A Multicenter, Open-Label, First-in-Human, Phase Ib/IIa Trial of EO2401, a Novel Multipeptide Therapeutic Vaccine, with and without PD-1 Check Point Inhibitor, Following Standard Treatment in Patients with Progressive Glioblastoma

Protocol # :
Glioblastoma, Adult
Disease Sites
Brain and Nervous System
Principal Investigator
Reardon, David, A.
Site Research Nurses
Chau, Johny, E.
Cifrino, Meghan
Doherty, Lisa
Lafrankie, Debra
Stefanik, Jennifer
Taubert, Christina, Elizabeth

Trial Description

The purpose of this study is to assess the safety, tolerability, immunogenicity, and
preliminary efficacy of EO2401 in patients with unequivocal evidence of progressive or first
recurrent glioblastoma.

Eligibility Requirements

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

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

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

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

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

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

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

24. Patients deprived of their liberty or under protective custody or guardianship.