Use of Individual Pharmacokinetically (PK)-Guided Sunitinib Dosing: A Feasibility Study in Patients With Advanced Solid Tumors

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01286896
Recruitment Status : Unknown
Verified October 2011 by The Netherlands Cancer Institute.
Recruitment status was:  Recruiting
First Posted : January 31, 2011
Last Update Posted : October 10, 2011
Information provided by (Responsible Party):
The Netherlands Cancer Institute

Brief Summary:

The purpose of this prospective study is to determine the safety and feasibility of pharmacokinetically (PK) guided dosing of sunitinib in 30 patients.

At day 15 ± 1day, day 29 ± 1day and after 8 weeks ± 1day of sunitinib treatment sunitinib and SU12662 trough levels will be measured. Depending on the sunitinib and SU12662 trough levels (and toxicity) dose adjustments will be made.

Condition or disease Intervention/treatment Phase
Malignant Solid Tumour Drug: Sunitinib Phase 1

Detailed Description:

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 schedule.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Use of Individual PK-guided Sunitinib Dosing: A Feasibility Study in Patients With Advanced Solid Tumors
Study Start Date : March 2011
Estimated Primary Completion Date : December 2011
Estimated Study Completion Date : December 2011

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arm Intervention/treatment
Experimental: Sunitinib
Sunitinib is administered in oral capsules of 12.5 mg. Patients will start with a continuous once-daily dose of 37.5 mg.
Drug: Sunitinib

Patients will start treatment with a continuous once-daily dose of 37.5 mg sunitinib. After 22 days the first dose modification will be performed based on the total trough levels (TTL) combined for sunitinib plus SU12662 as measured by dried blood spot (DBS) analyses taken at day 15 ± 1day. A second dose modification will be performed after 36 days (7 days after the first dose adjustment) based on the TTL taken at day 29 ± 1day. One treatment cycle is defined as 28 days.

After 8 weeks a third analyses for TTL will be performed without further consequences for sunitinib dosing. Patients will be evaluated by CT- or MRI-scans for the response to therapy at week 8, and thereafter every 12 weeks. One blood sample will be harvested for pharmacogenetic analyses.

Other Names:
  • Sutent®
  • SU 11248

Primary Outcome Measures :
  1. Number of Participants with Adverse Events as a Measure of Safety and Tolerability [ 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 ]
    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.

Secondary Outcome Measures :
  1. objective response rate [ Time Frame: 8 weeks after initiation and thereafter every 12 weeks until disease progression, 1 year in average ]
    To determine the objective response rate, CT-scan and/or MRI-scans will be performed 8 weeks after initiation of therapy and thereafter every 12 weeks until documented disease progression according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

  2. time to tumor progression [ Time Frame: Until the disease progression, 1 year in average ]
    To determine the time from start of study treatment to first documentation of objective tumor progression defined by 1.1 RECIST criteria performing CT/MRI scans 8 weeks after initiation of therapy and thereafter every 12 weeks

  3. validating the associations between genetic markers [ Time Frame: C1 D15 and C1 D29 and after 8 weeks ]

    To start with the validation of previously identified associations between genetic markers in the pharmacokinetic and pharmacodynamic pathways of sunitinib and the development of toxicities. At day 15 ± 1day, day 29 ± 1day and after 8 weeks ± 1day - PK: Fingerprick for dried blood spot analysis of total trough levels of sunitinib and SU12662.

    Once during cycle 1: EDTA blood samples for pharmacogenetic analyses

  4. tumor biopsy and peripheral blood sample for DNA sequencing [ Time Frame: Day -7 ]
    Seven days prior to study medication treatment the tumor boipsy and blood draw will be performed to support the validation of DNA sequencing of tissue derived from a tumor biopsy and to obtain the DNA profile of the patient's tumor in order to (i) identify correlations between the genetic profile of the tumor and toxicity and efficacy parameters of sunitinib , and (ii) identify patients who could have advantage of specific follow-up treatment strategies.

  5. Progression free survival [ Time Frame: Untill disease progression, 1 year in average ]
    Measuring the time between the study start and the RECIST defined disease progression on CT/MRI scans performed 8 weeks after initiation of therapy and thereafter every 12 weeks

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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 analysis;
  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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01286896

Contact: Neeltje Steeghs, MD, PhD 0031205122532

The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital Recruiting
Amsterdam, Netherlands, 1066CX
Contact: Neeltje Steeghs         
Principal Investigator: Neeltje Steeghs, MD, PhD         
Sponsors and Collaborators
The Netherlands Cancer Institute
Principal Investigator: Neeltje Steeghs, Md, PhD The Netherlands Cancer Institute

Responsible Party: The Netherlands Cancer Institute Identifier: NCT01286896     History of Changes
Other Study ID Numbers: M10PKS
2010-021454-20 ( EudraCT Number )
First Posted: January 31, 2011    Key Record Dates
Last Update Posted: October 10, 2011
Last Verified: October 2011

Keywords provided by The Netherlands Cancer Institute:
advanced solid tumors

Additional relevant MeSH terms:
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors