Phase I studies of imatinib mesylate combined with cisplatin and irinotecan in patients with small cell lung carcinoma.
ABSTRACT Small cell lung carcinoma (SCLC) cell lines commonly express KIT and its ligand, stem cell factor, suggesting an autocrine loop promoting cell growth. Imatinib inhibits KIT kinase activity. SCLC cells treated with imatinib in vitro undergo cell cycle arrest. Imatinib reduces resistance to irinotecan in vitro. Common metabolic pathways suggest there may be drug interactions between imatinib and irinotecan or cisplatin. In the current study, the authors investigated the feasibility of combining these drugs in the treatment of patients with SCLC.
Two Phase I studies were conducted independently at two institutions. Patients with extensive-disease SCLC underwent therapy with cisplatin, irinotecan, and imatinib using two similar regimens. In one study, immunohistochemical analysis of the expression of potential imatinib targets was performed on pretreatment biopsy specimens, and blood specimens were collected and analyzed for imatinib, irinotecan, and cisplatin pharmacokinetic parameters.
Nine patients were enrolled and were evaluable for toxicity. A high incidence of neutropenia, diarrhea, and thrombosis was observed that precluded dose escalation. Six patients were evaluable for response after four cycles; five patients experienced a partial response and the other patient had developed progressive disease. Four of six tumor specimens tested expressed platelet-derived growth factor receptor-alpha and two expressed KIT. Irinotecan clearance was found to be significantly decreased by imatinib (P < 0.04). No significant alteration in the disposition of cisplatin was observed.
The maximum tolerated dose for this combination with granulocyte-colony-stimulating factor support was identified as imatinib at a dose of 300 mg/day with irinotecan (at a dose of 65 mg/m(2)) and cisplatin (at a dose of 30 mg/m(2)) given on Days 1 and 8, every 21 days. The decreased irinotecan clearance may explain the high incidence of diarrhea and neutropenia noted in the current study.
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ABSTRACT: In this study, we have tried to find new targets and effective drugs for imatinib-resistant chronic myelogenous leukemia (CML) cells displaying loss of Bcr-Abl kinase target dependence. The imatinib-resistant K562/R1, -R2 and -R3 cells showed profound declines of Bcr-Abl level and concurrently exhibited up-regulation of Bcl-2 and Ku70/80, and down-regulation of Bax, DNA-PKcs and BRCA1, suggesting that loss of Bcr-Abl after exposure to imatinib might be accompanied by other cell survival mechanism. K562/R3 cells were more sensitive to camptothecin (CPT)- and radiation-induced apoptosis than K562 cells, indicating hypersensitivity of imatinib-resistant cells to DNA damaging agents. Moreover, when K562 cells were treated with the combination of imatinib with CPT, the level of Bax and the cleavage of PARP-1 and DNA-PK were significantly increased in comparison with the effects of each drug. Therefore, our study suggests that CPT can be used to treat CML with loss of Bcr-Abl expression.Cancer Letters 08/2007; 252(1):75-85. · 5.02 Impact Factor
- Clinical Lung Cancer 07/2010; 11(4):222. · 2.04 Impact Factor
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ABSTRACT: Molecular pathology involves study of nucleic acids, genes, and gene products.1–9 The development and progression of human cancers are linked to genetic instability and the accumulation of multiple genetic mutations, which can be investigated with the tools of molecular pathology.10–25 Molecular pathology provides a basis for understanding the biology of lung cancer,26–36 including its pathogenetic relationship to tobacco smoking,37–57 and increasingly is providing targets for therapeutic intervention. 58–78 In this section, we briefly review the basic terminology and concepts, as an introduction or refresher to subsequent sections of this chapter, and we discuss nucleic acids, genes, and gene products; replication, translation, and transcription; posttranslational modifications of gene products and protein degradation; transcription factors, cell surface receptors and signaling pathways, the cell cycle, apoptosis, cell survival and DNA damage repair; mutations; and microRNAs and siRNAs.05/2010: pages 47-157;
Phase I Studies of Imatinib Mesylate Combined with
Cisplatin and Irinotecan in Patients with Small Cell
Faye M. Johnson, M.D., Ph.D.1
Lee M. Krug, M.D.2
Hai T. Tran, Pharm.D.1
Stephanie Shoaf, M.S.3
Victor G. Prieto, M.D., Ph.D.4
Pheroze Tamboli, M.D.4
Beverly Peeples, B.S.N.1
Jyoti Patel, M.D.2
Bonnie S. Glisson, M.D.1
1Department of Thoracic Head and Neck Medical
Oncology, The University of Texas M. D. Anderson
Cancer Center, Houston, Texas.
2Thoracic Oncology Service, Department of Med-
icine, Memorial Sloan-Kettering Cancer Center,
New York, New York.
3Department of Pharmacy, The University of Texas
M. D. Anderson Cancer Center, Houston, Texas.
4Department of Pathology, The University of Texas
M. D. Anderson Cancer Center, Houston, Texas.
Supported by National Cancer Institute Grant NO1-
CM17105 (Memorial Sloan-Kettering Cancer Cen-
ter) and Novartis Pharmaceuticals (The University
of Texas M. D. Anderson Cancer Center).
Address for reprints: Bonnie S. Glisson, M.D., De-
partment of Thoracic Head and Neck Medical On-
cology, P.O. Box 301402, The University of Texas
M. D. Anderson Cancer Center, Houston, TX
Received April 28, 2005; revision received August
12, 2005; accepted August 16, 2005.
BACKGROUND. Small cell lung carcinoma (SCLC) cell lines commonly express KIT
and its ligand, stem cell factor, suggesting an autocrine loop promoting cell growth.
Imatinib inhibits KIT kinase activity. SCLC cells treated with imatinib in vitro
undergo cell cycle arrest. Imatinib reduces resistance to irinotecan in vitro. Com-
mon metabolic pathways suggest there may be drug interactions between imatinib
and irinotecan or cisplatin. In the current study, the authors investigated the
feasibility of combining these drugs in the treatment of patients with SCLC.
METHODS. Two Phase I studies were conducted independently at two institutions.
Patients with extensive-disease SCLC underwent therapy with cisplatin, irinotecan,
and imatinib using two similar regimens. In one study, immunohistochemical
analysis of the expression of potential imatinib targets was performed on pretreat-
ment biopsy specimens, and blood specimens were collected and analyzed for
imatinib, irinotecan, and cisplatin pharmacokinetic parameters.
RESULTS. Nine patients were enrolled and were evaluable for toxicity. A high
incidence of neutropenia, diarrhea, and thrombosis was observed that precluded
dose escalation. Six patients were evaluable for response after four cycles; five
patients experienced a partial response and the other patient had developed
progressive disease. Four of six tumor specimens tested expressed platelet-derived
growth factor receptor-? and two expressed KIT. Irinotecan clearance was found to
be significantly decreased by imatinib (P ? 0.04). No significant alteration in the
disposition of cisplatin was observed.
CONCLUSIONS. The maximum tolerated dose for this combination with granulo-
cyte–colony-stimulating factor support was identified as imatinib at a dose of 300
mg/day with irinotecan (at a dose of 65 mg/m2) and cisplatin (at a dose of 30
mg/m2) given on Days 1 and 8, every 21 days. The decreased irinotecan clearance
may explain the high incidence of diarrhea and neutropenia noted in the current
study. Cancer 2006;106:366–74. © 2005 American Cancer Society.
KEYWORDS: imatinib mesylate, cisplatin, irinotecan, small cell lung carcinoma, KIT.
Imatinib mesylate (STI571) is a potent tyrosine kinase inhibitor that
selectively inhibits the ABL family (ABL, BCR-ABL, ABL-related gene
[ARG]), platelet-derived growth factor receptor (PDGFR), and KIT
kinases1Imatinib has antitumor activity against chronic myelogenous
leukemia (CML)2and gastrointestinal stromal tumors3through its
inhibition of BCR-ABL and KIT kinases, respectively.
Small cell lung carcinoma (SCLC) cell lines and tumor specimens
commonly coexpress KIT and its ligand, stem cell factor (SCF).4–6
Treatment of SCLC cell lines with imatinib in vitro has been reported
dvances in the understanding of the molecular mechanisms of
cancer have led to novel biologic agents with antitumor effects.
© 2005 American Cancer Society
Published online 9 December 2005 in Wiley InterScience (www.interscience.wiley.com).
to inhibit SCF-mediated KIT activation and signal
transduction. Imatinib also induces growth inhibition
in SCLC cell lines and apoptosis when those cells are
grown in the presence of exogenous SCF.7,8Imatinib
was found to have modest antitumor activity in one of
three human SCLC cell lines injected subcutaneously
The efficacy of single-agent imatinib for SCLC was
evaluated in three Phase II studies and was not asso-
ciated with objective tumor regression.10–12However,
imatinib may affect tumor response when combined
with traditional cytotoxic agents by preventing tumor
regrowth between treatment cycles. Imatinib also may
prevent resistance to irinotecan by inhibiting the
ABCG2 transporter or increasing topoisomerase I ac-
In the current study, we report on the evaluation
of imatinib combined with irinotecan and cisplatin in
two trials for patients with SCLC. A variety of different
chemotherapy regimens have been used for SCLC and
none have been proven clearly superior.15The com-
bination of cisplatin and irinotecan was reported to be
superior to cisplatin and etoposide in terms of survival
for patients with extensive SCLC in a single Phase III
study.16The Memorial Sloan-Kettering Cancer Center
(MSKCC) trial used the same schedule of irinotecan
and cisplatin as was used in this Phase III study. In the
University of Texas M. D. Anderson Cancer Center
(MDACC) trial, we used a schedule based on a Phase II
study of weekly irinotecan and cisplatin in patients
with advanced nonsmall cell lung carcinoma.17In this
study, patients received weekly cisplatin at a dose of
30 mg/m2and irinotecan at a dose of 65 mg/m2for 4
weeks and then had 2 weeks with no chemotherapy
(“4 on–2 off”). Because many patients missed Weeks 3
and 4 of therapy, we gave patients weekly cisplatin at
a dose of 30 mg/m2and irinotecan at a dose of 65
mg/m2for 2 weeks followed by 1 week without che-
motherapy (“2 on–1 off”) to increase dose intensity.
There are potential pharmacokinetic interactions
between imatinib and chemotherapy. Imatinib is
principally metabolized by CYP3A4 to the N-demethyl
derivative; other cytochrome p450 enzymes play mi-
nor roles in its metabolism.18Imatinib also is a potent
CYP3A4/5. The coadministration of imatinib and
agents that are metabolized by cytochrome 450 en-
zymes may result in increased exposure to imatinib
and the coadministered agents. Irinotecan is a camp-
tothecin derivative that is converted by carboxyester-
ases to an active metabolite, 7-ethyl-10-hydroxycamp-
tothecin (SN-38).19,20SN-38 is conjugated further in
the liver and then excreted in the bile and urine. In
addition, irinotecan undergoes oxidation mediated by
CYP3A4/5 to various metabolites with varying degrees
of activity.19,20Cisplatin is a platinating agent with an
unclear metabolic pathway.21To the best of our
knowledge, no pharmacokinetic drug interactions
have been observed between irinotecan and cispla-
tin.22Given imatinib’s shared metabolic pathway with
irinotecan, combination therapy with these agents
may lead to increased irinotecan or imatinib exposure
In the current study, we conducted two indepen-
dent Phase I studies to establish the toxicity and max-
imum tolerated dose (MTD) of imatinib when com-
bined with irinotecan and cisplatin for the treatment
of patients with extensive SCLC. In the study con-
ducted at MDACC, tumors were evaluated for the ex-
pression of ABL, ARG, PDGFR-?, PDGFR-?, and KIT.
We collected pharmacokinetic data to assess the in-
teractions of these three agents when given concur-
rently. Because of the potential interaction between
irinotecan and imatinib, our starting dose of imatinib
was reduced to 300 mg from the standard 400 mg dose
used in treating CML patients. The study conducted at
MSKCC used the same drugs with a different schedule.
MATERIALS AND METHODS
Patients with a histologic/cytologic diagnosis of un-
treated SCLC, extensive disease, and asymptomatic
central nervous system metastases were eligible for
these studies. The inclusion criteria included measur-
able or evaluable disease; adequate performance sta-
tus (Zubrod performance status of 0-2 required at
MDACC and a Karnofsky score ? 70% required at
MSKCC); no prior invasive tumor within 5 years; and
adequate hematologic, hepatic, and renal function.
The studies were approved by the two institutional
review boards and patients provided written informed
consent.. Pretreatment tissue for immunohistochem-
istry was required for the MDACC study, but results
did not affect eligibility.
The doses of irinotecan and cisplatin were fixed, and
the dose of imatinib varied. A standard “3?3” design
was used, with the first cohort treated at Dose Level 0.
If no patients experienced a dose-limiting toxicity
(DLT), the next cohort would be treated at the next
higher dose level. The MTD was defined as that dose
producing a DLT in two of six patients or that dose
level immediately below the one producing a DLT in
at least three of six patients.
In the MDACC trial, patients received irinotecan
at a dose of 65 mg/m2intravenously [i.v.] and cisplatin
at a dose of 30 mg/m2i.v. on Days 1 and 8, every 21
Imatinib in Small Cell Lung Ca/Johnson et al. 367
days. Oral imatinib was administered Day 2 of the first
cycle (to allow for baseline pharmacokinetics on Day
1). There were 3 predefined dose levels of imatinib:
Dose Level 0 (300 mg daily), Level 1 (400 mg daily),
and Level 2 (600 mg daily). In the MSKCC trial, pa-
tients received irinotecan (at a dose of 60 mg/m2i.v.)
on Days 1, 8, and 15 and cisplatin (at a dose of 60
mg/m2i.v.) on Day 1 only of a 28-day cycle. Treatment
with oral imatinib was initiated at Dose Level 0 on Day
22 of Cycle 1 (1 week before Cycle 2). There were 3
predefined oral dose levels of imatinib: Dose Level 0
(400 mg daily), Level 1 (600 mg daily), and Level 2 (800
mg daily). Imatinib was continued after the comple-
tion of four cycles of chemotherapy until disease pro-
gression or unacceptable toxicity developed.
The starting dose level of imatinib was based on
the safety, tolerability, and serum levels of imatinib in
patients with CML. Higher doses may be beneficial in
patients with SCLC given the relatively high 50% in-
hibitory concentration (IC50) of imatinib (5 ?M) re-
ported in SCLC cell lines in vitro.
Using the National Cancer Institute (NCI) Com-
mon Toxicity Criteria, the DLT in the MDACC study
was defined as a Grade 3 or higher nonhematologic
toxicity (excluding nausea and emesis), Grade 4 neu-
tropenia lasting ? 7 days, febrile neutropenia, or
Grade 4 thrombocytopenia. The MSKCC study also
used NCI Common Toxicity Criteria with similar pa-
rameters to define the DLT: any Grade 4 hematologic
toxicity, neutropenic fever, a dose delay of ? 2 weeks,
creatinine ? 2 mg/L for ? 2 weeks, Grade 3 diarrhea
lasting ? 48 hours, any Grade 4 diarrhea, Grade 3
fatigue lasting ? 1 week, or any other Grade 3 or 4
The cisplatin infusions were given first, followed by
irinotecan. Imatinib was given daily beginning on Day
2 of Cycle 1 (at MDACC) or Day 22 of Cycle 1 (at
Weekly chemotherapy was delayed for 1 week if
the absolute neutrophil count was ? 1200 k/?L or the
platelet count was ? 100,000 k/?L. Nonhematologic
toxicity must have resolved to Grade 1 before chemo-
therapy could continue. If the creatinine clearance
was 40–59 mL/minute, cisplatin was given at a 50%
reduced dose. Cisplatin was withheld for a creatinine
clearance ? 40 mL/minute.
Evaluation of Response to Treatment
Pretreatment laboratory tests included a complete
blood count with differential and platelet count; ala-
nine aminotransferase (ALT), aspartate aminotrans-
ferase (AST), total bilirubin, alkaline phosphatase, to-
tal protein, albumin, calcium, electrolytes, blood urea
nitrogen (BUN), creatinine, and magnesium; and uri-
nalysis. A chest X-ray, electrocardiogram, computed
tomography (CT) scan of the chest and abdomen,
magnetic resonance imaging of the brain, and radio-
nuclide bone scans were obtained within 4 weeks of
the initiation of treatment.
Weekly laboratory tests included complete blood
count with differential and platelet count and electro-
lytes, magnesium, BUN, and creatinine. Alkaline
phosphatase, ALT, total bilirubin, calcium, and albu-
min were measured before each cycle. A medical on-
cologist evaluated each patient before every cycle..
Chest X-rays were obtained during Weeks 4, 7, and 13
in the MDACC study. Patients were restaged with CT
after Cycle 4 (at MDACC) and after Cycles 2 and 4 (at
World Health Organization criteria23(at MDACC)
and Response Evaluation Criteria in Solid Tumors
(RECIST) criteria (at MSKCC) were used to define re-
Pharmacokinetic studies were conducted in the
MDACC trial. Samples for determining plasma con-
centrations of imatinib were collected at the following
times: 0 (predose), 2 hours, 4 hours, 6 hours, and 8
hours after oral ingestion on Day 15 of Cycle 1 (ima-
tinib alone) and Day 1 of Cycle 2 (imatinib and che-
motherapy). Samples for determining irinotecan and
cisplatin concentrations were collected on Day 1 of
Cycle 1 (chemotherapy alone) and Cycle 2 (imatinib
and chemotherapy) at the following times: 0 (pre-
dose), 0.5 hours, 1.7 hours, 4 hours, 5.5 hours, and 8
hours after the initiation of irinotecan infusion and at
0 (predose), 1 hours, 3 hours, 4.5 hours, and 7 hours
after the initiation of cisplatin infusion. All samples
were collected into a heparinized vacutainer and sep-
aration was performed by centrifugation at 1500 rev-
olutions per minute for 10 minutes at 5 °C. For cispla-
tin, an additional separation step was taken to isolate
unbound cisplatin via ultracentrifugation.25Processed
samples were stored at ?70 °C.
The concentrations of imatinib were analyzed us-
ing a validated liquid chromatography/tandem mass
spectrometry method with a lower limit of quantita-
tion of 0.100 ng/mL.26We were unable to obtain
SN-38 to use as a standard to quantitate SN-38 levels.
The concentration of irinotecan was analyzed using a
validated high-performance liquid chromatography
method with fluorescence detection.27Concentrations
of cisplatin in plasma ultrafiltrate samples were ana-
lyzed using validated flameless atomic absorption
spectroscopy (Varian, Palo Alto, CA) with a graphite
368CANCER January 15, 2006 / Volume 106 / Number 2
tube atomizer assay.25The dynamic range for plati-
num was 50–400 ng/mL. All values calculated from
the calibration curve were converted to an equimolar
amount of cisplatin. For all analytic methods, the in-
terday and intraday coefficients of variation were
? 15%. Pharmacokinetic parameters for imatinib, iri-
notecan, and cisplatin were estimated using standard
3.1]; Pharsight Corporation, Mountain View, CA). For
irinotecan and cisplatin, the following parameters
were determined: elimination half-life (t1⁄2), maximum
plasma concentration (Cmax), time to reach Cmax(t
max), volume of distribution (V), and area under the
concentration time curve from zero to the last mea-
sured time point (AUC(0-t)). Statistical analysis was
completed using a Student t test for paired data (Sig-
maPlot 2002 [version 8.0], SPSS Inc., Chicago, IL).
Immunostaining was performed on pretreatment bi-
opsies from patients at MDACC. Routine immunohis-
tochemical protocols similar to a previous study28in
melanocytic lesions were used to detect KIT (Dako
Corporation, Carpinteria, CA), c-ABL, ARG, PDGFR-?,
and PDGFR-? (Santa Cruz Biotechnology, Santa Cruz,
CA). Antibody labeling was optimized using antigen
retrieval (treatment with pepsin at 37 °C for 10 min-
utes for PDGFR-? and PDGFR-?, microwave treat-
ment for 5 minutes for KIT) and no antigen retrieval
for c-ABL or ARG. Diaminobenzidine was used as a
chromogen. The percentage of positive cells and the
intensity of staining were semiquantitatively recorded
by 2 observers (V.G.P. and P.T.): ? 5%, 5% to ? 25%, ?
25% to ? 75%, or ? 75% of positive cells. Labeling
intensity was categorized into weak, moderate, or
strong. For a marker to be considered positive, the
intensity had to be moderate in ? 25% of the tumor
Patient Characteristics and Treatment Administration
Six patients were enrolled in the MDACC trial in two
separate cohorts (Table 1). Five underwent four cycles
each of therapy at Dose Level 0. One patient discon-
tinued therapy after two cycles because of preexisting
periodontal disease that required full-mouth dental
extractions before further chemotherapy. Four pa-
tients received maintenance imatinib for 3–5 months
after completing 4 cycles of chemotherapy. One pa-
tient required a dose reduction of irinotecan for Grade
3 diarrhea, nausea and emesis, and hypokalemia.
Granulocyte–colony-stimulating factor (G-CSF) was
added prophylactically for all patients in the second
treatment cohort because of neutropenia that was ob-
served in the first cohort. Because of toxicity, no ad-
ditional patients were enrolled at any other dose lev-
Three patients were enrolled at MSKCC (Table 1).
Only one patient remained in the study and under-
went all four cycles of chemotherapy. One patient
discontinued therapy after one cycle and never re-
ceived any imatinib because of toxicity (neutropenia
and diarrhea) from treatment with cisplatin and irino-
tecan alone. One patient completed three full cycles of
chemotherapy but was unable to complete Cycle 4
(Days 8 and 15) because of prolonged neutropenia.
Although maintenance imatinib was planned, none of
the patients received it because of early withdrawal for
toxicity and disease progression.
Toxicity (the MDACC Study)
The first three patients at MDACC experienced sub-
stantial neutropenia that required G-CSF support. Pa-
tient 1 experienced neutropenic fever during Course 3
and Patient 2 experienced a delayed granulocyte nadir
after Course 1. G-CSF was added for both patients,
and neither experienced significant neutropenia in
subsequent courses. Patient 3 had delayed Grade 2
neutropenia after Course 2 and therefore G-CSF was
added to Courses 3 and 4. However, this patient died
with neutropenic fever after Course 4. Because the
only DLT noted in the first cohort was neutropenia,
G-CSF was added prophylactically to the subsequent
cohort of three patients. The second cohort did not
experience significant neutropenia. There were no
other Grade 4 hematologic toxicities noted (Table 2).
Patient Characteristics of the MDACC and MSKCC Studies
No. of evaluable patients
(n ? 6)
(n ? 3)
Mean age in yrs (range)
59 (44–73) 72 (70–74)
MDACC: University of Texas M. D. Anderson Cancer Center; MSKCC: Memorial Sloan-Kettering Cancer
aA Zubrod performance status of 0-2 was required at the University of Texas M. D. Anderson Cancer
Center and a Karnofsky score ? 70% was required at Memorial Sloan-Kettering Cancer Center.
Imatinib in Small Cell Lung Ca/Johnson et al. 369
The most common nonhematologic toxicity was
diarrhea (Table 2). Only 1 patient experienced Grade 3
diarrhea, but 5 patients experienced Grade 2 diarrhea
in 19 of 22 chemotherapy courses (86%). Two patients
experienced thrombosis; one patient developed a
deep vein thrombosis (DVT) during Cycle 1 and both
had asymptomatic pulmonary emboli (PE) found on a
restaging chest CT scan after Cycle 4. The patient with
Grade 3 diarrhea also experienced Grade 3 hypokale-
mia. There were no other Grade 3 or 4 nonhemato-
logic toxicities reported.
The MTD was based on two of six patients, who
experienced nonhematologic DLTs: one patient with
PE and DVT and one patient with Grade 3 diarrhea
and Grade 3 hypokalemia. Although each of the first
three patients in the original cohort experienced sub-
stantial neutropenia, this was subsequently prevented
in all patients with the addition of G-CSF support.
The four patients who underwent imatinib main-
tenance therapy tolerated it well, with no serious tox-
icity reported. One patient with known liver metasta-
ses experienced pancreatitis after 3 months of
maintenance imatinib and died 3 weeks later. The
cause of the pancreatitis was not apparent on imaging.
Toxicity (the MSKCC Study)
All three patients at MSKCC experienced Grade 3 or 4
neutropenia, and two patients developed neutropenic
fever. There were no other Grade 4 hematologic tox-
icities reported. Diarrhea was the most common and
severe nonhematologic toxicity. One patient each ex-
perienced Grade 3 and Grade 4 diarrhea with associ-
ated electrolyte abnormalities (Table 2). One patient
developed a DVT after Cycle 2, was treated with hep-
arin, and subsequently experienced a left thigh hem-
orrhage. One patient experienced a Grade 3 elevation
of transaminases, and one patient experienced Grade
3 fatigue. All three patients experienced DLT, and no
additional patients were enrolled at any other dose
The pretreatment tissue of all six patients at the
MDACC was analyzed by immunohistochemistry for
KIT, ARG, ABL, PDGFR-?, and PDGFR-?. Those cases
with higher numbers of labeled cells tended to dem-
onstrate the strongest labeling intensity. Two patients’
tumors expressed KIT; of the other four tumors, two
focally expressed KIT (classified as negative) and two
were negative. No tumors expressed ABL, and only
one tumor expressed ARG. All tumors had some de-
gree of expression of PDGFR-? and PDGFR-?, but only
tumors from Patients 3 and 1, respectively, met the
criteria for positivity (Fig. 1). At MSKCC, one of two
evaluable patients was found positive for KIT by im-
Pharmacokinetic analyses of cisplatin and irinotecan
were completed in the MDACC study during Cycle 1
before imatinib administration and during Cycle 2
after patients had been receiving imatinib for 20 days
(Table 3). In the presence of chronic exposure to ima-
tinib, the mean irinotecan clearance decreased by 36%
(P ? 0.01), which increased the mean irinotecan ex-
posure from 1818 mg/L ? hour to 2925 mg/L ? hour.
Cisplatin clearance was found to be unaffected by
imatinib (P ? 0.77).
The plasma concentrations of imatinib were mea-
sured over 8 hours after a dose of imatinib on Day 15
of Course 1 (7 days after chemotherapy) and Day 1 of
Course 2 (the day of chemotherapy). There was signif-
icant interpatient variability in the serum levels of
imatinib (Fig. 2) and limited sampling led to difficul-
ties in evaluating the disposition of imatinib. The de-
gree of intrapatient variability was found to be lower.
All six patients enrolled at MDACC were found to have
marked tumor regression on chest X-ray after one
cycle. Four patients were evaluable for response after
all four cycles. All 4 patients experienced partial re-
MDACC and MSKCC Drug Toxicities
(n ? 6 patients)
(n ? 3 patients)
(n ? 6)
(n ? 22)
(n ? 3)
(n ? 9)
Anemia, Grade 3
Thrombocytopenia, Grade 3
Thrombosis, Grade 3
Electrolyte disorder, Grade
3 or 4
MDACC: University of Texas M. D. Anderson Cancer Center; MSKCC: Memorial Sloan-Kettering Cancer
aToxicity was graded according to the National Cancer Institute Common Toxicity Criteria.
370CANCER January 15, 2006 / Volume 106 / Number 2
sponses and subsequently developed progressive dis-
ease after 3–5 months of imatinib maintenance ther-
apy. Three of these patients had died at the time of last
follow-up (Table 4).
Two patients enrolled at MSKCC were evaluable
for response. One patient developed progressive dis-
ease 2 weeks after completing all 4 cycles of therapy.
The second achieved a partial response but experi-
FIGURE 1. Representative photomicrographs of immunohistochemical staining for (B) KIT and (D) platelet-derived growth factor receptor-? (PDGFR-?) in
pretreatment core needle biopsy specimens are shown along with corresponding hematoxylin (A) and eosin (C) stains. Original magnification ?400.
Effect of Imatinib on the Pharmacokinetics of Irinotecan and Cisplatin
Pharmacokinetic parameters of
irinotecan) or cisplatin
Cycle 1 Cycle 2
Fold changeP valueMean SD MeanSD
Irinotecan clearance (mL/hr/m2)
Irinotecan half-life (hrs)
Irinotecan, AUC (mg/L ? hr)
Cisplatin clearance (mL/hr/m2)
Cisplatin half-life (hrs)
Cisplatin, AUC (mg/L ? hr)
SD: standard devation; AUC: area under the curve.
Imatinib in Small Cell Lung Ca/Johnson et al.371
enced disease progression 10 weeks after the discon-
tinuation of treatment.
These Phase I studies were designed to determine the
MTD of imatinib when combined with irinotecan and
cisplatin in patients with extensive-disease SCLC.
There was unexpected toxicity at initial dose levels,
including a high frequency and degree of neutropenia
and diarrhea and the occurrence of thrombosis, that
was observed in both studies independently. Although
neutropenia was prevented by the addition of G-CSF,
we were unable to escalate the dose of imatinib in the
MDACC study because two patients experienced non-
hematologic DLT. Chronic exposure to imatinib led to
an increased half-life and AUC of irinotecan. We hy-
pothesize that inhibition of the oxidative pathways via
CYP3A4 of irinotecan by imatinib led to the decreased
clearance of irinotecan, leading to increased SN-38
metabolites via the carboxyesterases pathway and
therefore increased neutropenia and diarrhea. There
were no apparent alterations in the disposition of
cisplatin or imatinib.18
To our knowledge two other clinical trials to date
have evaluated imatinib and cytotoxic chemotherapy
in SCLC patients. A Phase I study of etoposide, cispla-
tin, and imatinib in patients with extensive-disease
SCLC closed after three patients were enrolled be-
cause of slow accrual. The regimen was not associated
with unexpected hematologic toxicity, significant di-
arrhea, or thrombosis (unpublished data). Preliminary
data from a Phase II trial of carboplatin (AUC ? 4, Day
1), imatinib (at a dose of 600 mg daily), and irinotecan
(at a dose of 60 mg/m2on Days 1, 8, and 15) demon-
strated reasonable tolerance with a very lose dose of
carboplatin and accrual was ongoing at last follow-
up.29Previous experience with imatinib as a single
agent or in combination with other types of chemo-
therapy for patients with leukemia or other solid tu-
mors does not appear to predict the toxicity we ob-
Diarrhea and neutropenia are common toxic ef-
fects of the combination of irinotecan and cisplatin.
These two studies used two different chemotherapy
schedules. In the MSKCC study, there was more Grade
3/4 diarrhea noted compared with the MDACC study.
However, with only three patients and six patients,
respectively, in each study, comparisons are problem-
atic. The weekly regimen on which the MDACC study
was based17actually had a higher rate of Grade 3/4
diarrhea compared with the regimen on which the
MSKCC study was based,16although the comparison
of these two published studies is hindered by the fact
that the patients had different malignancies and eth-
Although the neutropenia and diarrhea could be
due to decreased irinotecan clearance or the additive
toxicities of this combination, the reason for the
thrombosis is not clear. Thrombosis has not been
reported in patients with SCLC who were treated with
irinotecan and cisplatin,16but a 31% incidence of
thrombosis was reported in a Phase I trial of irinote-
can, cisplatin, 5-fluorouracil, and gemcitabine in pa-
tients with solid tumors.33A panel review of irinotecan
trials in patients with colorectal carcinoma defined a
vascular syndrome that included myocardial infarc-
tion, cerebrovascular accidents, and PE.34Arterial and
FIGURE 2. In the M. D. Anderson Cancer Center study, blood samples for
determining plasma concentrations of imatinib were collected at 0 (predose), 2
hours, 4 hours, 6 hours, and 8 hours after oral ingestion on Day 15 of Cycle 1
(solid symbols, without chemotherapy) and on Day 1 of Cycle 2 (open symbols,
with chemotherapy). Complete data were available for five patients, and only
data regarding Day 1 were available for Patient 4 (-x-) (3 ?g/mL equals
approximately 5 ?M of imatinib).
Time to disease progression
MDACC: University of Texas M. D. Anderson Cancer Center; MSKCC: Memorial Sloan-Kettering Cancer
Center; NA: not applicable.
aThe patient died during the study after achieving a partial response as determined by chest X-ray.
bThe patient left the study early for dental extraction, and experienced disease progression.
cThe patient was lost to follow-up at 44 weeks.
dThe patient left the study early because of toxicity.
372CANCER January 15, 2006 / Volume 106 / Number 2
venous thromboses also have been described in pa-
tients receiving cisplatin.35It has been hypothesized
that damage to tumor cells or the vascular endothe-
lium by chemotherapy may lead to the release of
procoagulant factors. Cisplatin prolongs the activation
of platelets when they are cocultured with peripheral
blood monocytes36and levels of von Willebrand factor
are reported to increase after the administration of
cisplatin.37In animal models, imatinib led to peritu-
moral blood clotting that may be the result of an
inhibition of KIT on mast cells.38Therefore, it is pos-
sible that the combination of these agents leads to an
increased risk of thrombosis.
Our finding of KIT expression in two of six SCLC
tissue samples is consistent with findings in the pub-
lished literature.4–6The results of the current study
also confirm previous findings demonstrating the fre-
quent expression of PDGFR-? in SCLC tumors.39To
our knowledge, the significance of the inhibition of
PDGFR kinases has not been determined for SCLC. It
is interesting to note that the cytostatic effects of ima-
tinib are not entirely dependent on KIT expression in
vitro7or in vivo,40suggesting that another target, such
as PDGFR or ABL, may be relevant. A larger sample
size is needed to determine the frequency of expres-
sion of PDGFR and ARG in patients with SCLC.
There were no objective responses to imatinib
reported in three Phase II trials, two of which required
KIT-positivity.10–12The most likely explanation for
these negative results is that KIT is not critical for the
survival and growth of SCLC. The relatively high IC50
of imatinib in vitro (approximately 5 ?M)7and a pau-
city of activating mutations in SCLC (8.3%)6support
this hypothesis. This does not preclude an additive
effect of imatinib with chemotherapy. Although there
was no synergy reported with etoposide or carboplatin
in vitro,7imatinib may reverse resistance to campto-
thecin analogs by inhibiting the ABCG2 transporter
(breast carcinoma resistance protein [BCRP]).13SCLC
cells express BCRP/ABCG2 in vitro, and inhibition via
antisense oligonucleotides can increase sensitivity to
To our knowledge, these are the first studies pub-
lished to date to examine the combination of cytotoxic
chemotherapy with imatinib in patients with SCLC. It
appears probable that the increased toxicity observed
with the addition of imatinib is because of decreased
irinotecan clearance. It might have been possible to
escalate the imatinib dose if the irinotecan dose was
reduced. However, we believed it was not appropriate
to reduce the dose of an effective drug to escalate the
dose of an experimental agent. A schedule in which
irinotecan is separated from the imatinib dose might
decrease the pharmacokinetic interactions. However,
this would theoretically also reduce therapeutic inter-
actions as well. Therefore, on the basis of the inability
to escalate the imatinib dose in this combination, the
problematic drug interaction, and the lack of single-
agent activity, we do not plan any further investigation
of the combination.
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374 CANCER January 15, 2006 / Volume 106 / Number 2