An early phase clinical trial to investigate EO2463, a novel cancer vaccine therapy, in patients with indolent Non-Hodgkin's Lymphoma.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Enterome

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

31 May 2021 → ongoing

Decision date (initial)

2024-02-19

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Enterome

External identifiers

EU CT number

2023-509254-58-00

EudraCT number

2020-003999-40

ClinicalTrials.gov

NCT04669171

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Others, Therapy, Pharmacogenetic

Phase 1: to define the recommended phase 2 dose (RP2D) for EO2463 monotherapy, and to confirm the safety of EO2463 at the monotherapy RP2D in combination with lenalidomide (EL), rituximab (ER), and lenalidomide/rituximab (ER^2).
Phase 2: to estimate the objective response rate (ORR) according to the Lugano Classification 2014 during EO2463 monotherapy.
An additional primary objective for the phase 2 part of the trial is to estimate the complete remission (CR)-rate according to the Lugano Classification 2014 during therapy with the combination of EO2463/lenalidomide/rituximab (ER).

Secondary objectives 5

1. safety and tolerability of EO2463 as monotherapy, and in combination with lenalidomide, rituximab, and lenalidomide/rituximab, for treatment of patients with FL and MZL
2. changes (depletion/expansion), including durations, of B and T cell, and immunoglobulin levels
3. immunogenicity in relation to T cells of OMP72, OMP64, OMP65, OMP66, and UCP2 that compose EO2463, including T cell cross-reactivity with the human B cell antigens CD20, CD22, CD37, and BAFF-receptor
4. ORR and duration of response (DOR) by the Lugano Classification 2014, and the Lymphoma Response to Immunomodulatory Therapy Criteria (LyRIC) 2016 by trial cohort
5. time to next anti-lymphoma therapy (TTT), progression-free survival (PFS) and overall survival (OS) by trial cohort.

Conditions and MedDRA coding

Indolent Non-Hodgkin's Lymphoma (Follicular Lymphoma; Marginal Zone Lymphoma)

Study design 3 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. For inclusion in Cohorts 1 and 4 patients should have relapsed/refractory, biopsy-proven grade 1, 2 or 3A, FL or MZL*, ECOG performance status 0 to 2, and have received at least one prior line of treatment
2. For inclusion in Cohort 2 patients should have newly diagnosed, previously untreated (non-definitive radiotherapy as only prior treatment is allowed), biopsy-proven grade 1, 2 or 3A, FL or MZL*, Ann Arbor stage III or IV, or Ann Arbor stage I or II when the patient is not eligible for definitive radiotherapy, ECOG performance status 0 or 1, low tumor burden by GELF criteria (low tumor burden defined as: no mass > 7 cm, < three masses >3 cm, no systemic or B-symptoms, no splenomegaly > 16 cm by scan (PET/CT or CT), no risk of vital organ compression, no leukemic phase > 5,000/μL circulating lymphocytes, and no cytopenia [defined as platelets < 100,000/μL, hemoglobin < 10 g/dL, or absolute neutrophil count <1,500/μL]), and not be in need of standard of care therapy according to the assessment of the treating physician.
3. For inclusion in Cohort 3 patients should have newly diagnosed, previously untreated (radiotherapy as only prior treatment is allowed), biopsy-proven grade 1, 2 or 3A, FL or MZL*, Ann Arbor stage III or IV, ECOG performance status 0 or 1, low tumor burden by GELF criteria (low tumor burden defined as: no mass > 7 cm, < three masses >3 cm, no systemic or B-symptoms, no splenomegaly > 16 cm by PET/CT or CT scan, no risk of vital organ compression, no leukemic phase > 5,000/µL circulating lymphocytes, and no cytopenia [defined as platelets < 100,000/µL, hemoglobin < 10 g/dL, or absolute neutrophil count <1,500/µL]), and be in need of therapy according to the assessment of the treating physician. * MZL includes the entities extranodal MZL (EMZL, i.e. MALT lymphoma), splenic MZL (SMZL), and nodal MZL (NMZL).
4. Patients with an age ≥ 18 years old.
5. Patients who are human leukocyte antigen (HLA)-A2 positive.
6. Patients should have radiologically measurable disease with a lymph node or tumor mass greater than or equal to 1.5 cm in at least one dimension.
7. Males or non-pregnant, non-lactating, females who are: a. female, post-menopausal (as defined in the protocol), b. female and male, surgically sterile (as defined in the protocol), c. female of childbearing potential with a negative highly sensitive serum pregnancy test within 72 hours prior to first administration of study treatment and use of a highly effective contraception from signing the Informed Consent Form (ICF) through the 30 days safety visit after the last study treatment dose administered; note, the male partner should in addition to the use of highly effective contraception by the female patient also use condoms, d. male patient with female partners of childbearing potential must use condoms from signing the ICF through the 30 days safety visit after the last study treatment dose administered; in addition, male patients must ensure that their partners of childbearing potential also use highly effective contraception as described in the protocol. In addition, for patients who are to be enrolled in a cohort including rituximab the following inclusion criteria are applicable: e. due to the long retention time of rituximab in patients with B cell depletion, females of childbearing potential must commit to use effective contraceptive methods (see protocol inclusion criteria 7d for details) during and for 12 months following treatment with rituximab. In addition, for patients who are to be enrolled in a cohort including lenalidomide the following inclusion criteria are applicable: f. females of reproductive potential: i. must avoid pregnancy for at least 4 weeks before beginning lenalidomide therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy, ii. must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control (see protocol inclusion criteria 7d for details), beginning 4 weeks prior to initiating treatment with lenalidomide, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of lenalidomide therapy, iii. must have two negative serum pregnancy tests prior to initiating therapy; the first test should be performed within 10-14 days and the second test within 24 hours prior to initiating lenalidomide therapy and then weekly during the first month, then monthly thereafter in females with regular menstrual cycles or every 2 weeks in females with irregular menstrual cycles. g. males: i. must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking lenalidomide and for up to 4 weeks after discontinuing lenalidomide, even if they have undergone a successful vasectomy. ii. must not donate sperm during treatment with lenalidomide and for up to 4 weeks after discontinuing lenalidomide.
8. Patients willing and able to comply with the scheduled visits, treatment plan, laboratory tests, and other study procedures indicated in the protocol.
9. Patients having received the information sheet and who have provided written informed consent prior to any study-related procedures.

Exclusion criteria 21

1. Patients treated with dexamethasone > 2 mg/day or equivalent (i.e. 13 mg/day of prednisone, or 53 mg/day of hydrocortisone) within 14 days before the first EO2463 administration.
2. Active central nervous system (CNS) metastasis; patients with history of CNS metastases are eligible if CNS disease has been radiographically and neurologically stable for at least 6 weeks prior to ICF signing and do not require corticosteroids (of any dose; for the CNS disease specifically) for symptomatic management.
3. Other malignancy or prior malignancy with a disease-free interval of less than 3 years prior to ICF signing; 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, e.g. patients with adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ are eligible.
4. Patients with clinically significant active infection, cardiac disease, significant medical or psychiatric disease/condition that, in the opinion of the Investigator, would make the administration of study drug hazardous to the patient, interfere with the evaluation of study results, interpretation of patient safety, or prohibit patient understanding of the informed consent procedure or compliance with the requirements of the protocol.
5. Patients with suspected autoimmune or active autoimmune disorder or known history of an autoimmune neurologic condition (e.g. Guillain-Barré syndrome).
6. Patients with history of solid organ transplantation or allogeneic hematopoietic stem cell transplantation.
7. Patients with history or known presence of tuberculosis.
8. Pregnant and breastfeeding patients.
9. Patients with history or presence of human immunodeficiency virus infection, active/chronic hepatitis B virus infection, and active hepatitis C virus infection.
10. 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.
11. Patients with a history of hypersensitivity to any excipient, or active substance, present in the pharmaceutical forms of applicable study treatments. In addition, patients with hypersensitivity to murine proteins should not receive rituximab.
12. Patients with grade 3B FL or transformation to an aggressive lymphoma subtype.
13. Patients treated with herbal remedies with immune stimulating properties or known to potentially interfere with major organ function.
14. Patients with only one prior treatment and a high-risk profile as defined by first progression of disease within 24 months of diagnosis (the exclusion is not applicable for patients with more than one prior line treatment).
15. Patients with prior exposure to EO2463.
16. Patients treated with immunotherapy (meaning immunostimulatory or immunosuppressive therapy; beside excluded, or allowed, compounds per other inclusion/exclusion criteria specifications), radionuclide therapy, radiotherapy, cytoreductive therapy, or received treatment with any other investigational agent within 28 days before the first EO2463 administration. Note, for symptom directed localized radiotherapy (e.g. for limited size lymph node(s)) the interval between radiotherapy and start of EO2463 administrations might, dependent on location and patient characteristics, be shorter than 28 days per the judgement of the treating physician, but should not be reduced to less than 14 days.
17. Patients to be included in Cohorts 1 and 4, and who have received rituximab or other B cell ablation therapy within 8 weeks of start of study treatment.
18. Patients to be included in Cohorts 1 and 4, and who have already progressed during prior treatment with the R2-regimen, i.e. an adequate combination of lenalidomide and rituximab.
19. Patients with abnormal laboratory values
20. Patients with persistent Grade 3 or 4 toxicities (according to NCI-CTCAE v5.0) after prior treatments; toxicities must be resolved since at least 2 weeks before study treatment start to Grade 1 or less. However, alopecia or other persisting toxicities Grade ≤ 2 not constituting a safety risk based on Investigator’s judgment are acceptable.
21. Patients to be included in Cohorts 4, who received prior CAR T-cell therapy and progressed within 6 months after this therapy.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. The primary endpoints of the phase 1 part of the trial are to define the recommended phase 2 dose (RP2D) for EO2463 monotherapy by applying a 3-by-3 trial design and defined acceptability levels for safety concern events (Cohort 1), and to confirm the safety of EO2463 at the monotherapy RP2D in combination with lenalidomide (EL; Cohort 4), rituximab (ER; Cohort 2), and lenalidomide/rituximab (ER^2; Cohorts 1 and 4).
2. The primary endpoint of the phase 2 part of the trial is to estimate the ORR according to the Lugano Classification, during EO2463 monotherapy (Cohort 1 weeks 1-6, Cohort 2 until (confirmed) disease progression, and Cohort 3 weeks 1-6), among patients evaluable for efficacy (i.e. patients having at least one tumor assessment post treatment start during EO2463 monotherapy).
3. An additional primary endpoint for the phase 2 part of the trial is to estimate the complete remission (CR)-rate according to the Lugano Classification 2014 during therapy with the combination of EO2463/lenalidomide/rituximab (ER) among patients evaluable for efficacy (i.e. patients having at least on tumor assessment post treatment start during combination therapy with ER).

Secondary endpoints 5

1. Incidences of adverse events (AEs), treatment-emergent AEs (TEAEs), serious AEs (SAEs), deaths, treatment discontinuations/delays, and laboratory abnormalities using the NCI-CTCAE v5.0 grading system. For EO2463 administered as monotherapy, and in combination with lenalidomide, rituximab, and lenalidomide/rituximab.
2. Level of changes (depletion/expansion), including durations, of B and T cells, and immunoglobulins, as measured in peripheral blood (FACS) and serum (electrophoresis or equivalent method), respectively.
3. % of patients with shown immunogenicity (expansion of specific T cells comparing samples taken at baseline versus on treatment in an individual patient determining if the patient has a positive response to the immunization, or not) in relation to the peptides that compose EO2463 by IFN-γ, ELISpot, and by intracellular cytokines staining, and multimers staining assays. Cross reactivities with the human B cell antigens CD20, CD22, CD37, and BAFF-receptor will also be evaluated by the same methods
4. ORR and DOR as described by the Lugano Classification 2014, and by the Lymphoma Response to Immunomodulatory Therapy Criteria (LyRIC) 2016 by trial cohort.
5. TTT, PFS and OS, as defined in the protocol

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 6

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Enterome

Sponsor organisation

Enterome

Address

94 Avenue Ledru Rollin

City

Paris

Postcode

75011

Country

France

Scientific contact point

Organisation

Enterome

Contact name

Chief Medical Officer

Public contact point

Organisation

Enterome

Contact name

Head of Regulatory Affairs

Third parties 12

Locations

3 EU/EEA countries · 8 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 20 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications