| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with unresectable, previously treated locally advanced or metastatic colorectal carcinoma. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with locally advanced or metastatic colorectal cancer who have been previsouly treated. |
|
| 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 | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061451 |
| E.1.2 | Term | Colorectal cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10052358 |
| E.1.2 | Term | Colorectal cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10010036 |
| E.1.2 | Term | Colorectal carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10052362 |
| E.1.2 | Term | Metastatic colorectal cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of this trial is to evaluate safety and tolerability of EO4010 in combination with nivolumab in patients with unresectable, previously treated locally advanced or metastatic colorectal carcinoma. |
|
| E.2.2 | Secondary objectives of the trial |
1. immunogenicity in relation to T cells of EO2317, EO2318, OMP10, OMP11, OMP12, and UCP2 that compose EO4010; T cell cross-reactivity with the human TAAs FOXM1, BIRC5/survivin, UBE2C, CDC20, and KIF2C will also be evaluated,
2. objective response rate (ORR), disease control rate (DCR), time to response (TTR), and duration of response (DOR),
3. progression-free survival (PFS) and PFS rate at 4 months, and
4. overall survival (OS).
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Provided written informed consent prior to any study-related procedures (initial consent is for screening part #1 procedures, and a second consent is for screening part #2 procedures; see Protocol Section 7.2 and Section 7.3, respectively). Patients must be able to understand and be willing to sign a written informed consent.
2. Histological confirmation of advanced non-resectable colorectal adenocarcinoma (confirmation at initial diagnosis is sufficient) which is mismatch repair proficient and microsatellite stable (according to local site standard testing procedures), i.e. patients with mismatch repair deficient or microsatellite instability-high metastatic disease cannot be recruited to this trial.
3. Patients with metastatic colorectal cancer who have been previously treated with, or are not considered candidates for (according to the judgement of the recruiting site physician; e.g., due to progression or unacceptable toxicity on the type of treatment, or type of treatment not indicated in the specific patient due to his/her disease characteristics - when appropriate a collaborative discussion between the recruiting physician and the Medical Monitor should be held to keep the study population consistent), therapies including fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-VEGF agents, and anti-EGFR agents.
4. Progression during or within 3 months following the latest administration of standard therapies as outlined in inclusion criterion #3.
5. Age ≥ 18 years old.
6. Human leukocyte antigen (HLA)-A2 positive.
7. ECOG performance status 0 or 1 (see Protocol Section 12.1).
8. Measurable disease according to Response Evaluation Criteria in Solid Tumors criteria (RECIST), version 1.1.
9. Patients with a life expectancy of at least 3 months as judged by the recruiting site physician.
10. Female patients of childbearing potential must have a negative serum pregnancy test within 72 hours prior to randomization.
11. Considering the embryofetal toxicity of the immune checkpoint inhibitor (ICI) shown in animals’ models, the following recommendations for contraception must be followed:
a. If not surgically sterile, female patients of childbearing potential age must use highly effective contraception from signing the Informed Consent Form (ICF) through 6 months after the last treatment dose administered. Highly effective contraception includes (according to Clinical Trial Facilitation Group: Recommendations related to contraception and pregnancy testing in clinical trials):
i. combined (estrogen and progesterone containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, transdermal,
ii. progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, implantable,
iii. intrauterine device (IUD),
iv. intrauterine hormone-releasing system (IUS),
v. bilateral tubal occlusion,
vi. vasectomized partner, and
vii. sexual abstinence when in line with the preferred and usual lifestyle of the patient (e.g. periodic abstinence is not considered a highly effective method).
In each case of delayed menstrual period (over 1 month between menstruations), confirmation of absence of pregnancy is strongly recommended. This recommendation also applies to women of childbearing potential with infrequent or irregular menstrual cycles.
b. If not surgically sterile, male with female partner of childbearing potential age must use condom from signing the ICF through 6 months after the last treatment dose administered. Males must ensure that their partners of childbearing potential use highly effective contraception also. Note, the contraception guidelines for males are not related to nivolumab but kept as a conservative precaution in this early development protocol in relation to EO4010.
12. Patients willing and able to comply with the scheduled visits, treatment plan, laboratory tests, and other study procedures indicated in the protocol. |
|
| E.4 | Principal exclusion criteria |
1. Patients treated with dexamethasone > 2 mg/day or equivalent (i.e., 13 mg/day of prednisone) within 14 days before randomization, unless required to treat an adverse event (AE).
2. Patients treated with radiotherapy within 12 weeks, and cytotoxic chemotherapy therapy within 28 days (or 5 half lives of the compound(s) administered if longer) before study treatment start.
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. However, alopecia, neuropathy, and other persisting toxicities not constituting a safety risk based on Investigator’s judgment are acceptable.
4. Patients who have received any prior treatment with compounds targeting PD1, PD-L1, CTLA-4, or similar compounds where general resistance against therapeutic vaccination approaches might have developed.
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, the current trial compound.
7. Patients with the following abnormal laboratory values:
a. Lymphocyte count decreased, grade 2 (lymphocytes <800 - 500/mm3; <0.8 - 0.5 x 10^9/L), or worse grade.
b. Hemoglobin < 10 g/dL (6.2 mmol/L); transfusion is acceptable to reach the value.
c. Absolute neutrophil count decrease (<1.5 x10^9/L).
d. Platelet count decrease (< 75 ×10^9/L).
e. Total bilirubin > 1.5 ×upper limit of normal (ULN; according to the performing laboratory’s reference ranges); except participants with Gilbert Syndrome who must have a total bilirubin level of < 3.0 xULN.
f. Alanine aminotransferase (ALT) > 3 ×ULN; if disease metastatic to the liver > 5 xULN.
g. Aspartate aminotransferase (AST) > 3 ×ULN; if disease metastatic to the liver > 5 xULN.
h. Serum creatinine increase (> 1.5 ×ULN).
i. Abnormal thyroid function per local laboratory levels;
9. Patients with clinically significant active infection, cardiac disease, significant medical or psychiatric disease/condition that, in the opinion of the Investigator, would interfere with the interpretation of patient safety or study results or that would prohibit the understanding or rendering of informed consent and compliance with the requirements of the protocol – including (but not limited to):
a. Bacterial sepsis, COVID-19, or other similarly severe infections (clinical assessment is the basis for exclusion of severe infections; if clinical suspicion, adequate testing should be performed to exclude severe infections).
b. New York Heart Association > Grade 2 congestive heart failure within 6 months prior to randomization (see Protocol Section 12.2).
c. Uncontrolled or significant cardiovascular disease
d. Stroke within 6 months prior to randomization.
e. Concurrent neurodegenerative disease.
f. Dementia or significantly altered mental status.
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; patients with history of CNS metastases are eligible if CNS disease has been radiographically and neurologically stable for at least 6 weeks prior to ICF signing and do not require corticosteroids for symptomatic management.
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, including herbal remedies, or herbal remedies known to potentially interfere with major organ function.
19. Patients who have received treatment with any other investigational agent, or participation in another clinical trial (clinical trial including active interventions; participation in clinical trials for data collection purposes only are permitted) within 28 days (or 5 half-lives if longer) prior to randomization. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Safety and tolerability of EO4010 in combination with nivolumab by a descriptive medical assessment of the combined profile of incidences of adverse events (AEs), treatment-emergent AEs (TEAEs), serious AEs (SAEs), deaths, reasons for treatment discontinuation/delays, and laboratory abnormalities using the NCI-CTCAE v5.0 grading system. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Continuous during study treatment and until Vd30 and Vd100. |
|
| E.5.2 | Secondary end point(s) |
1. Percentage of patients with shown immunogenicity (expansion of specific T cells comparing samples taken at baseline versus on treatment in an individual patient determining if the patient has a positive response to the immunization, or not) in relation to EO2317, EO2318, OMP10, OMP11, OMP12, and UCP2 that compose EO4010 by interferon-gamma (IFN-γ) enzyme-linked immunospot (ELISpot), and by intracellular cytokines staining, or multimers staining assays. Cross reactivities with the human TAAs FOXM1, BIRC5/survivin, UBE2C, CDC20, and KIF2C will also be evaluated by the same methods.
CT will be performed at w9 and thereafter every 8 weeks to evaluate:
o Objective Response Rate (ORR), defined as the proportion of patients with complete response (CR) and partial response (PR) according to the iRANO criteria
o Duration of Response (DoR), defined as the time interval from the date of first occurrence of CR or PR to the date of first documentation of disease progression or death from any cause, whichever occurs first.
o Disease Control Rate (DCR), defined as the proportion of patients with CR, PR, and Stable Disease (SD) according to the iRANO criteria
o Time to response (TTR)
3. PFS as described by RECIST 1.1 and iRECIST criteria, defined as the time interval from the date of first study treatment administration to the date of progression (by RECIST 1.1 or iRECIST criteria), or death due to any cause, whichever is earlier. Patients without progression or death are to be censored at the time of the last tumor assessment. The PFS rate at 4 months as assessed from the PFS survival curve.
4. OS 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.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| 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 | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| non-comparative, three sequential cohorts |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 4 |
| 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 |
| United States |
| France |
| Spain |
| Germany |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 54 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 54 |
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