A Phase I First-in-human Trial of Bvax (B-cell Vaccination) in Addition to Standard of Care Chemoradiotherapy for Newly Diagnosed Glioblastoma

Обзор

The objectives of this phase I first-in-human trial are to evaluate safety, feasibility, and preliminary efficacy of an individualized Bvax vaccine in addition to standard of care chemoradiation in patients with newly diagnosed glioblastoma.

Подробное описание

Patients will be enrolled following surgery or biopsy, confirming the diagnosis of glioblastoma. Leukapheresis may start any time after enrollment and before the start of adjuvant temozolomide (TMZ), ideally prior to starting radiation therapy (RT) with concomitant TMZ chemoradiation. Bvax vaccine production will occur during chemoradiation (TMZ/RT). Patients will first undergo leukapheresis for collection of peripheral blood mononuclear cells (PBMC) to produce Bvax. The CD19+ B cells will then be enriched for 4-1BBL+ cells that will be expanded in a cell culture and primed with tumor lysate from the patient's tissue. After passing quality control, the Bvax product will be cryopreserved at - 135oC. During the same process the CD8 T cells will be cryopreserved without further manipulation or expansion. Vaccine administration consisting of Bvax and autologous T cells will occur weekly, for a total of 4 doses. After completion of Bvax, patients may resume standard of care (SOC) with adjuvant TMZ with or without Tumor Treating Fields (TTFields), as clinically indicated.

Вмешательства

• Биопрепарат B-cell vaccination
  The study treatment includes dose-escalation of B-cell vaccine (Bvax) and a fixed dose of autologous CD8 T cells reinfusion integrated in the standard of care therapy for glioblastoma. Bvax is a biological product that is produced for each patient individually from the cells collected through leukapheresis. The Bvax treatment will be administrated once a week for a total of 4 doses. The following dose levels (DL) will be explored: * DL1: 0.5 x 106 Bvax/kg/injection and 2 x 106/kg/injection. *

Первичные конечные точки

• Incidence of adverse events [Срок оценки: Up to 90 days after the first dose of Bvax and/or T-cell]

Вторичные конечные точки (2)

• Progression-free survival (PFS) rate [Срок оценки: Up to five years]
• Overall survival (OS) rate [Срок оценки: Up to five years]

Критерии участия

Inclusion Criteria (for study participation)

• Histologically confirmed glioblastoma.

a. Adequate tissue is required for confirmation of diagnosis; a formalin-fixed and paraffin-embedded (FFPE) tissue block must be available for confirmation of diagnosis and possible additional molecular studies (if applicable)

• Fresh frozen tumor tissue available for preparation of vaccine (minimum of 1.5 grams) as detailed in the investigator's brochure (IB).
• No prior therapy other than surgery, or first-line therapy with standard chemoradiation.
• Age ≥ 18 years.
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
• Adequate organ and bone marrow function NOTE: Transfusions or growth factors to boost counts to an eligible level are not allowed.
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better.
• The effects of Bvax on the developing human fetus are unknown. For this reason and because other therapeutic agents used in this trial are known to be teratogenic, females of child-bearing potential (FOCBP) and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) from the time of informed consent, for the duration of study participation, and for 90 days following last dose of therapy.

• Should a female patient become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately.
• Men treated or enrolled on this protocol must also agree to use adequate contraception from the time of informed consent, for the duration of study participation, and 3 months after completion of administration.

NOTE: A FOCBP is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:

• Has not undergone a hysterectomy or bilateral oophorectomy
• Has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for > 12 months) FOCBP must have a negative pregnancy test before registration in the study.
• The ability to understand and the willingness to sign a written informed consent document.

Критерии исключения

• Have not recovered from adverse events from surgery or the ongoing chemoradiotherapy (i.e., have residual toxicities > Grade 2) with the exception of alopecia.
• Receiving any other investigational agents.
• A history of allergic reactions attributed to compounds of similar chemical or biologic composition to Bvax.

a. The Bvax drug product consists of: i. Active cellular component: Autologous CD19+ (4-1BBL+) B cells pulsed with autologous tumor lysate.

ii. Cryopreservation medium: CryoStor® CS10 (BioLife Solutions), a current Good Manufacturing Practice (cGMP)-grade, serum-free cryoprotectant containing 10% dimethyl sulfoxide (DMSO).

iii. Container closure system: OriGen Biomedical CryoStor® EVA freezing bag, made from biocompatible ethylene vinyl acetate (EVA).

• There are no animal-derived proteins, adjuvants, or foreign biologicals in the final drug product. Therefore, "compounds of similar chemical or biological composition" specifically refers to:

i. DMSO or DMSO-containing cryoprotectants, as hypersensitivity to DMSO has been reported in other cryopreserved cell therapy products.

ii. Excipients within CryoStor® CS10, which include pharmaceutical-grade buffer salts and electrolytes.

iii. EVA (ethylene vinyl acetate) materials used in the cryostorage bag, for individuals with rare known contact allergies to plastics or related compounds.

• An uncontrolled intercurrent illness, including, but not limited to, the following:

• Ongoing or active infection requiring systemic treatment
• Symptomatic congestive heart failure
• Unstable angina pectoris
• Cardiac arrhythmia
• Psychiatric illness/social situations that would limit compliance with study requirements
• Any other illness or condition that the treating investigator feels would interfere with study compliance or would compromise the patient's safety or study endpoints
• Psychiatric illness/social situations that would limit compliance with study requirements.
• Female patients who are pregnant or nursing. Pregnant or nursing women are excluded from this study because of the unknown risks of the study products.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 1 центр

• Northwestern University — Chicago

Публикации

• Zanetti M, Castiglioni P, Rizzi M, Wheeler M, Gerloni M. B lymphocytes as antigen-presenting cell-based genetic vaccines. Immunol Rev. 2004 Jun;199:264-78. doi: 10.1111/j.0105-2896.2004.00152.x. PMID 15233740
• Yuan Y, Hess KR, Hilsenbeck SG, Gilbert MR. Bayesian Optimal Interval Design: A Simple and Well-Performing Design for Phase I Oncology Trials. Clin Cancer Res. 2016 Sep 1;22(17):4291-301. doi: 10.1158/1078-0432.CCR-16-0592. Epub 2016 Jul 12. PMID 27407096
• Wennhold K, Thelen M, Schlosser HA, Haustein N, Reuter S, Garcia-Marquez M, Lechner A, Kobold S, Rataj F, Utermohlen O, Chakupurakal G, Theurich S, Hallek M, Abken H, Shimabukuro-Vornhagen A, von Bergwelt-Baildon M. Using Antigen-Specific B Cells to Combine Antibody and T Cell-Based Cancer Immunotherapy. Cancer Immunol Res. 2017 Sep;5(9):730-743. doi: 10.1158/2326-6066.CIR-16-0236. Epub 2017 Aug 4 PMID 28778961
• Trefzer U, Weingart G, Chen Y, Herberth G, Adrian K, Winter H, Audring H, Guo Y, Sterry W, Walden P. Hybrid cell vaccination for cancer immune therapy: first clinical trial with metastatic melanoma. Int J Cancer. 2000 Mar 1;85(5):618-26. doi: 10.1002/(sici)1097-0215(20000301)85:53.0.co;2-z. PMID 10699939
• Stupp R, Taillibert S, Kanner AA, Kesari S, Steinberg DM, Toms SA, Taylor LP, Lieberman F, Silvani A, Fink KL, Barnett GH, Zhu JJ, Henson JW, Engelhard HH, Chen TC, Tran DD, Sroubek J, Tran ND, Hottinger AF, Landolfi J, Desai R, Caroli M, Kew Y, Honnorat J, Idbaih A, Kirson ED, Weinberg U, Palti Y, Hegi ME, Ram Z. Maintenance Therapy With Tumor-Treating Fields Plus Temozolomide vs Temozolomide Alo PMID 26670971
• Stupp R, Taillibert S, Kanner A, Read W, Steinberg D, Lhermitte B, Toms S, Idbaih A, Ahluwalia MS, Fink K, Di Meco F, Lieberman F, Zhu JJ, Stragliotto G, Tran D, Brem S, Hottinger A, Kirson ED, Lavy-Shahaf G, Weinberg U, Kim CY, Paek SH, Nicholas G, Bruna J, Hirte H, Weller M, Palti Y, Hegi ME, Ram Z. Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone o PMID 29260225
• Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus PMID 15758009
• Schultze JL, Michalak S, Seamon MJ, Dranoff G, Jung K, Daley J, Delgado JC, Gribben JG, Nadler LM. CD40-activated human B cells: an alternative source of highly efficient antigen presenting cells to generate autologous antigen-specific T cells for adoptive immunotherapy. J Clin Invest. 1997 Dec 1;100(11):2757-65. doi: 10.1172/JCI119822. PMID 9389740

Идентификаторы

NCT: NCT07422896 · NU 25C11 · IND 31446

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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