To evaluate the safety and tolerability of escalating doses of oral sunitinib in combination with standard doses of intravenous ifosfamide in patients with solid malignancies.
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms benign
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Determination of the maximum tolerated dose (MTD) and dose-limiting toxicity
(DLT) of sunitinib when given in combination with standard doses of ifosfamide.
Secondary outcome
To determine the impact of sunitinib on ifosfamide pharmacokinetics and vice
versa.
To evaluate the impact of this combination on surrogate markers including VEGF
and soluble VEGF-R plasma levels and the number of circulating endothelial
cells (CECs)
To record any disease response
Background summary
The use of so-called targeted drugs, such as monclonal antibodies and tyrosine
kinase inhibitors is rapidly increasing in oncology. In particular in
combination with conventional chemotherapeutic drugs, the appliation of these
new drugs is attractive for several reasons.
Sunitinib is an inhibitor of the tyrosine kinases responsible for the signal
transduction of several proteins including c-kit and the receptors for Vascular
Endothelial Growth Factor (VEGF-R) and the Platelet Derived Growth Factor
(PDGF-R). Inhibition of these receptors by sunitinib leads to a
well-established antitumor effect in patients with gastrointestinal stroma
tumor and renal cell cancer. An antitumor effect can also be anticipated in
other tumor types which have a VEGF or PDGF mediated growth, such as soft
tissue sarcomas, testicular cancer and CNS tumors.
Ifosfamide is a one of the oldes chemotherapeutic agents and it is used in the
treatment of various tumor types.
A synergistic antitumor activity can be anticipated using sunitinib in
combination with ifosfamide since sunitinib can decrease chemoresistance by
inhibiting the production of anti-apoptotic proteins such as Bcl-2 and
survivin. Furthermore, it has been shown that conventional cytotoxic agents
induce VEGF production by tumor cells in vitro, and that increased VEGF tumor
levels are a predictive factor for poor outcome on systemic treatment in
humans. Since sunitinib inhibits both PDGF and VEGF-mediated activities, it can
be anticipated that co-treatment with sunitinib will render tumor cells more
prone to apoptotic triggers such as conventional chemotherapy.
Study objective
To evaluate the safety and tolerability of escalating doses of oral sunitinib
in combination
with standard doses of intravenous ifosfamide in patients with solid
malignancies.
Study design
A Phase I study with a classic 3+3 design. Three different dose cohorts of
daily sunitinib (12.5mg, 25mg and 37.5mg) will be evaluated in combination
with a fixed dose ifosfamide iv(3g/m2/day for three days) administered at
3-weekly intervals. After establishing the MTD with the 3-day ifosfamide
regimen, this MTD of sunitinib will also be evaluated with ifosfamide iv at
1.2g/m2/day for 5 days.
Intervention
not applicable
Study burden and risks
nvt
Groene Hilledijk 301
3075 EA Rotterdam
NL
Groene Hilledijk 301
3075 EA Rotterdam
NL
Listed location countries
Age
Inclusion criteria
- Histologically or cytologically proven advanced solid malignancy in patients for whom no better treatment than SU11248 and ifosfamide is available.
- Measurable (according to RECIST criteria) or evaluable disease.
- At least 4 weeks since any prior anti-tumor therapy and resolution of all toxicities induced by this prior anti-tumor treatment to CTC grade <= 1 (if not specified below) except alopecia.
- Age >= 18 years.
- WHO performance of 0-1 and a predicted life expectancy of at least 3 months.
- Adequate organ function defined as follows:
serum bilirubin <= 1.5 x ULN
serum AST and ALT <= 2.5 x ULN (in case of liver metastases, then AST/ALT must be <= 5 x ULN)
serum creatinine <= 1.5 x ULN creatinine clearance >= 60 ml/min and 2 functioning kidneys
ANC >= 1.5 x 109/L
platelets >= 100 x 109/L
hemoglobin >= 6.0 mmol/L
- Systolic blood pressure lower than 150 mmHg and diastolic blood pressure lower than 90 mmHg (treatment with 2 antihypertensive drugs is allowed)
Exclusion criteria
- severe/unstable angina or symptomatic congestive heart failure within 12 months prior to inclusion
- myocardial infarction, or cerebrovascular accident within 12 months prior to inclusion
- atrial fibrillation of any grade or ongoing cardiac dysrhythmias >= grade 2
- known human immunodeficiency virus (HIV) positivity
- use of prohibited co-medication as mentioned in paragraph 5.4
- pregnancy and / or breast feeding; for all women of child-bearing potential a negative pregnancy test will be required as well as the willingness to use adequate contraception during the study until 4 weeks after stopping treatment.
- signs or symptoms of CNS metastases (radiological assessment of potential CNS metastases is not required).
- any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be assessed with the patient before registration in the trial.
- other severe medical or psychiatric conditions that in the judgment of the investigator renders the patient inappropriate for inclusion in this study.
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 | EUCTR2006-005188-25-NL |
| CCMO | NL14454.078.06 |