Glioblastoma, Adult
Conditions
Keywords
Glioblastoma, Vaccine, Nivolumab, Bevacizumab, Safety, Tolerability
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.
Interventions
BIOLOGICALMultiple dose of EO2401
Multiple dose administration of EO2401 coadministered with or without nivolumab (and bevacizumab, US only) during the priming phase
Sponsors
Covance
Enterome
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety and Tolerability of EO2401 Monotherapy, EO2401 in Combination With Nivolumab , EO2401 in Combination With Nivolumab and Bevacizumab | From treatment start up to study end, assessed up to 27.5 months | Incidences of treatment-emergent Serious Adverse Events ( SAEs) using the National Cancer Institute-Common Terminology Criteria for AEs (NCI-CTCAE) v5.0. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Evaluation of Survival | From treatment start up to study end, assessed up to 44 months | 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 | 6 weeks after treatment start | At least one positive response (proof of CD8 T cells specific for the EO2401 mimic peptides and/or for the tumor associated antigen (TAA) target peptides) in either of the used immunomonitoring assays (i.e. CD8 T cell expansion in peripheral blood measured by tetramers/flow cytometry, and Spot-Forming Cells by IFN-γ ELISPOT, both methods applied ex vivo, i.e. without prolonged in vitro stimulation and after in vitro stimulation) |
Countries
France, Germany, Spain, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 EO2041 monotherapy followed by continued EO2401 in combination with nivolumab | 21 |
| Cohort 2 EO2041 in combination with nivolumab | 53 |
| Cohort 3 EO2041 in combination with nivolumab and bevacizumab | 26 |
| Total | 100 |
Baseline characteristics
| Characteristic | Total | Cohort 1 | Cohort 2 | Cohort 3 |
|---|---|---|---|---|
| Age, Continuous | 58 years | 58 years | 57 years | 60.5 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 0 Participants | 2 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 89 Participants | 19 Participants | 46 Participants | 24 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 7 Participants | 2 Participants | 5 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 0 Participants | 4 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 92 Participants | 19 Participants | 48 Participants | 25 Participants |
| Sex: Female, Male Female | 38 Participants | 7 Participants | 21 Participants | 10 Participants |
| Sex: Female, Male Male | 62 Participants | 14 Participants | 32 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 20 / 21 | 46 / 53 | 23 / 26 |
| other Total, other adverse events | 20 / 21 | 51 / 53 | 26 / 26 |
| serious Total, serious adverse events | 9 / 21 | 8 / 53 | 8 / 26 |
Outcome results
Primary
Safety and Tolerability of EO2401 Monotherapy, EO2401 in Combination With Nivolumab , EO2401 in Combination With Nivolumab and Bevacizumab
Incidences of treatment-emergent Serious Adverse Events ( SAEs) using the National Cancer Institute-Common Terminology Criteria for AEs (NCI-CTCAE) v5.0.
Time frame: From treatment start up to study end, assessed up to 27.5 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 | Safety and Tolerability of EO2401 Monotherapy, EO2401 in Combination With Nivolumab , EO2401 in Combination With Nivolumab and Bevacizumab | 9 Participants |
| Cohort 2 | Safety and Tolerability of EO2401 Monotherapy, EO2401 in Combination With Nivolumab , EO2401 in Combination With Nivolumab and Bevacizumab | 8 Participants |
| Cohort 3 | Safety and Tolerability of EO2401 Monotherapy, EO2401 in Combination With Nivolumab , EO2401 in Combination With Nivolumab and Bevacizumab | 8 Participants |
Primary
Safety and Tolerability of EO2401 Monotherapy, EO2401 in Combination With Nivolumab , EO2401 in Combination With Nivolumab and Bevacizumab
Incidences of treatment-emergent AEs (TEAEs) using the National Cancer Institute-Common Terminology Criteria for AEs (NCI-CTCAE) v5.0.
Time frame: From treatment start up to study end, assessed up to 27.5 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 | Safety and Tolerability of EO2401 Monotherapy, EO2401 in Combination With Nivolumab , EO2401 in Combination With Nivolumab and Bevacizumab | 21 Participants |
| Cohort 2 | Safety and Tolerability of EO2401 Monotherapy, EO2401 in Combination With Nivolumab , EO2401 in Combination With Nivolumab and Bevacizumab | 51 Participants |
| Cohort 3 | Safety and Tolerability of EO2401 Monotherapy, EO2401 in Combination With Nivolumab , EO2401 in Combination With Nivolumab and Bevacizumab | 26 Participants |
Primary
Safety and Tolerability of EO2401 Monotherapy, EO2401 in Combination With Nivolumab , EO2401 in Combination With Nivolumab and Bevacizumab
Incidences of deaths
Time frame: From treatment start up to study end, assessed up to 44 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 | Safety and Tolerability of EO2401 Monotherapy, EO2401 in Combination With Nivolumab , EO2401 in Combination With Nivolumab and Bevacizumab | 20 Participants |
| Cohort 2 | Safety and Tolerability of EO2401 Monotherapy, EO2401 in Combination With Nivolumab , EO2401 in Combination With Nivolumab and Bevacizumab | 46 Participants |
| Cohort 3 | Safety and Tolerability of EO2401 Monotherapy, EO2401 in Combination With Nivolumab , EO2401 in Combination With Nivolumab and Bevacizumab | 23 Participants |
Secondary
Assessment of the Immunogenicity of EO2316, EO2317, EO2318 (Three Components of the Therapeutic Vaccine), and Universal Cancer Peptide That Compose EO2401
At least one positive response (proof of CD8 T cells specific for the EO2401 mimic peptides and/or for the tumor associated antigen (TAA) target peptides) in either of the used immunomonitoring assays (i.e. CD8 T cell expansion in peripheral blood measured by tetramers/flow cytometry, and Spot-Forming Cells by IFN-γ ELISPOT, both methods applied ex vivo, i.e. without prolonged in vitro stimulation and after in vitro stimulation)
Time frame: 6 weeks after treatment start
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 | Assessment of the Immunogenicity of EO2316, EO2317, EO2318 (Three Components of the Therapeutic Vaccine), and Universal Cancer Peptide That Compose EO2401 | 17 Participants |
| Cohort 2 | Assessment of the Immunogenicity of EO2316, EO2317, EO2318 (Three Components of the Therapeutic Vaccine), and Universal Cancer Peptide That Compose EO2401 | 29 Participants |
| Cohort 3 | Assessment of the Immunogenicity of EO2316, EO2317, EO2318 (Three Components of the Therapeutic Vaccine), and Universal Cancer Peptide That Compose EO2401 | 20 Participants |
Secondary
Evaluation of Survival
Overall survival, defined as the time interval from the date of first study treatment administration to the date of death due to any cause
Time frame: From treatment start up to study end, assessed up to 44 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 | Evaluation of Survival | 9.6 months |
| Cohort 2 | Evaluation of Survival | 11.3 months |
| Cohort 3 | Evaluation of Survival | 12.1 months |