Inclusion Criteria:
1. Patients with unequivocal documented (including histological confirmation of
Glioblastoma-GB- at the primary diagnosis) evidence of first progression/recurrence
of GB on MRI, as defined by RANO criteria. 2. Patients with :
- - for Cohorts 1, 2a, and 3: at least 1 measurable lesion.
- - for Cohort 2b: no measurable enhancing disease.
- - for Cohort 2c: documented recurrence of GB deemed to be candidate for surgery.
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. 1. Radiation therapy must have been finished 28 days before first study treatment
administration. 2. Patients who received temozolomide as adjuvant therapy must have stopped the
treatment and have a wash-out period of 28 days before first study treatment
administration (6 weeks for nitrosoureas and 5 half lives for experimental
therapies)
3. 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)
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 sheet 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.
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) Note: The criterion implios the 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
first EO2401 administration (unless required to treat AE); the latter part of the
criterion should be checked at the time of treatment start.
2.
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). In detail, the following values apply as
exclusion criteria:
1. Hemoglobin < 10 g/dL (6.2 mmol/L)
2. White blood cell count decrease (< 3.0 × 109/L) or increase (> 10.0 × 109/L)
3. Absolute neutrophil count decrease (< 1.5 × 109/L)
4. Platelet count decrease (< 75 × 109/L)
5. Bilirubin > 1.5 × upper limit of normal per local laboratory levels; note,
patients with hypothyroidism only requiring hormone replacement therapy are
permitted to enroll, also patients with abnormal laboratory values judged by
the treating physician as clinically non-relevant.
6. Alanine aminotransferase > 3 × ULN. 7. Aspartate aminotransferase > 3 × ULN. 8. Serum creatinine increase (> 1.5 × ULN)
9. Abnormal thyroid function. 8. For patients who are planned to receive bevacizumab:
1. Patients with nephrotic syndrome. 2. Patients with proteinuria ≥ 2g/24 hours. 3. Patients with history or active gastrointestinal perforation and fistula. 4. Significant surgical procedure in the 4 weeks preceding the start of treatment
or planned surgery. 5. Unhealed wound. 6. Patient with recent (4 weeks) history of hemoptysis of ½ teaspoon or more of
red blood. 7. Thrombotic episode within 6 months. 8. Uncontrolled diabetes mellitus or hypertension. 9. 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.
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
- - including (but not limited to):
1.
Bacterial sepsis or other similarly severe infections. 2. New York Heart Association > Grade 2 congestive heart failure within 6 months
prior to study entry. 3. Uncontrolled or significant cardiovascular disease, including:
i. Myocardial infarction within 6 months prior to obtaining informed consent ii.
Uncontrolled/unstable angina within 6 months prior to obtaining informed consent
iii. Diagnosed or suspected congenital long QT syndrome iv. Any history of
clinically significant ventricular arrhythmias (such as ventricular tachycardia,
ventricular fibrillation, or Torsades de pointes) d. Stroke within 6 months prior
obtaining informed consent e. Concurrent neurodegenerative disease f. Dementia or
significantly altered mental status.
13. Patients with suspected autoimmune or active autoimmune disorder or known history of
an autoimmune neurologic condition (e.g., Guillain-Barré syndrome) Note, patients
with vitiligo, type I diabetes mellitus, hypothyroidism due to autoimmune condition
only requiring hormone replacement therapy, psoriasis not requiring systemic
therapy, or conditions not expected to recur in the absence of an external trigger
are permitted to enroll. 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 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.
