|- candidate number||14779|
|- NTR Number||NTR3967|
|- ISRCTN||ISRCTN wordt niet meer aangevraagd.|
|- Date ISRCTN created|
|- date ISRCTN requested|
|- Date Registered NTR||19-apr-2013|
|- Secondary IDs||2013-001567-24 M13PKP|
|- Public Title||PK-guided pazopanib dosing.|
|- Scientific Title||Use of individual PK-guided pazopanib dosing: A feasibility study in patients with advanced solid tumors.|
|- hypothesis||Maintaining a minimum threshold concentration is relevant for observing optimal benefit with pazopanib. Hurwitz et al demonstrated the interindividual variance in exposure, showing that flat-fixed dosing of 800 mg daily (the currently registered dose) results in inadequate trough levels in almost half of the patients. There seems to be a dose-exposure relationship suggesting that increasing the dose may result in more patients achieving adequate trough levels. However, the number of patients with doses above 800 mg/day are too limited to support this and prospective TDM studies have not been performed so far.|
The primary objective of this study is to assess the feasibility of using individual PK-guided pazopanib dosing in patients while controlling for unacceptable toxicity.
|- Healt Condition(s) or Problem(s) studied||Cancer, Malignancy , Adverse events, Efficacy, Pazopanib|
|- Inclusion criteria||1. Subjects must provide written informed consent prior to performance of study-specific procedures or assessments and must be willing to comply with treatment and follow up.|
Note: Procedures conducted as part of the subject’s routine clinical management (e.g., blood count, imaging study such as bone scan) and obtained prior to signing of informed consent may be utilized for screening or baseline purposes provided these procedures are conducted as specified in the protocol;
2. Age ≥ 18 years;
3. Histopathologically confirmed advanced tumors for which pazopanib is considered standard or patients with advanced or metastatic tumors for whom no standard therapy is available;
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1;
5. Evaluable disease according to RECIST 1.1 criteria;
6. Adequate organ system function as defined in Table 3.
Definitions for Adequate Organ Function:
A. Absolute neutrophil count (ANC): 1.5 X 109/L;
B. Hemoglobina: 5.6 mmol/L;
C. Platelets: 100 X 109/L;
D. Prothrombin time (PT) or international normalized ratio (INR)a: 1.2 X ULN;
E. Activated partial thromboplastin time (aPTT): 1.2 X ULN;
F. Total bilirubin: 1.5 X ULN;
G. Alanine amino transferase (ALT) and Aspartate aminotransferase (AST)b: 2.5 X ULN;
H. Serum creatinine: 133 µmol/L;
Or, if >133 µmol/L: Calculated creatinine clearance (ClCR): 30 mL/min to 50 mL/min;
I. Urine Protein: dipstick <2+;
Or, 24-hour urine protein <1g.
i.Subjects receiving anticoagulant therapy are eligible if their INR is stable and within the recommended range for the desired level of anticoagulation;
ii. Concomitant elevations in bilirubin and AST/ALT above 1.0 x ULN (upper limit of normal) are not permitted.
7. Women of childbearing potential must have a negative serum pregnancy test within 14 days of first dose of study treatment and agree to use effective contraceptionduring the study and for 14 days following the last dose of investigational product.
|- Exclusion criteria||1. Central nervous system (CNS) metastases at baseline, with the exception of those subjects who have previously-treated CNS metastases (surgery ± radiotherapy, radiosurgery, or gamma knife) and who meet both of the following criteria:|
A. Are asymptomatic;
B. Have no requirement for steroids or enzyme-inducing anticonvulsants in prior 4 week interval.
2. Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding including, but not limited to:
A. Active peptic ulcer disease;
B. Known intraluminal metastatic lesion/s with risk of bleeding;
C. Inflammatory bowel disease (e.g. ulcerative colitis, Chrohn’s disease), or other gastrointestinal conditions with increased risk of perforation;
D. History of abdominal fistula, gastrointestinal perforation, or intra abdominal abscess within 28 days prior to beginning study treatment.
3. Clinically significant gastrointestinal abnormalities that may affect absorption of investigational product including, but not limited to:
A. Malabsorption syndrome;
B. Major resection of the stomach or small bowel.
4. Corrected QT interval (QTc) > 480 msecs;
5. History of any one or more of the following cardiovascular conditions within the past 6 months:
A. Cardiac angioplasty or stenting;
B. Myocardial infarction;
C. Unstable angina;
D. Coronary artery bypass graft surgery;
E. Symptomatic peripheral vascular disease;
F. Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA).
6. Poorly controlled hypertension [defined as systolic blood pressure (SBP) of ≥140 mmHg or diastolic blood pressure (DBP) of ≥ 90mmHg].
Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry. Following antihypertensive medication initiation or adjustment, blood pressure (BP) must be re-assessed three times at approximately 2-minute intervals. At least 24 hours must have elapsed between anti-hypertensive medication initiation or adjustment and BP measurement. These three values should be averaged to obtain the mean diastolic blood pressure and the mean systolic blood pressure. The mean SBP / DBP ratio must be <140/90 mmHg (OR 150/90 mm Hg, if this criterion is approved by the Principle Investigator) in order for a subject to be eligible for the study;
7. History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months.
Note: Subjects with recent DVT who have been treated with therapeutic anti-coagulating agents for at least 6 weeks are eligible;
8. Major surgery or trauma within 28 days prior to first dose of investigational product and/or presence of any non-healing wound, fracture, or ulcer (procedures such as catheter placement not considered to be major surgery);
9. Evidence of active bleeding or bleeding diathesis;
10. Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels that increase the risk of pulmonary hemorrhage.
Note: Lesions infiltrating major pulmonary vessels (contiguous tumour and vessels) are excluded; however, the presence of a tumor that is touching, but not infiltrating (abutting) the vessels is acceptable (CT with contrast is strongly recommended to evaluate such lesions);
11. Recent hemoptysis (˝ teaspoon of red blood within 8 weeks before first dose of study drug);
12. Any serious and/or unstable pre-existing medical, psychiatric, or other condition that could interfere with subject’s safety, provision of informed consent, or compliance to study procedures;
13. Unable or unwilling to discontinue use of prohibited medications in for at least 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of study drug and for the duration of the study (Chapter 8.7);
14. Treatment with any of the following anti-cancer therapies:
A. Radiation therapy, surgery or tumor embolization within 14 days prior to the first dose of pazopanib OR;
B. Chemotherapy, immunotherapy, biologic therapy, investigational therapy or hormonal therapy within 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of Pazopanib.
15. Administration of any non-oncologic investigational drug within 30 days or 5 half lives whichever is longer prior to receiving the first dose of study treatment;
16. Any ongoing toxicity from prior anti-cancer therapy that is >Grade 1 and/or that is progressing in severity, except alopecia.
|- mec approval received||yes|
|- multicenter trial||yes|
|- Type||Single arm|
|- planned startdate ||1-aug-2013|
|- planned closingdate||1-dec-2014|
|- Target number of participants||30|
|- Interventions||PK guided dosing of pazopanib.|
|- Primary outcome||To determine the safety and feasibility of PK guided dosing of pazopanib.|
|- Secondary outcome||1. Evaluation of the dried blood spot procedure;|
2. To determine the objective response rate (according RECIST 1.1);
3. To determine the time to tumor progression and progression free survival.
|- Timepoints||1. After 8 weeks;|
2. After progression.
- Response rate, progressievrije overleving en survival meten we gebruikmakend van RECIST 1.1 met CT of MRI
|- Trial web site||N/A|
|- CONTACT FOR PUBLIC QUERIES||Dr. N. Steeghs|
|- CONTACT for SCIENTIFIC QUERIES||Dr. N. Steeghs|
|- Sponsor/Initiator ||Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital (NKI AVL) |
(Source(s) of Monetary or Material Support)
|- Brief summary||Patients will start receiving once oral pazopanib, dosed according to the standard dosing schedule of 800 mg continuous daily dosing. |
At day 8 ± 1day, a first trough level of pazopanib will be measured by LC-MS/MS. The outcome of the trough level measurement will be reported to the physician within maximally seven days after receipt of the samples. Trough levels should be ≥ 20.0 μg/mL. If the trough level is low and the patient does not show any treatment related ≥grade 2 toxicity, the daily pazopanib dose will be increased with 400 mg. During the entire treatment period, three moments of potential individual dose increments are defined. Pazopanib dose will not be decreased to less than 400 mg once daily and no further increased than to 2000 mg once daily.
|- Main changes (audit trail)|
|- RECORD||19-apr-2013 - 29-jun-2013|