective COX-2 inhibitor rofecoxib was withdrawn from the
market because of an increased number of thromboembolic
events (acute myocardial infarction and stroke) associated
with its long-term use (41). In December 2004, the National
Cancer Institute announced the early cessation of the
Adenoma Prevention with Celecoxib trial (42). The trial used
celecoxib for the prevention of colorectal polyps in high-risk
subjects. In this study, celecoxib was associated with a doserelated increase in death from cardiovascular events (42). The
risk was seen with long-term use of celecoxib and was not
evident before 12 months on study. The recent information on
the long-term safety of celecoxib in the chemoprevention
setting emphasized the importance of this trial to identify the
biologically active dose of celecoxib. Following notification
from Pfizer regarding new cardiovascular safety issues for
celecoxib, the exclusion criteria were modified to exclude any
patient with a prior history of myocardial infarction or stroke.
Moreover, in light of the long-term effects of high-dose
celecoxib, all subjects who remained on study at 12 months
were required to discontinue celecoxib and remain on
erlotinib alone. This amendment was applicable to two study
patients.
The most common toxicities seen were rash and diarrhea,
which is consistent with reports of toxicity using erlotinib alone
(8). The addition of celecoxib at increasing doses to 800 mg bid
www.aacrjournals.org
did not cause overlapping or additional toxicity. The single
patient who developed myocardial infarction was in cohort 1
(celecoxib, 200 mg bid), had a prior history of myocardial
infarction, and had been enrolled before the release of the
cardiovascular safety information. He had been off study drug,
and the event was judged to be unrelated to the study
medications. One patient developed a grade 3 gastrointestinal
bleed while on the combination therapy. The combination of
erlotinib and celecoxib at doses up to 800 mg bid is generally
well tolerated and did not reveal overlapping toxicity or
cardiovascular toxicity.
Based on these results and laboratory-based preliminary data,
a phase II trial of celecoxib at 600 mg bid and erlotinib versus
erlotinib plus placebo is planned to evaluate responses and
resistance to erlotinib in advanced NSCLC. This study defines
the OBD of celecoxib when combined with EGFR TKI and
shows objective responses with an acceptable toxicity profile.
The preclinical evidence indicating that PGE2 causes resistance
to EGFR TKI implicates COX-2 as an important target in
overcoming EGFR TKI resistance in lung cancer. The biological
importance of these pathways paired with the safety and initial
response findings in this phase I trial show that the potential
benefits of this combination seem to outweigh the risks and
warrant further study with the OBD of 600 mg bid for
celecoxib.
3387
Acknowledgments
We thank Cheryl Elzinga for her assistance in the preparation of this article.
Clin Cancer Res 2006;12(11) June 1, 2006
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Research.
Cancer Therapy: Clinical
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A Phase I Trial to Determine the Optimal Biological Dose of
Celecoxib when Combined with Erlotinib in Advanced Non−
Small Cell Lung Cancer
Karen L. Reckamp, Kostyantyn Krysan, Jason D. Morrow, et al.
Clin Cancer Res 2006;12:3381-3388.
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