The purpose of this phase I/II is to characterize the safety, tolerability, preliminary activity, pharmacokinetic (PK) and pharmacodynamics (PD) profile of TKI258 administered orally on a 5 days on/2 days off dosing schedule in adult patients with…
ID
Source
Brief title
Condition
- Renal and urinary tract neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To assess the frequency of clinical responder and no clinical benefiter at 8
weeks post-treatment.
Secondary outcome
- To assess the safety profile of TKI258 administered orally on a 5 days on/2
days off schedule in this patient population.
- To characterize the single and multiple-dose pharmacokinetic (PK) profiles of
oral TKI258 on a 5 days on/2 days off dosing schedule.
- To assess the effect of TKI258 on plasma biomarkers pre- and post-treatment:
* To evaluate concentrations of circulating growth factors, soluble receptors
(e.g. bFGF, VEGF, PlGF, sVEGFR1 and 2).
- To assess the relationship between dose and exposure of TKI258.
- To explore the relationship between PK and biomarker responses (PD) of
TKI258.
Background summary
Renal cell carcinoma (RCC) is expected to account for more than 35.000 new
diagnoses of cancer and over 12.000 cancer deaths in the United States during
2005. In Europe, the number of new diagnoses and cancer deaths from RCC is
approximately double that in the United States. In the Netherlands incidence of
RCC is 1500 per year. 1/3 has metastatic disease at time of diagnosis, 1/3 will
experience a relapse later on. Median survival for patients with metastatic
disease is about 13 months.
RCC is characterized by a high degree of resistance to chemotherapy. Interferon
Alfa and Interleukin-2 are standard therapies for patients with metastatic RCC.
Only a minority of treated patients experiences a favorable response. Recently
developed VEGF targeted therapies have demonstrated activity in advanced and
metastatic RCC.
There is no standard therapy available, once a patient's disease progresses
after VEGF targetd therapies. Therefore, the identification of new agents with
antitumor activity against RCC is of high priority.
Study objective
The purpose of this phase I/II is to characterize the safety, tolerability,
preliminary activity, pharmacokinetic (PK) and pharmacodynamics (PD) profile of
TKI258 administered orally on a 5 days on/2 days off dosing schedule in adult
patients with metastatic renal cell carcinoma (RCC) which have progressed
despite standard therapy or for whom no standard therapy exists. Study
CTKI258A2107 includes an abbreviated dose escalation part and a subsequent
safety/efficacy expansion part.
To determine the maximum tolerated dose (MTD) was the objective of the dose
escalation part of the study, which is already done.
The purpose of the dose expansion part is to investigate preliminary anti-tumor
activity of TKI258 in patients with metastatic RCC.
Study design
The dose expansion part will commence using the MTD determined in the dose
escalation part to further evaluate safety, tolerability and the preliminary
efficacy of TKI258. In the dose expansion part, the target population consists
of adult patients that must have been previously treated with sunitinib and/or
sorafenib and have measurable histologically or cytology confirmed progressive
advanced or metastatic renal cell carcinoma with predominant cell histology
(>50%).
A multinomial two-stage design will be used to evaluate the response rate and
lack of early disease progression during dose expansion. There will be 30
patients for stage I and additional 30 patients for stage II if the trial goes
to stage II.
Patients may continue treatment with TKI258 until the patient experiences
unacceptable toxicity that precludes any further treatment, disease
progression, and/or at the discretion of the investigator. Six months following
enrollment of the last patient in this trial, a continuation protocol will be
implemented for those patients who have not experienced
unacceptable toxicity and/or disease progression, and in the opinion of the
sponsor and investigator, who should continue to receive treatment with TKI258.
Intervention
TKI258 - oral - 5 days intake - 2 days no intake. MTD haas been determined. The
dose for the phase II part will be 500mg.
Study burden and risks
After the screening period patients will have to be hospitalized once a week in
the first month. In the second and third month the frequency of hospitalisation
will be once in the two weeks.
Tumour evaluation will be done during the screening period.
A heart function test will be donde once in the two weeks.
Use of TKI258 might cause side effects.
Raapopseweg 1
6824 DP Arnhem
NL
Raapopseweg 1
6824 DP Arnhem
NL
Listed location countries
Age
Inclusion criteria
Patients that must have been previously treated with sunitinib and/or sorafenib and mTor inhibitor. However, patients previously treated with other therapies (e.g. IL-2, IF-*) are also allowed to be enrolled and treated to determine the effect of TKI258 in patients who had not been treated with VEGF receptor tyrosine kinase inhibitor and mTOR therapy.
* Patients of Asian ethnicity: who failed standard treatment or for whom no standard therapy excists.
* Patients with at least one measurable lesion at baseline as per the RECIST.
* Serum creatinine * 1.5 x upper limit of normal (ULN)
* Absolute neutrophil count (ANC) * 1.5 x 109/L
* Platelets * 75 x 109/L
* Hemoglobin * 4.96 mmol/l
* Serum creatinine * 1.5 x upper limit of normal (ULN)
* Bilirubin * 1.5 x ULN
* AST (SGOT) and ALT (SGPT)* 2.5 x ULN, except for subjects with tumor
involvement of the liver who must have AST and ALT * 5 x ULN
* Amylase, Lipase * ULN
* Electrolyte levels should be within normal limits
* Urine dipstick: Negative for proteinuria or, if documentation of +1 results for protein on dipstick reading, then total urinary protein * 500 mg and measured creatinine clearance * 50 mL/min/1.73m2 from a 24-hour urine collection
Exclusion criteria
* Clinically significant cardiac disease (New York Heart Association, Class III or IV) or impaired cardiac function or clinically significant cardiac diseases, including any one of the following: LVEF < 45%, Complete left bundle branch block, use of a cardiac pacemaker, Congenital long QT syndrome, History or presence of ventricular tachyarrhythmia, unstable atrial fibrillation, Clinically significant bradycardia, Hypertension * Grade 2, QTc > 480 msec, Right bundle branch block + left anterior hemiblock (bifasicular block), Angina pectoris * 3 months prior to starting study drug, Acute Myocardial Infarction * 3 months prior to starting study drug.
* Uncontrolled infection.
* Diabetes mellitus with signs of clinically significant peripheral vascular disease.
* Previous pericarditis; clinically significant pleural effusion in the previous 12 months or current ascites requiring two or more interventions/month
* Known pre-existing clinically significant disorder of the hypothalamic-pituitary axis,
adrenal or thyroid glands.
* Prior acute or chronic pancreatitis
* Acute and chronic liver disease and all chronic liver impairment.
* Malabsorption syndrome or uncontrolled gastrointestinal toxicities with toxicity >NCI CTCAE grade 2.
* Patients with brain metastases as assessed by radiologic imaging (e.g. CT, MRI)
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 | EUCTR2007-004391-39-NL |
| ClinicalTrials.gov | NCT00715182 |
| CCMO | NL24734.078.08 |