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An Open-Label, Multicenter, Non-Randomized, Dose-Confirmation and Cohort-Expansion Phase 1b Study to Evaluate the Safety, Tolerability, and Anti-Tumor Activity of ATP128, VSV-GP128 and BI 754091, in Patients With Stage IV Colorectal Cancer

Description

Brief Summary
This is a multi-center, non-randomised Phase 1b study to evaluate the safety and tolerability of ATP128 alone or in combination with BI 754091 and of heterologous prime-boost ATP128 + VSV-GP128 in combination with BI 754091. ATP128 is a self-adjuvanted chimeric recombinant protein vaccine being developed in combination with programmed cell death 1 (PD-1) blockade for the treatment of microsatellite stable (MSS) patients not responding to PD-1 blockade. The PD-1 inhibitor being tested with ATP128 is the BI 754091 (Ezabenlimab) compound which belongs to the human immunoglobulin G4 (IgG4) subclass of antibodies. VSV-GP is a recombinant chimeric vesicular stomatitis virus (VSV, Indiana strain Rhabdoviridae) which carries the envelope glycoprotein (GP) of the visceral non neurotropic WE-HPI strain of the Lymphocytic choriomeningitis virus (LCMV, Arenaviridae) instead of the native VSV glycoprotein (G) and is developed as integral part of the prime-boost regimen together with ATP128. The Sponsor plans to enrol 96 patients with histologically or cytologically confirmed stage IV colorectal cancer coming form three different patient populations: - Cohort 1a: 6 patients with stage IV colorectal cancer (CRC) having failed standard of care (SoC) therapies - Cohorts 1b, 2a, 2c: 30 patients with stage IV microsatellite stable/mismatch repair-proficient (MSS/MMRp) CRC being in stable disease (SD) or partial response (PR) after first line of SoC (4-6 months duration at minimum) - Cohorts 2b, 4b: 30 patients with stage IV MSS/MMRp liver-limited disease Patients eligible for this study will be enrolled in one of the 8 cohorts depending on their disease: - Patients in Cohort 1a will receive ATP128 as single agent - Patients in Cohorts 1b, 2a, 2b, 2c will receive ATP128 in combination with BI 754091 - Patients in Cohorts 3, 4a, 4b will receive ATP128 and VSV-GP128 in combination with BI 754091


Phase

N/A

Inclusion and Exclusion Criteria

  • Cohort 1a
  • Ability to comprehend and willingness to provide written informed consent (ICF) for the study.
  • Age ≥ 18 years.
  • Patient with histologically or cytologically confirmed stage IV CRC who has failed standard therapies.
  • Must have received Standard of Care systemic treatment consisting of fluoropyrimidin- oxaliplatin and/or irinotecan based therapy for stage IV CRC disease.
  • 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.
  • Presence of at least one liver lesion amenable to repeated biopsy, ideally not the one being used for measuring.
  • Willingness to undergo two fresh liver biopsies (pre-treatment and on-treatment).
  • Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2.
  • Life expectancy of at least 3 months.
  • 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.
  • Adequate renal, hepatic, and hematologic functions as defined by laboratory parameters ≤ 7 days before study treatment initiation.
  • Absolute neutrophil count (ANC) ≥ 1.5 × 109/L.
  • Absolute lymphocyte count ≥ 0.5 × 109/L.
  • Platelets ≥ 100 × 109/L.
  • Hemoglobin level ≥ 9 g/dL.
  • 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.
  • 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.
  • Alanine aminotransferase/aspartate aminotransferase (ALT/AST) ≤ 2.5 × ULN or ≤ 5 x ULN in patients with hepatic involvement.
  • A female patient is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: Not a woman of childbearing potential (WOCBP) OR A WOCBP who agrees to use highly effective contraceptive methods during the treatment period and for at least 180 days after the last dose of study treatment and refrain from egg donation during this period.
  • 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. Cohorts 1b, 2a, 2c, 3 and 4a:
  • Ability to comprehend and willingness to provide written informed consent (ICF) for the study.
  • Age ≥ 18 years.
  • 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.
  • 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. Note: Patient may have also received prior adjuvant therapy for stage II or III colorectal cancer, however the adjuvant treatment for stage II and III will not be considered as a prior line of therapy in case of relapse more than 6 months after the end of treatment.
  • 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.
  • 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.
  • 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.
  • ECOG performance status 0 to 2.
  • Life expectancy of at least 6 months.
  • 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.
  • Adequate renal, hepatic, thyroid and hematologic functions as defined by laboratory parameters ≤ 7 days before study treatment initiation.
  • Absolute neutrophil count ≥ 1.5 × 109/L.
  • Absolute lymphocyte count ≥ 0.5 × 109/L.
  • Platelets ≥ 100 × 109/L.
  • Hemoglobin level ≥ 9 g/dL.
  • 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).
  • 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.
  • ALT/AST ≤ 2.5 × ULN or ≤ 5 × ULN in patients with hepatic involvement.
  • A female patient is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: Not a woman of childbearing potential (WOCBP) OR A WOCBP who agrees to use highly effective contraceptive methods during the treatment period and for at least 180 days after the last dose of study treatment and refrain from egg donation during this period.
  • 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. Specific to Cohorts 3, 4a, 4b:
  • Patient agrees to follow the instructions and precautions (see Section 4.4.1) related to potential VSV-GP128 shedding. Cohorts 2b and 4b:
  • Ability to comprehend and willingness to provide written informed consent (ICF) for the study.
  • Age ≥ 18 years.
  • Histologically or cytologically confirmed CRC and MSS/MMR proficient status confirmed by PCR/immunohistochemistry or NGS assay at local institution.
  • Radiological evidence (CT/MRI) of liver-limited stage IV CRC.
  • 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. Note: Patient may have also received prior adjuvant therapy for stage II or III colorectal cancer, however the adjuvant treatment for stage II and III will not be considered as a prior line of therapy in case of relapse more than 6 months after the end of treatment.
  • Absence of disease progression following neoadjuvant chemotherapy.
  • 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.
  • ECOG performance status 0 to 2.
  • Life expectancy of at least 12 months.
  • Adequate renal, hepatic, thyroid and hematologic functions as defined by laboratory parameters ≤ 7 days before study treatment initiation.
  • Absolute neutrophil count ≥ 1.5 × 109 /L.
  • Absolute lymphocyte count ≥ 0.5 × 109 /L.
  • Platelets ≥ 100 × 109/L.
  • Hemoglobin level ≥ 9 g/dL.
  • 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).
  • 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.
  • ALT/AST ≤ 2.5 × ULN or ≤ 5 × ULN in patients with hepatic involvement.
  • A female patient is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: Not a woman of childbearing potential (WOCBP) OR A WOCBP who agrees to use highly effective contraceptive methods during the treatment period and for at least 180 days after the last dose of study treatment and refrain from egg donation during this period.
  • 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.

  • All Cohorts:
  • Unwilling or unable to follow protocol requirements or to give informed consent.
  • Gastro-intestinal bowel obstruction (partial or complete).
  • Participation in any other study with an investigational study drug or device requires Medical Monitor approval.
  • Prior monoclonal antibody within 4 weeks or 5 half-lives (whichever is shorter) before administration of study treatment with the exception of bevacizumab (Avastin

Sites

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