First-in-Human, Phase 1b/2a Trial of a Multipeptide Therapeutic Vaccine in Patients With Progressive Glioblastoma (ROSALIE)

• ClinicalTrials.gov Identifier: NCT04116658
• Recruitment Status: Active, not recruiting
• First Posted: October 4, 2019
• Last Update Posted: December 1, 2023
• Sponsor: Enterome
• Collaborator: Covance
• Information provided by (Responsible Party): Enterome

Tracking Information

• First Submitted Date: September 30, 2019
• First Posted Date: October 4, 2019
• Last Update Posted Date: December 1, 2023
• Actual Study Start Date: July 13, 2020
• Estimated Primary Completion Date: December 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 3, 2019)

Safety and tolerability of EO2401: National Cancer Institute-Common Terminology Criteria for AEs (NCI-CTCAE) v5.0 [ Time Frame: Up to 24 months ]

Incidences of AEs, treatment-emergent AEs (TEAEs), Serious Adverse Events ( SAEs), deaths, and laboratory abnormalities using the National Cancer Institute-Common Terminology Criteria for AEs (NCI-CTCAE) v5.0.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: October 3, 2019)

• Evaluation of survival [ Time Frame: From end of treatment to at least 24 months after last patient enrollment ]
  Overall survival, defined as the time interval from the date of first study treatment administration to the date of death due to any cause
• Assessment of the immunogenicity of EO2316, EO2317, EO2318 (Three components of the therapeutic vaccine), and Universal Cancer Peptide that compose EO2401 [ Time Frame: Up to 24 months ]
  Immunogenicity will be assessed by Interferon-γ ELISpot

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: First-in-Human, Phase 1b/2a Trial of a Multipeptide Therapeutic Vaccine in Patients With Progressive Glioblastoma
• Official Title: A Multicenter, Open-Label, First-in-Human, Phase 1b/2a Trial of EO2401, a Novel Multipeptide Therapeutic Vaccine, With and Without Check Point Inhibitor, Following Standard Treatment in Patients With Progressive Glioblastoma
• Brief Summary: 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.

Detailed Description

This is a multicenter, Phase 1b/2a, First-In-Human study to assess the safety, tolerability, immunogenicity, and preliminary efficacy of EO2401 in patients with unequivocal evidence of progressive or first recurrent glioblastoma.

EO2401 is an innovative cancer peptide therapeutic vaccine based on the homologies between Tumor Associated Antigens and microbiome-derived peptides that will be administered alone and in combination with nivolumab, and nivolumab/bevacizumab to generate preliminary safety and efficacy data in patients with progressive glioblastoma.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Glioblastoma, Adult

Intervention

Biological: Multiple dose of EO2401

Multiple dose administration of EO2401 coadministered with or without nivolumab (and bevacizumab, US only) during the priming phase

Study Arms

• Experimental: Cohort 1
  Multiple dose of EO2041 monotherapy followed by continued EO2401 in combination with nivolumab
  Intervention: Biological: Multiple dose of EO2401
• Experimental: Cohort 2
  Multiple dose of EO2041 in combination with nivolumab
  Intervention: Biological: Multiple dose of EO2401
• Experimental: Cohort 3
  Multiple dose of EO2041 in combination with nivolumab and bevacizumab
  Intervention: Biological: Multiple dose of EO2401

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: January 30, 2023): 100
• Original Estimated Enrollment (submitted: October 3, 2019): 32
• Estimated Study Completion Date: December 2025
• Estimated Primary Completion Date: December 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: France, Germany, Spain, United States

Administrative Information

• NCT Number: NCT04116658
• Other Study ID Numbers: EOGBM1-18
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Enterome
• Original Responsible Party: Same as current
• Current Study Sponsor: Enterome
• Original Study Sponsor: Same as current
• Collaborators: Covance

Investigators

• Study Director: Jean-Michel Paillarse; Enterome

• PRS Account: Enterome
• Verification Date: November 2023