Abstract
Background
BIBF 1120 is an oral potent inhibitor of vascular endothelial growth factor receptor, fibroblast growth factor receptor and platelet-derived growth factor receptor, the three key receptor families involved in angiogenesis. This phase I, open-label dose-escalation study investigated BIBF 1120 combined with paclitaxel (Taxol) and carboplatin in first-line patients with advanced (IIIB/IV) non-small-cell lung cancer.
Patients and methods
Patients received BIBF 1120 (starting dose 50 mg b.i.d.) on days 2–21 and paclitaxel (200 mg/m2) and carboplatin [area under curve (AUC) = 6 mg/ml/min] on day 1 of each 21-day cycle. Primary end points were safety and BIBF 1120 maximum tolerated dose (MTD) in this combination. Pharmacokinetics (PK) profiles were evaluated.
Results
Twenty-six patients were treated (BIBF 1120 50–250 mg b.i.d.). BIBF 1120 MTD was 200 mg b.i.d. in combination with paclitaxel and carboplatin. Six dose-limiting toxicity events occurred during treatment cycle 1 (liver enzyme elevations, thrombocytopenia, abdominal pain, and rash). Best responses included 7 confirmed partial responses (26.9 % ); 10 patients had stable disease. BIBF 1120 200 mg b.i.d. had no clinically relevant influence on the PK of paclitaxel 200 mg/m2 and carboplatin AUC 6 mg/ml/min and vice versa.
Conclusions
BIBF 1120 MTD was 200 mg b.i.d when given with paclitaxel and carboplatin; this combination demonstrated an acceptable safety profile. No relevant changes in PK parameters of the backbone chemotherapeutic agents or BIBF 1120 were observed.
Keywords: angiogenesis, BIBF 1120, chemotherapy, NSCLC, pharmacokinetics, phase I
introduction
Non-small-cell lung cancer (NSCLC) is currently the leading cause of cancer death worldwide [1]. Modern platinum-containing cytotoxic chemotherapy offers modest benefits in the first-line setting for patients with advanced disease, but efficacy of different doublet regimens alone appears to have reached a plateau [2, 3]. The addition of bevacizumab, a monoclonal antibody directed against the vascular endothelial growth factor (VEGF) ligand, has been shown to potentiate the antitumor effect of first-line carboplatin and paclitaxel treatment [4]. The toxicity associated with the addition of bevacizumab to certain subgroups of patients in the initial phase II study restricted the population assessed within the Eastern Cooperative Oncology Group (ECOG) 4599 phase III study to exclude those patients with squamous cell lung cancer as well as those with a history of significant hemoptysis. Patients with central nervous system metastases were also excluded. However, safety data now exist for the use of bevacizumab in patients with treated brain metastases [5].
Significant cross talk and redundancy occur between angiogenic pathways, providing a molecular network for escape mechanisms if one proangiogenic factor is inhibited within a tumor. In light of this, patients often develop resistance to agents targeting VEGF alone [6].
BIBF 1120 is a novel triple angiokinase inhibitor, selectively targeting three receptor classes involved in the formation of blood vessels: VEGF receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR). BIBF 1120 inhibits all three VEGFR subtypes; PDGFRα and PDGFRβ and FGFR types 1, 2 and 3 [7]. In addition, molecular evidence exists for an active FGF signaling pathway in a subset of NSCLC cell lines; therefore, inhibiting FGF may have additional beneficial effects beyond known effects on angiogenesis [8]. BIBF 1120 is associated with significant tumor growth inhibition in all preclinical models investigated to date [7]. Phase I dose-escalation studies for BIBF 1120 monotherapy have investigated the maximum tolerated dose (MTD), safety and pharmacokinetics (PK) of BIBF 1120 in patients with a variety of advanced solid tumors [9, 10]. These studies defined the MTD as 250 mg for once- and twice-daily continuous dosing; however, as compared with once-daily dosing, twice-daily administration allowed increased drug exposure to cancer patients without additional toxicity. Data from phase I combination therapy trials indicate that BIBF 1120 is well tolerated and can be used in combination with standard chemotherapy. Specifically, BIBF 1120 can be safely given at a dose of 200 mg b.i.d. together with standard doses of paclitaxel and carboplatin in patients with advanced gynecological malignancies [11] and in combination with pemetrexed in previously treated NSCLC [12]. Dose-limiting toxicities (DLTs) observed in this latter study included elevated liver enzymes, vomiting, esophageal pain and nausea and fatigue. Of note, the observed BIBF 1120 adverse event (AE) profile from phase I monotherapy studies is largely nonoverlapping with both paclitaxel and carboplatin, suggesting that combination therapy could be both well tolerated and feasible.
This was a phase I, open-label dose-escalation study; the primary objective was to determine the MTD of BIBF 1120 combined with standard doses of paclitaxel and carboplatin in the first-line treatment of patients with advanced NSCLC. Secondary objectives included characterization of the safety and PK profiles of BIBF 1120, paclitaxel and carboplatin and preliminary assessment of the antitumor activity of this combination regimen.
patients and methods
study design
This was an open-label, dose-escalation study conducted in five centers in the United States between June 2005 and December 2007. Patients received i.v. paclitaxel (Taxol, Bristol-Myers Squibb Company, Princeton, NJ) (200 mg/m2 over 3 h) followed by i.v. carboplatin [area under curve (AUC) 6 mg/ml/min over 30 min] on day 1 of each treatment cycle and BIBF 1120 b.i.d. on days 2–21. The study used a standard 3 + 3 trial design based on DLT in treatment cycle 1.
Patients were assigned to escalating dose cohorts in order of their admission into the study. The starting dose of BIBF 1120 was 50 mg b.i.d. DLT was defined as toxic effects at least possibly related to treatment, and included gastrointestinal toxicity or hypertension of greater than Common Terminology Criteria for Adverse Events (CTCAE) grade 3, despite optimal supportive care/intervention, non-hematologic toxicity CTCAE grade ≥ 3, CTCAE grade 4 neutropenia that was uncomplicated (not associated with fever) for > 7 days, neutropenia of any duration associated with fever, platelet levels of < 25 000/μl or CTCAE grade 3 thrombocytopenia associated with bleeding requiring transfusion or the inability to resume BIBF 1120 dosing within 14 days of stopping due to treatment-related toxicity. DLTs observed in the first 21 days of treatment were used to determine the MTD. If one patient of three experienced a DLT within the first treatment cycle, up to three new patients were treated at that dose level. If two or more of up to six patients treated within one dose cohort experienced a DLT within the first treatment cycle, this dose level was considered nontolerated and the dosing level below that cohort was expanded to six patients, if appropriate. The MTD was defined as the highest dose at which no more than one of six subjects experienced a DLT within the first treatment cycle. Once the MTD was identified, additional patients were recruited into that dose cohort until a total of 12 patients were treated. Patients were considered assessable if they completed one 21-day treatment cycle or discontinued treatment due to a DLT.
Patients who experienced a DLT discontinued study medication but could resume treatment at a lower dose level if all clinically relevant toxic effects recovered to baseline within 2 weeks. After 4–6 cycles of combination therapy, patients who experienced clinical benefit (objective tumor response or absence of tumor progression) were eligible for treatment with BIBF 1120 monotherapy for a maximum of 10 21-day cycles.
This trial was carried out according to the Declaration of Helsinki and in accordance with the International Conference on Harmonization Harmonized Tripartite Guideline for Good Clinical Practice and other relevant local guidelines. Patients provided written informed consent.
study population
Adult patients with pathologically confirmed stage IIIB (including malignant pleural effusion) or stage IV NSCLC of all histologies, with a life expectancy of at least 3 months, an ECOG performance status of zero or one and measurable disease were eligible for this study. Patients who had received prior therapy for NSCLC, including chemotherapy, biological/targeted therapy or any investigational drug, were excluded from the trial. Those with active brain metastases were excluded, as were patients with gastrointestinal disorders that could interfere with the absorption of the study drug. Patients who had experienced a hemorrhagic or thromboembolic event in the past 12 months, or clinically significant hemoptysis in the past 3 months, and those with centrally located tumors with radiological evidence (computed tomography or magnetic resonance imaging) of local invasion of major blood vessels or who had significant cardiovascular disease were excluded. In addition, patients with total bilirubin > 1.5 mg/dl, alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 1.5 × upper limit of normal or serum creatinine > 1.5 mg/dl were excluded.
efficacy assessments
Objective tumor response was assessed according to RECIST (version 1.0) [13] at 6-week intervals after the start of BIBF 1120 treatment.
PK sampling and analysis
During treatment cycles 1 and 2, PK sampling was carried out on day 1 before paclitaxel administration and then at 3, 3.5, 4.5, 5, 6, 8 and 10 h after the start of the paclitaxel infusion. Of note, between 3 and 3.5 h after the start of paclitaxel infusion, carboplatin infusion occurred. On day 2, samples were obtained before BIBF 1120 administration and at 1, 2, 3, 4, 6, 8 and 10 h post BIBF 1120 administration. Samples were also collected on days 8 and 15 of treatment cycles 1 and 2 and on day 1 of repeated cycles.
A 5-ml volume of venous blood was collected and plasma concentrations of BIBF 1120, paclitaxel and total platinum were determined. Plasma concentrations of BIBF 1120 and paclitaxel were analyzed by validated assays based on high-performance liquid chromatography tandem mass spectrometry. For BIBF 1120, the lower limit of quantification was 0.5 ng/ml and the calibration curves were linear in a concentration range of 0.5–500 ng/ml BIBF 1120 using a plasma volume of 200 μl (analyses carried out at Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany). For paclitaxel, the lower limit of quantification was 2.5 ng/ml and the calibration curves were linear in a concentration range of 2.5–1000 ng/ml paclitaxel using a plasma volume of 100 μl (analyses carried out at AAI Pharma Deutschland GmbH & Co. KG, Neu-Ulm, Germany). Plasma concentrations of total platinum after administration of carboplatin were analyzed by a fully validated method using inductively coupled plasma mass spectrometry. The calibration curves of undiluted samples were linear over the range of concentrations from 2.5 to 1000 ng/ml total platinum using a plasma volume of 100 μl (analyses carried out at AAI Pharma Deutschland GmbH & Co. KG). Analyses of quality control samples along with the study samples demonstrated adequate accuracy and precision of the individual assays employed throughout the study (data not shown). PK parameters were calculated using WinNonlin® Professional (Version 5.0.1; Pharsight® Corporation, Cary, NC) and were assessed graphically and summarized by time point descriptive statistics using Statistical Analysis Software (SAS, v8.2; SAS Institute Inc., Cary, NC).
statistical analyses
The analyses in this trial were descriptive and exploratory. All patients who received BIBF 1120 were included in the safety analysis. The escalation scheme in this trial was such that there was an 80 % chance that at least two patients would experience a DLT for a given dose, if the chance of a DLT was 45 % –50 % for each patient. Toxic effects were graded according to the National Cancer Institute CTCAE, version 3.0.
results
patient population
The demographics and clinical characteristics of the 26 study participants are listed in Table 1. Twenty-three patients (88.5 % ) completed the initial 21-day treatment cycle. Fifteen patients (57.7 % ) discontinued study treatment due to disease progression; 11 (42.3 % ) discontinued due to toxicity.
Table 1.
Patient demographics and clinical characteristics
| Total (N = 26) | |
|---|---|
| Age (years) | |
| Mean | 62 |
| Min–max | 48–74 |
| Sex | |
| Male | 8 (31) |
| Female | 18 (69) |
| Smoking history | |
| Never smoker | 4 (15) |
| Ex-smoker | 18 (69) |
| Current smoker | 4 (15) |
| ECOG performance status | |
| 0 | 11 (42) |
| 1 | 15 (58) |
| Histology | |
| Adenocarcinoma | 13 (50) |
| Large cell | 4 (15) |
| Squamous cell | 3 (12) |
| Adenosquamous | 0 (0) |
| Not specified | 7 (27) |
| Prior surgery | 17 (65) |
| Prior radiotherapy | 6 (23) |
| Number of prior therapiesa | |
| 0 | 8 (31) |
| 1 | 8 (31) |
| 2 | 8 (31) |
| 3 | 2 (8) |
aAll prior therapies include prior surgery and prior anticancer radiotherapy; a patient could have had both prior surgery and radiotherapy.
ECOG, Eastern Cooperative Oncology Group.
safety and tolerability
All 26 patients were included in the safety and efficacy analyses. During the course of the study, 20 patients missed at least one dose of BIBF 1120. Of these patients, nine missed a dose during the first treatment cycle, including three who missed a dose because of a DLT. Over the entire treatment period, and across all dose cohorts, the dose of BIBF 1120 was reduced in six patients. One patient required two dose reductions from 200 to 150 mg b.i.d. and finally to 100 mg b.i.d. The mean duration of treatment was 126 days, with individual patient exposure to BIBF 1120 ranging from 8 to 389 days.
Table 2 summarizes AEs related to BIBF 1120 treatment. The most frequently reported AEs related to BIBF 1120 were diarrhea, fatigue and nausea. This mirrors the observations from BIBF 1120 monotherapy studies [9, 10]. Table 3 presents the DLTs observed during the initial 21 days of the study. BIBF 1120 at 250 mg b.i.d. was declared nontolerable as three of the three treated patients developed DLTs during the first treatment cycle (grade 3 gamma-glutamyltransferase (GGT) increase, ALT increase and grade 3 abdominal pain). The MTD of BIBF 1120, when given in combination with full dose paclitaxel and carboplatin, was therefore defined as 200 mg b.i.d. All DLTs were reversible following additional treatment or discontinuation of BIBF 1120. In the MTD cohort of 200 mg b.i.d. of BIBF 1120, 3 of 11 patients had a dose reduction to 150 mg b.i.d. BIBF 1120 within the first four cycles and 1 patient after cycle 4.
Table 2.
BIBF 1120 treatment-related adverse events in ≥ 10 % of patients in the total group
| AE | Number of patients ( % ) |
|---|---|
| Diarrhea | 14 (53.8) |
| Fatigue | 13 (50.0) |
| Nausea | 12 (46.2) |
| Vomiting | 6 (23.1) |
| Anorexia | 5 (19.2) |
| Flushing | 5 (19.2) |
| Pruritus | 5 (19.2) |
| Rash | 5 (19.2) |
| Increased ALT | 5 (19.2) |
| Increased AST | 5 (19.2) |
| Pruritus | 5 (19.2) |
| Rash | 5 (19.2) |
| Abdominal pain | 4 (15.4) |
| Blood alkaline phosphatase increase | 4 (15.4) |
| Constipation | 4 (15.4) |
| Hypertension | 4 (15.4) |
| Neutropenia | 4 (15.4) |
| Peripheral sensory neuropathy | 4 (15.4) |
| Dysgeusia | 3 (11.5) |
| Hyperhidrosis | 3 (11.5) |
| Leukopenia | 3 (11.5) |
| Myalgia | 3 (11.5) |
| Neuropathy peripheral | 3 (11.5) |
| Neuropathy | 3 (11.5) |
AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase.
Table 3.
DLTs observed during the initial 21-day treatment cycle
| BIBF 1120 dose | DLT (CTCAE grade) |
|---|---|
| 100 mg b.i.d. | Nausea (3)a, vomiting (3)a |
| 100 mg b.i.d. | Fatigue (3) |
| 200 mg b.i.d. | Thrombocytopenia (4) |
| 200 mg b.i.d. | ALT increased (3), AST increased (3) |
| 200 mg b.i.d. | ALT increased (3), GGT increased (3) |
| 200 mg b.i.d. | ALT increased (3), AST increased (3), rash (3) |
| 250 mg b.i.d. | Abdominal pain (3) |
| 200 mg b.i.d.b | Diarrhea (3)a, fatigue (3)a, GGT increased (3) |
| 250 mg b.i.d. | GGT increased (3)a, ALT increased (3)a |
aDLTs leading to study discontinuation.
bThis patient was originally assigned to the BIBF 1120 250 mg b.i.d. dose group and the dose reduced to BIBF 1120 200 mg b.i.d. in treatment period 1. Fatigue occurred when the patient received BIBF 1120 250 mg b.i.d., and diarrhea and GGT increase occurred when the patient received BIBF 1120 200 mg b.i.d.
ALT, alanine aminotransferase; AST, aspartate aminotransferase; CTCAE, common terminology criteria for adverse events; DLT, dose-limiting toxicity; GGT, gamma-glutamyltransferase.
Two deaths were reported during the course of the study, both of which were considered due to disease progression and not related to study medication. Hypertension of grade 1 or 2 in intensity was reported as an AE in eight patients (30.8 % ) and was related to BIBF 1120 in four of these patients. All patients with this AE were treated for hypertension except for one patient who recovered spontaneously.
efficacy
Overall, 22 patients (84.6 % ) experienced clinical benefit [partial response (PR) or stable disease (SD) without confirmation]. Seven patients (26.9 % ) achieved a confirmed PR. Within the 13 patients treated in the MTD group, 9 patients achieved a PR and 2 patients achieved SD; five of these patients achieved a confirmed PR. Median progression-free survival was 170 days (>24 weeks) for the MTD group. Five patients participated in the trial for > 6 months without disease progression.
pharmacokinetics
BIBF 1120
BIBF 1120 was absorbed moderately fast after oral administration when administered in combination with paclitaxel and carboplatin. Peak BIBF 1120 plasma concentrations were achieved around 2–4 h after dosing. Steady state was reached after 7 days and trough concentrations remained stable over the observed treatment cycles; however, moderate to high interpatient variability was observed (Figure 1A and Table 4). Generally, geometric mean (gMean) Cmax concentrations, as well as exposure (AUC), of BIBF 1120 increased with increasing doses of BIBF 1120 (data not shown). No terminal half-life and related PK parameters were calculated for BIBF 1120, due to the limited PK sampling duration (only up to 10 h after drug administration) for BIBF 1120 in this trial.
Figure 1.
(A) Individual and gMean drug plasma concentration–time profiles of BIBF 1120 given at 200 mg b.i.d. (linear scale). (B) Individual and gMean drug plasma concentration–time profiles of paclitaxel after a single dose on day 1 of treatment cycle 1 and treatment cycle 2 (semi-log scale). (C) Individual and gMean drug plasma concentration–time profiles of total platinum after a single dose on day 1 of treatment cycle 1 and treatment cycle 2 (semi-log scale).
Table 4.
BIBF 1120 pharmacokinetic parameters for the BIBF 1120 200 mg b.i.d. dose group by treatment cycle
| BIBF 1120 | Treatment cycle 1 |
Treatment cycle 2 |
||||
|---|---|---|---|---|---|---|
| n | gMean | gCV ( % ) | n | gMean | gCV ( % ) | |
| AUC0–12 [ng•h/ml) | 11 | 297 | 62.8 | 7 | 427 | 67.1 |
| Cmax (ng/ml) | 13 | 64.8 | 68.1 | 8 | 83.9 | 68.2 |
| tmaxa (h) | 13 | 3.00 | 2.00–6.00 | 8 | 2.00 | 1.95–6.00 |
gCV, geometric coefficient of variation.
aMedian and range.
paclitaxel
The plasma concentration–time profiles of paclitaxel on day 1 of treatment cycles 1 and 2 were comparable (Figure 1B). The gMean paclitaxel Cmax values varied across treatment cycles 1 (absence of BIBF 1120) and 2 (in the presence of BIBF 1120), increasing by ∼21 % (Table 5). A 20 % increase was observed between the gMean AUC0–∞ values for treatment cycles 1 and 2 (Table 5). The differences in Cmax and AUC0–∞ values between treatment cycles 1 and 2 were even smaller when data from all dose groups were considered (data not shown). There was not a statistically significant increase in Cmax and AUC0–∞ values between both treatment cycles (Figure 2A and B; P values for ratio outside interval of 0.8–1.25 were 0.189 and 0.190, respectively).
Table 5.
Paclitaxel pharmacokinetic parameters for the BIBF 1120 200 mg b.i.d. group by treatment cycle
| Paclitaxel | Treatment cycle 1, n = 8 |
Treatment cycle 2, n = 8 |
||||
|---|---|---|---|---|---|---|
| gMean | gCV ( % ) | Range | gMean | gCV ( % ) | Range | |
| Cmax (ng/ml) | 6020 | 29.2 | 4020–8880 | 7260 | 25.9 | 4710–10800 |
| AUC0–∞(ng•h/ml) | 18800 | 21.6 | 14500–25500 | 21900a | 27.9a | 14900–33600 |
| tmaxb (h) | 2.92 | 2.78 | 2.83–3.10 | 2.92 | 2.21 | 2.92–3.08 |
| t½(h) | 7.97 | 11.4 | 6.74–9.68 | 8.20a | 9.89a | 7.13–9.41 |
| CL (l/h) | 19.4 | 27.5 | 12.1–26.5 | 16.7a | 35.6a | 9.16–27.2 |
an = 7.
bMedian.
Figure 2.
(A) Individual Cmax values of paclitaxel after a single dose on day 1 of treatment cycle 1 and treatment cycle 2, for patients who received BIBF 1120 200 mg BID (MTD). (B) Individual AUC values of paclitaxel after a single dose on day 1 of treatment cycle 1 and treatment cycle 2, for patients who received BIBF 1120 200 mg BID (MTD).
carboplatin
The plasma concentration–time profiles of total platinum on day 1 of treatment cycles 1 and 2 were comparable (Figure 1C). Total platinum gMean Cmax concentrations were comparable between treatment cycles 1 and 2 (∼8 % increase). The gMean AUC0–∞ values increased by 18 % between treatment cycles 1 and 2 (Table 6). The differences in Cmax and AUC0–∞ values between treatment cycles 1 and 2 were even smaller when data from all dose groups were considered (data not shown). There was not a statistically significant increase in Cmax and AUC0–∞ values of total platinum between both treatment cycles (Figure 3A and B; P values for ratio outside interval of 0.8–1.25 were 0.187 and 0.093, respectively).
Table 6.
Carboplatin pharmacokinetic parameters for the BIBF 1120 200 mg b.i.d. dose group by treatment cycle
| Carboplatin | Treatment cycle 1, n = 6 |
Treatment cycle 2, n = 6 |
||||
|---|---|---|---|---|---|---|
| gMean | gCV ( % ) | Range | gMean | gCV ( % ) | Range | |
| Cmax (ng/ml) | 16900 | 19.5 | 13800–24400 | 18300 | 37.1 | 11000–28000 |
| AUC0–24 (ng•h/ml) | 57500 | 21.0 | 41400–73900 | 65900a | 32.8a | 41900–99700 |
| tmaxb (h) | 0.450 | 17.4 | 0.350–0.566 | 0.509 | 19.9 | 0.333–0.584 |
| t½ (h) | 9.67 | 12.9 | 7.81–11.4 | 11.0a | 4.46a | 10.5–11.8 |
| CL (ml/min) | 130 | 49.6 | 70.9–242.0 | 111a | 63.2a | 57.4–210 |
an = 5.
bMedian.
Figure 3.
(A) Individual Cmax values of carboplatin after a single dose on day 1 of treatment cycle 1 and treatment cycle 2, for patients who received BIBF 1120 200 mg BID (MTD). (B) Individual AUC values of carboplatin after a single dose on day 1 of treatment cycle 1 and treatment cycle 2, for patients who received BIBF 1120 200 mg BID (MTD).
discussion
The MTD (and recommended phase II dose) of BIBF 1120 is 200 mg b.i.d. when administered in combination with full dose paclitaxel and carboplatin in patients with advanced NSCLC.
At this dose, during treatment cycle 1, 2 patients of 13 experienced a DLT (grade 4 thrombocytopenia, grade 3 ALT increase, AST increase and rash). In contrast, at the nontolerated 250 mg b.i.d. dose, all three patients developed DLTs (grade 3 GGT increase and ALT increase, grade 3 abdominal pain and grade 3 GGT increase). At the MTD, the combination of BIBF 1120, paclitaxel and carboplatin was generally well tolerated, with a safety profile consistent with the known safety profiles for each individual agent. The most frequently reported AEs related to BIBF 1120 were gastrointestinal disorders (principally nausea, diarrhea and vomiting) and elevated AST and ALT levels. BIBF 1120 revealed a similar AE profile with respect to fatigue, nausea and diarrhea as compared with other VEGFR tyrosine kinase inhibitors and is consistent with the AEs and DLTs observed during BIBF 1120 monotherapy [9, 14, 15]. However, treatable hypertension related to BIBF 1120 therapy, although considered a class effect of anti-VEGF agents, was observed in a relatively low number of patients and was of grade 1 or 2 intensity. Although clinical efficacy was a secondary end point in this study, overall, 12 patients achieved a PR and 7 of these (26.9 % ) achieved a confirmed PR. Of note, two of these patients had squamous cell histology and one patient had a mixed large cell/squamous cell histology. Of the 13 patients treated in the MTD group, 9 patients achieved a PR (5 were confirmed) and 2 patients achieved SD as best response. This preliminary assessment demonstrated the potential antitumor activity of this combination regimen.
The BIBF 1120 exposure in the presence of paclitaxel and carboplatin within this trial appears comparable with that of BIBF 1120 monotherapy from historical data [9, 10, 16, 17]. When comparing the gMean values of AUC and Cmax of paclitaxel and carboplatin between treatment cycles 1 (absence of BIBF 1120) and 2 (presence of BIBF 1120), there were slight differences (Table 5 and Table 6). In the face of the high background exposure, variability of carboplatin [18, 19] and paclitaxel [20, 21], examination of drug plasma concentration–time profiles and PK parameters suggest that if any interaction (undetectable as statistically significant) within this small study were to exist, it is unlikely to be clinically significant, since the respective PK parameter values of both drugs in both treatment cycles were comparably ranged (Table 5 and 6). Additionally, there was no statistically significant difference for an increase or decrease of paclitaxel or carboplatin Cmax and AUC values detectable between both treatment cycles. Furthermore, due to the low patient numbers providing sufficient data for PK analysis in both treatment cycles, the study was not powered to show bioequivalence. Moreover, the paclitaxel PK data of treatment cycles 1 and 2 are in line with data in the literature [20, 21]. Also for carboplatin, the respective PK data observed in this trial during both treatment cycles 1 and 2 are in line with published PK data [18, 19, 22]. Based on these data, no clinically significant effect of BIBF 1120 on the PK of paclitaxel (200 mg/m2) or carboplatin (AUC 6 mg/ml/min) was obvious.
To summarize, the MTD of BIBF 1120 is 200 mg b.i.d. in combination with standard paclitaxel and carboplatin. This combination was well tolerated and demonstrated promising preliminary efficacy in patients with advanced NSCLC. The PK data from this trial suggest no drug–drug interaction between BIBF 1120, paclitaxel and carboplatin. Findings from this study support further investigation of this combination regimen in patients with NSCLC.
disclosure
RCD—research funding from Eli Lilly & Co. and ImClone Systems; AMT—research funding from Eli Lilly & Co., Novartis and Bayer; GAO—research funding from Pfizer, Genentech, Abraxis and Tragara and YZ, SW, PS and RK—employees of Boehringer Ingelheim.
Supplementary Material
acknowledgements
The authors would like to acknowledge the editorial assistance of Ogilvy Healthworld. Boehringer Ingelheim provided financial support for this assistance.
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