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ATP128: una vacuna para tratar el cáncer colorrectal.
Se trata de una vacuna de proteína recombinante quimérica autoadyuvante: consta de un péptido penetrante celular (CPP) para la administración del antígeno, un agonista peptídico TLR para la autoadyuvancia y un dominio antigénico múltiple (Mad). Se ha diseñado utilizando la plataforma tecnológica de vacunas propiedad de Amal, KISIMA.
BI-754091: Inhibidor del punto de control PD-1 (Boehringer Ingelheim)
Para 32 pacientes en total, 3 poblaciones diferentes:
*6 pacientes con CCR en estadio IV en los que han fracasado los tratamientos estándar (recibirán vacunas ATP128 en monoterapia).
*11 pacientes con CCR MSS en estadio IV en situación de enfermedad estable (MS) o respuesta parcial (RP) tras primera línea de SoC (6 meses de duración como mínimo) (recibirán la vacuna más anti PD-1).
*15 pacientes con CCR metastásico limitado al hígado en estadio IV MSS/MMRp (recibirán vacuna y anti PD-1 antes y después de la cirugía hepática)
Criterios clave de inclusión para todas las cohortes:
-Enfermedad medible
-No se permite ningún inhibidor del punto de control previo
-2 semanas de lavado de quimioterapia o terapia dirigida; 4 semanas de lavado de bevacizumab.

Criterios de inclusión

Criterios de inclusión:

Cohorte 1a

1. Ability to comprehend and willingness to provide written informed consent (ICF) for the study.
2. Age ≥ 18 years.
3. Patient with histologically or cytologically confirmed stage IV CRC who has failed standard therapies.
4. Must have received Standard of Care systemic treatment consisting of fluoropyrimidin- oxaliplatin and/or irinotecan based therapy for stage IV CRC disease.
5. Presence of at least 1 measurable lesion by computed tomography or magnetic resonance imaging per RECIST v1.1 as determined by the local site investigator/radiologist assessment.
6. Presence of at least one liver lesion amenable to repeated biopsy, ideally not the one being used for measuring.
7. Willingness to undergo two fresh liver biopsies (pre-treatment and on-treatment).
8. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2.
9. Life expectancy of at least 3 months.
10. Resolution of all toxicities and any toxic effect(s) of the most recent prior therapy to Grade 1 or less (except alopecia). Patients with ≤ Grade 2 neuropathy and Grade ≤ 2 fatigue are an exception and may enroll.
11. Adequate renal, hepatic, and hematologic functions as defined by laboratory parameters ≤ 7 days before study treatment initiation.
12. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L.
13. Absolute lymphocyte count ≥ 0.5 × 109/L.
14. Platelets ≥ 100 × 109/L.
15. Hemoglobin level ≥ 9 g/dL.
16. Measured or calculated creatinine clearance (glomerular filtration rate can also be used in place of creatinine clearance) ≥ 50 mL/min according to the formula of Cockcroft-Gault.
17. Total bilirubin ≤ 1.5 × upper limit of normal (ULN); if total bilirubin is > 1.5 x ULN then direct bilirubin must be ≤ 1.5 × ULN. Patients with known Gilbert's Syndrome may enroll if total bilirubin ≤ 3 × ULN.
18. Alanine aminotransferase/aspartate aminotransferase (ALT/AST) ≤ 2.5 × ULN or ≤ 5 x ULN in patients with hepatic involvement.
19. A female patient is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:

No es una mujer en edad fértil (WOCBP) O Una WOCBP que se compromete a utilizar métodos anticonceptivos altamente eficaces durante el período de tratamiento y durante al menos 180 días después de la última dosis del tratamiento del estudio y abstenerse de la donación de óvulos durante este período.
20. A male patient must agree to use a contraceptive during the treatment period and for at least 180 days after the last dose of study treatment and refrain from donating sperm during this period.

Cohortes 1b, 2a, 2c, 3 y 4a:

1. Ability to comprehend and willingness to provide written informed consent (ICF) for the study.
2. Age ≥ 18 years.
3. Histologically or cytologically confirmed CRC and MSS/MMR proficient status confirmed by polymerase chain reaction (PCR)/ immunohistochemistry or next generation sequencing (NGS) assay at local institution.
4. Must have received a first line of SoC systemic therapy (physician choice) for stage IV disease and completed the therapy. They must have an ongoing partial response (PR) or a stable disease (SD) at the completion of this therapy, completion of therapy as defined by the investigator, however, with a minimum number of 4 months.

Nota: El paciente también puede haber recibido tratamiento adyuvante previo para el cáncer colorrectal en estadio II o III; sin embargo, el tratamiento adyuvante para los estadios II y III no se considerará una línea de terapia previa en caso de recaída más de 6 meses después de finalizar el tratamiento.
5. Presence of at least 1 measurable lesion by computed tomography or magnetic resonance imaging per RECIST v1.1 as determined by the local site investigator/radiologist assessment.
6. Presence of at least one metastatic lesion amenable to paired biopsies (same lesion to be biopsied twice, at baseline and on D36), ideally not the one being used for measuring. However, liver lesions must be prioritized. Non-liver metastatic lesion biopsies may be collected only if the patient has no liver lesion or if the liver lesion is not amenable to paired biopsies (e.g. due to its size or location) or if the liver biopsy represents a risk or an undue inconvenience for the patient health/condition per Investigator judgment. In such cases, where a patient has no lesion amenable to biopsy at all, the paired biopsies may be waived by the Sponsor on a case-by-case basis.
7. Willingness to undergo two biopsies (liver lesion must be prioritized). If the Investigator judges the biopsies to be a risk or an undue inconvenience for the patient health/condition, they may be waived by the Sponsor on a case-by-case basis.
8. ECOG performance status 0 to 2.
9. Life expectancy of at least 6 months.
10. Has resolution of all toxicities and any toxic effect(s) of the most recent prior therapy to Grade 1 or less (except alopecia). Patients with ≤ Grade 2 neuropathy and Grade ≤ 2 fatigue are an exception and may enroll.
11. Adequate renal, hepatic, thyroid and hematologic functions as defined by laboratory parameters ≤ 7 days before study treatment initiation.
12. Absolute neutrophil count ≥ 1.5 × 109/L.
13. Absolute lymphocyte count ≥ 0.5 × 109/L.
14. Platelets ≥ 100 × 109/L.
15. Hemoglobin level ≥ 9 g/dL.
16. Measured or calculated creatinine clearance (glomerular filtration rate can also be used in place of creatinine clearance) ≥ 50 mL/min according to the formula of Cockcroft-Gault (see Appendix 6).
17. Total bilirubin ≤ 1.5 × ULN; if total bilirubin is > 1.5 x ULN then direct bilirubin must be ≤ 1.5 × ULN. Patients with known Gilbert's Syndrome may enroll if total bilirubin ≤ 3 × ULN.
18. ALT/AST ≤ 2.5 × ULN or ≤ 5 × ULN in patients with hepatic involvement.
19. A female patient is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:

No es una mujer en edad fértil (WOCBP) O Una WOCBP que se compromete a utilizar métodos anticonceptivos altamente eficaces durante el período de tratamiento y durante al menos 180 días después de la última dosis del tratamiento del estudio y abstenerse de la donación de óvulos durante este período.
20. A male patient must agree to use a contraceptive during the treatment period and for at least 180 days after the last dose of study treatment and refrain from donating sperm during this period.

Específico para las cohortes 3, 4a, 4b:

1. El paciente acepta seguir las instrucciones y precauciones (véase la sección 4.4.1) relacionadas con la posible excreción de VSV-GP128.

Cohortes 2b y 4b:

1. Ability to comprehend and willingness to provide written informed consent (ICF) for the study.
2. Age ≥ 18 years.
3. Histologically or cytologically confirmed CRC and MSS/MMR proficient status confirmed by PCR/immunohistochemistry or NGS assay at local institution.
4. Radiological evidence (CT/MRI) of liver-limited stage IV CRC.
5. Must have received first line neoadjuvant SoC systemic therapy (physician choice) for stage IV disease. May have received up to 16 weeks of this systemic SoC therapy.

Nota: El paciente también puede haber recibido tratamiento adyuvante previo para el cáncer colorrectal en estadio II o III; sin embargo, el tratamiento adyuvante para los estadios II y III no se considerará una línea de terapia previa en caso de recaída más de 6 meses después de finalizar el tratamiento.
6. Absence of disease progression following neoadjuvant chemotherapy.
7. Eligible for R0 complete liver metastasectomy (in case the primary tumor was already removed) or for R0 complete simultaneous combined resection (resection of both liver metastases and primary tumor in case the primary tumor is still in place) with curative intent.
8. ECOG performance status 0 to 2.
9. Life expectancy of at least 12 months.
10. Adequate renal, hepatic, thyroid and hematologic functions as defined by laboratory parameters ≤ 7 days before study treatment initiation.
11. Absolute neutrophil count ≥ 1.5 × 109 /L.
12. Absolute lymphocyte count ≥ 0.5 × 109 /L.
13. Platelets ≥ 100 × 109/L.
14. Hemoglobin level ≥ 9 g/dL.
15. Measured or calculated creatinine clearance (glomerular filtration rate can also be used in place of creatinine clearance) ≥ 50 mL/min according to the formula of Cockcroft-Gault (see Appendix 6).
16. Total bilirubin ≤ 1.5 × ULN; if total bilirubin is > 1.5 x ULN then direct bilirubin must be ≤ 1.5 × ULN. Patients with known Gilbert's Syndrome may enroll if total bilirubin ≤ 3 × ULN.
17. ALT/AST ≤ 2.5 × ULN or ≤ 5 × ULN in patients with hepatic involvement.
18. A female patient is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:

No es una mujer en edad fértil (WOCBP) O Una WOCBP que se compromete a utilizar métodos anticonceptivos altamente eficaces durante el período de tratamiento y durante al menos 180 días después de la última dosis del tratamiento del estudio y abstenerse de la donación de óvulos durante este período.
19. A male patient must agree to use a contraceptive during the treatment period and for at least 180 days after the last dose of study treatment and refrain from donating sperm during this period.

Criterios de exclusión

Criterios de exclusión:

Todas las cohortes:

1. Unwilling or unable to follow protocol requirements or to give informed consent.
2. Gastro-intestinal bowel obstruction (partial or complete).
3. Participation in any other study with an investigational study drug or device requires Medical Monitor approval.
4. Prior monoclonal antibody within 4 weeks or 5 half-lives (whichever is shorter) before administration of study treatment with the exception of bevacizumab (Avastin®), cetuximab (Erbitux®) and panitumumab (Vectibix®) which may have been received within 15 days from initiation of study treatment. Supportive care (e.g. denosumab) may be used before and during study treatment.
5. Prior therapy with checkpoint inhibitors (anti-programmed death 1 (anti-PD-1), anti-programmed death-ligand 1 (anti-PD-L1), anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4)). Patients must not have received any investigational immunotherapy neither.
6. Prior chemotherapy or targeted small molecule therapy within 15 days from initiation of study treatment.
7. Prior radiotherapy within 2 weeks of enrolment or within 4 weeks of enrolment in the case of radiation to central nervous system (CNS), which requires ≥ 4-week washout. Patients must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis.
8. Major (according the Investigator's judgment) surgery within 12 weeks before enrolment.
9. Known additional malignancy that is progressing or requires active treatment, or history of other malignancy within 2 years of study entry with the exception of cured basal cell or squamous cell carcinoma of the skin, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in situ of the cervix, ductal or lobular carcinoma in situ of the breast, or other non-invasive or indolent malignancy, or cancers from which the patient has been disease-free for > 1 year, after treatment with curative intent.
10. Immunosuppression including the continued use of systemic (at prednisone dose equivalent of > 10 mg) or topical steroids at or near the injection site (excluding inhaled and eye drop-containing corticosteroids) or the use of immunosuppressive agents for any concurrent condition. All other corticosteroids must be discontinued > 4 weeks prior to first study treatment administration.
11. Previous vaccination (either therapeutic and/or prophylactic) against mCRC.
12. Pregnant/nursing women or unwilling to comply with acceptable contraceptive methods during study course.
13. History of autoimmune disease including any active autoimmune disease except vitiligo or childhood asthma.
14. Dermatological disease requiring local immunosuppressive agent.
15. Chronic or concurrent active infectious disease requiring systemic antibodies, antifungal, or antiviral treatment.
16. Known medical history of human immunodeficiency virus (HIV) infection or known medical history of acquired immunodeficiency syndrome (AIDS). HIV testing is not required unless mandated by the local health authority.
17. Has known history of or is positive for hepatitis B (hepatitis B virus surface antigen [HBsAg] reactive) or hepatitis C (HCV RNA).

Nota: Deben realizarse pruebas para determinar la elegibilidad. - El ADN del virus de la hepatitis B debe ser indetectable y el HBsAg negativo en la visita de cribado.- Se permite la prueba de anticuerpos de la hepatitis C con fines de cribado en países en los que el ARN del VHC no forma parte del tratamiento estándar. En estos casos, se excluirá a los pacientes con anticuerpos del VHC positivos.- Los pacientes que hayan recibido tratamiento definitivo contra el VHC están autorizados si el ARN del VHC es indetectable en la visita de cribado.
18. Known active CNS metastasis and/or carcinomatous meningitis.
19. Known cerebral oedema.
20. Live vaccine received within 30 days before initiation of study treatment. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, Bacillus Calmette-Guérin, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed. however, intranasal influenza vaccines (FluMist®) are live attenuated vaccines and are not allowed. COVID-19 vaccines that are not live vaccines are allowed before and during study treatment. However, a COVID-19 vaccination should not occur within ± 2 days of ATP128 study drug and ± 15 days of VSV-GP128 study drug.
21. History of allergy or hypersensitivity to any of the study drugs or study drug components.
22. Any condition in the judgment of the Investigator which makes the patient unsuitable for trial participation.

Cohortes 1b, 2a, 2b, 2c, 3, 4a y 4b:
23. Has received more than 1 line of therapy for stage IV disease (neoadjuvant therapy in Cohort 2b counts as 1 line).
24. History of pneumonitis within the last 5 years.
25. Active interstitial lung disease (ILD)/pneumonitis or a history of ILD/pneumonitis requiring treatment with systemic steroids and/or whose pulse oximetry is less than 92% "on room air".
26. Any of the following cardiac criteria:

* Mean resting corrected QT interval (QTc) > 470 msec.
* Any clinically important abnormalities (as assessed by the Investigator) in rhythm, conduction, or morphology of resting ECGs, e.g., complete left bundle branch block, third degree heart block.
* Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years old, or any concomitant medication known to prolong the QT interval (according to institutional guidelines).
* Ejection fraction (EF) < 55% or the lower limit of normal of the institutional standard will be excluded. Only in cases where the Investigator (or the treating physician or both) suspects cardiac disease with negative effect on the EF will the EF be measured during screening using an appropriate method according to local standards to confirm eligibility (e.g. echocardiogram [ECHO], multi-gated acquisition scan [MUGA]. A historic measurement of EF no older than 6 months prior to first study treatment administration can be accepted provided that there is clinical evidence that the EF value has not worsened since this measurement in the opinion of the Investigator or the treating physician or both.

Específico para las cohortes 3, 4a, 4b:

1. Previous treatment with VSV-based agents.
2. Use of Tamoxifen within one month prior the initiation of study treatment.