A phase I open-label dose-escalation study of oral BIBF 1120 ...

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original article
Annals of Oncology 21: 370–375, 2010
doi:10.1093/annonc/mdp506
Published online 4 November 2009
A phase I open-label dose-escalation study of oral BIBF
1120 combined with standard paclitaxel and carboplatin
in patients with advanced gynecological malignancies
A. du Bois 1 *, J. Huober 2 , P. Stopfer 3 , J. Pfisterer 4 , P. Wimberger 5 , S. Loibl 6 , V. L. Reichardt 3 &
P. Harter 1
1 Department of Gynecology and Gynecologic Oncology, Dr. Horst Schmidt Klinik (HSK), Wiesbaden; 2 Department of Gynecology and Obstetrics, Tu¨bingen University,
Tu¨bingen; 3 Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach; 4 Department of Gynecology and Obstetrics, Kiel University, Kiel; 5 Department of Gynecology and
Obstetrics, Essen University, Essen and 6 Department of Gynecology and Obstetrics, Johann-Wolfgang-Goethe University, Frankfurt, Germany
Received 24 June 2009; revised 10 September 2009; accepted 25 September 2009
Background: The purpose of the phase I dose-escalation study was to evaluate the maximum tolerated dose (MTD)
of BIBF 1120, an oral triple angiokinase inhibitor of vascular endothelial growth factor, platelet derived growth factor
and fibroblast growth factor receptors, combined with paclitaxel and carboplatin.
Patients and methods: Patients with advanced gynecological malignancies received BIBF 1120 twice-daily (b.i.d.)
continuously at 100, 150, 200 or 250 mg, combined with paclitaxel (175 mg/m 2 ) and carboplatin (area under the curve
5 min mg/ml) every 3 weeks. The MTD, safety, pharmacokinetics (PK) and clinical activity were evaluated.
Results: Twenty-two patients were treated. Three experienced dose-limiting toxic effects in the first treatment cycle:
1 of 13 at 200 mg b.i.d. BIBF 1120 [diarrhea, common terminology criteria for adverse events (CTCAE) grade 3]; two of
two at 250 mg b.i.d. BIBF 1120 (elevated alanine aminotransferase and aspartate aminotransferase, CTCAE grade 3/4).
The MTD was defined as 200 mg b.i.d. Principal adverse events were gastrointestinal disorders. No clinically relevant
drug–drug interaction was observed after 20 days treatment with 200 mg b.i.d. BIBF 1120 on the PK of paclitaxel or
carboplatin and vice versa.
Conclusions: The MTD of BIBF 1120 in a 20-day continuous dosing regimen with standard-dose paclitaxel and
carboplatin was 200 mg b.i.d. This combination had an acceptable safety profile and no clinically relevant drug–drug
interactions. Further evaluation of this combination is warranted in this indication.
Key words: BIBF 1120, carboplatin, gynecological malignancies, paclitaxel, phase I
introduction
Even after optimal treatment, only a minority of patients with
stage III or IV ovarian cancer will be alive 5 years after diagnosis
[1]. This high mortality rate has been largely associated with
intrinsic and acquired resistance to currently available cytotoxic
agents. Novel treatment strategies are therefore required.
Angiogenesis is thought to play a central role in the
pathogenesis and clinical behavior of ovarian cancer, and
markers of increased angiogenesis are correlated with poor
prognosis [2]. The vascular endothelial growth factor (VEGF) is
a key mediator regulating angiogenesis [3, 4] and is expressed in
the majority of tumor specimens from patients with ovarian
cancer [5]. Early clinical data with the anti-VEGF agent
bevacizumab have demonstrated that patients with gynecological
cancers can benefit from antiangiogenic compounds [6–8].
*Correspondence to: Dr A. du Bois, Department of Gynecology and Gynecologic
Oncology, Dr. Horst Schmidt Klinik (HSK), Ludwig-Erhard-Street 100, D-65199
Wiesbaden, Germany. Tel: +49-611-433-7221; Fax: +49-611-2672;
E-mail: prof.dubois@googlemail.com
BIBF 1120 is an orally available triple angiokinase inhibitor
that simultaneously and potently inhibits vascular endothelial
growth factor receptors, platelet derived growth factor receptors
and fibroblast growth factor receptors [9]. In vivo studies
demonstrated that BIBF 1120 significantly inhibits tumor
growth in established xenografts in mice [9]. In a phase I
clinical study in patients with advanced solid tumors, BIBF 1120
had a favorable safety profile as twice-daily (b.i.d.) dosing up to
the maximum tolerated dose (MTD) of 250 mg b.i.d. [10].
The aim of this study was to determine the MTD of BIBF 1120
b.i.d. in combination with standard-dose paclitaxel and carboplatin
in patients with gynecological cancer. In addition, the safety,
tolerability, clinical activity, pharmacokinetics (PK) and drug–drug
interactions of BIBF 1120 in this dosing regimen were explored.
patients and methods
ª The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
study population
Patients with a histologically confirmed diagnosis of an advanced or
recurrent gynecological malignancy (epithelial ovarian cancer, endometrial
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Annals of Oncology original article
carcinoma, mixed mesenchymal tumor or cervical carcinoma) with an
indication for paclitaxel and carboplatin combination therapy were eligible
for this trial. Patients were aged ‡18 years with an Eastern Cooperative
Oncology Group [11] performance status of zero or one and must have
provided written informed consent. Patients who had received
radiotherapy, chemotherapy, immunotherapy or hormonal therapy within
4 weeks before the start of therapy were excluded.
study design
This study was an open-label phase I trial carried out according to the
Declaration of Helsinki and the International Conference on
Harmonization Tripartite Guideline for Good Clinical Practice. It was
approved by the local institutional review board and was conducted in five
centers in Germany from October 2005 to January 2007.
On day 1 of each treatment period, patients received a 3-h i.v. infusion of
paclitaxel (175 mg/m 2 ), immediately followed by a 30-min infusion of
carboplatin [area under the curve (AUC) 5 min mg/ml]. On days 2–21 of
each treatment phase, patients were administered a b.i.d. oral dose of BIBF
1120 (2 · 100 to 2 · 250 mg); patients did not receive BIBF 1120 on day 1 to
allow assessment of paclitaxel/carboplatin PK parameters before and after
continuous BIBF 1120 administration. Therapy was administered for
a maximum of six treatment periods. The trial used a 3 + 3 dose-escalation
design [12] in which the doses of standard chemotherapy (paclitaxel/
carboplatin) were held fixed and only BIBF 1120 was escalated. The following
dose levels of BIBF 1120 were planned: 100, 150, 200 and 250 mg b.i.d. The
MTD was defined as the dose at which 7 days; neutropenia CTCAE
grade 3/4 of any duration associated with fever >38.3°C; CTCAE grade 4
thrombocytopenia or CTCAE grade 3 thrombocytopenia associated with
bleeding requiring transfusion; inability to resume BIBF 1120 dosing within
14 days of stopping due to treatment-related toxicity. All DLT events that
occurred after the initial treatment period were classified as significant AEs.
PK sampling
Six milliliter of venous blood was collected at prespecified time points for
the determination of BIBF 1120, paclitaxel and carboplatin PK profiles
(supplemental data, available at Annals of Oncology online). Analysis was
carried out according to prespecified procedures (supplemental data,
available at Annals of Oncology online).
other outcome measures
Efficacy was monitored by objective tumor response, time to tumor
progression and assessment of cancer antigen (CA)-125 [14]. RECIST
criteria [15] were used. Patients were assessable for CA-125 response if they
had ovarian carcinoma, one or more pretreatment value >35 U/ml with the
exception of one local laboratory with the upper limit of normal of 65 U/l
and more than two CA-125 values available after first BIBF 1120
administration. Patients were deemed responders if, both at any time after
baseline and ‡28 days after baseline, CA-125 decreased by ‡50%, and if at
‡28 days after this first observation of CA-125 response, the reduction by
‡50% was maintained.
results
A total of 23 patients were enrolled; 22 met eligibility criteria
and were treated with BIBF 1120. Table 1 details the baseline
patient demographic characteristics.
Characteristics BIBF 1120 b.i.d. Total
100 mg
150 mg
200 mg
250 mg
(n = 22)
(n = 3)
(n = 4)
(n = 13)
(n = 2)
Age (years)
Median 52.0 63.0 57.0 57.5 58.0
Range
Performance status (ECOG), n (%)
47–64 61–66 32–71 49–66 32–71
0 3 (100) 4 (100) 9 (69) 1 (50) 17 (77)
1 0 (0) 0 (0) 3 (23) 1 (50) 4 (18)
2
Type of cancer, n (%)
0 (0) 0 (0) 1 (8) 0 (0) 1 (5)
Epithelial ovarian cancer 2 (67) 4 (100) 8 (62) 1 (50) 15 (68)
Endometrial cancer 0 (0) 0 (0) 2 (15) 0 (0) 2 (9)
Uterine sarcoma 0 (0) 0 (0) 2 (15) 0 (0) 2 (9)
Cervical cancer
Number of prior chemotherapies, n (%)
1 (33) 0 (0) 1 (8) 1 (50) 3 (14)
None 2 (67) 3 (75) 9 (69) 0 (0) 14 (64)
One 1 (33) 0 (0) 3 (23) 2 (100) 6 (27)
Two 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
Three or more 0 (0) 1 (25) 1 (8) 0 (0) 2 (9)
Previous radiotherapy, n (%) 0 (0) 0 (0) 4 (31) 1 (50) 5 (23)
ECOG, Eastern Cooperative Oncology Group.
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original article
MTD determination, safety and tolerability
According to initial dose of BIBF 1120, the number of patients
analyzed was as follows: 100 mg BIBF 1120 b.i.d., n = 3; 150 mg
BIBF 1120 b.i.d., n = 4; 200 mg BIBF 1120 b.i.d., n = 13 and 250
mg BIBF 1120 b.i.d., n = 2. The median total duration of
exposure to BIBF 1120 for all patients was 243.0 days (range
33–330 days). No dose reduction of paclitaxel or carboplatin
due to continuous administration of BIBF 1120 was necessary.
One exception was a patient with advanced uterine sarcoma,
who was first changed to carboplatin AUC 4 min mg/ml in the
second cycle due to thrombocytopenia and then to weekly
paclitaxel administration without carboplatin after starting
treatment cycle 4 due to thrombocytopenia. BIBF 1120 was
continued. One patient was given cisplatin instead of
carboplatin following an allergic reaction to the latter.
During the first treatment period, three patients experienced
DLTs: both patients from the 250-mg dose cohort reported
elevated aspartate aminotransferase (AST; CTCAE grade 3,
n = 1; CTCAE grade 4, n = 1) and alanine aminotransferase
(ALT; both CTCAE grade 3) levels; one patient from the 200mg
dose cohort experienced diarrhea (CTCAE grade 3). Hence,
the MTD for b.i.d. dosing of BIBF 1120 in combination with
paclitaxel and carboplatin was defined as 200 mg BIBF 1120
b.i.d.; a total of 13 patients were evaluated at the MTD.
Sixteen of 22 patients received all six planned cycles of
combination therapy and went on to receive BIBF 1120
monotherapy. Six patients discontinued combination therapy
earlier, most frequently due to AEs (n = 5), with one patient
withdrawing consent.
Over the entire study, including both combination and
monotherapy phases, nine patients reported DLTs. In addition
to the three patients who experienced DLTs in treatment period
1 as outlined above, there were four reports of DLTs in
treatment period 2 (increased AST and ALT, n = 1; neutropenia,
n = 1; thrombocytopenia, n = 2). There was one reported DLT
in treatment period 3 (febrile neutropenia) and one in treatment
period 8 during BIBF 1120 monotherapy (increased ALT).
Serious adverse events (SAEs), all requiring hospitalization,
were reported for seven (32%) patients over the entire study.
Treatment-related SAEs occurred exclusively in the 200-mg BIBF
1120 b.i.d. dose cohort and were as follows: diarrhea and
concomitant vomiting (n = 1); diarrhea and thrombocytopenia
(n = 1) and leucopenia, neutropenia, lung infiltration and
pyrexia (n = 1). SAEs not related to drug treatment were as
follows: ascites and dyspnea (n = 1), subileus (n = 1), fluid in
uterus and hydrometra (n = 1) and breast cancer (n = 1). Nine
patients (41%) discontinued treatment due to AEs, including one
patient during the first course of treatment. This patient had
grade 3 diarrhea which was not treated according to the
recommendations of the protocol. Those that were considered to
be BIBF 1120 related, as judged by the investigator, were serious
diarrhea and concomitant serious vomiting (n = 1), diarrhea
(n = 2) and thrombocytopenia (n = 2). The other reasons were
depression (n = 1) in a patient with history of depression, disease
progression (n = 1) and subileus (n = 1). In addition, one
patient had increased CA-125 levels, indicating disease
progression. This was reported as an AE and resulted in
discontinuation. There were no deaths reported during the study.
The most frequently reported AEs over the entire study were
gastrointestinal disorders (n = 22, 100%), mostly of grade 1
and 2. The most common AEs were alopecia (91%), diarrhea
(86%), fatigue (64%), myalgia (55%), nausea (59%) and
vomiting (55%). All other individual AEs were reported by less
than one-third of all patients. The incidence of drug-related
AEs, by highest CTCAE grade, occurring in the MTD cohort
(200 mg BIBF 1120 b.i.d.) and in the 250-mg BIBF 1120 b.i.d.
dose cohort, over the entire study is summarized in Table 2.
The incidence and pattern of AEs reported during the
combination therapy phase was similar to the cumulative
incidence and pattern of AEs for the entire study. The AE profile
during the monotherapy phase differed from the AE profile
Table 2. Drug-related adverse events, by highest CTCAE grade,
occurring in ‡10% or ‡grade 3, in patients treated at the MTD dose
cohort (200 mg BIBF 1120 b.i.d.; n = 13) and at the 250-mg b.i.d. dose
cohort (n = 2)
Adverse events Grade 1,
n
Grade 2,
n
Annals of Oncology
Grade 3,
n
Nausea 8 2
Vomiting 5 3
Diarrhea 8 3 4
Abdominal pain/dyspepsia 6
Fatigue 3 5 1
Anorexia 3
Hypokalemia 3
Pyrexia 2 2
Infection 1
Nasopharyngitis 6
Urinary tract infection 2 2
Hydrometra 1
Ascites/disease progression a
1
Myalgia 4 4
Arthralgia 3
Back pain/pain in extremity 2 2
Headache 4
Peripheral sensory neuropathy 3 4
Cough 2
Dyspnea 5
Alopecia 13
Erythema/rash 4
Nail disorder 2
Hot flush 2
Anemia 3
Leukocytopenia 2 1
Neutropenia 1 2
Thrombocytopenia 2 2
ALT 4
AST 2 1
GGT 2
Grade 4,
n
Adverse events of all courses are shown.
a
A single case of grade 3 ascites was reported to be potentially drug related
in a patient with advanced ovarian cancer.
CTCAE, common terminology criteria for adverse events; MTD, maximum
tolerated dose; ALT, alanine aminotransferase; AST, aspartate
aminotransferase; GGT, gamma-glutamyl transpeptidase.
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Annals of Oncology original article
during the entire study; the incidence of gastrointestinal
disorders was lower (56%) than during the entire study and the
incidences of skin and s.c. tissue disorder and musculoskeletal
and connective tissue disorders were markedly decreased
compared with combination therapy, mainly due to the absence
of any cases of alopecia or myalgia on BIBF 1120 monotherapy.
With the exception of liver enzymes, there were no clinically
meaningful differences between dose groups with respect to
median change from baseline in safety laboratory parameters.
There were incidences of elevated AST, ALT and GGT,
particularly in the 250-mg BIBF 1120 b.i.d. dose cohort, in
which two patients had CTCAE grade 3 or 4 elevations of AST
and/or ALT values during treatment period 1 that qualified as
DLT events. These, and indeed all deteriorations in safety
laboratory parameters, were reversible. During the entire study,
one incidence of hypertension (grade 2) occurred in the 200mg
b.i.d. dose tier.
pharmacokinetics
The PK parameters of paclitaxel and carboplatin are shown in
Table 3 and in supplemental data (available at Annals of
Oncology online). There were no clinically relevant drug–drug
interactions of 20-day continuous administration of 200 mg
BIBF 1120 b.i.d. on the PK of paclitaxel or carboplatin.
The drug plasma concentration–time profiles of BIBF 1120
after multiple oral administrations of 200 mg BIBF 1120 b.i.d.
are shown in supplemental data (available at Annals of Oncology
online). Following administration, maximum plasma
concentrations were mainly reached 1–4 h after dose. The
steady state for BIBF 1120 was reached, at the latest, after 7 days
of BIBF 1120 b.i.d. dosing. There was no deviation from a doseproportional
PK of BIBF 1120 (data not shown). During the
repeated dosing period of BIBF 1120 in combination with
carboplatin and paclitaxel, there were no systematic increases or
decreases in BIBF 1120 plasma concentrations.
dose reduction
One patient receiving 250 mg BIBF 1120 b.i.d. had her dose
reduced to 200 mg b.i.d. and one had her dose reduced first to
200 mg b.i.d. and then to 150 mg b.i.d.; both had increased
levels of AST/ALT of CTCAE grade 3 or 4. Two patients in the
200-mg b.i.d. cohort had their dose reduced to 150 mg b.i.d.
due to AST/ALT elevation (n = 1) and repeated episodes of
diarrhea (n = 1), and one patient in the 200-mg b.i.d. cohort
had her dose reduced to 100 mg.
clinical activity
Seven patients were assessable for tumor response according to
RECIST. One ovarian cancer patient (in the 200-mg b.i.d.
cohort) had a complete response (CR), four patients (two in
the 150-mg b.i.d. cohort, both with ovarian cancer, and two in
the 200-mg b.i.d. cohort) had a partial response (PR) and two
patients (in the 200-mg b.i.d. cohort) had stable disease (SD) as
their best response to therapy. Ten ovarian cancer patients were
assessable for CA-125 levels (five patients in first-line treatment
and five patients in second- or later-line treatment): all were
classed as responders. Five patients had progressive disease
during the study; progression-free survival (PFS) in these
patients ranged from 177 to 282 days.
discussion
The MTD of BIBF 1120 in this combination regimen was
determined to be 200 mg b.i.d., which is comparable to that
observed in another phase I trial of BIBF 1120 combined with
Table 3. Comparison of pharmacokinetic parameters of paclitaxel and carboplatin on the day of infusion before BIBF 1120 dosing (day 1 of treatment
period 1) and after continuous administration of BIBF 1120 for 20 days (day 1 of treatment period 2) for patients treated with 200 mg BIBF 1120 b.i.d
MTD Treatment period 1
(n = 13)
Treatment period 2 [n = 13
(paclitaxel); n = 12 (carboplatin)]
n = 11
gMean gCV (%) gMean gCV (%) gMean ratio
(TP2/TP1)
Paclitaxel
C max (ng/ml) 3370 45.5 4180 63.4 119.35 81.68–174.40
AUC0–N (ng h/ml) 10 900 39.2 13 900 42.4 125.33 90.98–172.66
t max a (h) 3.0 2.8–4.0 3.2 2.9–5.3
t ½ (h) 12.8 14.0 12.2 11.8
CL (l/h/m 2 ) 16.0 39.6 12.5 43.0
Carboplatin
C max (ng/ml) 16 600 19.0 16 400 19.6 92.99 83.16–103.98
AUC0–N (ng h/ml) 118 000 24.0 149 000 32.0 123.12 103.95–145.81
tmax a (h) 0.85 0.5–1.3 1.2 0.67–1.5
t ½ (h) 55.3 20.8 67.3 61.8
CL (l/h) 5.0 30.1 4.0 45.2
a Median and range.
MTD, maximum tolerated dose; gMean, geometric mean; gCV, geometric coefficient of variation; CI, confidence interval; Cmax, maximum measured
concentration of the analyte in plasma; AUC 0–N, area under the concentration–time curve of the analyte in plasma over the time interval from zero
extrapolated to infinity; tmax, time from (last) dosing to the maximum measured concentration of the analyte in plasma; t1/2, terminal half-life of the analyte
in plasma; CL, total clearance of analyte in plasma following intravascular administration.
90% CI
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original article
carboplatin and paclitaxel in patients with non-small-cell lung
cancer [16]. No dose reduction of paclitaxel or carboplatin due
to continuous administration of BIBF 1120 was necessary.
The combination of BIBF 1120 b.i.d. with paclitaxel and
carboplatin had an acceptable safety profile. The majority of
AEs were of CTCAE grade 1 or 2 and the most frequently
reported AEs were gastrointestinal disorders, primarily
diarrhea, nausea and vomiting. This AE profile is consistent
with those observed with other angiogenesis inhibitors [17–20].
In contrast to other angiogenesis inhibitors, however [17–19],
we did not observe any significant incidence of hypertension in
this study. Five patients reported grade 3 ALT elevations, two
patients had grade 3 AST elevations and there was one
incidence of grade 4 AST elevation. All these elevations were
found in the higher dose groups of BIBF 1120 (200 and 250 mg
b.i.d.) but resolved during the study and were reversible.
A 20-day continuous administration of BIBF 1120 in
combination with paclitaxel and carboplatin showed objective
antitumor activity in this mixed group of gynecological
patients. According to RECIST, one patient had a CR, four
patients had a PR and two patients had an SD as their best
overall response. All ten patients that were assessable for CA-
125 response were responders, and 9 of 10 remained so until
the end of the trial.
The addition of 200 mg b.i.d. BIBF 1120 appeared to have no
clinically significant effect on the PK parameters of paclitaxel or
carboplatin. When comparing geometric mean (gMean) AUC 0–N
and C max values of paclitaxel before and after BIBF 1120
treatment, an increase of 20%–25% was seen. This increase was
not considered clinically relevant as no systematic increases
were seen in either of the parameters between treatment
periods. With respect to carboplatin, after BIBF 1120
administration, gMean C max values were bioequivalent,
although a 25% increase in gMean AUC 0–N was observed.
Again, due to the apparent lack of systematic increase between
treatment periods, this was deemed to be clinically irrelevant.
Although this study was not sized formally to determine drug–
drug interactions, the gMean ratios and 90% confidence
intervals of AUC 0-N and C max between treatment period 1
(absence of BIBF 1120) and treatment period 2 (presence of
BIBF 1120) for each drug do not fall entirely within or out of
the 0.8–1.25 range for bioequivalence. However, given the high
background exposure variability of these drugs [21–23], these
data indicate that if any interaction (undetectable as statistically
significant) of BIBF 1120 treatment on the PK of a single dose
of 175 mg/m 2 paclitaxel or on a single dose of AUC 5 min mg/
ml carboplatin were to exist, it is unlikely to be clinically
significant.
The single-dose and steady-state PK parameters that were
observed in this study of BIBF 1120, administered in
combination with paclitaxel and carboplatin, are comparable to
those seen with single-agent dosing [24]. This indicates that
there were no unfavorable drug–drug interactions of paclitaxel
and carboplatin on the PK of BIBF 1120.
In conclusion, the MTD of BIBF 1120 was 200 mg b.i.d. in
a 20-day continuous dosing regimen with standard-dose
paclitaxel (175 mg/m 2 ) and carboplatin (AUC 5 min mg/ml) in
patients with advanced gynecological malignancies. This
treatment regimen was seen to have an acceptable safety profile,
consisting primarily of gastrointestinal disorders. There was no
effect of any clinically relevant drug–drug interaction of BIBF
1120, on the PK of either carboplatin or paclitaxel, and neither
drug appreciably altered the PK of BIBF 1120. The addition of
the novel triple angiokinase inhibitor BIBF 1120 does not
impair the application of standard paclitaxel/carboplatin, is
tolerable and offers an orally available new mode of antitumor
treatment. More advanced phase studies of BIBF 1120 in
patients with gynecological malignancies are warranted. The
Arbeitsgemeinschaft Gynaekologische Onkologie
Studiengruppe (AGO study group) is currently planning
a randomized evaluation of BIBF 1120 concomitant with
platinum–paclitaxel and as maintenance therapy in first-line
treatment of advanced ovarian cancer.
funding
Boehringer Ingelheim (minor < $10 000) to J.P.
acknowledgements
The authors thank G. Elser and team from the AGO study
office and P. Schantl and team from Schantl Monitoring.
disclosure
AdB and JH act as consultants for Boehringer Ingelheim
(minor

Annals of Oncology original article
11. Oken MM, Creech RH, Tormey DC et al. Toxicity and response criteria of the
Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5: 649–655.
12. Simon R, Freidlin B, Rubinstein L et al. Accelerated titration designs for phase I
clinical trials in oncology. J Natl Cancer Inst 1997; 89: 1138–1147.
13. Trotti A, Colevas AD, Setser A et al. CTCAE v3.0: development of
a comprehensive grading system for the adverse effects of cancer treatment.
Semin Radiat Oncol 2003; 13: 176–181.
14. Rustin GJ, Bast RC Jr., Kelloff GJ et al. Use of CA-125 in clinical trial evaluation
of new therapeutic drugs for ovarian cancer. Clin Cancer Res 2004; 10:
3919–3926.
15. Therasse P, Arbuck SG, Eisenhauer EA et al. New guidelines to evaluate
theresponsetotreatmentinsolidtumors.EuropeanOrganizationfor
Research and Treatment of Cancer, National Cancer Institute of the United
States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92:
205–216.
16. Camidge DR, Conkling P, Stephenson J et al. Pharmacokinetic (PK) analysis
of a phase I study of continuous oral treatment with the angiokinase inhibitor
BIBF 1120, in combination with carboplatin and paclitaxel in patients with
advanced non-small cell lung cancer (NSCLC). J Clin Oncol 2008; 26: (Abstr
3567).
17. Cobleigh MA, Langmuir VK, Sledge GW et al. A phase I/II dose-escalation trial of
bevacizumab in previously treated metastatic breast cancer. Semin Oncol 2003;
30: 117–124.
18. Ratain MJ, Eisen T, Stadler WM et al. Phase II placebo-controlled randomized
discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma.
J Clin Oncol 2006; 24: 2505–2512.
19. Rock EP, Goodman V, Jiang JX et al. Food and Drug Administration drug
approval summary: sunitinib malate for the treatment of gastrointestinal
stromal tumor and advanced renal cell carcinoma. Oncologist 2007; 12:
107–113.
20. Strumberg D, Richly H, Hilger RA et al. Phase I clinical and pharmacokinetic
study of the Novel Raf kinase and vascular endothelial growth factor receptor
inhibitor BAY 43-9006 in patients with advanced refractory solid tumors. J Clin
Oncol 2005; 23: 965–972.
21. Duffull SB, Robinson BA. Clinical pharmacokinetics and dose optimisation of
carboplatin. Clin Pharmacokinet 1997; 33: 161–183.
22. Gianni L, Kearns CM, Giani A et al. Nonlinear pharmacokinetics and metabolism
of paclitaxel and its pharmacokinetic/pharmacodynamic relationships in humans.
J Clin Oncol 1995; 13: 180–190.
23. Sonnichsen DS, Relling MV. Clinical pharmacokinetics of paclitaxel. Clin
Pharmacokinet 1994; 27: 256–269.
24. Stopfer P, Roth W, Mross KB et al. Pharmacokinetic characterization of BIBF
1120, an orally active triple angiokinase inhibitor (VEGFR, PDGFR, FGFR) in
advanced cancer patients. In AACR-NCI-EORTC International Conference on
Molecular Targets and Cancer Therapeutics Edition (Poster 73). Prague, Czech
Republic 2006.
Volume 21 | No. 2 | February 2010 doi:10.1093/annonc/mdp506 | 375
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