AB154 + AB122 for Glioblastoma

Not currently recruiting at 2 trial locations

Overseen By Tara McPartland

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Yale University

Must not be taking: Bevacizumab, Immune checkpoint inhibitors

Disqualifiers: Immunodeficiency, Active hepatitis, Autoimmune, others

Stay on Your Current Meds You can continue your current medications while participating

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment combination for individuals with glioblastoma, a type of brain cancer, who have experienced a recurrence after initial treatment. The trial tests two drugs, domvanalimab (AB154) and zimberelimab (AB122), to determine their safety and effectiveness. It consists of two parts: one assesses the safety of these drugs, and the other examines their effects in patients undergoing tumor removal surgery. Individuals with recurrent glioblastoma after at least one treatment and who are candidates for surgery may be suitable for this trial. As a Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment combination.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, there is a requirement to wait at least 4 weeks or 5 half-lives after the last dose of any investigational agent or other treatment before starting the study. It's best to discuss your specific medications with the trial team.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, there is a requirement to wait at least 4 weeks or 5 half-lives after the last dose of any investigational or other treatment before starting the study. It's best to discuss your specific medications with the study team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Previous studies have shown that the combination of domvanalimab and zimberelimab is safe. Research indicates that patients with various types of cancer, including solid tumors, generally tolerate these drugs well. Some studies report that the side effects resemble those of other immunotherapy treatments, making them expected and manageable.

Domvanalimab blocks a protein that can slow the immune system, while zimberelimab helps the immune system identify and attack cancer cells. Although these treatments are in the early stages of testing for glioblastoma, they have been tested in other conditions and have shown promising safety results.

In this early phase of testing, researchers focus on confirming the safety of the dosing schedule for brain tumor patients. Early-phase trials indicate that the treatment has not been extensively tested in humans yet, so while initial findings are positive, more data is needed to fully understand the safety in this specific condition. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for glioblastoma because they incorporate innovative immunotherapy agents, zimberelimab (AB 122) and domvanalimab (AB 154), which work by enhancing the body's immune response against cancer cells. Unlike the standard treatments, such as surgery, radiation, and chemotherapy, which directly target tumors, zimberelimab blocks the PD-1 pathway, helping the immune system recognize and attack tumor cells. Domvanalimab adds another layer of immune activation by targeting the TIGIT pathway, potentially improving immune cell effectiveness. This dual-action approach holds promise for better targeting and potentially improving outcomes for patients with this aggressive brain cancer.

What evidence suggests that this trial's treatments could be effective for glioblastoma?

Research shows that using domvanalimab and zimberelimab together could be promising for treating glioblastoma, a type of brain cancer. In this trial, participants will receive different combinations of these drugs. Some will receive domvanalimab and zimberelimab together, while others will receive one of the drugs as a single agent before surgery. Early studies in other types of cancer have shown positive results, such as patients with certain stomach cancers living for an average of 26.7 months. For glioblastoma, these drugs might help slow or stop the cancer's growth, although more detailed results are still under investigation. This combination targets key parts of the immune system, potentially overcoming some challenges in treating this aggressive brain tumor. ^{4 5 6 7 8}

Who Is on the Research Team?

Sylvia Kurz, MD

Principal Investigator

Professor of Neurology

Are You a Good Fit for This Trial?

Adults with first or second recurrence of glioblastoma, who've had radiation therapy and are suitable for tumor removal surgery. They must have a good performance status (able to carry out daily activities), adequate organ function, and agree to use birth control. Excluded are those on high steroid doses, prior immune checkpoint inhibitor treatment, known immunodeficiency or active hepatitis, other progressing cancers, active autoimmune disease requiring recent treatment, multifocal disease (Cohort B only), current serious infections or conditions that could affect trial participation.

Inclusion Criteria

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 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, An interval of >=12 weeks from the end of prior radiation therapy is required unless there is either: i) histopathologic confirmation of recurrent tumor, or ii) new enhancement on MRI outside of the radiation treatment field, An interval of >=3 weeks or 5 half-lives (whichever is longer) after the last administration of any investigational agent or any other treatment prior to first study dose, Female subjects of childbearing potential should have a negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Female subjects of childbearing potential must be willing to use 2 methods of birth control or be surgically sterile or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year. Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy.

- Serum total bilirubin ≤ 1.5 X ULN OR direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN

My kidney function is within the normal range.

Exclusion Criteria

I am currently being treated for an infection.

I have not received a live vaccine within the last 30 days.

My condition involves cancer in multiple locations.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment - Cohort A

Eligible patients receive intravenous domvanalimab combined with zimberelimab to confirm the safety of the dosing schedule in patients with brain tumors.

2 weeks

Multiple visits for dosing and monitoring

Pre-surgical Treatment - Cohort B

Patients receive a pre-surgical dose of domvanalimab and/or zimberelimab approximately two weeks prior to surgical resection.

2 weeks

1 visit (in-person) for dosing

Post-surgical Treatment - Cohort B

Following surgery, all patients initiate treatment with the combination of domvanalimab and zimberelimab.

2-6 weeks

Multiple visits for dosing and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, including adverse events and pharmacodynamic effects.

up to 2 years

What Are the Treatments Tested in This Trial?

Interventions

• AB122
• AB154

Trial Overview

The study tests AB154 combined with AB122 in patients with recurrent glioblastoma. It has two parts: Cohort A checks safety at specific dosages; Cohort B further evaluates safety and collects tissue/blood samples for research on how the drugs work within tumors. Participants will receive intravenous treatments of both drugs.

How Is the Trial Designed?

Group I: Zimberelimab (AB 122) Surgical Cohort (Cohort B2) Experimental Treatment 2 Interventions

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).

Group II: Zimberelimab (AB 122) + Domvanalimab (AB 154) Safety Cohort (Cohort A) Experimental Treatment 2 Interventions

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).

Group III: Placebo Surgical Cohort (Cohort B4) Experimental Treatment 1 Intervention

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).

Group IV: Domvanalimab (AB 154) Surgical Cohort (Cohort B1) Experimental Treatment 2 Interventions

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).

Group V: Domvanalimab (AB 154) + Zimberelimab (AB 122) Surgical Cohort (Cohort B3) Experimental Treatment 2 Interventions

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).

Who Is Running the Clinical Trial?

Yale University

Lead Sponsor

Trials

1,963

Recruited

3,046,000+

Arcus Biosciences, Inc.

Industry Sponsor

Trials

44

Recruited

7,500+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Intracerebral administration of ipilimumab (IPI) and nivolumab (NIVO) after maximal safe resection of recurrent glioblastoma (rGB) was found to be feasible and safe, with mild immune-related adverse events and no significant central nervous system toxicity observed.

The treatment resulted in a median overall survival of 38 weeks, which is favorable compared to historical data, suggesting that this approach may improve outcomes for patients with rGB.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intracerebral administration of CTLA-4 and PD-1 immune checkpoint blocking monoclonal antibodies in patients with recurrent glioblastoma: a phase I clinical trial. Duerinck, J., Schwarze, JK., Awada, G., et al.[2022]

The combination of temozolomide (TMZ) and metformin significantly increased cell death in glioblastoma (GBM) cell lines compared to using either drug alone, indicating a synergistic effect in fighting this aggressive cancer.

In an orthotopic mouse model, the combination treatment improved median survival rates, with the highest survival observed in the group receiving high-dose metformin and TMZ, suggesting that targeting fatty acid synthase (FASN) may be a promising therapeutic strategy for GBM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-Dose Metformin Plus Temozolomide Shows Increased Anti-tumor Effects in Glioblastoma In Vitro and In Vivo Compared with Monotherapy. Lee, JE., Lim, JH., Hong, YK., et al.[2022]

In a phase III study involving 716 patients with newly diagnosed glioblastoma, the addition of the immune checkpoint inhibitor nivolumab (NIVO) to standard radiotherapy (RT) and temozolomide (TMZ) did not significantly improve progression-free survival (PFS) or overall survival (OS) compared to placebo, with median OS of 28.9 months for NIVO versus 32.1 months for placebo.

The study found a higher rate of grade 3/4 treatment-related adverse events in the NIVO group (52.4%) compared to the placebo group (33.6%), indicating that while NIVO did not enhance efficacy, it was associated with increased toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase III trial of chemoradiotherapy with temozolomide plus nivolumab or placebo for newly diagnosed glioblastoma with methylated MGMT promoter. Lim, M., Weller, M., Idbaih, A., et al.[2023]

Nivolumab combined with radiotherapy and temozolomide (NIVO+RT+TMZ) is tolerable for patients with newly diagnosed glioblastoma, with no new safety concerns identified; however, higher rates of grade 3/4 treatment-related adverse events were observed compared to Nivolumab with radiotherapy alone (NIVO+RT).

The study found that overall survival (OS) was similar for patients with unmethylated MGMT promoter whether they received NIVO+RT+TMZ or NIVO+RT, indicating that the addition of temozolomide may not significantly improve outcomes in this subgroup.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus radiotherapy with or without temozolomide in newly diagnosed glioblastoma: Results from exploratory phase I cohorts of CheckMate 143. Omuro, A., Reardon, DA., Sampson, JH., et al.[2023]

In a phase II study involving 80 patients with recurrent glioblastoma, pembrolizumab combined with bevacizumab showed a 6-month progression-free survival (PFS-6) of 26% and a median overall survival (OS) of 8.8 months, indicating limited efficacy despite being well tolerated.

Pembrolizumab alone had a much lower PFS-6 of 6.7% and no objective responses, suggesting that while the combination therapy had some durable responses, neither treatment was effective enough for significant clinical benefit.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized Phase II and Biomarker Study of Pembrolizumab plus Bevacizumab versus Pembrolizumab Alone for Patients with Recurrent Glioblastoma. Nayak, L., Molinaro, AM., Peters, K., et al.[2022]

OS2966 is a novel monoclonal antibody targeting CD29/β1 integrin, which is overexpressed in glioblastoma and contributes to tumor growth and treatment resistance, making it a promising candidate for treating high-grade gliomas.

The Phase I clinical trial employs innovative methods such as convection-enhanced delivery (CED) for direct tumor treatment and real-time MRI visualization, aiming to improve therapeutic distribution and effectiveness in patients undergoing tumor resection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Convection-Enhanced Delivery of a First-in-Class Anti-β1 Integrin Antibody for the Treatment of High-Grade Glioma Utilizing Real-Time Imaging. Nwagwu, CD., Immidisetti, AV., Bukanowska, G., et al.[2021]

In a study involving 40 newly diagnosed and 86 recurrent glioblastoma patients, PD-L1 blockade with durvalumab did not meet primary efficacy endpoints, indicating it was ineffective in improving outcomes compared to standard treatments.

Recurrent glioblastoma patients exhibited significantly lower levels of circulating immune cell subsets, and the use of dexamethasone was associated with a reduction in these immune cells, suggesting that immune suppression may hinder treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Circulating Immune Cell and Outcome Analysis from the Phase II Study of PD-L1 Blockade with Durvalumab for Newly Diagnosed and Recurrent Glioblastoma. Nayak, L., Standifer, N., Dietrich, J., et al.[2023]

Nivolumab, an immune checkpoint inhibitor, is being investigated as a treatment for pediatric glioblastoma multiforme, a rare and aggressive brain cancer, to improve patient survival.

This report highlights a significant adverse effect of nivolumab, specifically bilateral optic neuritis, in a patient with grade 4 glioblastoma multiforme, indicating the need for careful monitoring of side effects during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bilateral Optic Neuritis Secondary to Nivolumab Therapy: A Case Report. Kartal, Ö., Ataş, E.[2019]

The monoclonal antibody D2C7 shows high binding affinity for both wild-type and mutant forms of the epidermal growth factor receptor (EGFR), indicating its potential to target a broader range of tumor cells in malignant glioma.

In animal studies, D2C7 demonstrated significantly better tumor delivery compared to other antibodies, suggesting it could enhance the efficacy of immunotherapy for patients with gliomas expressing these EGFR variants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radioimmunotargeting of malignant glioma by monoclonal antibody D2C7 reactive against both wild-type and variant III mutant epidermal growth factor receptors. Zalutsky, MR., Boskovitz, A., Kuan, CT., et al.[2021]

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