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    The EU Clinical Trials Register currently displays   44338   clinical trials with a EudraCT protocol, of which   7368   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    Summary
    EudraCT Number:2007-002962-37
    Sponsor's Protocol Code Number:NA_00008675
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2010-05-12
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2007-002962-37
    A.3Full title of the trial
    Phase I/II study of dalteparin, a low molecular weight heparin (LMWH), in combination with Sunitinib (SU11248), an oral, selective multitargeted tyrosine kinase inhibitor, as first line treatment, in patients with metastatic renal cell carcinoma
    A.4.1Sponsor's protocol code numberNA_00008675
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorVU Medical Center Amsterdam
    B.1.3.4CountryNetherlands
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name 1) SUTENT (Sunitinib Maleate) Capsules, Pfizer Inc., LAB-0317-2.0
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Inc
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameSunitinib maleate
    D.3.4Pharmaceutical form Capsule*
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPOral use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Information not present in EudraCT
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product Yes
    D.3.11.13.1Other medicinal product typebiochemical
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Fragmin, Pfizer Inc., LAB-0058-7.0
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Inc.
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namedalteparin sodium
    D.3.4Pharmaceutical form Concentrate for solution for injection
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Information not present in EudraCT
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.3.11.13.1Other medicinal product typeglycosaminoglycan
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Patients with metastatic or inoperable renal cell cancer
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    1.1 Objectives phase I study
    1 To determine the recommended dosing for the combination of Sunitinib and Dalteparin in patients with metastatic renal cell carcinoma.
    2 To evaluate safety and tolerability for the combination of Sunitinib and Dalteparin in patients with metastatic renal cell carcinoma.
    3 To determine early signs of clinical activity of the combination of Sunitinib and Dalteparin in patients with metastatic renal cell carcinoma.

    1.2 Primary Objectives phase II study
    1 To determine the proportion of patients with metastatic renal cell carcinoma receiving the combination of Sunitinib and Dalteparin as first line treatment, that is progression-free at 11 months.
    2 To determine the safety of the combination of Sunitinib and Dalteparin in patients with metastatic renal cell carcinoma.
    E.2.2Secondary objectives of the trial
    1.3 Secondary Objectives for phase I and phase II studies
    1 To determine the clinical response rate of Sunitinib and Dalteparin in patients with metastatic renal cell carcinoma.
    2 To determine time-to-progression (TTP) and overall survival amongst patients with metastatic renal cell carcinoma receiving Sunitinib and Dalteparin.
    3 To determine the effect of Sunitinib alone and Dalteparin alone compared to the combination of Dalteparin plus Sunitinib on plasma coagulation parameters.
    4 To determine the effect of Sunitinib alone and Dalteparin alone compared to the combination of Dalteparin plus Sunitinib on angiogenesis parameters in blood.
    5 To evaluate the modulation of tumor blood volume and vascular permeability in patients treated with Sunitinib and Dalteparin by DCE-MRI.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    3.1 Inclusion Criteria

    1) Patients must have histologically confirmed metastatic or unresectable renal cell carcinoma.
    2) Clear cell and non-clear renal carcinoma patients are eligible. Oncocytoma, collecting duct tumors and transitional cell carcinoma are NOT eligible.
    3) No prior systemic treatments for metastatic disease are permitted, including antiangiogenic therapy, immunotherapy, chemotherapy and investigational therapy.
    4) Patients with their primary tumor in place who are appropriate surgical candidates should be strongly encouraged to undergo nephrectomy prior to treatment initiation, based on the potential effect on survival.
    6) Prior palliative radiation to metastatic lesion(s) is permitted, provided there is at least one measurable and/or evaluable lesion(s) that has not been radiated.
    7) Radiation therapy must be completed >4 weeks prior to registration
    8) Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension as >20 mm with conventional techniques or as >10 mm with spiral CT scan (RECIST criteria).
    9) Age > 18 years.
    10) ECOG performance status ≤ 2.
    11) Patients must have normal organ and marrow function as defined below:
    • leukocytes >3,000/mm3
    • absolute neutrophil count >1,500/mm3
    • platelets >100,000/mm3
    • total bilirubin <1.5 x laboratory upper limit of normal
    • AST(SGOT)/ALT(SGPT) <2.5 x laboratory upper limit of normal
    • creatinine <1.5 x laboratory upper limit of normal or
    measured Creatinine clearance of >50 ml/min/1.73m2
    • PT/INR <1.5
    • Urine protein <1+; if >1+, 24 hour urine protein should be
    obtained and should be <1000 mg

    12) The effects of Sunitinib on the developing human fetus at the recommended therapeutic dose are unknown. For this reason and because angiogenesis inhibitors are known to be teratogenic, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
    13) Ability to understand and the willingness to sign a written informed consent document.
    14) The effect of this combination treatment on the risk for hemorrhage is unknown, but it is possible that it is increased. Therefore, except for Dalteparin that will be administered as a study drug, the patients should not take any other anticoagulants or anitiplatelet agents during the study, including but not limited to NSAID (any dose of aspirin), warfarin or other anticoagulants.
    E.4Principal exclusion criteria
    1) Prior therapy with Sunitinib.
    2) Patients may not be receiving any other investigational agents.
    3) Patients with known CNS metastases. Patients should have a head CT/MRI within 14 days prior to treatment initiation. Any imaging abnormality indicative of CNS metastases will exclude the patient from the study.
    4) Patients with a “currently active” second malignancy other than non-melanoma skin cancers are not eligible. Patients are not considered to have a “currently active” malignancy if they have completed anti-cancer therapy and are considered by their physician to be at less than 30% risk of relapse.
    5) Patients with a large (>2cm) pulmonary lesion involving the trachea or one of the main bronchus and any endobronchial lesion.
    6) History of allergic reactions attributed to compounds of similar chemical or biologic composition to Dalteparin.
    7) Evidence of bleeding diathesis within last 6 months.
    9) Serious or non-healing wound, ulcer or bone fracture or active peptic ulceration.
    10) Current therapeutic full-dose of anticoagulants, either warfarin or LMWH or unfractionated heparin.
    11) Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure (New York Association Class II, III, or IV), angina pectoris requiring nitrate therapy, recent myocardial infarction (< the last 6 months), cardiac arrhythmia, history of CVA within 6 months (thrombotic or hemorrhagic), hypertension (defined as blood pressure of >160 mmHg systolic and/or >90 mmHg diastolic on medication), hemorrhagic retinopathy, history of peripheral vascular disease, or psychiatric illness/social situations that would limit compliance with study requirements.
    12) Patients with an ejection fraction <50% by MUGA scan are not eligible.
    13) Pregnant women are excluded from this study because Sunitinib is an angiogenesis inhibitor agent with the potential for teratogenic or abortion inducing effects.
    14) History of abdominal fistula, gastrointestinal perforation or intra-abdominal abcess within 28 days prior to day 1 therapy.
    15) Invasive procedures defined as:
    -Major surgical procedure, open biopsy, or significant traumatic injury within 6 weeks prior to day 1 therapy.
    -Anticipation of need for major surgical procedures during the course of the study.
    -Core biopsy within 7 days prior to start therapy.
    E.5 End points
    E.5.1Primary end point(s)
    7.1 Primary Objectives Phase I part

    1 To determine the recommended dosing for the combination of Dalteparin and Sunitinib in patients with metastatic renal cell carcinoma.

    2 To evaluate safety and tolerability for the combination of Dalteparin and Sunitinib in patients with metastatic renal cell carcinoma.

    3. To determine early signs of clinical activity of the combination of Sunitinib and Dalteparin in patients with metastatic renal cell carcinoma.

    The MTD will be determined as described in the design section 5. Sample size for the phase I portion of the study will be between 6 and 18 patients. Toxicities in both phase I and phase II parts will be summarized by tabulation. Summaries will be made across all types of toxicities and by grade and type.

    7.2 Primary objectives Phase II

    1 To determine the proportion of patients with metastatic renal cell carcinoma receiving the combination of Sunitinib and Dalteparin as first line treatment, that is progression-free at 11 months.
    The primary efficacy endpoint of the phase II portion of the trial is the progression free survival (PFS) receiving the combination therapy. For each patient, the time of progression will be recorded. Any patient who discontinues treatment due to adverse reactions, refusal, or who goes on to receive alternate therapy will be considered censored at their last visit and be counted as having progressed. The sample size was determined based upon a Bryant Day Phase II clinical trial design, taking into account both activity as well as toxicity. The proportion of patients with 11 month PFS will be calculated with exact 95% confidence intervals. A total of 56 enrolled patients gives 90% (1-) power to distinguish a proportion of 0.7 (P1) from the null value of 0.5 (p0), using Phase II Clinical Trial Design (BRYANT & DAY) with a one-sided test of proportion and an alpha level of 0.1 (). This design also takes into account toxicity and aims for a toxicity rate between 30 and 50%.

    Interim analysis will be performed in this two stage design to analyze 11 month progression free survival and toxicity in 24 patients. (see detailed description of statistical analysis at paragraph 7.5). Kaplan-Meier curves will be used to summarize the pattern of PFS over time and the median time to progression will be calculated along with 95% confidence intervals.

    2 To determine the toxicity of the combination of Dalteparin and Sunitinib in patients with metastatic renal cell carcinoma.
    As described, toxicities will be tabulated and summarized overall and across grade and type according to CTC criteria. When grade 3 or 4 toxicity occurs in  50% of patients this will be evaluated as unacceptable toxicity and according to the two step evaluation design as described in paragraph 7.5 the study will be discontinued at an interim analysis of 24 patients. This relatively high percentage of toxicity is based on the details as given in the investigators brochure that Sunitinib monotherapy causes in 38% of patients toxicity that requires interruption of Sunitinib administration.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Safety of combination treatment of two approved drugs
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    historic controls
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The total accrual is expected to be 56 patients. The sample size in the Phase I portion of the study is expected to be 6-18 patients. For the phase II portion of the study, an additional maximum of 50 patients will be accrued resulting in 56 patients observed at the MTD for analysis with a planned interim analysis after 24 patients at the MTD. The sample size was determined based upon a Bryant Day Phase II clinical trial designs, taking into account both activity as well as toxicity.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state19
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 19
    F.4.2.2In the whole clinical trial 56
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2010-06-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2010-09-14
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2015-10-14
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