EO4010 in Previously Treated Metastatic Colorectal Carcinoma

This is an open-label, multicenter, FIH, phase 1/2 trial to assess safety, tolerability, immunogenicity, and preliminary efficacy of the microbial-derived therapeutic vaccine EO4010 in combination with nivolumab and/or bevacizumab for treatment of patients with unresectable, previously treated, metastatic colorectal cancer

• EO4010 (Drug), also known as Nivolumab, Bevacizumab: Sequential assignment

Primary outcomes

• Safety and Tolerability of EO4010 in Combination With Nivolumab and/or Bevacizumab [24 months]: Incidences of treatment-emergent Serious Adverse Events (SAEs) using the National Cancer Institute-Common Terminology Criteria for AEs (NCI-CTCAE) v5.0.

Secondary outcomes

• Percentage of Patients With Shown Immunogenicity Againts EO4010 (All Peptides) [Week 5 after first dose of EO4010]: Immunogenicity response of EO4010 (all peptides) for the three tests together: IFN-gamma ElISpot \[IVS\], IFN-gamma ElISpot \[NS\], multimer staining \[NS\]. A patient is defined as positive if the result of one of the three tests (IFN-gamma ElISpot \[IVS\], IFN-gamma ElISpot \[NS\], multimer staining \[NS\]) shows a positive response
• Overall Response Rate [24 months]: Defined as the percentage of patients who have a partial or complete response following Response Evaluation Criteria in Solid Tumors criteria
• Disease Control Rate [24 months]: Defined as the percentage of patients who have achieved complete response, partial response or stable disease following Response Evaluation Criteria in Solid Tumors criteria
• Time to Response [24 months]: Defined as the time interval from first study treatment administration to partial or complete response following Response Evaluation Criteria in Solid Tumors criteria
• Duration of Response [24 months]: Defined as the time interval from first study treatment administration to disease progression or death in patients who achieve complete or partial response following Response Evaluation Criteria in Solid Tumors criteria
• Progression Free Survival [24 months]: Defined as the time interval from the date of first study treatment administration to the date of progression following Response Evaluation Criteria in Solid Tumors criteria
• Overall Survival to the Date of Death Due to Any Cause. Patients Alive Will be Censored at the Date of the Last Documented Follow-up [24 months]: Defined as the time interval from the date of first study treatment administration to the date of death due to any cause. Patients alive will be censored at the date of the last documented follow-up

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Provided written informed consent
2. Histological confirmation of advanced non-resectable colorectal adenocarcinoma
3. Patients with metastatic colorectal cancer who have been previously treated with, or are not considered candidates for
4. Progression during or within 3 months following the latest administration of standard therapies
5. Age ≥ 18 years old
6. Human leukocyte antigen (HLA)-A2 positive
7. ECOG performance status 0 or 1
8. Measurable disease according to Response Evaluation Criteria in Solid Tumors criteria (RECIST)
9. Patients with a life expectancy of at least 3 months
10. Female patients of childbearing potential must have a negative serum pregnancy test
11. Patients following recommendations for contraception
12. Patients willing and able to comply with the study procedures

Exclusion Criteria:

1. Patients treated with dexamethasone > 2 mg/day or equivalent within 14 days before randomization, unless required to treat an adverse event
2. Patients treated with radiotherapy within 12 weeks, and cytotoxic chemotherapy therapy within 28 days
3. Patients with persistent Grade ≥ 2 toxicities (according to NCI-CTCAE v5.0). Toxicities must be resolved for at least 2 weeks to Grade 1 or less
4. Patients who have received any prior treatment with compounds targeting PD1, PDL1, CTLA-4, or similar compounds
5. Patients who have previously received trifluridine/tipiracil (TAS-102) or regorafenib
6. Patients with prior exposure to EO2401, EO2040, or EO4010, i.e. therapeutic vaccine compounds including all or some components of EO4010
7. Patients with the following abnormal laboratory values:

   1. Lymphocyte count decreased, grade 2 (lymphocytes <800 - 500/mm3; <0.8 - 0.5 x 109/L), or worse grade
   2. Hemoglobin < 10 g/dL (6.2 mmol/L); transfusion is acceptable to reach the value
   3. Absolute neutrophil count decrease (<1.5 x109/L)
   4. Platelet count decrease (< 75 ×109/L)
   5. Total bilirubin > 1.5 ×upper limit of normal
   6. Alanine aminotransferase (ALT) > 3 ×ULN; if disease metastatic to the liver > 5 xULN
   7. Aspartate aminotransferase (AST) > 3 ×ULN; if disease metastatic to the liver > 5 xULN
   8. Serum creatinine increase (> 1.5 ×ULN)
   9. Abnormal thyroid function per local laboratory levels
8. Other malignancy or prior malignancy with a disease-free interval of less than 3 years prior to ICF signing; except those treated with surgical intervention and an expected low likelihood of recurrence
9. Patients with clinically significant active infection, cardiac disease, significant medical or psychiatric disease/condition
10. Patients with suspected autoimmune or active autoimmune disorder or known history of an autoimmune neurologic condition (e.g., Guillain-Barré syndrome)
11. Patients with a history of solid organ transplantation or allogeneic hematopoietic stem cell transplantation
12. Patients with a history or known presence of tuberculosis
13. Pregnant and breastfeeding patients
14. Patients with a history or presence of human immunodeficiency virus (HIV) and/or active hepatitis B virus (HBV)/hepatitis C virus (HCV)
15. Uncontrolled central nervous system (CNS) metastasis
16. Patients who have received live or attenuated vaccine therapy used for prevention of infectious diseases including seasonal (influenza) vaccinations within 4 weeks of the first dose of study drug
17. Patients with a history of hypersensitivity to any excipient, or active substance, present in the pharmaceutical forms of applicable study treatments
18. Patients under treatment with immunostimulatory or immunosuppressive medications
19. Patients who have received treatment with any other investigational agent, or participation in another clinical trial

Participant flow

Outcome results

• Safety and Tolerability of EO4010 in Combination With Nivolumab and/or Bevacizumab (Primary), Count of participants, Participants: Overall (All Cohorts) 6; Cohort 1a (Overall) 0; Cohort 1a (Monotherapy) 0; Cohort 1a (Combo) 0; Cohorts 1b-1c-1d 0; Cohort 2 6; Cohort 3a 0
• Percentage of Patients With Shown Immunogenicity Againts EO4010 (All Peptides) (Secondary), Count of participants, Participants: Overall (All Cohorts) 17; Cohort 1a (Overall) 2; Cohorts 1b-1c-1d 0; Cohort 2 10; Cohort 3a 5
• Overall Response Rate (Secondary), Count of participants, Participants: Overall (All Cohorts) 1; Cohort 1a (Overall) 0; Cohorts 1b-1c-1d 0; Cohort 2 1; Cohort 3a 0
• Disease Control Rate (Secondary), Count of participants, Participants: Overall (All Cohorts) 6; Cohort 1a (Overall) 0; Cohorts 1b-1c-1d 0; Cohort 2 3; Cohort 3a 3
• Time to Response (Secondary), Median, months: Overall (All Cohorts) 10.5 (10.5 to 10.5); Cohort 1a (Overall) ; Cohorts 1b-1c-1d ; Cohort 2 10.5 (10.5 to 10.5); Cohort 3a
• Duration of Response (Secondary), Median, months: Overall (All Cohorts) 8.7 (NA to NA); Cohort 1a (Overall) ; Cohorts 1b-1c-1d ; Cohort 2 8.7 (NA to NA); Cohort 3a
• Progression Free Survival (Secondary), Median, months: Overall (All Cohorts) 1.9 (1.8 to 2.2); Cohort 1a (Overall) 1.8 (1.8 to NA); Cohorts 1b-1c-1d ; Cohort 2 1.8 (1.8 to 2.2); Cohort 3a 2.4 (1.8 to NA)
• Overall Survival to the Date of Death Due to Any Cause. Patients Alive Will be Censored at the Date of the Last Documented Follow-up (Secondary), Median, months: Overall (All Cohorts) 11.4 (9.7 to NA); Cohort 1a (Overall) NA (10.1 to NA); Cohorts 1b-1c-1d ; Cohort 2 11.2 (4.7 to NA); Cohort 3a NA (9.7 to NA)

Adverse events

Time frame: 24 months

Serious adverse events by term

Other adverse events by term

• Study Protocol (PDF, 2024-01-15)
• Statistical Analysis Plan (PDF, 2025-06-30)

• Jan Fagerberg, Study director, Enterome