| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Patients with circulating tumor DNA-defined minimal residual disease of colorectal cancer stage II, III, or IV after completion of curative therapy . | |
| E.1.1.1 | Medical condition in easily understood language | | Patients with minimal residual disease of colorectal cancer after completion of curative therapy . | |
| 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 | 10010033 | | E.1.2 | Term | Colorectal cancer stage II | | 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 | 10010034 | | E.1.2 | Term | Colorectal cancer stage III | | 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 | 10010035 | | E.1.2 | Term | Colorectal cancer stage IV | | 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 assess the 6-month ctDNA clearance rate at therapy with EO2040 in combination with nivolumab, in patients with ctDNA-defined MRD of stage II-IV colorectal cancer after completion of curative therapy.
and in sequence, provided the first objective has a positive outcome (see Primary Endpoint):
•The primary objective is, to assess the 6-month ctDNA clearance rate at therapy with EO2040 monotherapy, in patients with ctDNA-defined MRD of stage II-IV colorectal cancer after completion of curative therapy.
| |
| E.2.2 | Secondary objectives of the trial | To assess the following:
•safety and tolerability of study treatments,
•the 3-month ctDNA clearance rate,
•progression of colorectal cancer and death as disease-free survival (DFS),
•overall survival (OS),
•survival at 36 months after start of study therapy, and
•induction/expansion of T cells specific for EO2040, the components of EO2040, and the targeted nominal TAAs (BIRC5 and FOXM1). | |
| 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 (Consent #1 is for screening part #1 procedures, Consent #1B specifically for patients recruited in Germany to a prolonged screening for ctDNA after curative resection of liver metastases, and a final Consent #2 for screening part #2 procedures; see Section 7.2 and Section 7.3, respectively).
2.Histological confirmation of colorectal cancer (confirmation at initial diagnosis is sufficient).
3.Post R0-resection (i.e. microscopically margin-negative resection and no gross or microscopic tumor remaining in the primary tumor bed) of stages II, III, or IV CRC and completion of all planned standard of care perioperative and/or adjuvant therapies.
a.Note, if there is doubt the patient has received all relevant standard of care therapy, the patient should be discussed with the trial Medical Monitor, who can also defer the case for decision by the Global Coordinating Investigator.
4.Presence of minimal residual disease as defined by a positive ctDNA assay after completion of all planned standard of care therapies.
a.Note, patients may be identified for enrollment with any CLIA-certified, or similar certification outside of the USA, ctDNA assay for MRD as standard of care or in a surveillance trial. However, MRD status will be confirmed with the Signatera assay prior to initiation of study therapy (i.e. within the screening part #2 procedures) for all patients who have not had a Signatera research grade testing where all parameters from the testing can be provided for the current trial.
5.Age ≥ 18 years old.
6.Human leukocyte antigen (HLA)-A2 positive.
7.No evidence of radiographic disease (computer tomography or magnetic resonance imaging; optimized to detect metastatic disease, e.g. with contrast as applicable) that requires immediate therapeutic intervention as assessed by the treating physician, within 28 days of (before or after) a positive ctDNA assay.
a.Note, if there are lesions on scanning which are highly suspicious for being metastatic CRC even if no immediate therapeutic intervention is needed, this is a clear indication to NOT enroll the patient in the trial. At doubt the case should be discussed with the trial Medical Monitor, who can also defer the case for decision by the Global Coordinating Investigator.
b.Note, if the scanning is not done within -7 days/+28 days of the positive Signatera assay which is accepted as confirmatory test for the trial, the scanning needs to be repeated within the screening part #2 procedures.
8.ECOG performance status 0 or 1 (see Section 12.1).
9.Female patients of childbearing potential must have a negative serum pregnancy test within 72 hours prior to start of study therapy.
10.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 [104]):
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 EO2040.
11.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 start of study therapy, unless required to treat an adverse event (AE).
Note: patient should not receive treatment with dexamethasone > 2 mg/day or equivalent at the actual time of a screening visit (single time point assessment), and within 14 days before the start of study treatment (unless required to treat an AE); the latter part of the criterion should be checked at the time of start of treatment.
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 with the following abnormal laboratory values:
a.Hemoglobin < 10 g/dL (6.2 mmol/L); transfusion is acceptable to reach the value.
b.Absolute neutrophil count decrease (<1.5 x109/L).
c.Platelet count decrease (< 75 ×109/L).
d.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.
e.Alanine aminotransferase (ALT) > 3 ×ULN.
f.Aspartate aminotransferase (AST) > 3 ×ULN.
g.Serum creatinine increase (> 1.5 ×ULN).
h.Abnormal thyroid function per local laboratory levels; note, patients with hypothyroidism only requiring hormone replacement therapy, and patients with long term (judged by the treating physician) stable antithyroid therapy due to hyperthyroidism, are permitted to enroll. Patients with abnormal thyroid laboratory values judged by the treating physician as clinically non-relevant are also eligible.
6.Patients with presence of other concomitant active, invasive malignancies that may interfere with ctDNA analysis (known clonal hematopoiesis of unknown potential allowed).
7.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:
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 start of study therapy (see Section 12.2).
c.Uncontrolled or significant cardiovascular disease, including:
i.myocardial infarction within 6 months prior to start of study therapy,
ii.uncontrolled/unstable angina within 6 months prior to start of study therapy,
iii.diagnosed or suspected congenital long QT syndrome, and
iv.any history of clinically significant ventricular arrhythmias
d.Stroke within 6 months prior to start of study therapy.
e.Concurrent neurodegenerative disease.
f.Dementia or significantly altered mental status.
8.Patients with suspected autoimmune or active autoimmune disorder or known history of an autoimmune neurologic condition (e.g., Guillain-Barré syndrome).
9.Patients with a history of solid organ transplantation or allogeneic hematopoietic stem cell transplantation.
10.Patients with a history or known presence of tuberculosis.
11.Pregnant and breastfeeding patients.
12.Patients with a history or presence of human immunodeficiency virus (HIV) and/or active hepatitis B virus (HBV)/hepatitis C virus (HCV).
13.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.
14.Patients with a history of hypersensitivity to any excipient, or active substance, present in the pharmaceutical forms of applicable study treatments.
15.Patients under treatment with immunostimulatory or immunosuppressive medications, including herbal remedies, or herbal remedies known to potentially interfere with major organ function.
16.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 start of study therapy. | |
| E.5 End points |
| E.5.1 | Primary end point(s) | Response to therapy will be measured with a standard-of-care, CLIA certified ctDNA assay, or similar certification outside of the USA (timepoint 6 months).
Identification of somatic mutations in the blood will be confirmed by sequencing of the resected tumor using a CLIA-certified next-generation sequencing panel. Clearance of ctDNA will be characterized by the disappearance of all somatic mutations identified in the blood, as well as no appearance of any additional new somatic mutations.
The primary endpoint is response to treatment at 6 months, which is defined as having clearance of ctDNA, AND not having any radiographic evidence of recurrence at 6 months.
If at least 4 out of 17 patients in the Full Analysis Set (FAS; patients who received at least one dose of EO2040 and for whom no important protocol deviations occurred) show response to study therapy, the therapy will be declared successful. | |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | Response to treatment at 6 months
| |
| E.5.2 | Secondary end point(s) | 1.The safety and tolerability of study treatments will be determined 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.
2.Response to therapy at 3 months, defined as clearance of ctDNA, AND no radiographic evidence of recurrence (determination method will be the same as for the primary endpoints).
3.Disease-free survival (DFS) defined as the time from start of study treatment to the date of first documented CRC recurrence or death due to any cause, whichever occurs first. Patients alive without recurrence will be censored at the date of last follow-up time. Recurrence is defined by the appearance of one or more new CRC lesions on imaging and/or other clinical evaluation such as endoscopy.
4.Overall survival (OS), measured as the time from start of study treatment until death from any cause. Patients alive will be censored at the last time documented to be alive.
5.Survival at 36 months after start of study treatment, estimated via Kaplan-Meier estimates.
6.Immunogenicity and cross reactivity: Immunogenicity determined as 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, and UCP2 that compose EO2040 by interferon-gamma (IFN-γ) enzyme-linked immunospot (ELISpot), intracellular cytokines staining, and multimers staining assays. Cross reactivities with the TAAs BIRC5/survivin and FOXM1 will also be evaluated by the same methods. Note, cell availability at each sampling time sets the limit for tests possible to do, and the priority order is multimer staining and ELISpot firsthand, and then if possible intracellular cytokine staining (the latter might also intentionally not be done in all patients).
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| E.5.2.1 | Timepoint(s) of evaluation of this end point | 1.Safety and tolerability: Continuous during study treatment and until the Vd30 and Vd100
2.Response to therapy at 3 months,
3.Disease-free survival (DFS) from start of study treatment to the date of first documented CRC recurrence or death due to any cause, whichever occurs first.
4.Overall survival (OS), from start of study treatment until death from any cause.
5.Survival at 36 months after start of study treatment
6.Immunogenicity and cross reactivity: During every visit until week 13 (except week 9), at week 19 and week 27 and after week 27 every 3 months (+/- 7 days) for a maximum of 3 years from first study treatment.
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| 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 | | Immunogenicity Analyses. ctDNA assay . | |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| 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, two sequential cohort | |
| 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 | No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| 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 | |
| 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 | 6 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
