Primary: • To determine the safety and feasibility of PK guided dosing of sunitinib Secondary:• To determine the objective response rate (according RECIST 1.1)• To determine the time to tumor progression and progression free survival• To validate…
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Tumor response (RECIST): ORR, PR, TTP, PFS
Toxicity (CTC v4.2)
Secondary outcome
Pharmacokinetics (dried blood spots): total trough levels
Pharmacogenetics: polymorfism of genes involved in pharmacokinetic and
pharmacodynamic pathways.
Background summary
In a large percentage of patients on sunitinib treatment (30 - 50%), dose
reductions are required because of multiple grade 2 toxicities or due to grade
3 or 4 toxicities. Therefore, the currently used dosing schedule is not
optimal.
Recently, a dose-efficacy relation was established for sunitinib treatment.
This large meta-analysis of pharmacokinetic/pharmacodynamic data from studies
performed in mRCC patients, GIST patients and patients with solid tumors,
clearly showed a relationship between sunitinib exposure and efficacy and
tolerability. Both time to progression (TTP) and overall survival (OS) were
significantly better for mRCC patients with high area under the curve (AUC)
compared to low AUC. This was not only observed for sunitinib exposure but also
for its active metabolite SU12662. In addition, there was a significant
relationship between exposure and probability of partial response (PR) or
complete response (CR) in mRCC patients (p=0.00001), indicating that a dose
intensity in patients should be as high as possible.
Since this is a retrospective (meta-) analysis from patients treated in several
studies, we propose to perform a prospective feasibility study in 30 patients
with PK guided dosing of sunitinib. The number of patients with advanced renal
cell carcinoma is limited and since the safety of sunitinib treatment is
independent of tumour type, we decided to perform this feasibility study in a
*normal phase I* population consisting of patients with any advanced cancer
for whom no standard treatment options are available and who are in good
clinical condition. This will also shorten the time period to a randomized
controlled trial (RCT).
If PK guided once-daily continuous sunitinib dosing is feasible, a RCT in mRCC
patients will be performed comparing PK guided dosing with a standard sunitinib
dosing schedule.
Study objective
Primary:
• To determine the safety and feasibility of PK guided dosing of sunitinib
Secondary:
• To determine the objective response rate (according RECIST 1.1)
• To determine the time to tumor progression and progression free survival
• To validate previously identified associations between genetic markers in the
pharmacokinetic and pharmacodynamic pathways of sunitinib and the development
of toxicities.
Study design
A prospective feasibilty study of patients with solid tumors on a sunitinib
dosing schedule of 37.5 mg continous daily dosing.
On two fixed timepoints during the study there is a possibility to adjust the
dose of sunitinib based on total trough levels of the drug and its metabolite
in PK samples (dried blood spots) and a predefined dose modification scheme.
At t=8 weeks a third trough level measurement will be performed and patients
will be evaluated by CT- or MRI-scans for the response to therapy.
Treatment will be continued until progressive disease or until adverse events,
which require discontinuation of therapy, are observed.
Intervention
Patients will start receiving once daily oral sunitinib, dosed according to the
standard dosing schedule of 37.5 mg continuous daily dosing.
On two fixed timepoints during the study there is a possibility to adjust the
dose of sunitinib based on total trough levels of the drug and its metabolite
in PK samples (dried blood spots) and a predefined dose modification scheme.
Study burden and risks
The burden for the patient exists of weekly physical examinations, blood
hematology and blood chemistry parameters during the first 8 weeks, and monthly
thereafter. These assessments will guide the safety of the treatment. In
addition, the patient is asked to perform a finger prick at home three times
during the first 8 weeks of the study for pharmacokinetic assessments. In
short, this will give a minimal additional burden for patients compared to
treatment with regular patient care.
The possible benefit for patients within this study is the optimisation of the
dose which probably can lead to prevention of toxicities and treatment failure.
Therefore, we think that the possible benefits of this study can compensate for
the minimal burden associated with participation in this study.
Plesmanlaan 121
1066 CX Amsterdam
NL
Plesmanlaan 121
1066 CX Amsterdam
NL
Listed location countries
Age
Inclusion criteria
1. Patients with histopathologically confirmed advanced or metastatic solid tumors for whom sunitinib is standard therapy, of for whom no standard therapy is available;2. Age >= 18 years;;3. Able and willing to give written informed consent;;4. Able and willing to undergo blood sampling for pharmacogenetic and pharmacokinetic analysis;;5. Able to swallow oral medications;6. Life expectancy >= 3 months, allowing adequate follow up of toxicity evaluation and antitumor activity;;7. WHO performance status of 0 or 1;;8. Evaluable disease according to RECIST 1.1 criteria;;9. Minimal acceptable safety laboratory values
• ANC of >= 1.5 x 109 /L
• Platelet count of >= 100 x 109 /L
• Hepatic function as defined by serum bilirubin <= 1.5 x ULN, ASAT and ALAT <=
• 2.5 x ULN
• Renal function as defined by serum creatinine <= 1.5 x ULN or creatinine clearance >= 50 mL/min (by Cockcroft-Gault formula);;10. No radio- or chemotherapy or other investigational drug treatment within the last 4 weeks prior to study entry, with the exception of palliative radiotherapy (8Gy, or in the extremities).
Exclusion criteria
1. Current treatment in another therapeutic clinical trial;2. Congestive heart failure, myocardial infarction or coronary artery bypass graft in the previous six months, ongoing severe or unstable angina or any unstable arrhythmia requiring medication;3. Patients with known alcoholism, drug addiction and/or psychotic disorders in the history that are not suitable for adequate follow up;4. Women who are pregnant or breast feeding.;5. Both men and women enrolled in this trial must agree to use a reliable contraceptive method throughout the study (definition of adequate contraceptive methods will be based on the judgment of the principal investigator or a designated associate). ;6. Legal incapacity.;7. Known allergy/intolerance to sunitinib or any of the excipients.
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 | EUCTR2010-021454-20-NL |
| CCMO | NL32967.031.10 |