Primary objectivesTo evaluate the effect of the CYP1A2 inhibitor, fluvoxamine, on steady state pharmacokinetics of TKI258 in patients with advanced solid tumors, excluding breast cancerSecondary objectives• To characterize the safety and…
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
TKI258 (dovitinib) Pharmacokinetic parameters:
Primary - AUC 0-72h, Cmax; and secondary - T1/2, Cmin,ss, Tmax, AUC 0-24h
Secondary outcome
Incidence and severity of adverse events according to the CTCAE criteria
Version 4.03, unless otherwise specified; changes from baseline in clinical
laboratory tests, physical examinations, vital signs, ECGs, and cardiac imaging
Overall response based on investigator assessment and best overall response
using RECIST version 1.1
Background summary
Dovitinib (TKI258) inhibits three RTKs (VEGF, FGF, and PDGF) involved in tumor
cell growth.
Based on its potency as an inhibitor of these RTKs both in vitro and in vivo,
and the compound*s
oral availability, dovitinib has been investigated as a single agent in many
solid tumor studies.
Following a continuous daily dose, the time-dependent and nonlinear PK resulted
in dose-dependent time to reach steady state, as well as dose-dependent
accumulation at steady state.
Following a 5 days on/2 days off dosing schedule no accumulation was observed
at the tested dose levels of 500 mg/day and 600 mg/day. The MTD of the 5 days
on/2 days off dosing schedule was 500 mg/day because of 2 dose-limiting
toxicities observed at 600 mg/day. At MTD, steady state was achieved after the
second week, and the half-life at steady state was around 13 hours.
The maximum tolerated dose (MTD) of dovitinib is 400 mg/day for the continuous
once daily
dosing regimen and 500 mg/day for the 5 days on / 2 days off dosing regimen.
Based on safety data and preliminary evidence of clinical efficacy obtained in
Phase I and Phase II trials, 500 mg/day (MTD) on a 5 days on/2 days off dosing
schedule is being used in the ongoing pivotal phase III trial in advanced RCC
as well as ongoing phase II clinical trials.
Study CTKI258A2101, a phase 1 dose escalating study in patients with advanced
solid
tumors, provided evidence implicating CYP1A2 as a relevant metabolic pathway
for dovitinib.
No formal drug-drug interaction studies with dovitinib have been conducted.
Available data
from human, as well as in vitro studies, demonstrate that dovitinib has low or
no inhibition
potential for CYP450s. Dovitinib, however, does induce CYP1A2, CYP2C9 and
CYP2C19 functional activities, as well as CYP3A4 mRNA; hence co-administration
with substrates of CYP1A2/2C9/2C19/3A4 could
reduce the exposure of these substrates.
In the current study dose selection for dovitinib is based principally on
consideration of safety while still allowing for a robust evaluation of
inhibition of the dovitinib clearance pathway. Fluvoxamine is a strong CYP1A2
inhibitor. Given the fact that ~1/3 of administered dose of dovitinib is
eliminated via the CYP1A1/A2 pathway, complete inhibition of CYP1A2 by
fluvoxamine could result in about 33% increase of dovitinib exposure on the day
that fluvoxamine is administered. Due to the potential safety risk posed by the
increase in dovitinib exposure, a dose of 400 mg rather than the maximum
tolerated dose (MTD) of 500 mg has been selected for this study during the PK
phase.
During the DDI test, dovitinib will be administered at a dose of 400 mg on a 5
days on/2 days off dosing schedule. At the 400 mg dose level, pharmacodynamic
activity as well as preliminary evidence of efficacy have been observed. After
completion of the DDI test patients will be given the option to continue
treatment with dovitinib at 500 mg/day (MTD) on a 5 days on/2 days off dosing
schedule, provided these patients do not have any toxicities which would
preclude treatment with the 500 mg dose.
Study objective
Primary objectives
To evaluate the effect of the CYP1A2 inhibitor, fluvoxamine, on steady state
pharmacokinetics of TKI258 in patients with advanced solid tumors, excluding
breast cancer
Secondary objectives
• To characterize the safety and tolerability of TKI258 following a 5 days on/2
days off dosing schedule in patients with advanced solid tumors, excluding
breast cancer
• To evaluate preliminary evidence of anti-tumor activity of TKI258 in patients
with advanced solid tumors, excluding breast cancer
Study design
A multi-center, open-label, single-sequence, crossover, drug-drug interaction
(DDI) study to assess the effect of the CYP1A2 inhibitor, fluvoxamine, on the
PK of dovitinib in patients with advanced solid tumors, excluding breast cancer.
The study will consist of 2 phases: a Pharmacokinetic (PK) phase. The DDI test
will be conducted in the PK phase. The DDI test will assess the steady state PK
profile of dovitinib when administered alone and in the presence of the CYP1A2
inhibitor, fluvoxamineThe PK phase will last 28 days. On days 19 and 26 full pk
will be assessed. On days 26-27 and 28 fluvoxamin will be taken.
After the PK phase the patient may continue in a clinical treatment phase.
Intervention
Dovitinib (TKI258) capsules in a 5 days on/ 2 days off schedule
PK phase: 300mg
Clinical treatment phase: 500mg
Fluvoxamin 100mg on day 22, 23, 24, 25, 26, 27 and 28 in the Pk phase
Study burden and risks
Side effects of dovitinib and fluvoxamin.
Most common possible side effects of dovitinib are: Diarrhea, nausea, vomiting,
asthenia, fatigue, decreased, headache, dyspnea, anemia, constipation, rash,
abdominal pain, fever, cough, increased liverfunction tests, distortion of the
sense of taste, hypertriglyceridemia, hypertension, weight decreased, periferal
edema, urinary track infection, backpain, dizziness, dyspepsia, dry mouth and
thrombocytopenia.
Most common side effects of fluvoxamin are: somnolence, insomnia, nervousness,
tremor, nausea, dyspepsia, anorexia, vomiting, abnormal ejaculation, asthenia,
and sweating.
Unexpected serious adverse evetn: aphasia (transient), pneumonitis, cardiac
tamponade, colon fistula, asymptomatic aortic dissection, osteonecrosis of the
jaw and reversible leucoencephalopathy syndrome.
Fluvoxamine may increase the side effects or lessen the effectiveness of some
medications.
other risk / inconveniences: taking blood mayu cause pain, bleeding and/or
bruising. Patients will be exposed to radiation (CT-scan, MUGA-scan and
X-rays). The rdiation will not exceed tha maximum ranges that are set within
the Netherlands. Allergic reaction on contrast used for CT-scans may occur.
Raapopseweg 1
Arnhem 6824 DP
NL
Raapopseweg 1
Arnhem 6824 DP
NL
Listed location countries
Age
Inclusion criteria
1. Patients diagnosed with either an advanced solid tumor, excluding breast cancer, or advanced hepatocellular carcinoma, which has progressed despite standard therapy, or for which no standard therapy exists
2. ECOG performance status <= 2
3. Absolute neutrophil count >= 1.5 x 109/L
4. Platelets >= 100 x 109/L
5. Hemoglobin >= 8.0 g/dL = 4.96 mmol/L
6. Serum creatinine <= 1.5 x ULN or 24-hour urine collection creatinine clearance >= 30 mL/min/1.73m2 (>= 50 mL/min/1.73m2 in the presence of proteinuria as defined in inclusion criterion #9) or,
Serum creatinine > 1.5 - 3 x ULN with calculated creatinine clearance >= 30 mL/min using the Cockcroft-Gault equation
7. Serum total bilirubin <= 1.5 x ULN
8. AST and ALT <= 3.0 x ULN
9. Urine dipstick negative for proteinuria or, if documentation of +1 results (+ 2 for patients with RCC) for protein on dipstick reading, then total urinary protein <= 500 mg and measured creatinine clearance >= 50 L/min/1.73m3 from a 24 hour urine collection
10. Patients with a life expectance of > 3 month
Exclusion criteria
1. Patients with brain metastases as assessed by mandatory radiologic imaging at screening
2. Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention
3. Prior anticancer therapies:
•targeted small molecule therapy <= 2 weeks prior to starting study drug,
•monoclonal antibody, immunotherapy, hormonal therapy, or chemotherapy <= 4 weeks prior to starting study drug,
•nitrosourea or mitomycin-C <= 6 weeks prior to starting study drug
•radiotherapy <= 4 weeks prior to starting the study drug (palliative radiotherapy for bone lesions <= 2 weeks prior to starting study drug is allowed)
and not recovered from anti-cancer therapy related toxicities
4. Major surgery <= 4 weeks prior to starting study treatment, or who have not recovered from side effects of such therapy
5. Pulmonary embolism or untreated deep venous thrombosis within 6 months prior to starting study drug
6. Impaired cardiac function or clinically significant cardiac diseases, including any of the following:
•History or presence of serious uncontrolled ventricular arrhythmias
•Clinically significant resting bradycardia
•LVEF < 50% (ECHO)or < 45% (MUGA)
•Myocardial infarction, severe/unstable angina, coronary artery bypass graft, congestive heart failure, cerebrovascular accident, transient ischemic attack within 6 months prior to starting study drug
•Uncontrolled hypertension defined by a SBP >= 160 mm Hg and/or DBP >= 100 mm Hg, with or without anti-hypertensive medication(s). Initiation or adjustment of antihypertensive medication(s) is allowed prior to study entry
7. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of dovitinib.
8. Cirrhosis, chronic active hepatitis, or chronic persistent hepatitis.
9. Current use of prasugrel, clopidogrel, or full dose anticoagulation treatment with therapeutic doses of warfarin. Treatment with low doses of warfarin (e.g., <= 2 mg/day) or locally accepted low doses of acetylsalicylic acid (up to 100 mg daily) is allowed.
10. Other concurrent severe and/or uncontrolled concomitant medical conditions
11. Use of potent and moderate CYP1A2 inhibitors or potent and moderate CYP3A inhibitors within 5 days prior to starting study treatment, or during the PK phase (i.e., days 1-28, inclusive, of the PK phase).
12. CYP1A2 inducers (including tobacco) or CYP3A inducers within 30 days prior to starting study treatment, or during the PK phase (i.e., days 1-28, inclusive, of the PK phase))
13. Actively taking antidepressants, benzodiazepines, serotonergic drugs, and/or monoamine oxidase inhibitors (MAOIs).
14. Expected alcohol intake to exceed 1 drink/day within 3 days prior to the days of blood sample collection for PK assessment in the PK phase (i.e., <= 3 days prior to days 19 and 26 of the PK phase) and throughout the timeframe they are taking fluvoxamine (i.e., days 26, 27 and 28 of the PK phase).
15. Grapefruits, pomegranates, star fruits, Seville oranges or products containing the juice of each within 3 days prior to the days of blood sample collection for PK assessment in the PK phase (i.e., <= 3 days prior to days 19 and 26 of the PK phase).
16. Homeopathic or naturopathic medicines within 5 days prior to the days of blood sample collection for PK assessment in the PK phase (i.e., <= 5 days prior to days 19 and 26 of the PK phase). Note: vitamin supplements are allowed
17.Non-steroidal anti-inflammatory medications and/or aspirin on days of fluvoxamine dosing (i.e., d ays 26, 27 and 28 of the PK phase). Low doses of acetylsalicylic acid (up to 100 mg daily) to prevent cardiovascular events or stroke is allowed.
18. Pregnant or breast-feeding women
19. Women of child-bearing potential, not employing two forms of highly effective contraception.
20. Fertile males not willing to use contraception, as stated above. Fertile males must use condom with spermicide during the study and 3 months after the end of study treatment
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2012-001546-18-NL |
| ClinicalTrials.gov | NCT01596647 |
| CCMO | NL40697.031.12 |