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Use of Individual PK-guided Sunitinib Dosing: A Feasibility Study in Patients With Advanced Solid Tumors

Phase 1
18 Years
Open (Enrolling)
Malignant Solid Tumour

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Trial Information

Use of Individual PK-guided Sunitinib Dosing: A Feasibility Study in Patients With Advanced Solid Tumors

Sunitinib is an orally available inhibitor of vascular endothelial growth factor (VEGFR),
platelet-derived growth factor (PDGF), cytokine receptor (c-KIT), and receptor tyrosine
kinase (FLT-3) activity. Sunitinib is proven effective as single agent in several solid
tumor types and is approved for use in advanced renal cell cancer (RCC) and
imatinib-resistant or -intolerant gastrointestinal stromal tumors (GISTs). However, in a
large percentage of patients (30 and 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.
Target plasma concentrations of sunitinib plus metabolite (N-desethyl sunitinib) are in the
range of 50 to 100 ng/mL, as deduced from pharmacokinetic (PK) / pharmacodynamic (PD)
preclinical data. Since the dose-efficacy relation for sunitinib treatment is solely
established in 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. 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

Inclusion Criteria:

1. Histopathologically confirmed advanced tumors for which sunitinib is considered
standard or patients with advanced or metastatic tumors for whom no standard therapy
is available;

2. Age more then 18 years;

3. Able and willing to give written informed consent;

4. Able and willing to undergo blood sampling for pharmacogenetic and pharmacokinetic

5. Able and willing to undergo a tumor biopsy for DNA sequencing;

6. Able to swallow oral medications

7. Life expectancy more then 3 months, allowing adequate follow up of toxicity
evaluation and antitumor activity;

8. WHO performance status of 0 or 1;

9. Evaluable disease according to RECIST 1.1 criteria;

10. 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);

11. No radio- or chemotherapy or other investigational drug treatment within the last 4
weeks prior to study entry, with the exception of palliative radiotherapy (8 Gy or on
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

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Number of Participants with Adverse Events as a Measure of Safety and Tolerability

Outcome Description:

To determine the safety and feasibility of PK guided dosing of sunitinib, weekly physical examination, blood hematology and blood chemistry parameters in the first 2 cycles, and monthly thereafter, will guide the safety of the treatment.

Outcome Time Frame:

During treatment with sunitinib Adverse Events will be recorded up to 30 days after treatment. Patient will remain on treatment untill the disease progression, 1 year in average

Safety Issue:


Principal Investigator

Neeltje Steeghs, Md, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

The Netherlands Cancer Institute


Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Study ID:




Start Date:

March 2011

Completion Date:

December 2011

Related Keywords:

  • Malignant Solid Tumour
  • advanced solid tumors
  • Neoplasms