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    Summary
    EudraCT Number:2009-016669-27
    Sponsor's Protocol Code Number:P10-
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2010-01-28
    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 number2009-016669-27
    A.3Full title of the trial
    A phase II study to investigate the efficacy of RAD001 (Afinitor®, everolimus) in patients with irresectable recurrent or metastatic differentiated, undifferentiated (anaplastic) and medullary thyroid carcinoma
    A.3.2Name or abbreviated title of the trial where available
    THYRRAD, CRAD001CNL08T
    A.4.1Sponsor's protocol code numberP10-
    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 SponsorLeiden University Medical Center
    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 RoleComparator
    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 Afinitor
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis europharm limited
    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 nameEverolimus
    D.3.2Product code Eu/1/09/538/001-006
    D.3.4Pharmaceutical form Tablet
    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 typeProtein kinase inhibitors
    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 irresectable recurrent or metastatic differentiated, undifferentiated (anaplastic) and medullary thyroid carcinoma will be treated in a phase II study to investigate the efficacy of RAD001 (Afinitor®, everolimus).
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine the efficacy of RAD001 in patients with progressive irresectable recurrent or metastatic differentiated thyroid carcinoma
    E.2.2Secondary objectives of the trial
    -To determine maximum percentage of tumor reduction
    -To describe activity time to event endpoints
    -To assess toxicity
    -To determine evolution of serum thyroglobulin (Tg)
    -To perform explorative pharmacogenomic, pharmacokinetic and translational studies
    -To investigate efficacy of RAD001 in patients with progressive metastases or inoperable recurrent disease of undifferentiated (anaplastic) or medullary thyroid cancer
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Investigation of the influence of genotype/phenotype on the pharmacokinetics of RAD001, 24-01-2010, version 1:
    The objective of this sub-study is to investigate the influence of genotype/phenotype on the pharmacokinetics of RAD001. Furthermore, we want to investigate whether blood levels are predictive for the anti-tumor effect.
    E.3Principal inclusion criteria
    TARGET POPULATION:
    Patients with differentiated thyroid cancer comprise the main part of this study. A total number of 28 patients with differentiated thyroid cancer will be studied.

    Inclusion Criteria:
    • Age > 18 years
    • Karnofsky performance score > 70%
    • Patients with differentiated thyroid carcinoma (i.e. papillary and follicular carcinomas)
    • Patients must have undergone total thyroidectomy (and having received thyrosuppressive therapy afterwards)
    • Patients with no RaI uptake in tumor as proven by RaI scintigraphy performed after prior RaI therapy
    • Patients with insufficient RaI uptake as proven by progression of lesions despite accumulation of RaI
    • Patients with a maximum cumulative dosis of RaI
    • The patient has documented progressive disease (PD) on computerized tomography (CT), magnetic resonance imaging (MRI), bone scan or X-ray, per RECIST v1.1 at screening compared with a previous image done within 14 months of screening
    • Measurable tumor according to RECIST v1.1 criteria (see Section 7 on "evaluation of response"). Patients must have clinically and/or radiographically documented measurable disease. All radiology studies must be performed within 28 days prior to registration
    • The subject has no other diagnosis of malignancy (unless non-melanoma skin cancer, carcinoma in situ of the cervix, or a malignancy diagnosed ≥ 2 years previously) and currently has no evidence of malignancy (unless non-melanoma skin cancer or carcinoma in situ of the cervix).
    • Patients with history of brain metastasis who are neurologically stable following definitive radiation and/or surgery and do not require corticosteroids will be permitted.

    Laboratory Requirements - within 14 days prior to enrollment:
    • Patients with adequate bone marrow function defined as ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x 109/L, Hb ≥ 5.6 mmol/L
    • Patients with adequate liver function defined as serum bilirubin ≤ 1.5 x ULN, ALT and AST ≤ 2.5x ULN. Patients with known liver metastases are allowed to have an AST and ALT ≤ 5x ULN.
    • Patients with adequate renal function defined as serum creatinine ≤ 2 x ULN.
    • Women of childbearing potential must have a negative serum or urine pregnancy test within 14 days prior to the first dose of study drug.
    • Patients must give written informed consent for inclusion in the study according to local guidelines.

    Patients with progressive metastases or inoperable recurrent disease of undifferentiated (anaplastic) or medullary thyroid cancer will also have the opportunity to participate in this study, since there is a lack of therapeutic options for these patients. The same inclusion and exclusion criteria will be used, apart from the criteria on RaI therapy, since this is not applicable for undifferentiated or medullary thyroid cancer. We will analyse these patients as separate cohorts. Patients with undifferentiated or medullary thyroid cancer will be treated and evaluated according to the same criteria as the patients included with differentiated thyroid cancer. A minimum of 7 undifferentiated thyroid cancer patients and 7 medullary thyroid cancer patients will be analysed for response rate; if no responses are found in these patient groups, further investigation of RAD001 in undifferentiated or medullary thyroid cancer patients is not warranted.
    E.4Principal exclusion criteria
    Exclusion Criteria:
    • Patients receiving chemotherapy, immunotherapy, radiation therapy or any other investigational agent within 4 weeks of the first dose of study drug, or sunitinib and/or sorafenib within 2 weeks of the first dose of RAD001. Patients must have recovered from effects of prior therapy.
    • Patients who have previously received RAD001 or other mTOR inhibitors.
    • Patients with known hypersensitivity to RAD001 or other rapamycin analogs (sirolimus, temsirolimus), or to its excipients.
    • Patients receiving chronic, systemic treatment with corticosteroids or another
    immunosuppressive agent (except corticosteroids with a daily dosage equivalent to
    prednisone ≤ 20 mg for adrenal insufficiency). Patients receiving corticosteroids must be on a stable dose for ≥ 4 weeks prior to the first dose of RAD001. Topical or inhaled corticosteroids are permitted.
    • Patients with an active bleeding diathesis.
    • Patients who have undergone major surgery within 4 weeks prior to starting study drug (e.g., intra-thoracic, intra-abdominal, or intra-pelvic), open biopsy, or significant traumatic injury, or who have not recovered from the side effects of any of the above.
    • Patients with any severe and/or uncontrolled medical conditions such as unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤ 6 months, serious uncontrolled cardiac arrhythmia, uncontrolled hyperlipidemia, active or uncontrolled severe infection, cirrhosis, chronic or persistent active hepatitis or severely impaired lung function. Investigation of LVEF can be performed in case of doubt for in/exclusion.
    • Uncontrolled diabetes (fasting glucose > 2 x ULN).
    • Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not willing to use effective birth control methods. If barrier contraceptives are used, they must be continued throughout the study by both sexes.
    E.5 End points
    E.5.1Primary end point(s)
    Primary endpoint:
    -Objective Response Rate according to RECIST version 1.1. in patients with progressive irresectable recurrent or metastatic differentiated thyroid carcinoma

    Secondary endpoints:
    -Maximum percentage of tumor reduction for target lesions (waterfall plot)
    -Progression-free survival and overall survival (time to event)
    -Toxicity and serious adverse events according to NCI Common Terminology Criteria for Adverse Events Version 4.0
    -Evolution of serum thyroglobulin (Tg) during treatment
    -Explorative pharmacogenomic, pharmacokinetic and translational studies
    -Objective Response Rate according to RECIST version 1.1 in patients with progressive metastases or inoperable recurrent disease of undifferentiated (anaplastic) or medullary thyroid cancer

    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 Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    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 Information not present in EudraCT
    E.8.1.2Open Information not present in EudraCT
    E.8.1.3Single blind Information not present in EudraCT
    E.8.1.4Double blind Information not present in EudraCT
    E.8.1.5Parallel group Information not present in EudraCT
    E.8.1.6Cross over Information not present in EudraCT
    E.8.1.7Other Information not present in EudraCT
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    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 No
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.7Trial has a data monitoring committee No
    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
    All patients will be treated with RAD001 at a once daily oral dose of 10 mg until either:
    • Tumor progression determined by the investigator according to RECIST criteria
    • Unacceptable toxicity
    • Death
    • Discontinuation from the study for any other reason
    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 months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    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 Information not present in EudraCT
    F.3.3.2Women of child-bearing potential using contraception Information not present in EudraCT
    F.3.3.3Pregnant women Information not present in EudraCT
    F.3.3.4Nursing women Information not present in EudraCT
    F.3.3.5Emergency situation Information not present in EudraCT
    F.3.3.6Subjects incapable of giving consent personally Information not present in EudraCT
    F.3.3.7Others Information not present in EudraCT
    F.4 Planned number of subjects to be included
    F.4.1In the member state42
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    There are no standard therapies after Sorafenib or RAD001. So, patients who are progressive on RAD001 and have received Sorafenib earlier on, will receive best supportive care or are offered a phase I trial.
    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 Decision2010-02-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2010-04-14
    P. End of Trial
    P.End of Trial StatusOngoing
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