| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced, relapsed Clear Cell Renal Cell Carcinoma |
| Carcinoma de Células Renales variante de Células Claras avanzado/recidivante |
|
| E.1.1.1 | Medical condition in easily understood language |
| Renal Cell Carcinoma |
| Carcinoma de Células Renales |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10038396 |
| E.1.2 | Term | Renal carcinoma recurrent |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To characterize the safety and tolerability of DFF332 as a single agent and in combination with Everolimus, or Spartalizumab plus Taminadenant in patients with advanced ccRCC and HIF (hypoxia-inducible factor) stabilizing mutations. |
| Caracterizar la seguridad y tolerabilidad de DFF332 en monoterapia y en combinación con everolimus o spartalizumab más taminadenant en pacientes con CCRcc avanzado y mutaciones estabilizantes en HIF (factor inducible por hipoxia). |
|
| E.2.2 | Secondary objectives of the trial |
To assess the preliminary anti-tumor activity of DFF332 as a single agent and in combination with Everolimus, or Spartalizumab plus Taminadenant.
To characterize the PK of DFF332 as a single agent and in combination with Everolimus, or Spartalizumab plus Taminadenant. |
Evaluar la actividad antitumoral preliminar de DFF332 en monoterapia y en combinación con everolimus, o spartalizumab más taminadenant.
Caracterizar la PK de DFF332 en monoterapia y en combinación con everolimus, o spartalizumab más taminadenant. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
For dose escalation and expansion arms on SA and combos, with the exception of Arm1B:
1. Male and female ≥ 18 years of age
2. Histologically confirmed and documented clear cell renal cell carcinoma (ccRCC). Disease must be measureable as determined by RECIST v1.1.
3. Patient with unresectable, locally advanced or metastatic ccRCC with documented disease progression following therapy with PD-1/L1 checkpoint inhibitor and a VEGF targeted therapy as monotherapy or in combination.
Escalation: No restriction on the number of prior treatments
Expansion: Up to 3 prior lines of treatment for advanced/metastatic disease
4. ECOG performance status ≤ 1
For basket arm (Arm 1B):
1. Male and female of age ≥ 12 years of age.
2. Histologically confirmed and documented malignancies in the context of the following cancer predisposing syndromes/disorders or harboring somatic mutations on one of these genes:
• Malignancies with VHL mutations (e.g. Von Hippel-Lindau disease)
• Malignancies with FH mutations (e.g. Hereditary leiomyomatosis and renal cell carcinoma)
• Malignancies with mutations in SDHD, SDHAF2, SDHC, SDHB, SDHA (e.g. Hereditary paraganglioma and pheochromocytoma syndrome)
• Malignancies with EPAS1/HIF2A mutations
• Malignancies with ELOC/TCEB1 mutations
3. Patients must have either metastatic disease or locally advanced disease that is unresectable or that patients be unfit for resection or other treatment modalities. Patients must have received prior standard therapy appropriate for their tumor type and stage of disease, and have no available therapies of proven clinical benefit; or in the opinion of the investigator, would be unlikely to tolerate or derive clinically meaningful benefit from appropriate standard of care therapy.
4. For patients age ≥ 16 years: ECOG performance status ≤ 1
For patients age ≥ 12 and < 16 years: Lansky performance status ≥ 70 |
En los grupos de escalada y expansión de dosis en monoterapia y en combinación, a excepción del grupo 1B:
1. Pacientes de ambos sexos >=18 años de edad.
2. Carcinoma de células renales variante de células claras (CCRcc) confirmado histológicamente y documentado. La enfermedad debe medirse según lo determinado por RECIST v1.1.
3. Paciente con CCRcc irresecable, localmente avanzado o metastásico con progresión de la enfermedad documentada después del tratamiento con el inhibidor de puntos de control inmunitario PD-1/L1 y un tratamiento dirigido a VEGF en monoterapia o en combinación.
Escalada: no hay ninguna restricción en el número de tratamientos previos.
Expansión: hasta 3 líneas previas de tratamiento para la enfermedad avanzada/metastásica.
4. Estado funcional del ECOG <=1.
En el grupo cesta (grupo 1B):
1. Pacientes de ambos sexos >=12 años de edad.
2. Tumores malignos histológicamente confirmados y documentados en el contexto de los siguientes trastornos/síndromes que predisponen al cáncer o con mutaciones somáticas en uno de estos genes:
•Tumores malignos con mutaciones en VHL (p. ej., enfermedad de Von Hippel-Lindau).
•Tumores malignos con mutaciones en FH (p. ej., leiomiomatosis hereditaria y carcinoma de células renales).
•Tumores malignos con mutaciones en SDHD, SDHAF2, SDHC, SDHB, SDHA (p. ej., paraganglioma hereditario y síndrome de feocromocitoma).
•Tumores malignos con mutaciones en EPAS1/HIF2A.
• Tumores malignos con mutaciones en ELOC/TCEB1.
3. Los pacientes deben tener enfermedad metastásica o enfermedad localmente avanzada e irresecable o no ser aptos para la resección ni otras modalidades de tratamiento. Los pacientes deben haber recibido tratamiento estándar previo adecuado para su tipo de tumor y estadio de la enfermedad, y no tener tratamientos disponibles de beneficio clínico probado; o que, según el investigador, sería poco probable que toleraran u obtuvieran un beneficio clínicamente significativo del tratamiento estándar adecuado.
4. Para pacientes >=16 años de edad: Estado funcional del ECOG <=1.
Para pacientes >=12 y <16 años de edad: estado funcional de Lansky >=70. |
|
| E.4 | Principal exclusion criteria |
1. Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but limited to surgery, radiation and/or corticosteroids. Patients with treated symptomatic brain metastases should be neurologically stable for 4 weeks post-treatment prior to study entry and at doses ≤ 10 mg per day prednisone or equivalent for at least 2 weeks before administration of any study treatment.
2. History of seizure disorder and/or extrapyramidal symptoms.
3. Known additional malignancy that is progressing or requires active treatment within the past 3 year(s). Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer or other tumors that will not affect life expectancy.
4. Patients having out of range lab values during screening and before the first dose of study treatment. Out of range lab values are defined as:
5. Absolute neutrophil count (ANC) <1.0 × 109/L
6. Platelets <75 × 109/L
7. Hemoglobin (Hgb) < 10g/dL
8. Serum creatinine > 1.5 × ULN or creatinine clearance < 60mL/min using Cockcroft-Gault formula
9. Total bilirubin > 1.5 × ULN , except for patients with Gilbert’s syndrome > 3.0 × ULN or direct bilirubin > 1.5 × ULN
10. Aspartate aminotransferase (AST) > 3 × ULN
11. Alanine aminotransferase (ALT) > 3 × ULN
12. Serum electrolytes ≥ grade 2 despite adequate supplementation.
13. Treatment with any of the following anti-cancer therapies prior to the first dose of study treatment within the stated timeframes:
14. ≤ 4 weeks for radiation therapy or limited field radiation for palliation within ≤ 2 weeks prior to the first dose of study treatment.
15. ≤ 4 weeks or ≤ 5 half-lives (whichever is shorter) for chemotherapy or biological therapy (including monoclonal antibodies) or continuous or intermittent small molecule therapeutics or any other investigational agent.
16. ≤ 6 weeks for cytotoxic agents with major delayed toxicities, such as nitrosourea and mitomycin C.
17. ≤ 4 weeks for immuno-oncologic therapy, such as CTLA-4, PD-1, or PD-L1 antagonists.
18. Patients who have undergone major surgery ≤ 4 weeks prior to first dose of study treatment or who have not recovered for the surgical procedure.
19. 5. Patient previously treated with a HIF2alpha inhibitor. |
1. Metástasis cerebrales sintomáticas o no controladas que requieren tratamiento concurrente, incluyendo cirugía, radiación o corticosteroides. Los pacientes que hayan recibido tratamiento para metástasis cerebrales sintomáticas deberán ser neurológicamente estables durante las 4 semanas posteriores al tratamiento antes de entrar en el estudio y a dosis <=10 mg al día de prednisona o equivalente durante al menos las 2 semanas anteriores a la administración de cualquier tratamiento del estudio.
2. Antecedentes de crisis comicial o síntomas extrapiramidales.
3. Tumor maligno adicional que haya progresado o requerido tratamiento activo durante los tres últimos años. Las excepciones incluyen carcinoma basocelular de la piel, carcinoma de células escamosas de la piel que se hayan sometido a un tratamiento potencialmente curativo, cáncer de cuello uterino in situ u otros tumores que no afectarán a la esperanza de vida.
4. Pacientes que presenten valores analíticos fuera de rango durante la selección y antes de la primera dosis del tratamiento del estudio. Los valores de laboratorio fuera de rango se definen como:
5. Recuento absoluto de neutrófilos (RAN) <1,0 × 109/l.
6. Plaquetas <75 × 109/l.
7. Hemoglobina (Hgb) < 10 g/dl.
8. Creatinina sérica >1,5 × LSN o aclaramiento de creatinina <60 ml/min según la fórmula de Cockcroft-Gault.
9. Bilirrubina total >1,5 × LSN, excepto en los pacientes con síndrome de Gilbert >3,0 x LSN o bilirrubina directa >1,5 × LSN.
10. Aspartato aminotransferasa (AST) >3 × LSN.
11. Alanino aminotransferasa (ALT) >3× LSN.
12. Electrolitos en suero de grado >=2 a pesar de una suplementación adecuada.
13. Tratamiento con alguna de las siguientes terapias antineoplásicas antes de la primera dosis del tratamiento del estudio durante los periodos indicados:
14. <=4 semanas de radioterapia o radiación de campo limitado de carácter paliativo durante <=2 semanas antes de la primera dosis del tratamiento del estudio.
15. <=4 semanas o <=5 vidas medias (el menor de estos valores) en el caso de quimioterapia o terapia biológica (que incluya anticuerpos monoclonales), tratamiento con moléculas pequeñas continuo o intermitente o cualquier otro fármaco en investigación.
16. <=6 semanas en el caso de fármacos citotóxicos con toxicidades retardadas importantes, como nitrosourea y mitomicina C.
17. <=4 semanas en el caso de terapia inmunooncológica, como antagonistas de CTLA-4, PD-1 o PD-L1.
18. Pacientes que se hayan sometido a una cirugía mayor <=4 semanas antes de la primera dosis del tratamiento del estudio o que no se hayan recuperado de dicho procedimiento quirúrgico.
19. Paciente tratado anteriormente con un inhibidor de HIF2alfa. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Incidence and severity of adverse events (AEs) and serious adverse events (SAEs), including changes in laboratory parameters, vital signs and electrocardiograms (ECGs)
• Tolerability: Dose interruptions, reductions and dose intensity for both dose escalation and expansion
• Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 (28 days) for DFF332 as a single agent and in combinations |
•Incidencia e intensidad de los acontecimientos adversos (AA) y acontecimientos adversos graves (AAG), incluidos los cambios en los parámetros de laboratorio, las constantes vitales y los electrocardiogramas (ECG).
•Tolerabilidad: Interrupciones, reducciones e intensidad de la dosis en la escalada y la expansión de dosis.
•Incidencia de toxicidades limitantes de dosis (DLT) de DFF332 en monoterapia y en combinación en el ciclo 1 (28 días). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At protocol define timepoints until End of study |
| En el protocolo se definen las etapas hasta el final del estudio. |
|
| E.5.2 | Secondary end point(s) |
• Overall Response Rate (ORR), Best Overall Response (BOR), Progression Free Survival (PFS) (for RD only), Duration of Response (DOR) (for RD only), Disease Control Rate (DCR) per RECIST v1.1
• Plasma concentration of DFF332 and Taminadenant, whole blood concentration of Everolimus, serum concentration of Spartalizumab, and derived PK parameters for each analyte |
•Tasa de respuesta global (ORR), mejor respuesta global (BOR), supervivencia libre de progresión (PFS) (solo para DR), duración de respuesta (DOR) (solo para DR) y tasa de control de la enfermedad (DCR) según RECIST v1.1.
• Concentración en plasma de DFF332 y taminadenant, concentración en sangre de everolimus, concentración en suero de spartalizumab y parámetros PK derivados de cada analito. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At protocol define timepoints until End of study |
| En el protocolo se definen las etapas hasta el final del estudio. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Tolerability |
| Tolerabilidad |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
|
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 5 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Japan |
| Singapore |
| Taiwan |
| United States |
| Belgium |
| France |
| Italy |
| Spain |
| Czechia |
|
| E.8.7 | Trial 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
|
| The end of the study will be when 80% of the patients at the RD have completed the follow-up for disease progression or discontinued the study for any reason, and all patients have completed treatment and the 30 day safety follow-up period. |
| El fin de estudio ocurrirá cuando el 80% de los pacientes en la DR hayan completado el seguimiento para progresión de enfermedad o hayan interrumpido el estudio por cualquier motivo, y todos los pacientes hayan completado el tratamiento y el periodo de seguimiento de seguridad de 30 días. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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