AB154 Combined With AB122 for Recurrent Glioblastoma

NCT04656535 | Active Not Recruiting Early Phase 1 DMC FDA Drug

• 2 other identifiers: 2000028799R01CA266757
• Study Type: interventional
• Target: 46
• Locations: 1 country
• Sites: 3

Brief Summary

This is a phase 0/I exploratory study. Patients at first or second recurrence of glioblastoma will be enrolled. The study will be divided into two cohorts: Cohort A (safety cohort) and Cohort B (surgical patient cohort). Cohort A: Eligible patients will be sequentially enrolled to receive intravenous domvanalimab combined with zimberelimab (N=6). Domvanalimab will be given at a dose of 10 mg/kg and zimberelimab will be given at a dose of 240 mg (flat). The dosing was determined in a separate study in solid tumors; this cohort will confirm the safety of the dosing schedule in patients with brain tumors. Cohort B: Expansion surgical cohort. The purpose of cohort B is to provide an additional safety evaluation of domvanalimab + zimberelimab as well as tissue and blood for exploratory ancillary studies investigating the effects of domvanalimab + zimberelimab in the tumor and tumor microenvironment. A total of 46 patients will be enrolled in this cohort.

Conditions

Glioblastoma

Keywords

Glioblastoma; Recurrent; PD1; TIGIT; Immunotherapy

Outcome Measures

Primary Outcomes (1)

• Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] associated with the combination AB122 and AB154 in patients with recurrent glioblastoma

  Adverse events will be listed individually by patient and treatment group. The number of patients experiencing each adverse event will be summarized by organ and grade. The number and percentage of patients with adverse events in the different categories will be summarized by treatment group.

  through study completion, an average of 2 years

Secondary Outcomes (2)

• Single cell RNA sequencing of tumor and blood after exposure to AB154 with and without AB122

  through study completion, an average of 2 years

• Tregs and CD8 T cells ratio by immunofluorescence

  through study completion, an average of 2 years

Study Arms (5)

Zimberelimab (AB 122) + Domvanalimab (AB 154) Safety Cohort (Cohort A)

EXPERIMENTAL

Eligible patients will be sequentially enrolled to receive intravenous domvanalimab (AB 154) combined with zimberelimab (AB 122) (N=6). domvanalimab (AB 154) will be given at a dose of 10 mg/kg and zimberelimab (AB 122) will be given at a dose of 240 mg (flat).

Drug: Zimberelimab; Drug: Domvanalimab

Domvanalimab (AB 154) Surgical Cohort (Cohort B1)

EXPERIMENTAL

Candidates for surgical resection will be enrolled and initiate study treatment approximately two weeks prior to the resection. The pre-surgical dose (neoadjuvant treatment) will be double-blinded. B1 (N=10): domvanalimab (AB 154) single agent (10 mg/kg) + placebo Following surgery, all patients will initiate treatment with the combination of domvanalimab (AB 154) and zimberelimab (AB 122). Domvanalimab (AB 154) will be given at a dose of 10 mg/kg and zimberelimab (AB 122) will be given at a dose of 240 mg (flat).

Drug: Domvanalimab; Drug: Placebo

Zimberelimab (AB 122) Surgical Cohort (Cohort B2)

EXPERIMENTAL

Candidates for surgical resection will be enrolled and initiate study treatment approximately two weeks prior to the resection. The pre-surgical dose (neoadjuvant treatment) will be double-blinded. B2 (N=10): zimberelimab (AB 122) single agent (240 mg) + placebo Following surgery, all patients will initiate treatment with the combination of domvanalimab (AB 154) and zimberelimab (AB 122). Domvanalimab (AB 154) will be given at a dose of 10 mg/kg and zimberelimab (AB 122) will be given at a dose of 240 mg (flat).

Drug: Zimberelimab; Drug: Placebo

Domvanalimab (AB 154) + Zimberelimab (AB 122) Surgical Cohort (Cohort B3)

EXPERIMENTAL

Candidates for surgical resection will be enrolled and initiate study treatment approximately two weeks prior to the resection. The pre-surgical dose (neoadjuvant treatment) will be double-blinded. B3 (N=10): domvanalimab (AB 154, 10 mg/kg) + zimberelimab (AB 122, 240 mg) Following surgery, all patients will initiate treatment with the combination of domvanalimab (AB 154) and zimberelimab (AB 122). Domvanalimab (AB 154) will be given at a dose of 10 mg/kg and zimberelimab (AB 122) will be given at a dose of 240 mg (flat).

Drug: Zimberelimab; Drug: Domvanalimab

Placebo Surgical Cohort (Cohort B4)

EXPERIMENTAL

Candidates for surgical resection will be enrolled and initiate study treatment approximately two weeks prior to the resection. The pre-surgical dose (neoadjuvant treatment) will be double-blinded. B4 (N=10): Two placebo infusions Following surgery, all patients will initiate treatment with the combination of domvanalimab (AB 154) and zimberelimab (AB 122). Domvanalimab (AB 154) will be given at a dose of 10 mg/kg and zimberelimab (AB 122) will be given at a dose of 240 mg (flat).

Drug: Placebo

Interventions

Domvanalimab DRUG

Domvanalimab (AB 154) is a humanized immunoglobulin G1 (IgG1) monoclonal antibody that targets TIGIT.

Domvanalimab (AB 154) + Zimberelimab (AB 122) Surgical Cohort (Cohort B3); Domvanalimab (AB 154) Surgical Cohort (Cohort B1); Zimberelimab (AB 122) + Domvanalimab (AB 154) Safety Cohort (Cohort A)

Placebo DRUG

Saline placebo comparator for pre-surgery treatment in cohort B4

Domvanalimab (AB 154) Surgical Cohort (Cohort B1); Placebo Surgical Cohort (Cohort B4); Zimberelimab (AB 122) Surgical Cohort (Cohort B2)

Zimberelimab DRUG

Zimberelimab (AB122) is a fully human immunoglobulin G4 (hIgG4) monoclonal antibody (mAb) that targets PD-1.

Domvanalimab (AB 154) + Zimberelimab (AB 122) Surgical Cohort (Cohort B3); Zimberelimab (AB 122) + Domvanalimab (AB 154) Safety Cohort (Cohort A); Zimberelimab (AB 122) Surgical Cohort (Cohort B2)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Grade IV glioma (glioblastoma and its variants according to the World Health Organization 2021), confirmed in tissue at time of initial diagnosis. Tumors with an IDH 1 or 2 mutation are excluded. Sequencing of IDH 1 and 2 is not required but, at a minimum, a negative result for the presence of IDH-1 R132H mutation on IHC is required for eligibility.
• First or second recurrence after treatment. Prior treatment must include at least radiation therapy.
• Measurable contrast enhancing tumor by Response Assessment in Neuro-Oncology (RANO) criteria. Not required for post-surgery eligibility for treatment in cohort B.
• Age ≥18 years.
• Karnofsky performance status ≥80 (≥ 70 for eligibility for treatment after surgery in cohort B).
• Patients must have adequate organ and marrow function as defined below within 14 days of treatment
• Absolute neutrophil count (ANC) ≥1,500 /mcL
• Platelets ≥100,000 / mcL
• Hemoglobin ≥9 g/dL or ≥ 5.6 mmol/L without transfusion or Erythropoietin (EPO) dependency (within 7 days of assessment)
• Serum creatinine ≤1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≥ 60 mL/min for subject with creatinine levels \> 1.5 X institutional ULN
• Serum total bilirubin ≤ 1.5 X ULN OR direct bilirubin ≤ ULN for subjects with total bilirubin levels \> 1.5 ULN
• aspartate aminotransferase (SGOT) and alanine transaminase (SGPT) ≤ 2.5 X ULN
• Albumin \>2.5 mg/dL
• International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
• Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants

You may not qualify if:

• Patients who have been treated with bevacizumab. Note: Previous use of intra-arterial bevacizumab may be allowed, contingent upon review and approval by study principal investigator and sponsor.
• Patients who have not recovered from adverse events due to prior therapy (i.e. \>Grade 1) with the exception of alopecia and fatigue.
• Patients with multifocal disease. (Cohort B only)
• Subjects requiring escalating or chronic supraphysiologic doses of corticosteroids (\> 10 mg/d of prednisone equivalent or \> 2 mg dexamethasone) for control of disease at the time of registration.
• Patients receiving previous or current treatment with an immune checkpoint inhibitor.
• Patients with a known diagnosis of immunodeficiency, including Human Immunodeficiency Virus (HIV) or acquired immunodeficiency syndrome (AIDS).
• Has known active Hepatitis B (e.g., Hepatitis B surface antigen reactive) or Hepatitis C (e.g., Hepatitis C Virus RNA \[qualitative\] is detected)
• Has a known history of active tuberculosis (Bacillus Tuberculosis).
• Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Has known history of, or any evidence of active, non-infectious pneumonitis.
• Has an active infection requiring systemic therapy.
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.

Sponsors & Collaborators

• National Cancer Institute (NCI): collaborator
• Arcus Biosciences, Inc.: collaborator
• Yale University: lead

Study Sites (3)

University of California San Francisco

San Francisco, California, 94143, United States

Location

Yale University

New Haven, Connecticut, 06519, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

MeSH Terms

Conditions

Glioblastoma; Recurrence

Interventions

zimberelimab

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Sylvia Kurz, MD

  Professor of Neurology

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: Masking will only occur in the surgical cohort B (4 arms) during the first cycle prior to surgery. The masking will be removed after surgery and all patients will receive open label treatment with both zimberelimab and domvanalimab.
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Neurology

Model Details: After the initial safety cohort confirms the safety of the dosing schedule an expansion surgical cohort will be enrolled and this cohort will be randomized to one of four treatment arms for the first cycle prior to surgery,

Study Record Dates

• First Submitted: November 18, 2020
• First Posted: December 7, 2020
• Study Start: April 21, 2021
• Primary Completion: March 17, 2026
• Study Completion (Estimated): December 31, 2026
• Last Updated: April 17, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)