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ATP128：治疗结直肠癌的疫苗。
它是一种自佐剂嵌合重组蛋白疫苗：由用于递送抗原的细胞穿透肽（CPP）、用于自佐剂的TLR肽激动剂和多抗原结构域（Mad）组成。它是利用阿迈勒的专利疫苗技术平台 KISIMA 设计的。
BI-754091：PD-1 检查点抑制剂（勃林格殷格翰公司）
共有 32 名患者，3 种不同的人群：
*6 名标准疗法 (SoC) 治疗失败的 IV 期 CRC 患者（将接受 ATP128 疫苗单药治疗）
*11 例 IV 期 MSS CRC 患者在接受一线 SoC（至少持续 6 个月）治疗后病情稳定 (SD) 或部分应答 (PR)（将接受疫苗和抗 PD-1 治疗）
*15 例 IV 期 MSS/MMRp 肝转移性 CRC 患者（将在肝脏手术前后接受疫苗和抗 PD-1 治疗）
所有队列的主要纳入标准：
-可测量的疾病
-以前未使用过检查点抑制剂
-停用化疗或靶向治疗 2 周；停用贝伐珠单抗 4 周。

纳入标准

纳入标准

组群 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:

非育龄妇女（WOCBP）或同意在治疗期间和最后一次治疗后至少 180 天内使用高效避孕方法并在此期间不捐献卵子的育龄妇女。
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.

组别 1b、2a、2c、3 和 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.

注：患者可能也曾接受过 II 期或 III 期结直肠癌的辅助治疗，但如果在治疗结束后 6 个月以上复发，II 期和 III 期的辅助治疗将不被视为前一种治疗方法。
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:

非育龄妇女（WOCBP）或同意在治疗期间和最后一次治疗后至少 180 天内使用高效避孕方法并在此期间不捐献卵子的育龄妇女。
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.

针对第 3、第 4a 和第 4b 组：

1.患者同意遵守与 VSV-GP128 潜在脱落相关的说明和预防措施（见第 4.4.1 节）。

第 2b 和第 4b 组：

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.

注：患者可能也曾接受过 II 期或 III 期结直肠癌的辅助治疗，但如果在治疗结束后 6 个月以上复发，II 期和 III 期的辅助治疗将不被视为前一种治疗方法。
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:

非育龄妇女（WOCBP）或同意在治疗期间和最后一次治疗后至少 180 天内使用高效避孕方法并在此期间不捐献卵子的育龄妇女。
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.

排除标准

排除标准：

所有组群：

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).

注：必须进行检测才能确定是否符合资格。- 筛查时乙型肝炎病毒 DNA 必须检测不到，HBsAg 必须阴性。在这些情况下，HCV 抗体阳性患者将被排除在外。 - 如果在筛查就诊时检测不到 HCV RNA，则允许对 HCV 患者进行明确治疗。
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.

组别 1b、2a、2b、2c、3、4a 和 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.

针对第 3、第 4a 和第 4b 组：

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