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    Summary
    EudraCT Number:2017-001483-38
    Sponsor's Protocol Code Number:BAY1163877/19131
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Temporarily Halted
    Date on which this record was first entered in the EudraCT database:2018-02-02
    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 ConcernedSpain - AEMPS
    A.2EudraCT number2017-001483-38
    A.3Full title of the trial
    An international, multicenter, Phase 1b/2 study of rogaratinib (BAY 1163877) in combination with atezolizumab as first-line treatment in cisplatin-ineligible patients with FGFR-positive locally advanced or metastatic urothelial carcinoma
    Estudio internacional, multicéntrico fase 1b/2 de Rogaratinib (BAY 1163877) en combinación con atezolizumab como tratamiento de primera línea en pacientes no candidatos a cisplatino con FGFR positivos con carcinoma urotelial metastásico o localmente avanzado.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase 1b/2 study of rogaratinib (BAY 1163877) in combination with atezolizumab in urothelial carcinoma
    Estudio fase 1b/2 de Rogaratinib (BAY 1163877) en combinación con atezolizumab en carcinoma urotelial.
    A.3.2Name or abbreviated title of the trial where available
    Phase 1b/2 study of pan FGFR inhibitor
    Estudio Fase 1b/2 de inhibidor pan FGFR
    A.4.1Sponsor's protocol code numberBAY1163877/19131
    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 Addressn/a
    B.5.3.2Town/ cityBerlin
    B.5.3.3Post code13342
    B.5.3.4CountryGermany
    B.5.4Telephone number0034.900102372
    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 nameRogaratinib
    D.3.2Product code BAY 1163877
    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.3.9.3Other descriptive nameBAY1163877
    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 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 Tecentriq 1,200 mg concentrate for solution for infusion
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Limited
    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 nameAtezolizumab
    D.3.4Pharmaceutical form Injection
    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 INNATEZOLIZUMAB
    D.3.9.1CAS number 1380723-44-3
    D.3.9.2Current sponsor codeAtezolizumab
    D.3.9.4EV Substance CodeSUB178312
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number60
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCoated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    FGFR-positive locally advanced or metastatic urothelial carcinoma
    Carcinoma urotelial localmente avanzado o metastásico con FGFR positivo
    E.1.1.1Medical condition in easily understood language
    urothelial carcinoma
    carcinoma urotelial
    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 No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Part A:
    • To determine the safety and tolerability of rogaratinib in combination with atezolizumab in patients with FGFR-positive locally advanced or metastatic urothelial carcinoma
    • To determine the recommended Phase 2 dose (RP2D) of rogaratinib in combination with atezolizumab in this patient population.

    Part B:
    • To compare progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by blinded independent central review of rogaratinib in combination with atezolizumab over placebo in combination with atezolizumab in untreated patients with FGFR positive locally advanced or metastatic urothelial carcinoma.
    Parte A:
    •Determinar la seguridad y tolerabilidad de rogaratinib en combinación con atezolizumab en pacientes con carcinoma urotelial localmente avanzado o metastásico positivo para FGFR
    •Determinar la dosis recomendada para la fase 2 (DRF2) de rogaratinib en combinación con atezolizumab en esta población de pacientes.

    Parte B:
    •Comparar la supervivencia libre de progresión (SLP) según la versión 1.1 de los criterios de evaluación de la respuesta en tumores sólidos (RECIST v1.1) mediante revisión centralizada independiente enmascarada de rogaratinib en combinación con atezolizumab frente a placebo en combinación con atezolizumab en pacientes no tratados con carcinoma urotelial localmente avanzado o metastásico positivo para FGFR.
    E.2.2Secondary objectives of the trial
    Part A:
    • To assess the efficacy of the combination of rogaratinib and atezolizumab in this patient population.
    • To characterize the pharmacokinetics (PK) of rogaratinib in combination with atezolizumab in this patient population

    Part B:
    • To further characterize the pharmacokinetics of rogaratinib in combination with atezolizumab in this patient population
    • To further assess the efficacy of the combination of rogaratinib and atezolizumab in this patient population
    • To evaluate the safety and tolerability of rogaratinib in combination with atezolizumab in this patient population
    Parte A:
    • Evaluar la eficacia de la combinación de rogaratinib y atezolizumab en esta población de pacientes.
    • Caracterizar la farmacocinética (FC) de rogaratinib en combinación con atezolizumab en esta población de pacientes

    Parte B:
    •Caracterizar la farmacocinética de rogaratinib en combinación con atezolizumab en esta población de pacientes.
    •Evaluar la eficacia de la combinación de rogaratinib y atezolizumab en esta población de pacientes.
    •Evaluar la seguridad y tolerabilidad de rogaratinib en combinación con atezolizumab en esta población de pacientes.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Part A:
    • Male/female patients >= 18 years of age (at least age of legal maturity)
    • Urothelial carcinoma (transitional cell carcinoma) including urinary bladder, renal pelvis, ureters, urethra, meeting all of the following criteria:
    o Histologically confirmed.
    o Patients with mixed histology are required to have a dominant transitional cell pattern
    o Locally advanced (T4, any N; or any T, N2-3) or metastatic disease (any T, any N and M1)
    Note: 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)
    • 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
    • Measurable disease according to RECIST v1.1
    • ECOG PS 0 or 1
    • Adequate hematological and end organ function
    • Recovery to NCI CTCAE v.4.03 Grade 0 or 1 level or recovery to baseline preceding the prior treatment from any previous drug / procedure-related toxicity (patients with persistent alopecia, anemia [hemoglobin >= 9 g/dl], and / or hypothyroidism can be included)
    • No prior systemic treatment for locally advanced or metastatic urothelial carcinoma. For patients who received prior adjuvant/neoadjuvant chemotherapy or chemo-radiation for urothelial carcinoma, a treatment-free interval > 12 months between the last treatment administration and the date of recurrence is required in order to be considered treatment-naïve in the metastatic setting. Prior local intra-vesical chemotherapy/local immunotherapy allowed if completed at least 4 weeks before first study drug administration
    • Ineligibility for cisplatin-based chemotherapy
    • Negative serum pregnancy test in women of childbearing potential (performed within 7 days before the first treatment). Negative results must be available before the first study drug administration
    • WOCBP + fertile men must agree to use adequate contraception when sexually active from signing of ICF for study treatment eligibility until at least 5 months after last study drug administration. Investigator or designated associate is requested to advise 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
    • IUD/IUS
    • Bilateral tubal occlusion/vasectomized partner
    • Sexual abstinence
    o Periodic abstinence + withdrawal are not acceptable methods of contraception.
    Male patients with female partner of childbearing potential must use condom+ ensure that an additional form of contraception is also used during treatment + until 12 weeks after last study drug administration
    Part B:
    • Male/female patients >= 18 years of age (at least age of legal maturity)
    • Urothelial carcinoma (transitional cell carcinoma) including urinary bladder, renal pelvis, ureters, urethra, meeting all of the following criteria:
    o Histologically confirmed
    o Patients with mixed histology are required to have a dominant transitional cell pattern.
    o Locally advanced (T4, any N; or any T, N2-3) or metastatic disease (any T, any N, and M1)
    Note: 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)
    • 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
    • Measurable disease according to RECIST v1.1
    • ECOG PS 0 or 1
    • Adequate haematological and end organ function
    • Recovery to NCI CTCAE v.4.03 Grade 0 or 1 level or recovery to baseline preceding the prior treatment from any previous drug / procedure-related toxicity (patients with persistent alopecia, anemia [hemoglobin ≥ 9 g/dl for Cohort B1, +/ or hypothyroidism can be included)
    • No prior systemic treatment for locally advanced or metastatic urothelial carcinoma. For patients who received prior adjuvant/neoadjuvant chemotherapy or chemo-radiation for urothelial carcinoma, a treatment-free interval > 12 months between the last treatment administration and the date of recurrence is required in order to be considered treatment-naïve in the metastatic setting. Prior local intra-vesical chemotherapy or local immunotherapy is allowed if completed at least 4 weeks before randomization
    • Ineligibility for cisplatin-based chemotherapy
    • Pregnancy serum test and contraception part identical with Part A
    Parte A:
    •Pacientes de ambos sexos >= 18 años (al menos la edad de madurez legal)
    •Carcinoma urotelial documentado (carcinoma de células transicionales), que incluye vejiga urinaria, pelvis renal, uréteres y uretra, y que cumpla todos los criterios siguientes:
    o Histológicamente confirmado.
    o Es necesario que los pacientes con histología mixta tengan un patrón dominante de células transicionales.
    o Enfermedad localmente avanzada (T4, cualquier N; o cualquier T, N2-3) o metástasis (cualquier T, cualquier N y M1).
    •FGFR1 elevado o 3 niveles de expresión de ARNm (puntuación RNAscope de 3+ o 4+; la medición forma parte de este protocolo) en la muestra de biopsia tumoral de archivo o reciente
    •Al menos 1 lesión medible según RECIST v1.1 en TAC o RM mejorado con contraste.
    •No haber recibido tratamiento sistémico previo para un carcinoma urotelial localmente avanzado o metastásico. En el caso de pacientes que recibieron quimiorradioterapia o quimioterapia adyuvante/neoadyuvante previamente para el carcinoma urotelial, es necesario que hayan pasado más de 12 meses sin tratamiento entre la administración del último tratamiento y la fecha de la recidiva para considerarlo sin tratamiento previo en el entorno metastásico. Se permite la quimioterapia intravesical local previa o la inmunoterapia local previa si finalizó al menos 4 semanas antes de la primera administración del fármaco del estudio.
    •Inelegibilidad para la quimioterapia con cisplatino
    •ECOG 0 o 1.
    •Función hematológica y orgánica adecuada
    •Recuperación según NCI, versión 4.03 (CTCAE del NCI v.4.03) o nivel de recuperación de grado 0 o 1 hasta el valor inicial anterior al tratamiento previo de cualquier toxicidad relacionada con un fármaco/procedimiento.
    • Test embarazo negativo en suero en mujeres en edad fértil (realizado dentro de los 7 días antes del primer tratamiento. Resultados negativos deben estar disponibles antes de la primera administración del fármaco en estudio.
    • Mujeres en edad fértil + hombre fértiles deben estar de acuerdo en el uso de anticoncepción cuando sean sexualmente activos desde la Firma de la HIP-CI para la elegibilidad del tratamiento del estudio hasta como mínimo 5 meses tras la última administración del fármaco del estudio. El investigador o un asociado designado deberá informar al paciente como alcanzar un control del embarazo de manera altamente efectiva. Los métodos anticonceptivos altamente eficaces incluyen (tasas de fallo inferiores al 1% por año):
    • Anticonceptivos hormonales Combinados asociados con inhibidores de la ovulación que contienen estrógenos y progesterona (oral, intravaginal, transdérmicol) y solo progesterona (oral, inyectable, implantes)
    • DIU
    • Oclusión Bilateral tubal/pareja vasectomizada
    • Abstinencia Sexual
    o Abstinencia periódica no es un método anticonceptivo aceptable.
    Pacientes masculinos con pareja femenina que esté en edad fértil deben usar preservativo y asegurar que un método anticonceptivo adicional es usado durante el tratamiento y hasta 12 semanas después de la última administración del fármaco del estudio.
    ParteB:
    •Pacientes de ambos sexos >= 18 años (al menos la edad de madurez legal)
    •Carcinoma urotelial documentado (carcinoma de células transicionales), que incluye vejiga urinaria, pelvis renal, uréteres y uretra, y que cumpla todos los criterios siguientes:
    oHistológicamente confirmado.
    oEs necesario que los pacientes con histología mixta tengan un patrón dominante de células transicionales.
    oEnfermedad localmente avanzada (T4, cualquier N; o cualquier T, N2-3) o metástasis (cualquier T, cualquier N y M1).
    •FGFR1 elevado o 3 niveles de expresión de ARNm (puntuación RNAscope de 3+ o 4+; la medición forma parte de este protocolo) en la muestra de biopsia tumoral de archivo o reciente
    •Al menos 1 lesión medible según RECIST v1.1 en TAC o RM mejorado con contraste
    •No haber recibido tratamiento sistémico previo para un carcinoma urotelial localmente avanzado o metastásico. En el caso de pacientes que recibieron quimiorradioterapia o quimioterapia adyuvante/neoadyuvante previamente para el carcinoma urotelial, es necesario que hayan pasado más de 12 meses sin tratamiento entre la administración del último tratamiento y la fecha de la recidiva para considerarlo sin tratamiento previo en el entorno metastásico. Se permite la quimioterapia intravesical local previa o la inmunoterapia local previa si finalizó al menos 4 semanas antes de la aleatorización.
    •Inelegibilidad para la quimioterapia con cisplatino
    •ECOG 0 o 1.
    •Función hematológica y orgánica adecuada
    •Recuperación según los criterios terminológicos comunes para acontecimientos adversos del NCI, versión 4.03 (CTCAE del NCI v.4.03) o nivel de recuperación de grado 0 o 1 hasta el valor inicial anterior al tratamiento previo de cualquier toxicidad relacionada con un fármaco/procedimiento.
    • Test de embarazo negativo en suero y anticoncepción idéntica a la Parte A.
    E.4Principal exclusion criteria
    Part A:
    • Inability to swallow oral medications
    • Any malabsorption condition
    • Current diagnosis of retinal disorders including retinal detachment, retinal pigment epithelial detachment (RPED), serous retinopathy or retinal vein occlusion
    • Previous or concurrent cancer except
    o cervical carcinoma in situ
    o treated basal-cell carcinoma or squamous cell skin cancer
    o localized prostate cancer treated with curative intent and absence of prostate-specific antigen (PSA) relapse or incidental prostate cancer (T1/T2a, Gleason score <= 6 and PSA < 10 ng/mL undergoing active surveillance and treatment-naïve)
    o any other cancer curatively treated > 3 years before the first study drug administration
    • Investigational drug treatment outside of this study during or within 4 weeks before the first study drug administration
    • Ongoing or previous treatment with anti-FGFR directed therapies (e.g. receptor tyrosine kinase inhibitors including rogaratinib or FGFR-specific antibodies)
    • Previous assignment to treatment during this study
    • Severe (CTCAE v.4.03 Grade 3) infections within 4 weeks before the first study drug administration, including but not limited to hospitalization for complication of infection, bacteremia, or severe pneumonia
    • History of autoimmune disease except: a) autoimmune-related hypothyroidism clinically stable on thyroid replacement hormone; b) controlled Type-I diabetes mellitus on a stable dose of insulin regimen
    • History or current condition of uncontrolled cardiovascular disease
    • Systolic/diastolic blood pressure <= 100/60 mmHg and heart rate >= 100/min
    • Renal failure requiring peritoneal dialysis or hemodialysis
    • Current evidence of endocrine alteration of calcium phosphate homeostasis (e.g. parathyroid disorder, history of parathyroidectomy, tumor lysis, tumoral calcinosis, paraneoplastic hypercalcemia)
    • Concomitant therapies that are known to increase serum calcium or phosphate levels and that cannot be discontinued or switched to a different medication before start of study treatment
    • Evidence or history of bleeding diathesis or coagulopathy
    • Any hemorrhage / bleeding event CTCAE v.4.03 >= Grade 3 within 4 weeks before the first study drug administration

    Part B:
    • Inability to swallow oral medications
    • Any malabsorption condition
    • Current diagnosis of retinal disorders including retinal detachment, retinal pigment epithelial detachment (RPED), serous retinopathy or retinal vein occlusion
    • Previous or concurrent cancer except
    o cervical carcinoma in situ
    o treated basal-cell carcinoma or squamous cell skin cancer
    o localized prostate cancer treated with curative intent and absence of prostate-specific antigen (PSA) relapse or incidental prostate cancer (T1/T2a, Gleason score <= 6, and PSA <= 10 ng/mL undergoing active surveillance and treatment-naïve
    o any other cancer curatively treated > 3 years before randomization
    • Ongoing or previous anti-cancer treatment within 4 weeks before randomization
    • Ongoing or previous treatment with anti-FGFR directed therapies (e.g. receptor tyrosine kinase inhibitors including rogaratinib or FGFR-specific antibodies)
    • Previous assignment to treatment during this study
    • Severe (CTCAE v.4.03 Grade 3) infections within 4 weeks before randomization, including but not limited to hospitalization for complication of infection, bacteremia, or severe pneumonia
    • History of autoimmune disease except: a) autoimmune-related hypothyroidism clinically stable on thyroid replacement hormone; b) controlled Type-I diabetes mellitus on a stable dose of insulin regimen
    • History or current condition of uncontrolled cardiovascular disease
    • Systolic/diastolic blood pressure <= 100/60 mmHg and heart rate >= 100/min
    • Renal failure requiring peritoneal dialysis or hemodialysis
    • Current evidence of endocrine alteration of calcium phosphate homeostasis (e.g. parathyroid disorder, history of parathyroidectomy, tumor lysis, tumoral calcinosis, paraneoplastic hypercalcemia)
    • Concomitant therapies that are known to increase serum calcium or phosphate levels and that cannot be discontinued or switched to a different medication before randomization
    • Evidence or history of bleeding diathesis or coagulopathy
    • Any hemorrhage / bleeding event CTCAE v.4.03 >= Grade 3 within 4 weeks before randomization.
    Parte A:
    •Incapacidad de tragar los medicamentos por vía oral
    •Cualquier trastorno de malabsorción
    •Diagnóstico actual de cualquier trastorno retiniano, incluidos desprendimiento de retina, desprendimiento del epitelio pigmentoso de la retina (DEPR), retinopatía serosa u oclusión venosa retiniana
    •Cáncer previo o concomitante excepto
    o carcinoma cervical in situ
    o carcinoma basocelular o carcinoma de células escamosas tratados
    o cáncer de próstata localizado tratado con intención curativa y ausencia conocida de recidiva del antígeno prostático específico (PSA) o cáncer de próstata incidental (T1/T2a, escala de Gleason <= 6 y APS < 10 ng/ml sometidos a vigilancia activa y que no hayan recibido tratamiento previo).
    o cualquier otro cáncer tratado curativamente > 3 años antes de la primera administración del fármaco del estudio
    •Tratamiento en curso o previo con terapias dirigidas contra el FGFR (p. ej., inhibidores de receptores tirosina-cinasa, incluidos rogaratinib o anticuerpos específicos del FGFR)
    •Asignación previa a un tratamiento durante este estudio
    •Infecciones graves (CTCAE v.4.03 grado >= 3) en las 4 semanas previas a la primera administración del fármaco del estudio, que incluyen, entre otras cosas, hospitalización por complicaciones de infección, bacteriemia o neumonía grave
    •Antecedentes de enfermedad autoinmunitaria, excepto: a) hipotiroidismo autoinmunitario clínicamente estable con hormona sustitutiva tiroidea; b) diabetes mellitus de tipo I controlada con una dosis estable de insulina
    •Antecedentes o síntomas actuales de enfermedad cardiovascular no controlada
    •Presión arterial sistólica/diastólica <= 100/60 mmHg y frecuencia cardíaca concurrente ≥ 100/min
    •Insuficiencia renal que requiere diálisis peritoneal o hemodiálisis
    •Signos actuales de alteración endocrina de la homeostasis del fosfato de calcio (p. ej., trastorno paratiroideo, antecedentes de paratiroidectomía, lisis tumoral, calcinosis tumoral, hipercalcemia paraneoplásica)
    •Tratamientos concomitantes de los que se sabe que aumentan los niveles séricos de calcio o fosfato y que no pueden interrumpirse ni sustituirse por un medicamento diferente antes del inicio del tratamiento del estudio
    •Signos o antecedentes de diátesis hemorrágica o coagulopatía
    •Cualquier hemorragia/episodio hemorrágico de grado >= 3 según los CTCAE v.4.03 en las 4 semanas previas a la primera administración del fármaco del estudio

    Parte B:
    •Incapacidad de tragar los medicamentos por vía oral
    •Cualquier trastorno de malabsorción
    •Diagnóstico actual de cualquier trastorno retiniano, incluidos desprendimiento de retina, desprendimiento del epitelio pigmentoso de la retina (DEPR), retinopatía serosa u oclusión venosa retiniana
    •Cáncer previo o concomitante excepto
    o carcinoma cervical in situ
    o carcinoma basocelular o carcinoma de células escamosas tratados
    o cáncer de próstata localizado tratado con intención curativa y ausencia conocida de recidiva del antígeno prostático específico (PSA) o cáncer de próstata incidental (T1/T2a, escala de Gleason <= 6 y APS <= 10 ng/ml sometidos a vigilancia activa y que no hayan recibido tratamiento previo).
    o cualquier otro cáncer tratado curativamente > 3 años antes de la aleatorización
    •Tratamiento en curso o previo con terapias dirigidas contra el FGFR (p. ej., inhibidores de receptores tirosina-cinasa, incluidos rogaratinib o anticuerpos específicos del FGFR)
    •Asignación previa a un tratamiento durante este estudio
    •Infecciones graves (CTCAE v.4.03 grado >= 3) en las 4 semanas previas a la aleatorización, que incluyen, entre otras cosas, hospitalización por complicaciones de infección, bacteriemia o neumonía grave
    •Antecedentes de enfermedad autoinmunitaria, excepto: a) hipotiroidismo autoinmunitario clínicamente estable con hormona sustitutiva tiroidea; b) diabetes mellitus de tipo I controlada con una dosis estable de insulina
    •Antecedentes o síntomas actuales de enfermedad cardiovascular no controlada
    •Presión arterial sistólica/diastólica <= 100/60 mmHg y frecuencia cardíaca concurrente >= 100/min
    •Insuficiencia renal que requiere diálisis peritoneal o hemodiálisis
    •Signos actuales de alteración endocrina de la homeostasis del fosfato de calcio (p. ej., trastorno paratiroideo, antecedentes de paratiroidectomía, lisis tumoral, calcinosis tumoral, hipercalcemia paraneoplásica)
    •Tratamientos concomitantes de los que se sabe que aumentan los niveles séricos de calcio o fosfato y que no pueden interrumpirse ni sustituirse por un medicamento diferente antes de la aleatorización.
    •Signos o antecedentes de diátesis hemorrágica o coagulopatía
    •Cualquier hemorragia/episodio hemorrágico de grado >= 3 según los CTCAE v.4.03 en las 4 semanas previas a la aleatorización.
    E.5 End points
    E.5.1Primary end point(s)
    Part A:
    • The incidence of DLTs used to determine the MTD and/or RP2D
    • The incidence of treatment-emergent adverse events (TEAEs)
    • The incidence of treatment-emergent drug-related TEAEs
    • The incidence of treatment-emergent serious adverse events

    Part B:
    • Treatment efficacy as assessed by progression-free survival, as assessed by RECIST 1.1
    Parte A:
    • La incidencia de DLT se usará para determinar la MDT y/o DRF2
    • La incidencia de los efectos adversos tratamiento-emergente (EATEs)
    • La incidencia de los EATEs tratamiento-emergente relacionados con el fármaco
    • La incidencia de los efectos adversos graves tratamiento-emergente

    Parte B:
    • Eficacia del tratamiento evaluada a través de la supervivencia libre de progresión según RECIST 1.1
    E.5.1.1Timepoint(s) of evaluation of this end point
    Part A:
    • Safety - throughout the study
    • MTD – up to 21 days

    Part B:
    • RECIST - every 9 weeks
    Parte A:
    • Seguridad - durante el estudio
    • MDT – hasta los 21 días

    Parte B:
    • RECIST - cada 9 semanas
    E.5.2Secondary end point(s)
    Part A:
    • Treatment efficacy as assessed by Objective response rate (ORR), as assessed by RECIST 1.1
    • Cmax of rogaratinib
    • AUC(0-8) of rogaratinib

    Part B:
    • The incidence of treatment-emergent adverse events (TEAEs)
    • The incidence of treatment-emergent drug-related TEAEs
    • The incidence of treatment-emergent serious adverse events
    • Change in vital signs, physical finding and clinical laboratory results
    • Treatment efficacy as assessed by Disease control rate (DCR), as assessed by RECIST 1.1
    • Treatment efficacy as assessed by Duration of response (DOR), as assessed by RECIST 1.1
    • Treatment efficacy as assessed by Objective response rate (ORR), as assessed by RECIST 1.1
    • Treatment efficacy as assessed by Overall survival (OS), as assessed by RECIST 1.1
    • Rogaratinib and Atezolizumab pharmacokinetic concentration data
    Parte A:
    • Eficacia del tratamiento evaluada a través de la Ratio Objetiva de Respuesta (ROR), según RECIST 1.1
    • Cmax de rogaratinib
    • AUC(0-8) de rogaratinib

    Part B:
    • La incidencia de los efectos adversos tratamiento-emergente (EATEs)
    • La incidencia de los EATEs tratamiento-emergente relacionados con el fármaco
    • La incidencia de los efectos adversos graves tratamiento-emergente (EATEs)
    • Cambio en los signos vitales, hallazgos físicos y resultados del laboratorio clínico.
    • Eficacia del tratamiento evaluada a través de la Ratio de control de la enfermedad (RCE), según RECIST 1.1
    • Eficacia del tratamiento evaluada a través de la Duración de la respuesta(DR), según RECIST 1.1
    • Eficacia del tratamiento evaluada a través de la Ratio Objetiva de la Respuesta (ROR), según RECIST 1.1
    • Eficacia del tratamiento evaluada a través de la Supervivencia Global, según RECIST 1.1
    • Datos concentrados de farmacocinética de Rogaratinib y Atezolizumab
    E.5.2.1Timepoint(s) of evaluation of this end point
    Part A:
    • RECIST - every 9 weeks
    • PK – up to C5D1

    Part B:
    • Safety - throughout the study
    • PK – up to C5D1
    Parte A:
    • RECIST - cada 9 semanas
    • FC – hasta el C5D1

    Parte B:
    • Seguridad- durante el estudio
    • FC – hasta el C5D1
    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 No
    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 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
    efficacy, PK, safety
    Eficacia, Farmacocinética, seguridad
    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 Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Parte A diseño abierto; Parte B diseño doble ciego
    Part A open design; Part B double blind design
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA21
    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
    Austria
    France
    Germany
    Italy
    Japan
    Korea, Republic of
    Spain
    United States
    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
    LVLS
    Última visita del último sujeto
    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 months10
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months10
    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.1.2.1Number of subjects for this age range: 76
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 114
    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 state4
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 127
    F.4.2.2In the whole clinical trial 190
    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 Decision2018-04-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-04-18
    P. End of Trial
    P.End of Trial StatusTemporarily Halted
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