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    Summary
    EudraCT Number:2016-004340-11
    Sponsor's Protocol Code Number:17403
    National Competent Authority:Slovakia - SIDC (Slovak)
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2018-02-13
    Trial results View 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 ConcernedSlovakia - SIDC (Slovak)
    A.2EudraCT number2016-004340-11
    A.3Full title of the trial
    A randomized, open label, multicenter Phase 2/3 study to evaluate the efficacy and safety of rogaratinib (BAY 1163877) compared to chemotherapy in patients with FGFR-positive locally advanced or metastatic urothelial carcinoma who have received prior platinum-containing chemotherapy
    Randomizované, otvorené, multicentrické skúšanie fázy 2/3 hodnotiace účinnosť a bezpečnosť rogaratinibu (BAY 1163877) v porovnaní s chemoterapiou u pacientov s FGFR-pozitívnym, lokálne pokročilým alebo metastatickým uroteliálnym karcinómom, ktorí boli predtým liečení chemoterapiou na báze platiny.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase 2/3 study of rogaratinib (pan FGFR inhibitor) vs chemotherapy in patients with locally advanced or metastatic urothelial carcinoma with a high amount of specific cell growth factor receptors 1 and 3 (FGFR1 and 3) in the tumor cells
    Skúšanie fázy 2/3 porovnávajúce rogaratinib (BAY 1163877) s chemoterapiou u pacientov s FGFR-pozitívnym, lokálne pokročilým alebo metastatickým uroteliálnym karcinómom.
    A.4.1Sponsor's protocol code number17403
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorBayer AG
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportBayer AG
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBayer AG
    B.5.2Functional name of contact pointBayer Clinical Trials Contact
    B.5.3 Address:
    B.5.3.1Street AddressCPT Team / Ref: "EU CTR"/ Bayer AG
    B.5.3.2Town/ cityBerlin
    B.5.3.3Post code13342
    B.5.3.4CountryGermany
    B.5.6E-mailclinical-trials-contact@bayer.com
    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 No
    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 nameBAY 1163877 hydrochloride coated tablet 200 mg
    D.3.2Product code BAY 1163877 hydrochloride coated tablet 200 mg
    D.3.4Pharmaceutical form Coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNROGARATINIB
    D.3.9.2Current sponsor codeBAY 1213802 hydrate
    D.3.9.3Other descriptive nameBAY 1163877 hydrochloride hydrate
    D.3.9.4EV Substance CodeSUB188629
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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) No
    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 No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    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 No
    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.IMP: 2
    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 Docetaxel cell pharm
    D.2.1.1.2Name of the Marketing Authorisation holdercell pharm GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 nameDocetaxel cell pharm
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDOCETAXEL
    D.3.9.1CAS number 114977-28-5
    D.3.9.4EV Substance CodeSUB12492MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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) No
    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 No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    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 No
    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.IMP: 3
    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 Paclitaxel Aurobindo
    D.2.1.1.2Name of the Marketing Authorisation holderPUREN Pharma GmbH & Co. KG
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 namePaclitaxel Aurobindo
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPACLITAXEL
    D.3.9.1CAS number 33069-62-4
    D.3.9.4EV Substance CodeSUB09583MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number6
    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) No
    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 No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    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 No
    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.IMP: 4
    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 Javlor
    D.2.1.1.2Name of the Marketing Authorisation holderPierre Fabre Médicament
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameJavlor
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNVINFLUNINE
    D.3.9.1CAS number 162652-95-1
    D.3.9.4EV Substance CodeSUB00063MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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) No
    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 No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    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 No
    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.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
    mRNA FGF receptor 1 and 3 positive locally advanced or metastatic
    urothelial carcinoma progressed after prior platinum-containing
    chemotherapy
    E.1.1.1Medical condition in easily understood language
    Locally advanced or metastatic bladder cancer with a high amount
    of specific cell growth factor receptors 1 and 3 (FGFR1 and 3) in the
    tumor
    cells
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10064467
    E.1.2Term Urothelial carcinoma
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Primary objective of this trial is to demonstrate the superiority of rogaratinib over chemotherapy in
    terms of prolonging overall survival of urothelial carcinoma patients with
    FGFR positive tumors.

    The objective for the Phase 2 part of the study is to demonstrate the efficacy of rogaratinib over chemotherapy in terms of objective response rate of urothelial carcinoma patients with FGFR positive tumors.
    E.2.2Secondary objectives of the trial
    Secondary objective of this trial is to evaluate additional efficacy including the following variables:
    Progression-free survival (PFS)
    Objective response rate (ORR)
    Disease control rate (DCR)
    Duration of response (DOR)
    and to evaluate the safety of rogaratinib (adverse events)
    Tertiary objectives are:
    Patient-reported outcome (PRO)
    Evaluate biomarkers to investigate the drug (i.e. mode-of-action-related)
    Pharmacokinetics
    effect and/or safety) and/or the pathomechanism of the disease.
    Pharmacokinetics
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Existence of archival or fresh biopsy for FGFR testing.
    FGFR testing of patients will be performed at the investigators’ discretion up to a max. of 90 days prior to start of screening (signing of informed consent for study treatment eligibility). Investigators should ensure all patients will be eligible in terms of disease status and lines of treatment within this timeframe. If the patient is positive for FGFR 1 and/or 3 and is unable start screening by 90 days after FGFR testing, the patient may still be considered for screening after discussion with the sponsor’s designated medical representative and approval by the sponsor
    Male or female patients ≥ 18 years of age (at least age of legal
    maturity).
    Documented urothelial carcinoma (transitional cell carcinoma) including urinary bladder, renal pelvis, ureters, urethra, meeting all of the following criteria:
    Histologically or cytologically confirmed. Patients with mixed histologies are required to have a dominant transitional cell pattern.
    Locally advanced (T4b, any N; or any T, N 2−3) or metastatic disease (any T, any N and M1).
    Locally advanced bladder cancer must be unresectable i.e. invading the pelvic or abdominal wall (stage T4b) or presenting with bulky nodal disease (N2-3).
    ECOG Performance Status of 0 or 1.
    Disease progression during or following treatment with at least one platinum-containing regimen (patients should have been treated for at least 2 cycles). In patients who received prior adjuvant/neoadjuvant platinum-containing chemotherapy, progression had to occur within 12 months of treatment.
    High FGFR1 or 3 mRNA expression levels (RNAscope score of 3+ or 4+; measurement is part of this protocol) in archival or fresh tumor biopsy specimen.
    At least 1 measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST v.1.1) in contrast enhanced (unless contraindicated) CT or MRI.
    Adequate laboratory and organ function:
    Absolute neutrophil count (ANC) ≥ 1,500/mm3
    Platelet count ≥ 100,000/mm3
    Hemoglobin ≥ 9.0 g/dL (without transfusion or erythropoietin within 4 weeks before randomization).
    Total bilirubin ≤ 1.5 times the upper limit of normal (ULN). Known Gilbert syndrome is allowed if total bilirubin is ≤ 3 x ULN.
    Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN (≤ 5 x ULN for patients with liver involvement of their cancer).
    Alkaline phosphatase limit ≤ 2.5 x ULN (≤ 5 x ULN for patients with liver and bone involvement of their cancer).
    Lipase < 2 x ULN
    Glomerular filtration rate (GFR) ≥ 30 mL/min/1.73 m2 according to Modification of Diet in Renal Disease (MDRD) abbreviated formula.
    International normalized ratio (INR) ≤ 1.5  ULN, and partial thromboplastin time (PTT) or activated PTT (aPTT) ≤ 1.5  ULN. Patients being treated with anticoagulant, e.g. warfarin or heparin, will be allowed to participate provided no prior evidence of an underlying abnormality in these parameters exists. Close monitoring of at least weekly evaluations will be performed until INR is stable based on a pre-dose measurement as defined by the local standard of care.
    Women of childbearing potential (WOCBP) and fertile men must agree to use adequate contraception when sexually active from signing of the ICF for study treatment eligibility until at least 12 weeks after the last study drug administration. The investigator or a designated associate is requested to advise the patient how to achieve highly effective birth control. Highly effective (failure rate of less than 1% per year) contraception methods include:
    Combined (estrogen and progesterone containing: oral, intravaginal, transdermal) and progesterone-only (oral, injectable, implantable) hormonal contraception associated with inhibition of ovulation.
    Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS).
    Bilateral tubal occlusion or vasectomized partner (provided that partner is the sole sexual partner and has received medical assessment of the surgical success).
    Sexual abstinence (reliability to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient).
    Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
    Male patients with a female partner of childbearing potential must use a condom and ensure that an additional form of contraception is also used during treatment and until 12 weeks after last study drug administration.
    Negative serum pregnancy test in women of childbearing potential (performed within 7 days before randomization). Negative results must be available prior to study drug administration.
    E.4Principal exclusion criteria
    Previous or concurrent cancer except:
    cervical carcinoma in situ
    treated basal-cell or squamous cell skin carcinoma
    any cancer curatively treated > 3 years before randomization
    ocuratively treated incidental prostate cancer (T1/T2a)
    Symptomatic metastatic brain or meningeal tumors unless the patient is > 6 months from definitive therapy, has no radiological evidence of tumor growth and is clinically stable with respect to the tumor at randomization. Also the patient must not be undergoing acute steroid therapy or taper (chronic steroid therapy is acceptable provided that the dose is stable for one month prior to and following screening radiographic studies).
    Known human immunodeficiency virus (HIV) infection.
    Renal dialysis.
    Any malabsorption condition.
    Breast-feeding.
    Ongoing or previous treatment with anti-FGFR directed therapies (e.g. receptor tyrosine kinase inhibitors including rogaratinib or FGFR-specific antibodies) or with taxanes or vinflunine.
    More than two prior lines of systemic anti-cancer therapy for urothelial carcinoma.
    Ongoing or previous anti-cancer treatment within 4 weeks before randomization:
    Patients who have received prior treatment with anti-CTLA-4 may be enrolled provided at least 5 half-lives (approximately 75 days) have elapsed before randomization.
    Prior cancer vaccines and cellular immunotherapy are permitted.
    Previous radiotherapy is acceptable under the following conditions:
    Therapeutic radiotherapy ≥ 3 weeks before the baseline tumor scan.
    Palliative radiotherapy for bone metastases or soft tissue lesions is allowed and should be completed >7 days prior to baseline tumor scan.
    Lesions at the site of previous radiotherapy should have evidence of progressive disease if this is the only site of disease.
    Anti-cancer therapy is defined as any agent or combination of agents with clinically proven anti-tumor activity administered by any route with the purpose of affecting the malignancy, either directly or indirectly, including palliative and therapeutic endpoints.
    Use of strong inhibitors and inducers of CYP3A4 (see Appendix 16.1) should have been stopped 2 weeks before randomization.
    Concomitant therapies that are known to increase serum calcium or phosphate levels and cannot be discontinued or switched to a different medication before randomization.
    Substance abuse, medical, psychological or social conditions that may interfere with the patient’s participation in the study or evaluation of the study results.
    Major surgery, or significant trauma within 4 weeks before randomization (central line surgery is not considered major surgery).
    Unresolved toxicity higher than National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 4.03 (CTCAE v.4.03) Grade 1 attributed to any prior therapy/procedure excluding alopecia, anemia and/or hypothyroidism.
    History or current condition of an uncontrolled cardiovascular disease including any of the following conditions:
    Congestive heart failure (CHF) NYHA > Class 2.
    Unstable angina (symptoms of angina at rest) or new-onset angina (within last 3 months before randomization).
    Myocardial infarction (MI) within past 6 months before randomization.
    Unstable cardiac arrhythmias requiring anti-arrhythmic therapy. Patients with arrhythmia under control with anti-arrhythmic therapy such as beta-blockers or digoxin are eligible.
    Arterial or venous thrombotic events or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 3 months before randomization.
    Current evidence of endocrine alteration of calcium phosphate homeostasis (e.g. parathyroid disorder, history of parathyroidectomy, tumor lysis, tumoral calcinosis, paraneoplastic hypercalcemia).
    Current diagnosis of any retinal detachment, retinal pigment epithelial detachment (RPED), serous retinopathy or retinal vein occlusion.
    Active infection with hepatitis B or C, requiring treatment
    Active infections (≥ CTCAE v.4.03 Grade 3)
    Evidence or history of bleeding diathesis or coagulopathy
    Any hemorrhage / bleeding event ≥ CTCAE v.4.03 Grade 3 within 4 weeks before randomization.
    Seizure disorder requiring therapy
    Serious, non-healing wound, ulcer or bone fracture
    Any condition that is unstable or could jeopardize the safety of the patient and his/her compliance in the study.
    Inability to swallow oral medications.
    Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation.
    Previous assignment to study treatment during this study.
    Investigational drug treatment outside of this study during or within 4 weeks before randomization.
    Close affiliation with the investigational site; e.g. a close relative of the investigator, dependent person (e.g. employee or student of the investigational site).



    E.5 End points
    E.5.1Primary end point(s)
    Overall survival is the primary efficacy variable.
    The primary efficacy variable is overall survival (OS). OS data will be considered mature and the final OS analysis (i.e. primary completion) will be performed when approximately a total of 232 PIK3CA and RAS WT patients have died, in accordance with the power calculations specified for the full analysis set (FAS). For the primary efficacy variable of overall survival, a hierarchical fixed-sequence procedure based on stratified log-rank test controlling type I error at a level of 0.025 (one-sided) will be conducted for the WT population first (step 1). A full alpha of 0.025 (one-sided) will be passed on to OS in all study population and some selected secondary endpoints (step 2), if and only if the null hypothesis of OS for WT population is rejected.in the following sequence: step 1) WT population; step 2) all study population. Step 2 will be tested if and only if the null hypothesis of step 1) is rejected. Details on controlling family-wise type I error within step 2 for OS in all study population and selected secondary endpoints will be specified in the Statistical Analysis Plan (SAP).
    In addition, the hazard ratio (rogaratinib / chemotherapy) for OS and its 95% confidence interval will be calculated using the Cox model, stratified by the same factors used for randomization, for both PIK3CA and/or RAS WT and all study population (referred as “both populations” below). Kaplan-Meier (KM) estimates for OS and KM survival curves will also be presented for each treatment arm and both populations. The KM estimates at time points such as 3 months, 6 months etc. together with corresponding 95% confidence intervals as well as the differences of these estimates will also be calculated between the rogaratinib arm and the chemotherapy arm for both populations.


    This study follows a Phase 2/3 design with interim analysis, meaning the patients recruited to the Phase 2 part of the study will automatically continue to the Phase 3 part without interruption if futility is not demonstrated at the 1st interim ORR analysis. The Phase 2 part will end at the time of the cut-off for the 1st interim ORR analysis. To help structure the protocol flow, we present this Phase 2/3 study as one study protocol with two interim analyses, while the first interim indicates the end of the Phase 2 part, and the second and final analyses are considered as the Phase 3 part including Phase 2 patients in the analyses.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Final OS analysis: at approx. 232 deaths in WT population (approx. 44.9 months after the start of randomization).
    In addition, two interim analyses are planned:
    1st interim ORR analysis (Phase 2 part):
    At approx. the first 116 PIK3CA and RAS WT patients complete 4.5 months of Treatment.
    2nd interim OS analysis (Phase 3 part):
    At approx. 116 deaths in PIK3CA and RAS WT patients (50% of 232 total death events in WT population, approx. 28.7 months after start of randomization).
    E.5.2Secondary end point(s)
    Secondary efficacy variables include PFS, ORR, DCR and DOR based on independent central review assessments.
    Secondary efficacy variables including progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) and duration of response (DOR) (see Section 9.4 for definitions) will be analyzed based on final database when approximately a total of 232 PIK3CA and RAS WT patients have died.
    The formal testing procedure controlling family-wise type I error of 0.025 as one-sided for PFS and ORR in WT and all study population will be specified in a separate Statistical Analysis Plan (SAP) document. Further analysis details with respect to PFS, ORR, DCR and DOR are summarized below.
    For analyses of PFS, in both populations, the two treatment arms will be compared using a log-rank test stratified by the same stratification factors as used in the analyses of the primary variable, based on independent central review assessments. The hazard ratio (rogaratinib / chemotherapy) and 95% confidence interval will be provided. KM estimates and KM curves will also be presented for each treatment arm. The KM estimates at time points such as 2 months, 4 months etc. together with corresponding 95% confidence intervals as well as the differences of these estimates between the rogaratinib arm and the chemotherapy arm will also be calculated.
    ORR as well as DCR will be compared between treatment arms using the Cochran-Mantel-Haenszel (CMH) test adjusting for the same stratification factors as used in the analyses of the primary variable, based on independent central review assessments for both populations. Estimates and 95% confidence intervals will be computed for each treatment arm. The differences in ORR and DCR between the rogaratinib and chemotherapy arms and the corresponding 95% confidence intervals will also be calculated.
    For both populations, summary statistics will be displayed for all best response categories: CR, PR, SD, Non CR/Non PD, PD by central radiographic imaging, and PD by clinical judgment. Frequency counts and percentages with exact 95% confidence intervals will be displayed.
    Since the responders are not a randomized group, no statistical testing will be performed for DOR. Analysis of DOR will be descriptive in nature for both populations based on central review assessments. KM estimates and KM curves will be displayed for each treatment arm.
    Analyses based on investigator’s review assessments will also be performed for PFS, ORR, DCR and DOR as sensitivity analyses.

    Summary of adverse events (AEs) is considered as a secondary variable objective for the study. Descriptive tables will be presented by treatment arm for both populations. AEs will be summarized by the Medical Dictionary for Regulatory Activities (MedDRA) terms (v.20.0 or later) and worst grade based on the National Cancer Institute (NCI) Common Terminology Criteria Adverse Event (CTCAE), version 4.03. For all events, the relationship to treatment and the severity of the event will be determined by the investigator and summarized by treatment for both populations.

    PRO data as measured by the EORTC QLQ-C30 and EQ-5D will be analyzed to assess differences in health-related Quality of Life (HRQoL) and health utility values between treatment arms based on time-adjusted Area Under the Curve (AUC) using all available data.

    Patients’ biomarker status at baseline will be correlated with treatment effect in OS, PFS and response to explore which biological targets may be particularly important in defining the appropriate therapeutic population for the agent. Biomarker analyses and results will be provided in a separate report.

    Pharmacokinetic variables
    The samples collected on Day 1 of Cycles 1 through 5 at pre-dose and between 0.5 and 1.5 hours post-dose will document a longitudinal exposure under steady state condition. The longitudinal exposure data will be used in exposure-response modelling of adverse events and clinical responses. Evaluation of the data described above will be presented in a separate report. In the clinical study report, only plasma concentration data for all analytes will be listed.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary efficacy variables will be analyzed based on final database when approximately a total of 232 PIK3CA and RAS WT patients have died (approx. 44.9 months after the start of randomization).
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis Yes
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA107
    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 No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Austria
    Belgium
    Brazil
    Canada
    China
    Czech Republic
    Denmark
    Finland
    France
    Germany
    Hong Kong
    Hungary
    Ireland
    Israel
    Italy
    Japan
    Korea, Democratic People's Republic of
    Netherlands
    Poland
    Portugal
    Russian Federation
    Singapore
    Slovakia
    Spain
    Sweden
    Switzerland
    Taiwan
    United Kingdom
    United States
    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
    For each participating EU country, the end of the study according to the EU Clinical Trial Directive will be reached when the last visit of the last patient for all centers in the respective country has occurred.
    The end of the study as a whole will be reached when the last visit of the last patient has been achieved in all participating centers (EU and non-EU), or the primary completion event has been reached, whichever comes later.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days11
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months7
    E.8.9.2In all countries concerned by the trial days11
    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.1.2.1Number of subjects for this age range: 976
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 651
    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 Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    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 state13
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 925
    F.4.2.2In the whole clinical trial 1627
    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)
    None
    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 Decision2018-03-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-02-16
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-10-27
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