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

NCT01286896

Last updated date
Study Location
The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital
Amsterdam, , 1066CX, Netherlands
Contact
0031205122532

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Eligibility Criteria
condition
The disease, disorder, syndrome, illness, or injury that is being studied.
Malignant Solid Tumour
Sex
Females and Males
Age
Pediatric Trials: 0-17 Years
Adult Trials: 18+ Years
18 + years
Inclusion Criteria
The factors, or reasons, that allow a person to participate in a clinical study.
Show details

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
The factors, or reasons, that prevent a person from participating in a clinical study.
Show details


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

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Advanced Information
Descriptive Information
Brief Title  ICMJE Use of Individual Pharmacokinetically (PK)-Guided Sunitinib Dosing: A Feasibility Study in Patients With Advanced Solid Tumors
Official Title  ICMJE Use of Individual PK-guided Sunitinib Dosing: A Feasibility Study in Patients With Advanced Solid Tumors
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.

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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Malignant Solid Tumour
Intervention  ICMJE 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
Study Arms  ICMJE 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.
Intervention: Drug: Sunitinib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Unknown status
Estimated Enrollment  ICMJE
 (submitted: January 28, 2011)
30
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2011
Estimated Primary Completion Date December 2011   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study:All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Netherlands
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01286896
Other Study ID Numbers  ICMJE M10PKS
2010-021454-20 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party The Netherlands Cancer Institute
Study Sponsor  ICMJE The Netherlands Cancer Institute
Collaborators  ICMJE Pfizer
Investigators  ICMJE
Principal Investigator:Neeltje Steeghs, Md, PhDThe Netherlands Cancer Institute
PRS Account The Netherlands Cancer Institute
Verification Date October 2011

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP