| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced Metastatic Pancreatic Cancer |
| Cáncer de páncreas metastásico Avanzado |
|
| E.1.1.1 | Medical condition in easily understood language |
| Pancreatic Cancer |
| Cáncer de páncreas |
|
| 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 | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10033605 |
| E.1.2 | Term | Pancreatic cancer metastatic |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare the efficacy of AM0010 in combination with FOLFOX versus FOLFOX alone in patients with metastatic pancreatic cancer as measured by OS. |
| Comparar la eficacia de AM0010 en combinación con FOLFOX frente a FOLFOX en monoterapia en pacientes con cáncer de páncreas metastásico determinada mediante la SG. |
|
| E.2.2 | Secondary objectives of the trial |
To compare the efficacy of AM0010 in combination with FOLFOX versus FOLFOX alone as measured by:
• PFS
• ORR by RECIST v.1.1
To compare the safety and tolerability of AM0010 in combination with FOLFOX versus FOLFOX alone. |
Comparar la eficacia de AM0010 en combinación con FOLFOX frente a FOLFOX en monoterapia determinada mediante:
•SLP
•TRG conforme a los criterios RECIST v.1.1
Comparar la seguridad y la tolerabilidad de AM0010 en combinación con FOLFOX frente a FOLFOX en monoterapia. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. The presence of metastatic pancreatic adenocarcinoma plus 1 of the following:
a. Histological diagnosis of pancreatic adenocarcinoma confirmed pathologically,
OR
b. Pathologist confirmed histological/cytological diagnosis of adenocarcinoma consistent with pancreas origin in conjunction with either:
i. The presence of a mass in the pancreas, OR
ii. A history of resected pancreatic adenocarcinoma.
2. Measureable disease per RECIST v.1.1
3. Patient must have documented tumor progression during or following a gemcitabine containing regimen to treat metastatic disease.
4. Only one prior gemcitabine containing therapy and no other prior therapies for metastatic disease.
5. Diagnosis of tumor progression (by CT or MRI scan or clinical progression) on first -line therapy within 28 days prior to randomization.
6. Male or non-pregnant, non-lactating female, ≥ 18 years or age.
a. If a female patient is of child-bearing potential, as evidenced by regular menstrual periods, she must have a negative serum pregnancy test (β-hCG) documented prior to the first administration of study drug.
b. If sexually active, the patient must agree to use contraception considered adequate and appropriate by the Investigator during the period of administration of study drugs. In addition, male and female patients must utilize contraception after the end of the treatment as recommended in the individual drugs comprising FOLFOX product’s Summary of Product Characteristics or Prescribing Information provided in the study manual and the AM0010 Investigator’s Brochure.
7. Provide signed written informed consent.
8. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0
–1; two observers will be required to assess ECOG. If discrepant, the one with the worst assessment will be considered to be true.
9. Patient must have completed prior chemotherapy at least 2 weeks (washout period) prior to randomization and recovered from toxicity to Grade 1 or baseline.
10. Patients must not have received previous radiation therapy, surgery, or investigational therapy for the treatment of advanced metastatic disease. Patients having received cytotoxic doses of gemcitabine or any other chemotherapy in the adjuvant setting are not eligible for this study.
11. Willingness and ability to comply with study requirements.
12. Patient has adequate organ function by the following laboratory assessments at baseline (obtained ≤21 days prior to randomization):
Hematologic
* Platelets ≥100×109/L
* Hemoglobin ≥9.0 g/dL
* Absolute Neutrophil Count (ANC) ≥1.5×109/L
* Patient has acceptable coagulation values obtained ≤21 days prior to randomization as demonstrated by prothrombin time (PT) and partial thromboplastin time (PTT) ≤1.5 ULN (if on Coumadin, patient must be changed to LMW heparin (LMWH) or on Factor Xa anticoagulant with a half
-life of less than 24 hours.
Hepatic
* AST/ALT ≤ 3 × ULN (if liver metastases are present, ≤ 5 × ULN)
* Alkaline phosphatase ≤ 2.0 × ULN (if liver metastases are present, ≤ 5 × ULN)
* Total bilirubin ≤ 1.5 × ULN
* Albumin ≥ 3.0
Renal
* Serum creatinine < 2.0 or calculated creatinine clearance ≥ 60 mL/min for patients with serum creatinine levels above the institutional normal value. If using creatinine clearance, actual body weight should be used for calculating creatinine clearance (e.g., using Modification of Diet in Renal Disease (MDRD) formula, (Levey, Coresh et al. 2006). For patients with a body mass index (BMI) > 30 kg/m2, lean body weight should be used instead.
13. Patient must have a life expectancy of ≥ 4 months in the opinion of the
Investigator
14 No peripheral neuropathy (< Grade 2)
15. No known history of dihydropyrimidine dehydrogenase deficiency (DPD) |
1.La presencia de adenocarcinoma pancreático metastásico más uno de los siguientes:
a.Diagnóstico histológico de adenocarcinoma pancreático confirmado mediante examen anatomopatológico O
b.Diagnóstico histológico/citológico de adenocarcinoma confirmado por el anatomopatólogo compatible con origen pancreático, junto con:
i.La presencia de una masa tumoral en el páncreas O
ii.Antecedentes de adenocarcinoma pancreático resecado.
2.Enfermedad mensurable conforme a los criterios RECIST v.1.1.
3.El paciente debe presentar progresión el tumor documentada durante o después de una pauta de tratamiento con gemcitabina para tratar la metástasis, según la exploración de TC o RM.
4.Un único tratamiento previo con una pauta con gemcitabina y ningún otro tratamiento para la metástasis.
5.Diagnóstico de progresión del tumor (progresión clínica o según TC o RM) durante el tratamiento de primera línea en los 28 días previos a la aleatorización.
6.Varones o mujeres no embarazadas ni en período de lactancia, de ≥18 años de edad.
a.Si una paciente tiene capacidad de procrear, manifestada por menstruaciones regulares, deberá aportar una prueba de embarazo en suero (β-hCG) negativa documentada antes de la primera administración de los fármacos del estudio.
b.Si es sexualmente activa, la paciente deberá comprometerse a utilizar un método anticonceptivo considerado adecuado por el investigador durante el período de administración del fármaco del estudio. Además, los pacientes de ambos sexos deben utilizar métodos anticonceptivos después del final del tratamiento según se recomienda en el resumen de las características del producto o en la ficha técnica proporcionada en el manual del estudio.
7.Firma del consentimiento informado por escrito.
8.Estado funcional (EF) del Eastern Cooperative Oncology Group (ECOG) de 0 o 1; serán necesarios dos observadores para evaluar el ECOG. En caso de discrepancia, se considerará válida la peor evaluación.
9.El paciente deberá haber completado la quimioterapia anterior al menos 2 semanas (período de reposo farmacológico) antes de la aleatorización y haberse recuperado de la toxicidad hasta un grado 1 o hasta el estado basal.
10.Los pacientes no pueden haber recibido previamente radioterapia ni tratamientos experimentales para el tratamiento de la metástasis avanzada. Los pacientes que hayan recibido dosis citotóxicas de gemcitabina o de cualquier otro quimioterápico como adyuvante no son elegibles para este estudio.
11.Disposición y capacidad para cumplir los requisitos del estudio.
12.Pacientes con función orgánica adecuada conforme a los parámetros sanguíneos siguientes en el momento basal (obtenidos ≤21 días antes de la aleatorización):
Hematológicos
*Plaquetas ≥100 x 109/l
*Hemoglobina ≥9,0 g/dl
*Recuento absoluto de neutrófilos (RAN) ≥1,5 x 109/l
*El paciente presenta valores de coagulación aceptables determinados ≤21 días antes de la aleatorización, según demuestra el tiempo de protrombina (TP) y el tiempo de tromboplastina parcial (TTP) ≤1,5 LSN (si el pacientes recibe Coumadin, se le cambiará a heparina BPM (HBPM) o factor II oral o un inhibidor de Xa con una semivida inferior a 24 horas).
Hepáticos
*AST/ALT ≤3 x LSN (en caso de metástasis hepáticas, ≤5 x LSN)
*Fosfatasa alcalina ≤2,0 x LSN (en caso de metástasis hepáticas, ≤5 x LSN)
*Bilirrubina total ≤1,5 x LSN
*Albúmina ≥ 3,0
Renales
*Creatinina sérica <2,0 o aclaramiento de creatinina calculado ≥60 ml/min en pacientes con concentraciones séricas de creatinina por encima o por debajo del valor normal del centro. Si se utiliza el aclaramiento de creatinina, se utilizará el peso corporal real para calcular el aclaramiento de creatinina (p. ej., con la fórmula de MDRD). En pacientes con un índice de masa corporal (IMC) >30 kg/m2, se utilizará en su lugar el peso corporal magro.
13.El paciente debe tener una esperanza de vida de ≥4 meses, en opinión del investigador.
14.Ausencia de neuropatías periféricas (< grado 2).
15.Ausencia de antecedentes de deficiencia en dihidropirimidina deshidrogenasa (DPD). |
|
| E.4 | Principal exclusion criteria |
1. Diagnosis of pancreatic islet neoplasm, acinar cell carcinoma, non-adenocarcinoma (i.e., lymphoma, sarcoma), adenocarcinoma originating from the biliary tree, or cystadenocarcinoma.
2. Patient has experienced a decrease in ECOG PS between screening visit and within 72 hours prior to randomization.
3. Patient on Coumadin and not willing to change to LMW H or oral Factor II or Xa inhibitor with half -life of less than 24 hours.
4. Patient has received prior treatment with AM0010 or fluoropyrimidine/platinum containing regimen.
5. History of prior malignancy, except for adequately treated in situ cancer or basal cell or squamous cell skin cancer or other cancers (e.g., breast, prostate) for which the patient has been disease free for at least 3 years.
6. Any serious medical condition, laboratory abnormality, psychiatric illness, or comorbidity that, in the judgment of the investigator, would make the patient inappropriate for the study.
7. Serious systemic fungal, bacterial, viral, or other infection that is not controlled or requires intravenous antibiotics.
8. Patients who are intolerant to gemcitabine containing regimens are not eligible.
9. History of positivity (regardless of immune status) for human immunodeficiency virus (HIV).
10. Known history of chronic active or active viral hepatitis A, B, or C infection
11. Clinically significant bleeding within two weeks prior to randomization (e.g., gastrointestinal (GI) bleeding, intracranial hemorrhage).
12. Pregnant or lactating women.
13. Patients with a history of immune mediated neurological disorders such as multiple sclerosis, Guillain-Barré, or inflammatory CNS/PNS disorders.
14. Myocardial infarction within the last 6 months prior to randomization, symptomatic congestive heart failure (New York Heart Association Classification > Class II, (Appendix E), unstable angina, or unstable cardiac arrhythmia requiring medication.
15. Clinically significant ascites defined as requiring ≥ 1 paracentesis every 2 weeks.
16. Major surgery, defined as any surgical procedure that involves general anesthesia and a significant incision (i.e., larger than what is required for placement of central venous access, percutaneous feeding tube, or biopsy), within 28 days prior to randomization or anticipated surgery during the study period.
17. Prior history of receiving immune modulators including, but not limited to, anti-CTLA4, anti-PD1, anti-PD-L1 18.
18. Peripheral neuropathy (> Grade 1)
19. Known history of dihydropyrimidine dehydrogenase deficiency (DPD) |
1.Diagnóstico de neoplasia de los islotes pancreáticos, carcinoma de células acinares, carcinoma no adenoide (es decir, linfoma, sarcoma), adenocarcinoma originado en el árbol biliar o carcinoma quístico adenoide.
2.El paciente ha experimentado una disminución el EF del ECOG entre la visita basal y las 72 horas previas a la aleatorización.
3.Pacientes en tratamiento con Coumadin que no estén dispuestos a cambiar a HBPM, factor II oral o un inhibidor de Xa con una semivida inferior a 24 horas.
4.Pacientes que hayan recibido tratamiento previo con AM0010 o una pauta con fluoropirimidina/platino.
5.Pacientes que hayan mostrado intolerancia a una pauta con gemcitabina.
6.Antecedentes de neoplasias malignas previas, excepto en el caso de cánceres localizados tratados correctamente o cáncer basocelular o espinocelular de piel u otros cánceres (p. ej., de mama o de próstata), de las que el paciente lleve recuperado al menos 3 años.
7.Cualquier afección médica grave, anomalía analítica, enfermedad psiquiátrica o enfermedad concomitante que, en opinión del investigador, desaconseje la participación del paciente en el estudio.
8.Infección sistémica grave micótica, bacteriana, vírica o de otro tipo que no esté controlada o que precise antibióticos intravenosos.
9.Antecedentes de positividad (con independencia de la situación inmunitaria) para el virus de la inmunodeficiencia humana (VIH).
10.Antecedentes conocidos, infección activa crónica o enfermedad activa por los virus de la hepatitis A, B o C.
11.Hemorragia de importancia clínica en las dos semanas previas a la aleatorización (p. ej., hemorragia digestiva (GI), hemorragia intracraneal).
12.Mujeres embarazadas o en período de lactancia.
13.Pacientes con antecedentes de trastornos neurológicos de mecanismo inmunitario, como la esclerosis múltiple, el síndrome de Guillain-Barré o trastornos inflamatorios del SNC/SNP.
14.Infarto de miocardio en los últimos 6 meses antes de la aleatorización, insuficiencia cardíaca congestiva sintomática (>clase II de la New York Heart Association Classification), angina inestable o arritmia cardíaca inestable que precise medicación.
15.Ascitis de importancia clínica (que precisa ≥1 paracentesis cada 2 semanas).
16.Cirugía mayor, definida como cualquier procedimientos quirúrgico que precise anestesia general y una incisión importante (esto es, más grande que la necesaria para la colocación de una vía venosa central, una sonda de alimentación percutánea o una biopsia) en los 28 días previos a la aleatorización o una incisión quirúrgica programada que coincide con el período de estudio.
17.Antecedentes de tratamiento con inmunomoduladores como anti-CTLA4, anti-PD1 o anti-PD-L1, entre otros.
18.Neuropatía periférica (> grado 1).
19.Antecedentes conocidos de deficiencia en dihidropirimidina deshidrogenasa (DPD). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of this study is OS is defined as the time from date of randomization to death due to any cause. |
| La variable principal es la SG definida como el tiempo entre la fecha de la randomización y la muerte por cualquier causa. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Throughout entire study duration |
| Durante toda la duración del estudio |
|
| E.5.2 | Secondary end point(s) |
The secondary endpoints of the study include:
• PFS is defined as the time from date of randomization to the earlier of first documentation of definitive disease progression or death due to any cause
• ORR is defined as the proportion of patients who achieve a CR or PR as assessed by RECIST v.1.1 |
Los criterios de valoración secundarios del estudio incluyen:
• SLP se define como el tiempo desde la fecha de randomización a lo que ocurra ante la primera documentación de la progresión definitiva de la enfermedad o la muerte por cualquier causa
• TRG se define como la proporción de pacientes que alcanzan un RP o RC según lo evaluado por RECIST v.1.1 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Throughout entire study duration |
| Durante toda la duración 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 | Yes |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| 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 | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 17 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 65 |
| 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 |
| Australia |
| Austria |
| Belgium |
| Canada |
| France |
| Germany |
| Ireland |
| Italy |
| Korea, Republic of |
| Poland |
| Spain |
| Taiwan |
| United Kingdom |
| United States |
|
| E.8.7 | Trial 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
|
| After occurence of 393 deaths. |
| Despues de que ocurran 393 muertes. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| 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 | 3 |
| 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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