Targ Oncol (2008) 3:3–11
`DOI 10.1007/s11523-007-0070-5
`
`ORIGINAL RESEARCH
`
`Phase I and pharmacokinetic study of vatalanib plus
`capecitabine in patients with advanced cancer
`
`Richard L. Schilsky & David Geary & Linda Skoog &
`Apurva A. Desai & Joyce Valickas & Bee-Lian Chen &
`Eric Masson & Dirk Laurent & Cynthia Pendowski &
`Everett E. Vokes & Mark J. Ratain
`
`Received: 11 October 2007 / Revised: 21 November 2007 / Accepted: 22 November 2007 / Published online: 18 December 2007
`# Springer-Verlag 2007
`
`Abstract Angiogenesis inhibition is now a proven thera-
`peutic strategy in treatment of several solid tumors.
`Vatalanib is a potent
`inhibitor of all known vascular
`endothelial growth factor
`receptor
`(VEGFR)
`tyrosine
`kinases. In view of
`the effectiveness of angiogenesis
`inhibitor therapy when combined with chemotherapy and
`the established role of capecitabine in treatment of
`colorectal and breast cancer, we undertook a phase I
`clinical
`trial of
`the combination of capecitabine and
`vatalanib with the goal of developing a combination oral
`regimen. The study objectives were to determine the
`maximally tolerated dose of vatalanib that could be safely
`administered daily with capecitabine given orally for 14 out
`of 21 days to patients with advanced cancer; to characterize
`the safety,
`tolerability, and pharmacokinetic profile of
`vatalanib given in combination with capecitabine; and to
`describe any pharmacokinetic interactions between the
`drugs. The study had an initial dose escalation phase
`followed by a dose expansion phase. During the dose
`
`R. L. Schilsky : D. Geary : L. Skoog : A. A. Desai : E. E. Vokes :
`M. J. Ratain
`University of Chicago,
`Chicago, IL, USA
`J. Valickas : B.-L. Chen : E. Masson : C. Pendowski
`Novartis Oncology,
`Hanover, NJ, USA
`
`D. Laurent
`Bayer Schering Pharma,
`Berlin, Germany
`
`R. L. Schilsky (*)
`Section of Hematology/Oncology, University of Chicago,
`5841 S. Maryland Ave.,
`MC2115 Chicago, IL 60637, USA
`e-mail: rschilsk@medicine.bsd.uchicago.edu
`
`escalation phase, cohorts of at least three patients each were
`treated with capecitabine and escalating doses of vatalanib
`until
`the maximally tolerated dose of vatalanib was
`determined. Vatalanib given continuously at a dose of
`1,250 mg/day could be safely combined with capecitabine
`at a dose of 2,000 mg/m2/day given for 14 of 21 days.
`Dose-limiting toxicities of the combination included fa-
`tigue, hypertension, dizziness, and proteinuria. Vatalanib
`did not alter the pharmacokinetics of 5-FU,
`the active
`metabolite of capecitabine. Vatalanib and capecitabine can
`be safely combined without unexpected toxicities or
`significant pharmacokinetic interactions.
`
`Keywords Vatalanib . Capecitabine . Angiogenesis .
`Phase I . Vascular endothelial growth factor receptor
`
`Introduction
`
`Angiogenesis inhibition is now a proven therapeutic strategy
`with established clinical benefit in treatment of colorectal
`cancer [1], non-small cell lung cancer [2], breast cancer [3],
`and renal cell cancer [4, 5]. Vascular endothelial growth
`factor (VEGF), secreted by tumor cells and macrophages, is
`a multifunctional cytokine that
`increases microvascular
`permeability and directly stimulates endothelial cell growth
`and angiogenesis [6]. The angiogenic signal is transmitted
`via cell surface receptors (VEGFR1 and 2) located on the
`tumor vascular endothelium. Commercially available anti-
`angiogenic agents interact with either the VEGF ligand
`(bevacizumab) or one or more VEGF receptors (sorafenib,
`sunitinib) to inhibit tumor angiogenesis.
`Vatalanib (PTK787/ZK222584), an oral agent belonging
`to the chemical class of aminophthalazines,
`is a potent
`inhibitor of all known vascular endothelial growth factor
`
`Ex. 1111-0001
`
`

`

`4
`
`Targ Oncol (2008) 3:3–11
`
`receptor (VEGFR) tyrosine kinases (VEGFR1, 2 and 3) [7].
`Vatalanib inhibits both VEGFR1 (IC50=0.077 μM) and
`VEGFR2 (IC50=0.037 μM) kinases with slightly greater
`potency against VEGFR2. Vatalanib also inhibits other
`kinases belonging to the same family of protein tyrosine
`kinases such as the platelet-derived growth factor (PDGF)
`receptor β tyrosine kinase (IC50=0.58 μM), c-kit protein
`tyrosine kinase (IC50=0.73 μM), and c-Fms (IC50=1.4 μM)
`[7]. The antitumor and anti-metastatic effects of vatalanib
`were assessed in various rodent tumor models, using either
`human tumors in immunodeficient mice or rodent synge-
`neic tumors. Results show that vatalanib inhibits growth of
`subcutaneously implanted human tumor xenografts in
`immunodeficient nude mice, associated with a reduced
`number of microvessels in the interior of the tumors.
`Vatalanib has demonstrated inhibition of growth of primary
`tumors and metastases in several animal models and has
`additive or synergistic cytotoxicity with irinotecan and
`gemcitabine [7–10].
`In phase I monotherapy studies, a group of central
`nervous system (CNS) symptoms (euphoria,
`imbalance,
`unsteady gait, lightheadedness, vertigo, dizziness, disorien-
`tation, and ataxia) appeared to be the primary dose-related
`toxicity of vatalanib [11, 12]. These symptoms usually
`occurred during the first week of treatment and were self-
`limited. Other toxicities were nausea, vomiting, hyperten-
`sion, proteinuria, and elevation of liver function tests [13].
`No hematologic toxicity was observed. During chronic
`dosing studies in rats, effects on the duodenum ranging
`from diffuse hyperplasia of
`the mucosa to infiltrative
`growth with invasion of the intestinal wall were demon-
`strated on histopathological examination [14]. No such
`changes were observed in mice or dogs. Because of these
`findings, clinical trials of vatalanib have incorporated pre-
`treatment and post-treatment upper gastrointestinal (GI)
`x-rays and endoscopy. No drug-related duodenal abnormal-
`ities have been observed in human studies thus far.
`In vitro studies using human and animal liver micro-
`somes have shown that vatalanib is metabolized by a
`number of liver P450 isoenzymes (CYP 1A2, CYP 2A6,
`CYP 2C8, CYP 2C9, CYP 2C19, CYP 2D6, CYP 2E1 and
`CYP 3A4), but predominantly by CYP 3A4 [15]. While in
`vitro results do not always reliably translate into human
`studies,
`they suggest
`that vatalanib could decrease the
`clearance of any co-administered drug metabolized by one
`or more of these P450 enzymes.
`Capecitabine, an oral fluoropyrimidine, is indicated as
`first-line treatment of patients with metastatic colorectal
`carcinoma when treatment with fluoropyrimidine therapy
`alone is preferred, as adjuvant treatment for early stage
`colon cancer and for
`the treatment of patients with
`metastatic breast cancer resistant to both paclitaxel and an
`anthracycline-containing chemotherapy regimen [16–18].
`
`In view of the effectiveness of angiogenesis inhibitor
`therapy when combined with chemotherapy and the
`established role of capecitabine in treatment of colorectal
`and breast cancer, we undertook a phase I clinical trial of
`the combination of capecitabine and vatalanib. The study
`objectives were to determine the maximally tolerated dose
`(MTD) of vatalanib that could be safely administered daily
`with capecitabine administered orally for 14 out of 21 days
`to patients with advanced cancer; to characterize the safety,
`tolerability, biologic activity, and pharmacokinetic profile
`of vatalanib given in combination with capecitabine; and to
`describe any pharmacokinetic interactions between these
`drugs. Since capecitabine is not metabolized by the
`cytochrome P450 system, we did not expect to observe a
`significant drug interaction with vatalanib. However,
`preliminary pharmacokinetic data from this study revealed
`that exposure to capecitabine and its metabolites, 5′-FUDR,
`and particularly 5-fluorouracil (5-FU), was higher follow-
`ing co-administration with vatalanib, raising the possibility
`that vatalanib could increase exposure to 5-FU. However,
`since capecitabine has non-linear pharmacokinetics and its
`exposure is known to increase [19] with repeated dosing,
`we decided to undertake a more extensive pharmacokinetic
`evaluation during the dose-expansion phase of this study to
`determine whether or not a drug interaction with vatalanib
`occurs.
`
`Patients and methods
`
`Adult patients (>18 years) with histologically confirmed
`advanced cancer that was refractory to standard therapy or
`for which there was no standard therapy were eligible to be
`enrolled in the study. Patients were not permitted to have
`received more than four prior chemotherapy regimens for
`metastatic disease and at least 4 weeks must have elapsed
`(6 weeks for nitrosoureas or mitomycin-C) since the last
`dose of chemotherapy. Patients could not have received
`immunotherapy, radiation therapy or surgery within 2 weeks
`of entry on study and must have recovered from the side
`effects of any prior treatment. Patients were required to
`have measurable or non-measurable disease according to
`Response Evaluation Criteria in Solid Tumors (RECIST)
`criteria [20], a Karnofsky performance status of at least
`70%, and a life expectancy of at least 3 months. Organ
`function was required to meet the following parameters:
`absolute neutrophil count (ANC) ≥1.5×109/L; hemoglobin
`(Hgb) ≥9 g/dL; platelets ≥100×109/L; aspartate amino-
`transferase (AST/SGOT) and alanine aminotransferase
`(ALT/SGPT) ≤3.0×upper limit of normal (ULN); serum
`bilirubin ≤1.5×ULN; serum creatinine ≤1.5×ULN; 24-hour
`creatinine clearance ≥50 mL/min; and total urinary protein
`in a 24-hour urine collection ≤500 mg.
`
`Ex. 1111-0002
`
`

`

`Targ Oncol (2008) 3:3–11
`
`5
`
`Patients were excluded from participation if they had a
`hematologic malignancy, known bone marrow involvement
`by tumor, a history of a primary central nervous system (CNS)
`malignancy or CNS metastases, or if they had previously
`received a bone marrow or stem cell transplant. Pregnant and
`lactating women were excluded from participation because of
`concerns about administering cytotoxic and antiangiogenic
`therapy to a developing fetus or nursing infant. Patients were
`also excluded if they had concurrent severe and/or uncon-
`trolled medical disease (i.e., uncontrolled diabetes, congestive
`cardiac failure, myocardial infarction within 6 months, poorly
`controlled hypertension, history of labile hypertension, history
`of poor compliance with antihypertensive treatment, chronic
`renal disease, or active uncontrolled infection); acute or
`chronic liver disease (e.g., hepatitis, cirrhosis); a confirmed
`diagnosis of HIV infection; gastrointestinal (GI) dysfunction
`or GI disease that could significantly alter the absorption of
`vatalanib; or were taking warfarin. The protocol was approved
`by the University of Chicago Institutional Review Board, and
`all patients provided written informed consent for their
`participation.
`
`Study design and treatment administration
`
`The study included a dose-escalation phase followed by a
`dose-expansion phase. During the dose-escalation phase,
`cohorts of at least three patients were treated with capecitabine
`and escalating doses of vatalanib until
`the MTD was
`determined. The capecitabine starting dose was 2,500 mg/
`m2/day given in divided dose, however this was subsequent-
`ly reduced to 2,000 mg/m2/day due to significant toxicity in
`the initial patient cohorts. Vatalanib was provided by Bayer
`Schering Pharma as 250 mg tablets. It was administered once
`daily, within 30 min of completing a meal, at doses ranging
`from 750 mg/day, the lowest dose shown to have biological
`effects in monotherapy studies, to 1,250 mg/day, the highest
`dose planned. Vatalanib dosing was begun on day 2 of cycle
`1 and was then continued without interruption. Patients were
`instructed to take vatalanib immediately prior to taking
`capecitabine. Escalation of
`the vatalanib dose was to
`continue until the MTD was determined based on observed
`toxicities in cycle 1 of treatment.
`The first three patients at each dose level were observed
`for at least 21 days before the next cohort of new patients
`was treated at the next higher dose level. Patients who did
`not receive all doses of study drug for reasons other than
`drug toxicity were considered non-evaluable for the MTD
`determination and were replaced.
`If no dose-limiting toxicity (DLT) was seen in a cohort
`of three patients at a given dose level, the next cohort of
`three new patients was treated at the next higher dose level.
`If treatment-related DLT was encountered in one patient,
`then at least three additional patients were enrolled at the
`
`same dose level. If DLT was not observed in the additional
`patients, new patients were treated at the next higher dose
`level. Similarly, if the incidence of DLT among six patients
`was one in six, then the next cohort was treated at the next
`higher dose level. When a minimum of
`two patients
`experienced DLT at a given dose level, that dose level
`was defined as the DLT dose level and dose escalation was
`stopped. A maximum of six patients could be treated at the
`DLT dose level. Once the DLT dose level was established,
`up to three more patients were enrolled at the previous
`lower dose level up to a maximum of six patients. The
`recommended dose for further study (MTD dose level) was
`defined as the vatalanib dose at which no more than one of
`six patients experienced DLT with at least two patients
`experiencing DLT at the next higher dose level.
`DLT was defined as National Cancer Institute Common
`Toxicity Criteria (CTC) grade 4 neutropenia lasting 5 or
`more days; grade 4 thrombocytopenia of any duration; any
`grade 3–4 drug-related adverse event except alkaline
`phosphatase elevation, nausea/vomiting or grade 3 hyper-
`tension (following protocol amendment); CTC grade 2 or
`higher proteinuria or hematuria; CTC grade 3 ataxia/
`dizziness lasting more than 10 days or CTC grade 4
`dizziness/ataxia of any duration. Known toxicities of
`capecitabine were not considered DLTs unless they were
`thought to be exacerbated by vatalanib.
`During the dose-expansion phase, the plan was to enroll
`22 evaluable patients at the recommended doses determined
`in the dose escalation phase to evaluate potential PK
`interactions. This number of patients was considered
`sufficient to have 80% power to detect a 20% change in
`5-FU AUC when capecitabine was administered with
`vatalanib. During this phase of the study, capecitabine
`was given alone during cycle 1 and capecitabine plus
`vatalanib were given in cycle 2 and continued in subse-
`quent cycles.
`
`Patient assessment
`
`Patients were evaluated by a physician on day 1 of each 21-
`day cycle. A complete blood count, differential count,
`platelets, and serum chemistries were obtained on days 1
`and 8 of cycle 1, then on day 1 of each subsequent cycle.
`Coagulation parameters and urine protein were assessed on
`day 1 of each cycle. Patients underwent upper GI examination
`by double contrast barium meal prior to beginning treatment
`and again after 12 weeks of treatment. Tumor measurements
`were obtained at baseline and every 2 cycles.
`
`Pharmacokinetic sampling and analysis
`
`the study blood
`During the dose-escalation phase of
`samples were obtained according to the following schedule:
`
`Ex. 1111-0003
`
`

`

`6
`
`Targ Oncol (2008) 3:3–11
`
`Table 1 Patient characteristics: dose-escalation phase
`
`Dose-expansion phase
`
`41
`29
`12
`30
`5
`6
`61 (34–78)
`100 (70–100)
`
`Blood sampling for capecitabine and its metabolites was
`performed as described above on days 1 and 14 of cycle 1,
`and on days 1 and 14 of cycle 2.
`Blood samples were collected into pre-cooled vacutainer
`tubes and immediately centrifuged at 4°C (ca. 2,000×g,
`10 min). Following centrifugation, plasma was transferred
`by pipette to a polypropylene, cryogenic, freezing vial and
`stored frozen at −80°C until shipment and analysis.
`
`Patient characteristics
`
`Number of patients
`Male
`Female
`White
`Black
`Other
`Median age, year
`Median KPS
`Prior treatment
`Chemotherapy alone
`Chemotherapy + RT
`Diagnosis
`Colorectal
`Head and neck
`Sarcoma
`Renal
`Pancreas
`Unknown
`Esophagus
`Gastric
`GIST
`Mesothelioma
`Neuroendocrine
`Ovary
`
`17
`24
`
`10
`7
`5
`4
`3
`3
`2
`2
`2
`1
`1
`1
`
`Analytical methods
`
`Capecitabine, 5′-DFUR, and 5-FU were measured in
`plasma by Xendo Laboratories, Groningen, The Nether-
`lands, using a validated liquid-chromatography mass
`spectroscopy assay with a lower limit of quantitation of
`25 ng/mL for capecitabine and 5′-DFUR, and 5 ng/mL for
`5-FU (16). Pharmacokinetic (PK) parameters of capecita-
`bine, 5′-DFUR and 5FU were estimated by non-compart-
`mental PK analysis using WinNonlin® (Pharsight, Carry,
`NC). Dose administration records for all patients during
`cycles 1 and 2 were reviewed, and profiles were excluded
`from the PK analysis if there were dose reductions of either
`capecitabine or vatalanib.
`Descriptive statistics were provided for all PK parame-
`ters by analyte and study day. For Tmax, median, minimum
`and maximum were determined. For all other PK param-
`eters, geometric means and coefficient of variation (CV%)
`were calculated. Analyses were conducted separately for
`the three analytes. Following log-transformation, PK
`parameters (AUC0–last and Cmax) were analyzed using a
`linear mixed effects model, including terms for study day as
`a fixed factor and subject as a random factor. Three
`comparisons were performed:
`
`1. Cycle 1, day 14 versus cycle 1, day 1: the accumulation
`of capecitabine with multiple dosing
`2. Cycle 2, day 1 versus cycle 1, day 1: the interaction of
`vatalanib with capecitabine at a single dose for both drugs
`
`GIST gastrointestinal stromal
`status, RT radiation therapy
`
`tumor, KPS Karnofsky performance
`
`1. Day 1, cycle 1: Blood samples for measurement of
`capecitabine and its metabolites (5 mL, EDTA tube)
`were obtained pre-treatment then at 30 min, 1, 2, 3, 4,
`6, and 8 h after the capecitabine dose.
`2. Day 14, cycle 1: Blood samples (5 mL, EDTA tube for
`capecitabine and 3 mL, heparinized tube for vatalanib)
`were obtained pre-treatment then at 30 min, 1, 2, 3, 4,
`6, 8 and 24 h after dosing.
`3. Day 21, cycle 1: Blood samples for vatalanib were
`obtained as on day 14.
`
`Table 2 Dose-escalation phase: dose-limiting toxicity cycle 1
`
`PTK dose
`(mg)
`
`Cape dose
`(mg/m2)
`
`Number of
`patients
`
`Number of patients evaluable
`for DLTa
`
`Number of cycles for evaluable
`patients
`
`Number of patients
`with DLT
`
`750
`1,000
`750
`1,000
`1,250
`
`2,500
`2,500
`2,000
`2,000
`2,000
`
`11
`4
`7
`15
`6
`
`6
`2
`3
`12
`6
`
`23
`8
`19
`54
`41
`
`1 (f)
`2 (f, h)
`0
`2 (d; h, s, c)
`1 (p)
`
`a Some patients not evaluable for DLT due either to rapid disease progression and failure to complete cycle 1 or to interruption of study drug
`during cycle 1
`c cerabrovascular accident secondary to hypertension, d dizziness, f fatigue, h hypertension, s seizure, p proteinuria, PTK vatalanib, Cape
`capecitabine, DLT dose-limiting toxicity
`
`Ex. 1111-0004
`
`

`

`Targ Oncol (2008) 3:3–11
`
`Table 3 Patients with hand-
`foot syndrome during
`dose-escalation phase
`
`a Worst grade per patient
`
`Vatalanib/capecitabine dose level
`
`Number of patients
`
`Grade 1a
`
`Grade 2
`
`Grade 3
`
`750/2,500
`1,000/2,500
`750/2,000
`1,000/2,000
`1,250/2,000
`
`11
`4
`7
`15
`6
`
`2
`1
`0
`1
`2
`
`0
`0
`3
`1
`1
`
`2
`3
`2
`8
`1
`
`7
`
`3. Cycle 2, day 14 versus cycle 1, day 14: the interaction of
`vatalanib with capecitabine at steady state for both drugs.
`
`Results
`
`Of the 74 patients enrolled in the study, nine patients never
`received vatalanib due to rapid disease progression. Thus
`we report results of the 65 patients who received the
`combination of capecitabine and vatalanib, 41 in the dose-
`escalation phase and 24 in the dose-expansion phase.
`
`Dose-escalation phase
`
`The characteristics of the 41 patients enrolled in the dose-
`escalation phase of the study are summarized in Table 1.
`Their median age was 61 years (range, 34–78 years),
`median Karnofsky performance status 100 (range, 70–100)
`and all had previously been treated with either chemother-
`apy or chemotherapy and radiation therapy. The dose levels
`tested and dose-limiting toxicities are summarized in
`Table 2. Patients enrolled in the first
`two dose levels
`received capecitabine at the standard dose of 2,500 mg/m2/
`day. However, three of eight evaluable patients in the first
`two dose levels experienced dose-limiting hypertension and
`fatigue, and five patients experienced grade 3 hand-foot
`syndrome (Table 3). As it was not possible to determine
`whether these toxicities were related primarily to capecita-
`bine, vatalanib or
`the combination,
`the protocol was
`amended to reduce the dose of capecitabine to 2,000 mg/
`m2/day for all new patients and to re-start the vatalanib dose
`escalation. An additional 28 patients were enrolled of
`whom 21 were fully evaluable for DLT determination.
`
`The non-evaluable patients had either rapid disease pro-
`gression resulting in removal from therapy or failure to
`receive all doses of study drug during cycle 1. No DLTs
`the 750 mg (vatalanib)/2,000 mg/m2
`were observed at
`(capecitabine) dose level so additional patients were
`enrolled at the next dose level of 1,000 mg/2,000 mg/m2.
`At
`this dose level, one patient experienced grade 3
`hypertension, one patient experienced grade 3 dizziness
`that lasted longer than 10 days, and a third patient had a
`seizure and cerebrovascular accident
`in the setting of
`uncontrolled grade 4 hypertension. This patient was a
`44 year old woman with metastatic colorectal cancer and no
`previous history of hypertension. Two seizures occurred on
`day 12 of cycle 1 of therapy following several days of
`headache and complaints of blurred vision. On admission to
`the hospital, the patient was awake and oriented with a
`normal neurological examination. A CT scan of the brain
`was normal however a magnetic resonance imaging scan of
`the brain revealed a patchy increase in T2 signal in the right
`parietal and both occipital lobes that was interpreted as a
`possible ischemic infarct. The patient was removed from
`protocol therapy, treated successfully with anti-seizure and
`anti-hypertensive medications and discharged after three
`days with normalization of her blood pressure and without
`neurological sequelae.
`In view of these toxicities and with permission of the
`study sponsor and the IRB, a total of 12 evaluable patients
`were enrolled at this dose level. The protocol was also
`amended to remove grade 3 hypertension, i.e., hypertension
`requiring therapy or more intensive therapy than previously,
`as a dose-limiting toxicity. No changes were made to the
`protocol specifications for patient monitoring. When no
`additional DLTs were observed, enrollment was begun in
`the final planned dose level of 1,250 mg/2,000 mg/m2. As
`
`Table 4 Number of patients with grade 2 events related to vatalanib (any cycle)
`
`Vatalanib/capecitabine dose
`level
`
`Number patients/
`cycles
`
`Fatigue Anorexia HBP*
`
`Proteinuria
`
`Liver function tests
`elevation
`
`Hives
`
`Pain
`
`750/2,500
`1,000/2,500
`750/2,000
`1,000/2,000
`1,250/2,000
`
`*HBP high blood pressure
`
`11/36
`4/20
`7/24
`15/62
`6/41
`
`2
`1
`0
`0
`0
`
`0
`1
`1
`0
`0
`
`0
`1
`1
`0
`0
`
`0
`1
`0
`0
`2
`
`0
`0
`0
`1
`0
`
`0
`0
`0
`1
`0
`
`0
`1
`0
`0
`0
`
`Ex. 1111-0005
`
`

`

`8
`
`Targ Oncol (2008) 3:3–11
`
`Table 5 Patient characteristics: dose-expansion phase
`
`Table 7 Best response to treatment-all evaluable patients (n=56)
`
`24
`15
`9
`21
`2
`1
`64 (23–79)
`90 (70–100)
`
`Best response
`
`Number
`of
`patients
`
`Median number
`of cycles received
`(range)
`
`Partial response
`Stable diseasea
`Stable disease
`unconfirmed
`Progressive disease
`
`5
`21
`10
`
`20
`
`6 (6–12)
`8 (4–16)
`2 (2–3)
`
`2
`
`Number of patients
`Male
`Female
`White
`Black
`Other
`Median age, y
`Median KPS
`Prior treatment
`Chemotherapy + RT
`Chemotherapy alone
`Diagnosis
`Head and neck
`Esophagus
`Pancreas
`Breast
`Unknown
`Colorectal
`Endometrial
`Ovary
`Sarcoma
`Thyroid
`
`14
`10
`
`5
`4
`3
`3
`3
`2
`1
`1
`1
`1
`
`a Stable disease is no progression at day 84 on treatment (after 4
`cycles). Stable disease unconfirmed is stable disease after 2 cycles of
`treatment without confirmatory assessment at day 84.
`
`All had been previously treated with chemotherapy or
`chemotherapy and radiation therapy. All patients at this
`dose level received vatalanib at 1,250 mg/day continuously
`with capecitabine at 2,000 mg/m2/day in divided dose for
`14 days of each 21 day cycle. Table 6 summarizes the
`treatment-related grade 3 or higher adverse events experi-
`enced by these patients. Vascular thromboembolism (5 deep
`venous thrombosis, 1 pulmonary embolism) and hand-foot
`syndrome were the most common serious adverse events,
`along with transaminase elevation and fatigue. Of 109
`cycles of therapy administered during the dose-expansion
`phase, 33 were delayed or interrupted due to a treatment-
`related adverse event. Follow-up upper GI x-rays did not
`reveal any abnormalities considered to be treatment-related
`in patients enrolled in either the dose escalation or dose
`expansion phases of the study.
`
`Tumor response to treatment
`
`The best response to treatment noted among the 56 patients
`with evaluable disease enrolled in both phases of the study
`is summarized in Table 7. Five patients had a partial
`response, while 21 patients had confirmed stable disease
`
`Table 8 Characteristics of patients with confirmed partial response
`(n=5)
`
`Age
`
`Prior therapy
`
`Diagnosis
`
`Dose level
`(Vatalanib–
`capecitabine)
`
`48
`67
`
`66
`68
`71
`
`Cisplatin, gefitinib, RT
`5-FU, carboplatin,
`hydroxyurea, paclitaxel,
`bevacizumab, gefitinib, RT
`RT
`Cisplatin, irinotecan, sorafenib
`5-FU, irinotecan, oxaliplatin
`
`Head/neck
`Head/neck
`
`750/2,000
`1,000/2,000
`
`Head/neck
`Esophageal
`Colon
`
`1,000/2,000
`1,250/2,000
`1,000/2,500
`
`KPS Karnofsky performance status, RT radiation therapy
`
`only one of six patients at this dose level developed DLT
`(proteinuria), 1,250 mg/2,000 mg/m2 was determined to be
`a safe dose level for further testing. Table 4 summarizes
`grade 2 toxicities related to vatalanib that occurred during
`the dose-escalation phase of the study.
`
`Dose-expansion phase
`
`The characteristics of the 24 patients enrolled in this phase
`of the study are summarized in Table 5. Their median age
`was 64 years (range 23–79 years), and their median
`Karnofsky performance status was 90 (range, 70–100).
`
`Table 6 Dose-expansion phase toxicity: number of patients with
`treatment-related ≥Grade 3 adverse events (n=24)
`
`Adverse event
`
`Number of patients
`
`Deep venous thrombosis/pulmonary embolism 6
`Hand-Foot Syndrome
`6
`Liver function tests elevation
`4
`Fatigue
`4
`Hypertension
`2
`Anemia
`2
`Abdominal pain
`2
`Diarrhea
`2
`Thrombocytopenia
`1
`Agitation
`1
`Dizziness
`1
`Confusion
`1
`Vomiting
`1
`Hypokalemia
`1
`
`Ex. 1111-0006
`
`

`

`Targ Oncol (2008) 3:3–11
`
`9
`
`Discussion
`
`This study demonstrated that vatalanib can be safely
`combined with a commonly used dose of capecitabine
`without unexpected toxicities. Dose-limiting toxicities of the
`combination included fatigue, hypertension, dizziness and
`proteinuria, all known side effects of vatalanib administered
`as a single agent. Hand-foot syndrome, the most prominent
`side effect of capecitabine, occurred commonly at all dose
`levels, and it was not possible to determine if its frequency or
`severity might have been exacerbated by co-administration of
`vatalanib. This toxicity was the most common reason for dose
`delay or modification during the dose-expansion phase of the
`study. Whereas hand-foot syndrome has been reported as a
`common toxicity of other VEGFR inhibitors such as
`sorafenib [4],
`it has not been a prominent
`toxicity in
`vatalanib clinical trials [11, 13], and it seems most likely
`that the hand-foot syndrome observed in this trial was due
`primarily to capecitabine.
`A major goal of this study was to determine whether co-
`administration of vatalanib with capecitabine resulted in a
`significant pharmacokinetic interaction. Although systemic
`exposure to capecitabine was increased by up to 35% in the
`presence of vatalanib, this was felt to be clinically insignifi-
`cant as capecitabine is pharmacologically inactive and plasma
`exposure of its active metabolite 5-FU was not affected by co-
`administration of these drugs. Interestingly, 5-FU exposure
`increased by 52% between day 1 of cycle 1 and day 14 of
`cycle 1 when capecitabine was given as a single agent for
`14 days. This time-dependent change in exposure has been
`previously reported but remains unexplained given the short
`elimination half-life of 5-FU in plasma [19].
`As shown in Table 7, the combination of vatalanib and
`capecitabine has antitumor activity, with five of 56
`evaluable patients achieving a partial response to treatment.
`Notably, three of the five patients with a partial response had
`head and neck cancer, all of whom were previously treated,
`suggesting that this regimen might be worthy of further
`exploration in that disease. Clearly though,
`the non-
`randomized design of this phase I trial makes it impossible
`to determine whether vatalanib adds anything to the known
`antitumor activity of capecitabine. Indeed, the recommended
`dose and schedule of vatalanib determined in this study
`(1,250 mg continuous daily dosing) is identical
`to that
`employed in the CONFIRM 1 and CONFIRM 2 random-
`ized, placebo controlled trials of FOLFOX-4 with or without
`vatalanib in first- or second-line treatment of patients with
`advanced colorectal cancer [21, 22]. Both of these trials
`failed to demonstrate clinical benefit from addition of
`vatalanib to chemotherapy, although in both a subset of
`patients characterized by high serum LDH could be
`identified who appeared to derive some benefit from the
`combination of chemotherapy with vatalanib. Concerns
`
`Fig. 1 Mean plasma concentration versus time profiles of 5-FU after
`single dose with and without vatalanib (PTK/ZK) (Day 1)
`
`after 4 cycles and received a median of 8 cycles of therapy.
`Three of the five patients with a partial response had head
`and neck cancer (larynx, sinus, salivary duct) (Table 8).
`
`Pharmacokinetic results
`
`Tables 9, 10, 11, 12 and Figs 1 and 2 summarize the mean
`pharmacokinetic parameters of capecitabine and 5-FU with
`or without concomitant dosing with vatalanib in the dose-
`expansion phase of the study. Capecitabine AUC was
`increased by up to 35% with vatalanib, but this was not
`associated with major changes in exposure of the active
`metabolite 5-FU. Table 13 summarizes the mean pharma-
`cokinetic parameters of 5-FU without vatalanib in cycle 1.
`Notably, 5-FU exposure significantly increased between
`day 1 and 14 upon continuous dosing with capecitabine
`alone in cycle 1.
`
`Fig. 2 Mean plasma concentration versus time profiles of F-FU after
`single dose with and without vatalanib (PTK/ZK) (Day 14)
`
`Ex. 1111-0007
`
`

`

`10
`
`Targ Oncol (2008) 3:3–11
`
`Table 9 Pharmacokinetic (PK) parameters of capecitabine ± vatalanib on day 1
`Cycle 1 (− vatalanib) n=29
`
`PK parameters – units
`
`Cycle 2 (+ vatalanib) n=23
`
`Geo. mean ratio (± vatalanib) (90% CI)
`
`Tmax – h Median (range)
`Cmax – ng/mL Mean (CV%)
`AUC0–t – ng*h/mL Mean (CV%)
`T 1/2 el – h Mean (CV%)
`
`1.45 (0.5–6)
`3,651 (111%)
`5,143 (53%)
`0.50 (44%)
`
`1.08 (0.5–6)
`3,806 (97%)
`6,995 (54%)
`0.58 (37%)
`
`NA
`0.99 (0.72–1.37)
`1.35 (1.10–1.66)
`NA
`
`Table 10 Pharmacokinetic (PK) parameters of capecitabine ± vatalanib on day 14
`Cycle 1 (− vatalanib) n=24
`
`PK parameters – units
`
`Cycle 2 (+ vatalanib) n=19
`
`Geo. Mean Ratio (± vatalanib) (90% CI)
`
`Tmax – h Median (range)
`Cmax – ng/mL Mean (CV%)
`AUC0–t – ng*h/mL Mean (CV%)
`T 1/2 el – h Mean (CV%)
`
`0.58 (0.00–6)
`3,595 (112%)
`4,997 (80%)
`0.52 (44%)
`
`1.12 (0.6–6)
`3,445 (109%)
`6,663 (73%)
`0.60 (32%)
`
`NA
`0.96 (0.67–1.38)
`1.34 (1.07–1.68)
`NA
`
`Table 11 Pharmacokinetic (PK) parameters of 5-FU ± vatalanib on day 1
`Cycle 1 (− vatalanib) n=29
`
`PK parameters – units
`
`Cycle 2 (+ vatalanib) n=23
`
`Geo. mean ratio (± vatalanib) (90% CI)
`
`Tmax – h Median (range)
`Cmax – ng/mL Mean (CV%)
`AUC0–t – ng*h/mL Mean (CV%)
`T 1/2 el – h Mean (CV%)
`
`1.17 (0.5–6)
`186 (78%)
`339 (49%)
`0.76 (47%)
`
`2.00 (0.5–6)
`149 (82%)
`327 (54%)
`1.13 (50%)
`
`NA
`0.78 (0.58–1.07)
`0.96 (0.81–1.13)
`NA
`
`Table 12 Pharmacokinetic (PK) parameters of 5-FU ± vatalanib on day 14
`Cycle 1 (− vatalanib) n=25
`
`PK parameters – units
`
`Cycle 2 (+ vatalanib) n=19
`
`Geo. mean ratio (± vatalanib) (90% CI)
`
`Tmax – h Median (range)
`Cmax – ng/mL Mean (CV%)
`AUC0–t – ng*h/mL Mean (CV%)
`T 1/2 el – h Mean (CV%)
`
`1.08 (0.00–6)
`242 (111%)
`526 (53%)
`0.77 (42%)
`
`2.00 (0.58–6)
`248 (61%)
`571 (46%)
`0.88 (27%)
`
`NA
`1.01 (0.72–1.41)
`1.07 (0.89–1.28)
`NA
`
`Table 13 Pharmacokinetic (PK) parameters of 5-FU without vatalanib in cycle 1
`
`PK parameters – units
`
`Tmax – h Median (range)
`Cmax – ng/mL Mean (CV%)
`AUC0–t – ng*h/mL Mean (CV%)
`T 1/2 el – h Mean (CV%)
`
`Day 1 n=29
`
`1.17 (0.5–6)
`186 (79%)
`339 (49%)
`0.76 (47%)
`
`Day 14 n=25
`
`1.08 (0.00–6)
`242 (111%)
`526 (53%)
`0.77 (42%)
`
`Geo. mean ratio (± vatalanib) (90% CI)
`
`NA
`1.27 (0.94–1.71)
`1.52 (1.29–1.79)
`NA
`
`Ex. 1111-0008
`
`

`

`Targ Oncol (2008) 3:3–11
`
`11
`
`have also been raised as to whether a single daily dose of
`vatalanib is sufficient to produce a sustained anti-angiogenic
`effect given that the drug has a short half-life in serum and
`appears to induce its own metabolism during chronic
`administration [23]. In data not shown in this paper, we
`were able to determine that capecitabine does not alter the
`pharmacokinetic behavior of vatalanib. Thus, additional