| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Neuroendocrine neoplasms (Grade 3 well-differentiated neuroendocrine tumours (NET) or poorly differentiated neuroendocrine carcinomas (NEC)) |
| Neoplasias neuroendocrinas (tumores neuroendocrinos (TNE) Grado 3 bien diferenciados o carcinomas neuroendocrinos (CNE) Grado 3 mal diferenciados) |
|
| E.1.1.1 | Medical condition in easily understood language |
| neuroendocrine tumours |
| tumores neuroendocrinos |
|
| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10057270 |
| E.1.2 | Term | Neuroendocrine carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10052399 |
| E.1.2 | Term | Neuroendocrine tumour |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | 10062476 |
| E.1.2 | Term | Neuroendocrine tumor |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 evaluate the efficacy of 177Lu-DOTATATE plus nivolumab in Grade 3 neuroendocrine tumours or neuroendocrine carcinoma. |
| Evaluar la eficacia de 177Lu-DOTATATO más nivolumab en tumores neuroendocrinos ó carcinomas neuroendocrinos de Grado 3. |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the efficacy of 177Lu-DOTATATE plus nivolumab in Grade 3 neuroendocrine tumours or neuroendocrine carcinoma by additional measures.
- To evaluate impact on survival of 177Lu-DOTATATE plus nivolumab and to evaluate safety of the combination. |
- Evaluar la eficacia de 177Lu-DOTATATO más nivolumab en tumores neuroendocrinos ó carcinomas neuroendocrinos de Grado 3 mediante parámetros adicionales.
- Evaluar el impacto sobre la supervivencia de 177Lu-DOTATATO más nivolumab y evaluar la seguridad de la combinación. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Patients having voluntarily signed and dated an and dated an IRB/IEC-approved written informed consent form in accordance with regulatory and institutional guidelines before the performance of any protocol-related procedures.
2) Patients with advanced/metastatic, histologically confirmed, well-differentiated grade Grade 3 NET or poorly-differentiated NEC of the pancreas, gastrointestinal tract and unknown primary site at diagnosis or after progression to one systemic treatment. Patients will be enrolled in two cohorts based on the therapy of their aforementioned cancer:
Cohort 1: Patients with no previous chemotherapy.
Cohort 2: Patients who have received one line of chemotherapy.
3) Age > or =18 years.
4) Patients must have measurable disease based on RECIST v.1.1 meeting the following criteria:
a) Lesions that have had external beam radiotherapy or loco-regional therapies such as radiofrequency ablation or liver embolization must show evidence of progressive disease based on RECIST v.1.1 to be deemed a target lesion.
b) Patients in cohort 2 must show evidence of disease progression by radiologic image techniques according to RECIST v.1.1 within 3 months prior to signing informed consent.
5) Confirmed presence of somatostatin receptors on tumour lesions based on positive PET-Gallium (SomaKit) imaging within 8 weeks prior to enrolment in the study. At least one lesion should have an uptake of 64-Gallium higher than the normal liver according to investigator judgement.
6) Karnofsky Performance Score > or = 60 and Eastern Cooperative Oncology Group (ECOG) performance status (PS) < or = 2.
7) Life expectancy of > or = 6 months.
8) Adequate normal organ and marrow function as defined below:
a) Haemoglobin concentration > or = 8.0 g/dL (5.0 mmol/L).
b) WBC > or = 2x109/L (2000/mm3).
c) Platelets > or =75x109/L (75x103/mm3).
9) Adequate renal function defined as serum creatinine < or =150 μmol/L or 1.7 mg/dL, or a creatinine clearance or measured glomerular filtration rate (using plasma clearance methods) of > or = 50 mL/min.
10) Adequate hepatic function defined as total bilirubin < or =3 x ULN and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < or = 2.5 x ULN (< or = 5 x ULN if liver metastases are present).
11) Serum albumin > or = 3.0 g/dL (or serum albumin < 3.0 g/dL if prothrombin time is within the normal range).
12) Female patients must either be of non-reproductive potential (i.e., post-menopausal by history: > or =60 years old and no menses for > or =1 year without an alternative medical cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry. Both women and men must agree to use a medically acceptable method of contraception throughout the treatment period and for six months after discontinuation of treatment. Acceptable methods of contraception include intrauterine device, oral contraceptive, subdermal implant and/or double barrier.
13) Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow-up.
14) Recovery to Grade < or = 1 from any adverse event (AE) derived from previous treatment (excluding alopecia and/or cutaneous toxicity and/or asthenia). |
1) Los pacientes deberán firmar y fechar voluntariamente un consentimiento informado por escrito aprobado por el Comité Ético correspondiente según los requisitos regulatorios antes de que se inicie ningún procedimiento relacionado con el estudio.
2) Pacientes con TNE Grado 3 bien diferenciado ó CNE Grado 3 mal diferenciado avanzado/metastásico de páncreas, tracto gastrointestinal o de origen desconocido en el momento del diagnóstico o tras progresión a un tratamiento sistémico previo. Los pacientes serán asignados a alguna de las dos cohortes según el tratamiento que previamente hubiera recibido para el tumor:
Cohorte 1: Pacientes sin quimioterapia previa.
Cohorte 2: Pacientes que ya han recibido una línea de quimioterapia.
3) Edad mayor ó igual a 18 años.
4) Los pacientes deben tener enfermedad medible basada en los siguientes criterios RECIST v.1.1:
a) Las lesiones que hayan sido sometidas a radioterapia externa o a tratamientos loco-regionales como ablación por radiofrecuencia o embolización hepática, deberán mostrar evidencia de enfermedad progresiva por RECIST 1.1 para ser consideradas como lesión diana.
b) Los pacientes en la cohorte 2 deben mostrar evidencia de progresión por técnicas de imagen radiológicas según RECIST v.1.1. en los 3 meses previos a la firma del consentimiento informado.
5) Presencia confirmada de receptores de somatostatina en las lesiones del tumor mediante un PET-Galio (SomaKit) positive dentro de las 8 semanas previas a la inclusión en el estudio. Al menos una lesión debe presentar una captación de 64Galio mayor que la del tejido hepático normal según criterio del investigador.
6) Puntuación Karnofsky > o = 60 y estado functional ECOG < o = 2.
7) Expectativa de vida de 6 meses o más.
8) Adecuada función de la médula ósea definida como:
a) Concentración de hemoglobina > o = 8.0 g/dL (5.0 mmol/L).
b) Leucocitos > o = 2x109/L (2000/mm3).
c) Plaquetas > o =75x109/L (75x103/mm3).
9) Adecuada función renal definida como una creatinina sérica < o =150 μmol/L ó 1.7 mg/dL, ó un aclaramiento de creatinina ó tasa de filtración glomerular (empleando métodos de aclaramiento plasmático) de > o = 50 mL/min.
10) Adecuada función hepática definida como una bilirrubina total < o =3 x LSN, AST y ALT < o = 2.5 x LSN (< o = 5 x LSN en presencia de metástasis hepáticas).
11) Albúmina sérica ≥ 3.0 g/dL (ó < 3.0 g/dL si el tiempo de protrombina está dentro del rango normal).
12) Las pacientes deben o bien haber perdido capacidad reproductora (por ejemplo, mujeres postmenopáusicas por historia clínica: > o =60 años y sin reglas durante > o = 1 año sin causa médica alternativa que pudiera explicarlas, o historia de histerectomía, o de ligadura tubárica bilateral, o historia de ooforectomía bilateral), o deben tener una prueba de embarazo negativo al entrar en el estudio. Tanto varones como mujeres deben comprometerse a emplear un método anticonceptivo aceptable altamente eficaz a lo largo del estudio y hasta seis meses después de haber terminado el tratamiento. Métodos anticonceptivos aceptables incluyen dispositivo intrauterino, anticoncepción hormonal oral, implante subdérmico y/o doble barrera.
13) El paciente desea y es capaz de cumplir con los procedimientos del protocolo durante la duración del estudio incluyendo los tratamientos prescritos y las visitas y exámenes fijados incluyendo el seguimiento.
14) Recuperación a Grado < o = 1 tras cualquier efecto adverso derivado de tratamiento previo (excluyendo alopecia, toxicidad cutánea y/o astenia). |
|
| E.4 | Principal exclusion criteria |
1) Lung neuroendocrine tumours, carcinomas or carcinoids.
2) Treatment with >30 mg Octreotide LAR at 3-4 weeks intervals within 12 weeks prior to enrolment in the study.
3) Peptide receptor radionuclide therapy (PRRT) at any time prior to enrolment in the study.
4) Targeted surgery, radiotherapy (external beam), chemotherapy, embolization, interferons, mTOR-inhibitors or other investigational therapy within 12 weeks prior to enrolment in the study. In Cohort 2, chemotherapy should be administered at least 4 weeks prior to first dose of the treatment.
5) Prior treatment with anti-PDL-1/anti-PD-1 or anti-CTL-4 therapy.
6) Known brain metastases, unless these metastases have been treated and stabilized for at least 24 weeks prior to enrolment in the study. Patients with a history of brain metastases must have a head CT with contrast to document stable disease prior to enrolment in the study.
7) Uncontrolled congestive heart failure (NYHA II-IV).
8) Uncontrolled diabetes mellitus as defined by a fasting blood glucose >2 ULN.
9) Any patient receiving treatment with short-acting Octreotide, which cannot be interrupted for 24 h before and 24 h after the administration of 177Lu-DOTATATE , or any patient receiving treatment with Octreotide LAR, which cannot be interrupted for at least 6 weeks before the administration of 177Lu-DOTATATE, unless the tumour uptake observed by Somakit imaging during continued Octreotide treatment is at least as high as normal liver uptake observed by planar imaging.
10) Acute or chronic hepatitis B (e.g., Hepatitis B surface antigen reactive), hepatitis C (e.g., HCV RNA [qualitative] is detected) or known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
11) Active, known, or suspected autoimmune disease within the past 2 years. NOTE: Patients with Type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) and Grave’s disease not requiring systemic treatment within the past 2 years are not excluded.
12) Patients with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of start of study treatment. NOTE: Inhaled or topical steroids, and systemic steroid doses > 10 mg daily prednisone equivalent for adrenal replacement are permitted in the absence of active autoimmune disease.
13) Active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis).
14) History of allogeneic organ transplant.
15) Known hypersensitivity to nivolumab, 177Lu-DOTATATE or its excipients.
16) Patients with any other significant medical, psychiatric, or surgical condition, currently uncontrolled by treatment, which may interfere with completion of the study. Patients must have recovered from the effects of major surgery or significant traumatic injury at least 14 days before starting treatment.
17) Prior external beam radiation therapy to more than 25% of the bone marrow.
18) Urinary incontinence.
19) Subjects with previous malignancies (except non-melanoma skin cancers, and the following in situ cancers: bladder, gastric, esophageal, colon, endometrial, cervical/dysplasia, melanoma, or breast) unless a complete remission was achieved at least 5 years prior to study entry AND no additional therapy is required during the study period
20) Prisoners or patients who are compulsory detained. |
1) Tumores neuroendocrinos, carcinomas o carcinoides de pulmón.
2) Tratamiento con >30 mg Octreótido LAR a intervalo de 3-4 semanas dentro de las 12 semanas previas a entrar en este estudio.
3) Terapia radioisotópica de receptor peptídico (peptide receptor radionuclide therapy:PRRT) en cualquier momento previo a la inclusión en el estudio.
4) Terapia dirigida, radioterapia externa, quimioterapia, embolización, interferones, inhibidores mTOR o cualquier otro tratamiento experimental en las 12 semanas previas a la inclusión en el estudio. En la cohorte 2 la quimioterapia debería ser administrada al menos 4 semanas antes de la primera dosis del tratamiento.
5) Tratamiento previo con fármacos anti-PDL1/anti-PD1 o anti-CTL4.
6) Metástasis cerebrales conocidas, salvo que estas metástasis hayan sido tratadas y estén estables durante al menos 24 semanas antes de la inclusión en el estudio. A los pacientes con antecedentes de metástasis cerebrales debe hacérseles una TAC craneal con contraste para documentar la enfermedad estable antes de entrar en el estudio.
7) Insuficiencia cardiaca congestiva no controlada (NYHA II-IV).
8) Diabetes mellitus no controlada definida como un nivel de glucosa en ayunas >2 LSN.
9) Cualquier paciente que esté recibiendo tratamiento con octreótido de acción corta y que no pueda interrumpirse durante 24 horas antes y otras 24 horas después de la administración de177Lu-DOTATATO, o cualquier paciente que reciba tratamiento con octreótido LAR en el que no pueda interrumpirse durante al menos 6 semanas antes de la administración de 177Lu-DOTATATO, salvo que la captación del tumor observada por SomaKit durante el tratamiento con octreótido sea al menos tan alta como la captación hepática normal observada por imagen planar.
10) Hepatitis B crónica o aguda (ej., AgHBs detectado), hepatitis C (ej., ARN-VHC cualitativo presente) o historia de infección por VIH (anticuerpos frente a VIH1/2).
11) Enfermedad autoimmune activa, conocida o sospechada en los últimos 2 años. NOTA: Pacientes con diabetes mellitus tipo I, hipotiroidismo residual por tiroiditis autoimmune que solo necesiten reemplazo hormonal, alteraciones cutáneas (como vitíligo, psoriasis o alopecia) y enfermedad de Graves que no necesite tratamiento sistémico en los últimos dos años, no serán excluidos.
12) Pacientes con cualquier trastorno que requiera tratamiento sistémico con corticoides (> 10 mg de equivalente de prednisona diarios) u otras medicaciones inmunosupresoras dentro de los 14 días previos al inicio del tratamiento del estudio. NOTA: los esteroides tópicos o inhalados, y las dosis sistémicas menores de 10 mg de equivalente de prednisona para reemplazo adrenal son permitidas en ausencia de enfermedad autoinmune activa.
13) Enfermedad inflamatoria intestinal activa o documentada con anterioridad (Enfermedad de Crohn, colitis ulcerosa).
14) Trasplante alogénico previo.
15) Hipersensibilidad conocida a nivolumab, 177Lu-DOTATATE o a sus excipientes.
16) Pacientes con cualquier otra condición médica, psiquiátrica o quirúrgica significativa, actualmente no controlada con el tratamiento recibido, que pueda interferir con la realización del estudio. Los pacientes deben haberse recuperado de los efectos de una cirugía mayor o de un traumatismo importante durante al menos 14 días antes de empezar el tratamiento del estudio.
17) Radioterapia externa previa sobre más del 25% de la médula ósea.
18) Incontinencia urinaria.
19) Sujetos con cáncer previo (salvo cáncer cutáneo no melanoma, y los siguientes tumores in situ: vejiga, estómago, esófago, colon, endometrio, cérvix, melanoma ó mama) salvo que se haya logrado una remisión completa al menos 5 años antes de entrar en el estudio, y que no se necesite tratamiento adicional para ninguno de estos tumores durante el estudio.
20) Prisioneros o pacientes que están detenidos contra su voluntad. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Overall Response Rate (ORR) by RECIST v.1.1 at 15 weeks of treatment (+/-1 week). |
| Tasa de Respuesta Total (ORR en inglés) mediante RECIST v.1.1 a las 15 semanas de tratamiento (+/-1 semana). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| treatment week 15 |
| semana 15 de tratamiento |
|
| E.5.2 | Secondary end point(s) |
• Overall Response Rate (ORR) at 31 weeks of treatment (+/- 1 week).
• Overall Response Rate (ORR) by Choi and modified RECIST for immune based therapeutics (iRECIST).
• Progression-free Survival (PFS).
• Number and Grade of Adverse Events by CTCAE v.5 criteria.
• Overall Survival (OS). |
• ORR a las 31 semanas de tratamiento (+/- 1 semana).
• ORR por criterios de Choi y por iRECIST.
• Supervivencia libre de progresión (PFS).
• Número e intensidad de los Efectos Adversos según los criterios del CTCAE v.5.
• Supervivencia Global (OS). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Treatment week 31
• Through the study |
• Semana 31 de tratamiento
• A lo largo 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 | Yes |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| 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 | 1 |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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-study date (clinical cut-off) is defined as 60 days after the last patient’s treatment discontinuation (last patient-last visit), or 12 months after accrual of the last evaluable patient, whichever occurs first. |
| La fecha final del studio (punto de corte clínico) es definida como 60 días después de la detención del tratamiento del último paciente incluido (última visita del último paciente, LPLV), o 12 meses tras la inclusión del último sujeto evaluable, lo que antes ocurra. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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