| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Progressive or recurrent Glioblastoma (PG) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Progressive or recurrent Form of a Certain Type of Malignant Brain Cancer |
|
| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10018336 |
| E.1.2 | Term | Glioblastoma |
| 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 first-in-human (FIH) trial of EO2401 is to evaluate the safety and tolerability of EO2401 as monotherapy and in combination with nivolumab, and nivolumab/bevacizumab in patients with progressive glioblastoma (GB). The safety and tolerability
evaluation include assessments of different patient populations within
the group of patients with recurrent GB: i) Cohorts 1a, 2a, and 3
evaluate patients with measurable disease, ii) Cohort 2b evaluates
patients with non-measurable disease (after surgery of recurrent
disease, i.e. adjuvant treatment), and iii) Cohort 2c evaluates a
neoadjuvant/surgery/adjuvant treatment concept. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives are:
•The evaluation of survival
•The evaluation of tumor progression and response by magnetic resonance imaging (MRI) assessment using the Immunotherapy Response Assessment in Neuro-Oncology (iRANO) criteria
•To assess the immunogenicity of EO2316, EO2317, EO2318, and universal cancer peptide 2 (UCP2) that compose EO2401 by interferon-gamma (IFN-γ) enzyme-linked immunospot (ELISpot), and by intracellular cytokines staining, or multimers staining assays. Cross reactivities with the human tumor associated antigens (TAAs) interleukin 13 receptor alpha-2 (IL-13Rα2), survivin also called baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5), and forkhead box M1 (FOXM1) will also be tested.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Patients with unequivocal documented (including histological confirmation of GB at the primary diagnosis) first progression/recurrence of GB on MRI, as defined by RANO criteria
2.Patients with:
• for Cohorts1, 2a, and 3: at least 1 measurable lesion
• for Cohort 2b: no measurable enhancing disease (defined as less than 1x1 cm in maximum bi-perpendicular plane)
• for Cohort 2c: documented recurrence of GB deemed to be candidate for surgery as standard-of-care at the local institution, and for which the resection can safely be postponed for 4-6 weeks per local institutional guidance and treating physician judgement. In addition, for inclusion in Cohort 2c the patient must consent to mandatory collection of tissue samples from the time of diagnosis (if logistically available), and the planned surgery after neoadjuvant study therapy (see also Section 7.1.1).
3. Patients
3.Patients with an age ≥ 18 years old
4.Patients who are human leukocyte antigen (HLA)-A2 positive
5.Patients with an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 or Karnofsky performance status ≥ 70
6.Patients should have received standard primary therapy, including surgery (biopsy, incomplete or complete resection), radiation, temozolomide, if applicable
a.Radiation therapy must have been finished at least 28 days before first study treatment administration
b.Patients who received temozolomide as adjuvant therapy must have stopped the treatment and have a wash-out period of at least 28 days before first study treatment administration (6 weeks for nitrosoureas and at least 4 weeks, or 5 half-lives if longer, for experimental therapies, if this type of therapies have been included as components of adjuvant therapy)
c .Patients with unmethylated methylguanine-DNA-methyltransferase (MGMT) promoter can be included even if they have not received temozolomide prior to the inclusion in this clinical study). Note, patients to be enrolled to the trial at sites in Germany should have received temozolomide for their primary treatment irrespective of MGMT methylation status; i.e. both concurrent with radiotherapy and as adjuvant therapy post radiotherapy, when applicable as standard therapy.
7.Female patients of childbearing potential must have a negative serum pregnancy test within 72 hours prior to dosing
8.Considering the embryofetal toxicity of the nivolumab shown on 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 included:
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
iv.Intrauterine hormone-releasing system
v.Bilateral tubal occlusion
vi.Sexual abstinence.
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 must use condom from signing the ICF through 8 months after the last treatment dose administered. Males must ensure that their partners of childbearing potential use highly effective contraception also.
9.Patients having received the information sheets and who have provided written informed consent prior to any study-related procedures
10.Patients willing and able to comply with the scheduled visits, treatment plan, laboratory tests, and other study procedures indicated in the protocol.
Please refer to the Protocol for all Inclusion Criteria. |
|
| 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 the first EO2401 administration, unless required to treat an adverse event (AE)
2.Patients treated with radiotherapy, and cytoreductive therapy within 28 days (6 weeks for nitrosoureas) before the first EO2401 administration. In addition, patients should not have received any prior treatment with compounds targeting PD-1, PD-L1, CTLA-4, or similar compounds where general resistance against therapeutic vaccination approaches might have developed; also patients should not have received systemic anti-Tumor treatment or radiotherapy for their progressive or first recurrent GB
3.Patients with tumors primarily located in the infra-tentorial segment
4.Patients with known radiological evidence of extracranial metastases
5.Patients with presence of new hemorrhage (excluding, stable Grade 1) or uncontrolled seizure
6.Patients with significant leptomeningeal disease
7.Patients with abnormal (≥ Grade 2 National Cancer Institute-Common Terminology Criteria for AEs [NCI-CTCAE] version 5.0) laboratory values for hematology, liver, and renal function (serum creatinine).
8.For patients who are planned to receive bevacizumab:
a.Patients with nephrotic syndrome
b.Patients with proteinuria ≥ 2g/24 hours
c.Patients with history or active gastrointestinal perforation and fistula
d.Significant surgical procedure in the 4 weeks preceding the start of treatment or planned surgery
e.Unhealed wound
f.Patient with recent (4 weeks) history of hemoptysis of ½ teaspoon or more of red blood
g.Thrombotic episode within 6 months
h.Uncontrolled diabetes mellitus or hypertension
i.Posterior reversible encephalopathy syndrome
9.Patients with persistent Grade 3 or 4 toxicities (according to NCI-CTCAE v5.0). Toxicities must be resolved since at least 2 weeks to Grade 1 or less. However, alopecia or other persisting toxicities Grade ≤ 2 not constituting a safety risk based on Investigator’s judgment is acceptable
10.Patients with contraindication to contrast-enhanced MRI
11.Other malignancy or prior malignancy with a disease-free interval of less than 3 years except those treated with surgical intervention and an expected low likelihood of recurrence such as basal cell or squamous cell skin cancer, or carcinoma in situ. Patients with adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ are eligible.
12.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 evaluation of EO2401 or interpretation of patient safety or study results or that would prohibit the understanding or rendering of informed consent (i.e. only consent able patients can be enrolled in the study) and compliance with the requirements of the protocol
13.Patients with suspected autoimmune or active autoimmune disorder or known history of an autoimmune neurologic condition (e.g., Guillain-Barré syndrome).
14.Patients with history of solid organ transplantation or hematopoietic stem cell transplantation
15.Patients with history or known presence of tuberculosis
16.Pregnant and breastfeeding patients
17.Patients with history or presence of human immunodeficiency virus and/or potentially active hepatitis B virus/hepatitis C virus
18.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
19.Patients with a history of hypersensitivity to any excipient present in the pharmaceutical form of investigational medicinal product
20.Patients under treatment with immunostimulatory or immunosuppressive medications, including herbal remedies or herbal remedies known to potentially interfere with major organ function
21.Patients with known drug and alcohol abuse
22.Patients with known or underlying medical or psychiatric condition that, in the Investigator’s opinion, would make the administration of study drug hazardous to the patient or obscure the interpretation of toxicity determination or AEs
23.Patients who have received treatment with any other investigational agent, or participation in another clinical trial (clinical trial including active interventions are prohibited; participation in clinical trials for data purpose collection purposes only are permitted) within 28 days prior to first study treatment administration and during the treatment period. Note, for investigational agents there should be a wash-out period of at least 28 days, or 5 half-lives if longer, before first study treatment administration.
24.Patients deprived of their liberty or under protective custody or guardianship.
Please refer to the Protocol for all Exclusion Criteria. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint includes the incidences of AEs, treatment-emergent AEs (TEAEs), serious AEs (SAEs), deaths, and laboratory abnormalities using the NCI-CTCAE v5.0.
Safety endpoints will be assessed by review of summaries of AEs (or TEAEs)/SAEs, unless otherwise stated. Adverse events will be categorized by system organ class and preferred term using the current Medical Dictionary for Regulatory Activities version and will be graded according to NCI-CTCAE v5.0.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Adverse events will be monitored throughout the study. Adverse events will be collected from the time informed consent is signed and continue until 30 days after the last study treatment is administered, until all serious or study treatment-related toxicities have resolved or are determined to be “chronic” or “stable,” completion of the patient’s participation, study termination (e.g., patient lost to follow-up), or the Investigator or designee and Sponsor agree that follow-up is no longer necessary, whichever occurs first.
|
|
| E.5.2 | Secondary end point(s) |
The secondary endpoints are:
•Overall survival (OS), defined as the time interval from the date of first study treatment administration to the date of death due to any cause
•The tumor progression and response by MRI measurements every 8 weeks using the iRANO criteria evaluated by:
o Progression-free Survival (PFS), using the iRANO criteria and defined as the time interval from the date of first study treatment administration to the date of first occurrence of progression or death from any cause, whichever occurs first
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
•The immunogenicity of EO2316, EO2317, EO2318, and UCP2 that compose EO2401, by IFN γ ELISpot, and by intracellular cytokines staining, or multimers staining assays. Cross reactivities with the human TAAs IL-13Rα2, BIRC5 (survivin), and FOXM1 will also be tested.
|
|
| 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 |
|
| 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.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 9 |
| 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
|
| Last Visit Last Patient (LVLP) |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
