Kliniska prövningar Nct sida

Summary
EudraCT Number:2021-003669-36
Sponsor's Protocol Code Number:MS100070_0119
National Competent Authority:Spain - AEMPS
Clinical Trial Type:EEA CTA
Trial Status:Ongoing
Date on which this record was first entered in the EudraCT database:2022-05-02
Trial results
A. Protocol Information
A.1Member State ConcernedSpain - AEMPS
A.2EudraCT number2021-003669-36
A.3Full title of the trial
A Phase II, Multicenter, Randomized, Open Label, Parallel-Arm, Umbrella Study of Avelumab (MSB0010718C) in Combination with Other Anti-Tumor Agents as a Maintenance Treatment in Participants with Locally Advanced or Metastatic Urothelial Carcinoma Whose Disease Did Not Progress with First Line Platinum-Containing Chemotherapy
Estudio en paraguas de fase II, multicéntrico, aleatorizado, abierto y con grupos paralelos para evaluar avelumab (MSB0010718C) en combinación con otros antineoplásicos como tratamiento de mantenimiento en participantes con carcinoma urotelial localmente avanzado o metastásico sin progresión con quimioterapia de primera línea con un derivado del platino
A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
A Study of the Safety and Efficacy of Various Combinations of Avelumab as Therapy in Locally Advanced or Metastatic Urothelial Carcinoma
estudio para evaluar la seguridad y la eficacia de distintas combinaciones de avelumab como tratamiento del carcinoma urotelial localmente avanzado o metastásico
A.3.2Name or abbreviated title of the trial where available
JAVELIN Bladder Medley
JAVELIN vejiga Medley
A.4.1Sponsor's protocol code numberMS100070_0119
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 SponsorMerck Healthcare KGaA
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 supportMerck Healthcare KGaA
B.4.2CountryGermany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1Name of organisationMerck Healthcare KGaA
B.5.2Functional name of contact pointCommunication Center
B.5.3 Address:
B.5.3.1Street AddressFrankfurter Str. 250
B.5.3.2Town/ cityDarmstadt
B.5.3.3Post code64293
B.5.3.4CountryGermany
B.5.4Telephone number+34900810 844
B.5.5Fax number+496151722000
B.5.6E-mail[email protected]
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 BAVENCIO
D.2.1.1.2Name of the Marketing Authorisation holderMerck Europe B.V.
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 nameBAVENCIO
D.3.2Product code MSB0010718C
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 INNAvelumab
D.3.9.2Current sponsor codeMSB0010718C
D.3.9.3Other descriptive nameAnti PD-L1
D.3.9.4EV Substance CodeSUB180078
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 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 Yes
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 Trodelvy
D.2.1.1.2Name of the Marketing Authorisation holderGilead Sciences Ireland UC
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 namesacituzumab govitecan
D.3.2Product code IMMU-132
D.3.4Pharmaceutical form Powder for 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 INNSACITUZUMAB GOVITECAN
D.3.9.2Current sponsor codeIMMU-132
D.3.9.4EV Substance CodeSUB191213
D.3.10 Strength
D.3.10.1Concentration unit mg/kg milligram(s)/kilogram
D.3.10.2Concentration typeequal
D.3.10.3Concentration number10
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) 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.IMP: 3
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.3.2Product code M6223
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 INNM6223
D.3.9.2Current sponsor codeM6223
D.3.9.3Other descriptive nameMSB0011570C
D.3.9.4EV Substance CodeSUB260695
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 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 Yes
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 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.3.2Product code NKTR-255
D.3.4Pharmaceutical form Powder for 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 INNAvipendekin pegol
D.3.9.2Current sponsor codeNKTR-255
D.3.10 Strength
D.3.10.1Concentration unit µg/kg microgram(s)/kilogram
D.3.10.2Concentration typeequal
D.3.10.3Concentration number3
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 Yes
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 typeNKTR-255 is a novel immunotherapeutic anticancer drug candidate that consists of rhIL-15 covalently bound to a 40 kDa polyethylene glycol (PEG) moiety.
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
Advanced or metastatic urothelial carcinoma whose disease did not progress with 1L platinum-containing chemotherapy.
Carcinoma urotelial localmente avanzado o metastásico sin progresión con quimioterapia de primera línea con un derivado del platino
E.1.1.1Medical condition in easily understood language
Bladder cancer
Cáncer de vejiga
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 PT
E.1.2Classification code 10005003
E.1.2Term Bladder cancer
E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
E.1.3Condition being studied is a rare disease No
E.2 Objective of the trial
E.2.1Main objective of the trial
-To evaluate PFS of maintenance treatment with avelumab treatment combination regimens compared to maintenance avelumab monotherapy.
-To evaluate the safety and tolerability of avelumab combination regimens.
- Evaluar la SSP del tratamiento de mantenimiento con distintos tratamientos con avelumab y otros antineoplásicos en comparación con la monoterapia de mantenimiento con avelumab.
- Evaluar la seguridad y la tolerabilidad de los distintos tratamientos con avelumab y otros antineoplásicos.
E.2.2Secondary objectives of the trial
-To evaluate OS of maintenance treatment with avelumab combination regimens compared to maintenance avelumab monotherapy followed by subsequent anticancer treatment.
-To evaluate OR of maintenance treatment with avelumab combination regimens compared to maintenance avelumab monotherapy.
-To evaluate DoR of maintenance treatment with avelumab combination regimens compared to maintenance avelumab monotherapy.
-To collect PK concentration data of avelumab, M6223, SG (derived from total SN-38 and unconjugated SN-38), and NKTR-255 to contribute to respective PopPK analyses and exposure-response analyses.
-To characterize the immunogenicity of avelumab administered alone or in combination with SG, NKTR-255 or M6223.
To characterize the immunogenicity of M6223, SG or NKTR-255 in combination with avelumab.
-To evaluate the effect of maintenance treatment with avelumab combination regimens compared to maintenance avelumab monotherapy on disease related physical symptoms.
- Evaluar la SVG del tratamiento de mantenimiento con distintos tratamientos con avelumab y otros antineoplásicos en comparación con la monoterapia de mantenimiento con avelumab seguido de un tratamiento antineoplásico posterior.
- Evaluar la RO del tratamiento de mantenimiento con distintos tratamientos con avelumab y otros antineoplásicos en comparación con la monoterapia de mantenimiento con avelumab.
- Evaluar la duración de la respuesta del tratamiento de mantenimiento con distintos tratamientos con avelumab y otros antineoplásicos en comparación con la monoterapia de mantenimiento con avelumab.
E.2.3Trial contains a sub-study No
E.3Principal inclusion criteria
1.Are ≥ 18 years of age at the time of signing the informed consent.
2.Has
a.Histologically confirmed, unresectable locally advanced or metastatic urothelial carcinoma. Both transitional cell and mixed transitional/non- transitional cell histologies are allowed, but transitional cell carcinoma must be the predominant histology.
b.Documented Stage IIIA/IIIB with N1-N3, or Stage IV disease (per American Joint Committee on Cancer/International Union for Cancer Control Tumor Node Metastasis system, 8th edition) at the start of first line chemotherapy.
3. Prior 1L chemotherapy must have consisted of at least 4 cycles and no more than 6 cycles of gemcitabine + cisplatin and/or gemcitabine + carboplatin. No other chemotherapy regimens are allowed in this study. (Note: Switch between platinum agents due for toxicity to complete a total of - 4 to 6 cycles first line platinum-based chemotherapy is acceptable).
4.The last dose of first line chemotherapy must have been received no less than 4 weeks, and no more than 10 weeks, prior to randomization in the present study.
5.Participants without progressive disease as per RECIST v1.1 guidelines (i.e., with an ongoing CR, PR, or SD) following completion of 4 to 6 cycles of 1L chemotherapy.
Eligibility based on this criterion will be determined by Investigator review of pre chemotherapy and post chemotherapy radiological assessments (CT/MRI scans).
6.All participants must provide archival formalin-fixed paraffin embedded (FFPE) tumor tissues (ideally < 6 months old prior to participant enrollment) from most recent primary or metastatic tumor biopsy or resection obtained prior to treatment with first line chemotherapy but within 24 months prior to randomization, with no intervening systemic anticancer therapy between the time the tissue was obtained and initiation of first line chemotherapy. If an archival FFPE tissue block cannot be provided, 15 or more unstained slides (15 slides minimum) will be acceptable. In addition, fresh baseline tumor samples (collected within 28 days before first dose) may be collected at Screening if archival tissue biopsy is not available. Provision of a tumor biospecimen is required for randomization into the study. The sample must be submitted to the Central Laboratory prior to randomization and deemed acceptable to allow the patient to randomize. Refer to the Central Laboratory Manual for additional specifications.
7.Participants who are willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.
8.Estimated life expectancy of at least 3 months.
9.Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.
10.Adequate bone marrow function, including:
a.Absolute neutrophil count (ANC) ≥ 1,500/mm3 or ≥ 1.5 × 109/L;
b.Platelets ≥ 100,000/mm3 or ≥ 100 × 109/L;
c.Hemoglobin ≥ 9 g/dL (may have been transfused).
11.Adequate renal function, defined as estimated creatinine clearance ≥ 30 mL/min as calculated using the Cockcroft-Gault equation or by 24-hour urine collection for creatinine clearance or according to the local institutional standard method.
12.Adequate liver function, including:
a.Total serum bilirubin ≤ 1.5 × upper limit of normal (ULN);
b.Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN, or, for participants with documented metastatic disease to the liver, AST and ALT levels ≤ 5 × ULN.
13.All sexes allowed. The Investigator confirms that each participant agrees to use appropriate contraception and barriers, if applicable. The contraception, barrier, and pregnancy testing requirements are below.

Please see Protocol for more details about this inclusion criteria.

14.Capable of giving signed informed consent, as indicated in Appendix 2, which includes compliance with the requirements and restrictions listed in the ICF and this protocol.
15.Participants with known human immunodeficiency virus (HIV) infections are eligible if the following criteria are met:
16.Participants with hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infections are eligible if the following criteria are met:

Please see Protocol for more details about inclusion criteria 15 and 16.
1. Tener ≥ 18 años de edad al momento de firmar el consentimiento informado.
2. Tener: a) un carcinoma urotelial metastásico o localmente avanzado no resecable confirmado histológicamente. Se permiten tanto las histologías de células transicionales como las mixtas de células transicionales/no transicionales, pero el carcinoma de células transicionales debe ser la histología predominante.
b) Estadio IIIA/IIIB documentado con N1-N3, o enfermedad en estadio IV (según el sistema de metástasis de nódulo tumoral del Comité Conjunto Estadounidense sobre el Cáncer/Unión Internacional para el Control del Cáncer, 8.ª edición) al comienzo de la quimioterapia de primera línea.
3. La quimioterapia previa de 1 L debe haber consistido en al menos 4 ciclos y no más de 6 ciclos de gemcitabina + cisplatino y/o gemcitabina + carboplatino. No se permiten otros regímenes de quimioterapia en este estudio. (Nota: Cambiar entre agentes de platino debido a la toxicidad para completar un total de - 4 a 6 ciclos de quimioterapia basada en platino de primera línea es aceptable).
4. La última dosis de quimioterapia de primera línea debe haber sido recibida no menos de 4 semanas y no más de 10 semanas antes de la aleatorización en el presente estudio.
5. Participantes sin enfermedad progresiva según las pautas RECIST v1.1 (es decir, con RC, PR o SD en curso) después de completar de 4 a 6 ciclos de quimioterapia de 1 litro.
La elegibilidad basada en este criterio será determinada por la revisión del investigador de las evaluaciones radiológicas previas a la quimioterapia y posteriores a la quimioterapia (tomografías computarizadas/resonancias magnéticas).
6. Todos los participantes deben proporcionar tejidos tumorales fijados en formalina e incluidos en parafina (FFPE) de archivo (idealmente < 6 meses antes de la inscripción del participante) de la biopsia o resección del tumor primario o metastásico más reciente obtenida antes del tratamiento con quimioterapia de primera línea pero dentro de los 24 meses anteriores a la aleatorización, sin tratamiento anticanceroso sistémico intermedio entre el momento en que se obtuvo el tejido y el inicio de la quimioterapia de primera línea. Si no se puede proporcionar un bloque de tejido FFPE de archivo, se aceptarán 15 o más portaobjetos sin teñir (15 portaobjetos como mínimo). Además, las muestras tumorales iniciales frescas (recolectadas dentro de los 28 días anteriores a la primera dosis) se pueden recolectar en la selección si no se dispone de una biopsia de tejido de archivo. Se requiere el suministro de una muestra biológica del tumor para la aleatorización en el estudio. La muestra debe enviarse al Laboratorio Central antes de la aleatorización y considerarse aceptable para permitir que el paciente sea aleatorizado. Consulte el Manual del laboratorio central para obtener especificaciones adicionales.
7. Participantes que estén dispuestos y sean capaces de cumplir con las visitas programadas, los planes de tratamiento, las pruebas de laboratorio y otros procedimientos del estudio.
8. Esperanza de vida estimada de al menos 3 meses.
9. Estado funcional (PS) 0 o 1 del Grupo Oncológico Cooperativo del Este (ECOG).
10. Función adecuada de la médula ósea, incluyendo:
a. Recuento absoluto de neutrófilos (RAN) ≥ 1500/mm3 o ≥ 1,5 × 109/L;
b. Plaquetas ≥ 100.000/mm3 o ≥ 100 × 109/L;
c. Hemoglobina ≥ 9 g / dL (puede haber sido transfundida)
11. Función renal adecuada, definida como un aclaramiento de creatinina estimado ≥ 30 ml/min calculado mediante la ecuación de Cockcroft-Gault o mediante la recolección de orina de 24 horas para el aclaramiento de creatinina o según el método estándar institucional local.
12. Función hepática adecuada, que incluye:
a. Bilirrubina sérica total ≤ 1,5 × límite superior normal (LSN);
b. Aspartato aminotransferasa (AST) y alanina aminotransferasa (ALT) ≤ 2,5 × ULN o, para participantes con enfermedad metastásica documentada en el hígado, niveles de AST y ALT ≤ 5 × ULN.
13. Todos los sexos permitidos. El Investigador confirma que cada participante acepta usar métodos anticonceptivos y barreras apropiados, si corresponde. Los requisitos de anticoncepción, barrera y pruebas de embarazo se encuentran a continuación.
Consulte el Protocolo para obtener más detalles sobre este criterio de inclusión.
14. Capaz de dar consentimiento informado firmado, como se indica en el Apéndice 2, que incluye el cumplimiento de los requisitos y restricciones enumerados en el ICF y este protocolo.
15. Los participantes con infecciones conocidas por el virus de la inmunodeficiencia humana (VIH) son elegibles si se cumplen los siguientes criterios:
16. Los participantes con infecciones por el virus de la hepatitis B (VHB) y/o el virus de la hepatitis C (VHC) son elegibles si se cumplen los siguientes criterios:
Consulte el Protocolo para obtener más detalles sobre los criterios de inclusión 15 y 16.
E.4Principal exclusion criteria
1.Participants with symptomatic central nervous system (CNS) metastases requiring steroids. Participants with diagnosed CNS metastases are eligible if they have completed treatment, recovered from the acute effects of radiation therapy or surgery prior to randomization and off steroid treatment 7 days before randomization, have discontinued corticosteroid treatment for these metastases for at least 4 weeks, and are neurologically stable.
2.Persisting toxicity related to prior therapy NCI-CTCAE v5.0 Grade > 1; however, alopecia, sensory neuropathy Grade ≤ 2 is acceptable, or other Grade ≤ 2 adverse events not constituting a safety risk based on the Investigator’s judgment are acceptable.
3.Diagnosis of any other malignancy unless a complete remission without further recurrence was achieved and the participant was deemed to have been cured with no additional therapy required or anticipated to be required. The exceptions to this criterion may include carcinoma in situ of cervical, colorectal, breast, or all localized prostate cancer that is not being treated. Possible exceptions to this criterion will be discussed on a by participant basis according to medical need.
4.Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent. Participants with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible.
5.Current significant cardiac conduction abnormalities, including corrected QT interval (QTcF, corrected with Fridericia formula) prolongation of > 450 ms on triplicate 12-lead ECG or impaired cardiovascular function.
6.Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication (except for atrial fibrillation that is well controlled with antiarrhythmic medication).
7.Active infection 48 hours before randomization requiring systemic therapy.
8.Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥ 3), any history of anaphylaxis, or uncontrolled asthma (i.e., 3 or more features of asthma symptom control per the Global Initiative for Asthma 2015).
9.Known prior or suspected hypersensitivity to study drugs or any component in their formulations.
10.Diagnosis of prior immunodeficiency or organ transplant requiring immunosuppressive therapy.
11.Pregnant female participants; breastfeeding female participants; and female participants of childbearing potential who are unwilling or unable to use a highly effective method of contraception as outlined in the protocol for the duration of the study and for at least 30 days after the last dose of investigational product.
12.Other severe acute or chronic medical conditions including but not limited to inflammatory bowel disease (colitis, Crohn's disease) or gastrointestinal (GI) perforation within 6 months of enrollment, pneumonitis, and pulmonary fibrosis; psychiatric condition including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormality that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the participants inappropriate for entry into this study.
13.Prior adjuvant or neoadjuvant systemic therapy within 12 months of randomization.
14.Prior immunotherapy with IL-2, IL-15, IFN-α, or an anti PD-1, anti PD-L1, anti PD-L2, anti CD137, or CTLA-4 antibody (including ipilimumab), anti TROP2, any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways, or any of the investigational drugs used in combination with avelumab.
15.Major surgery ≤ 4 weeks or major radiation therapy ≤ 2 weeks prior to randomization. Prior palliative (pain management or hemostatic) radiotherapy is permitted, provided it has been completed at least 48 hours prior to randomization.
16.Current or prior use of immunosuppressive medication within 7 days prior to randomization, EXCEPT the following:
a.Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra-articular injection);
b.Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent;
c.Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).

Please refer to Protocol for the full list.
1. Participantes con metástasis sintomáticas del sistema nervioso central (SNC) que requieren esteroides. Los participantes con metástasis del SNC diagnosticadas son elegibles si han completado el tratamiento, se han recuperado de los efectos agudos de la radioterapia o la cirugía antes de la aleatorización y no han recibido tratamiento con esteroides 7 días antes de la aleatorización, han interrumpido el tratamiento con corticosteroides para estas metástasis durante al menos 4 semanas y están neurológicamente estables
2. Toxicidad persistente relacionada con la terapia previa NCI-CTCAE v5.0 Grado > 1; sin embargo, la alopecia, la neuropatía sensorial de Grado ≤ 2 son aceptables u otros eventos adversos de Grado ≤ 2 que no constituyen un riesgo de seguridad según el juicio del Investigador son aceptables.
3. Diagnóstico de cualquier otra neoplasia maligna a menos que se lograra una remisión completa sin recurrencia adicional y se considerara que el participante se había curado sin necesidad de terapia adicional o que no se anticipara que fuera necesaria. Las excepciones a este criterio pueden incluir carcinoma in situ de cuello uterino, colorrectal, de mama o todo cáncer de próstata localizado que no esté siendo tratado. Las posibles excepciones a este criterio se discutirán por participante según la necesidad médica.
4. Enfermedad autoinmune activa que puede empeorar al recibir un agente inmunoestimulador. Son elegibles los participantes con diabetes tipo I, vitíligo, psoriasis o enfermedad hipotiroidea o hipertiroidea que no requieran tratamiento inmunosupresor.
5. Alteraciones significativas actuales de la conducción cardíaca, incluida la prolongación del intervalo QT corregido (QTcF, corregido con la fórmula de Fridericia) de > 450 ms en un ECG triplicado de 12 derivaciones o una función cardiovascular alterada.
6. Enfermedad cardiovascular clínicamente significativa (es decir, activa): accidente cerebrovascular/accidente cerebrovascular (< 6 meses antes de la inscripción), infarto de miocardio (< 6 meses antes de la inscripción), angina inestable, insuficiencia cardíaca congestiva (clasificación de la New York Heart Association Clase II) , o arritmia cardíaca grave que requiera medicación (excepto la fibrilación auricular que está bien controlada con medicación antiarrítmica).
7. Infección activa 48 horas antes de la aleatorización que requiere tratamiento sistémico.
8. Reacciones de hipersensibilidad grave conocidas a los anticuerpos monoclonales (Grado ≥ 3), cualquier antecedente de anafilaxia o asma no controlada (es decir, 3 o más características de control de los síntomas del asma según la Iniciativa Global para el Asma 2015).
9. Hipersensibilidad previa conocida o sospecha a los fármacos del estudio o a cualquier componente de sus formulaciones.
10. Diagnóstico de inmunodeficiencia previa o trasplante de órgano que requiera terapia inmunosupresora.
11. Mujeres embarazadas; periodo de lactancia; mujeres en edad fértil que no quieran/no puedan usar un método anticonceptivo altamente efectivo como se describe en el protocolo.
12. Otras afecciones médicas agudas o crónicas graves que incluyen, entre otras, enfermedad inflamatoria intestinal (colitis, enfermedad de Crohn) o perforación gastrointestinal (GI) dentro de los 6 meses posteriores a la inscripción, neumonitis y fibrosis pulmonar; condición psiquiátrica que incluye ideación o comportamiento suicida reciente (en el último año) o activo; o anormalidad de laboratorio que puede aumentar el riesgo asociado con la participación en el estudio o la administración del tratamiento del estudio o puede interferir con la interpretación de los resultados del estudio y, a juicio del investigador, haría que los participantes no sean apropiados para participar en este estudio.
14. Inmunoterapia previa con IL-2, IL-15, IFN-α o un anticuerpo anti PD-1, anti PD-L1, anti PD-L2, anti CD137 o CTLA-4 (incluido ipilimumab), anti TROP2, cualquier otro anticuerpo o fármaco dirigido específicamente a la coestimulación de células T o vías de puntos de control inmunitarios, o cualquiera de los fármacos en investigación utilizados en combinación con avelumab.
15. Cirugía mayor ≤ 4 semanas o radioterapia mayor ≤ 2 semanas antes de la aleatorización. Se permite la radioterapia paliativa previa (control del dolor o hemostática), siempre que se haya completado al menos 48 horas antes de la aleatorización.
16. Uso actual o anterior de medicamentos inmunosupresores dentro de los 7 días anteriores a la aleatorización, EXCEPTO lo siguiente:
a.Esteroides intranasales, inhalados, tópicos o inyecciones de esteroides locales (p. ej., inyección intraarticular)
b.Corticoides sistémicos a dosis fisiológicas ≤ 10 mg/día de prednisona o equivalente;
c.Esteroides como premedicación para reacciones de hipersensibilidad (p. ej., premedicación para tomografía computarizada).
Consulte Protocolo para ver la lista completa.
E.5 End points
E.5.1Primary end point(s)
-PFS as defined from date of randomization to PD according to RECIST v1.1 as assessed by Investigator or death, occurring within two scheduled tumor assessments after last evaluable assessment or randomization.
-Occurrence of TEAEs, treatment- related AEs, and AESIs as per Qualitative Toxicity Scale (NCI-CTCAE 5.0).
- SSP definida como el tiempo transcurrido desde la fecha de la aleatorización hasta la progresión del cáncer conforme a los criterios RECIST v1.1 según la evaluación del investigador o la muerte, producida en el plazo de las dos evaluaciones tumorales programadas después de la última evaluación medible o la aleatorización.
- Incidencia de AAST, AA relacionados con el tratamiento y AAEI según la escala de toxicidad cualitativa (NCI-CTCAE 5.0).
E.5.1.1Timepoint(s) of evaluation of this end point
PFS will be evaluated when 56 PFS events per treatment-control comparison have been observed (interim analysis). Then it will be evaluated again when 65 PFS events per treatment-control comparison have been observed (primary analysis).

Occurrence of TEAEs, treatment- related AEs, and AESIs will be monitored during safety DMCs as well as for interim and primary analysis as defined for the PFS endpoint.
La SLP se evaluará cuando se hayan observado 56 eventos de SLP por comparación de tratamiento y control (análisis intermedio). Luego se volverá a evaluar cuando se hayan observado 65 eventos de SLP por comparación de tratamiento y control (análisis primario).

La ocurrencia de EAETs, EA relacionados con el tratamiento y AESI se monitorizará durante los DMC de seguridad, así como también para el análisis intermedio y primario como se define para el criterio de valoración de SLP.
E.5.2Secondary end point(s)
-OS as measured by time from randomization to death.
-OR according to RECIST v1.1 assessed by Investigator.
-DoR according to RECIST v1.1 assessed by Investigator defined as time from first documentation of objective response to PD or death, occurring within two scheduled tumor assessments after last evaluable assessment or randomization.
-Concentration will be listed and descriptively summarized as appropriate. Population PK and exposure-response results will be reported separately in a standalone report, as it may also include data from other studies.
-Immunogenicity of avelumab, SG, NKTR-255 and M6223, as measured by ADA assay.
-Change from baseline score of NCCN FACT FBlSI-18 DRS-P.
- La SVG se define como el tiempo transcurrido desde la aleatorización hasta la muerte.
- RO conforme a los criterios RECIST v1.1 según la evaluación del investigador.
- Duración de la respuesta conforme a los criterios RECIST v1.1 según la evaluación del investigador, definida como el tiempo transcurrido desde la primera documentación de respuesta objetiva hasta la progresión del cáncer o la muerte, producida en el plazo de dos evaluaciones tumorales programadas después de la última evaluación medible o la aleatorización.
- La concentración se indicará y resumirá de forma descriptiva según proceda.
Los resultados de FC poblacional y de exposición-respuesta se notificarán por separado en un informe independiente, ya que se pueden incluir también los datos de otros estudios.
- Inmunogenia de avelumab, SG, NKTR-255 y M6223, medida mediante análisis de AAF.
- Cambio con respecto a la puntuación inicial en la subescala de SFRE de NCCN FACT FBlSI-18.
E.5.2.1Timepoint(s) of evaluation of this end point
OS, OR and DoR will be evaluated when 56 PFS events per treatment control comparison have been observed (interim analysis). Then it will be evaluated again when 65 PFS events per treatment-control comparison have been observed (primary analysis).

PK will be evaluated for safety DMCs as well as for interim and primary
analysis as defined above.

Immunogenicity and change from baseline score of NCCN FACT FBlSI-18 DRS-P will be evaluated for primary analysis.
OS, OR y DoR se evaluarán cuando se hayan observado 56 eventos de PFS por comparación de control de tratamiento (análisis intermedio). Luego se volverá a evaluar cuando se hayan observado 65 eventos de SLP por comparación de tratamiento y control (análisis primario).

PK se evaluará para los DMC de seguridad, así como para el análisis intermedio y primario como se define anteriormente.

La inmunogenicidad y el cambio con respecto a la puntuación inicial de NCCN FACT FBlSI-18 DRS-P se evaluarán para el análisis primario.
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 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 trial4
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 concerned11
E.8.5The trial involves multiple Member States Yes
E.8.5.1Number of sites anticipated in the EEA57
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
Belgium
Canada
Denmark
France
Germany
Greece
Italy
Korea, Republic of
Spain
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
The end of the study is defined as the date of two years after treatment start of the last participant or until all the participants discontinued the study, whichever occurs first.
El final del estudio se define como la fecha de dos años después del inicio del tratamiento del último participante o hasta que todos los participantes interrumpieron el estudio, lo que ocurra primero.
E.8.9 Initial estimate of the duration of the trial
E.8.9.1In the Member State concerned years4
E.8.9.1In the Member State concerned months2
E.8.9.1In the Member State concerned days
E.8.9.2In all countries concerned by the trial years4
E.8.9.2In all countries concerned by the trial months2
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: 252
F.1.3Elderly (>=65 years) No
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 state22
F.4.2 For a multinational trial
F.4.2.1In the EEA 152
F.4.2.2In the whole clinical trial 252
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)
Participants will be offered continued access to the study intervention that they received during the study after study completion, when appropriate, within defined limitations and as described below.
A los participantes se les ofrecerá acceso continuo a la intervención del estudio que recibieron durante el estudio después de la finalización del estudio, cuando corresponda, dentro de las limitaciones definidas y como se describe a continuación.
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 Decision2022-07-14
N.Ethics Committee Opinion of the trial applicationFavourable
N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
N.Date of Ethics Committee Opinion2022-07-07
P. End of Trial
P.End of Trial StatusOngoing