AB154 + AB122 for Glioblastoma

Recruiting in Palo Alto (17 mi)

+2 other locations

Overseen by Sylvia Kurz, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase < 1

Waitlist Available

Sponsor: Yale University

Must not be taking: Bevacizumab, Immune checkpoint inhibitors

Disqualifiers: Immunodeficiency, Active hepatitis, Autoimmune, others

Stay on Your Current Meds

No Placebo Group

Trial Summary

What is the purpose of this trial?

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.

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.

What data supports the effectiveness of the drug AB154 + AB122 for glioblastoma?

Research on similar drugs like nivolumab, which is also an immune checkpoint inhibitor, shows potential in treating glioblastoma by enhancing the body's immune response against cancer cells. ^{1 2 3 4 5}

What makes the drug AB154 + AB122 unique for treating glioblastoma?

AB154 (Domvanalimab) and AB122 (Zimberelimab) are unique because they are immune checkpoint inhibitors that target specific proteins to boost the body's immune response against cancer cells, which is a different approach compared to traditional chemotherapy or radiation. This combination aims to enhance the immune system's ability to fight glioblastoma, a highly aggressive brain cancer. ^{5 6 7 8 9}

Research Team

Sylvia Kurz, MD

Principal Investigator

Professor of Neurology

Eligibility Criteria

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.

Treatment Details

Interventions

• AB122 (Monoclonal Antibodies)
• AB154 (Monoclonal Antibodies)

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.

Participant Groups

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+

Nancy J. Brown

Yale University

Chief Medical Officer since 2020

MD from Yale School of Medicine

Peter Salovey

Yale University

Chief Executive Officer since 2013

PhD in Psychology from Yale University

Arcus Biosciences, Inc.

Industry Sponsor

Trials

44

Recruited

7,500+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Dr. Douglas R. Lowy

National Cancer Institute (NCI)

Chief Executive Officer since 2023

MD from New York University School of Medicine

Dr. Monica Bertagnolli

National Cancer Institute (NCI)

Chief Medical Officer since 2022

MD from Harvard Medical School

Findings from Research

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]

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]

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]

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]

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]

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]

References

1. United States 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. [2023]

2. England 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. [2023]

3. Korea (South) 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. [2022]

4. United States 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. [2021]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Bilateral Optic Neuritis Secondary to Nivolumab Therapy: A Case Report. [2019]

6. England 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. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Phase III trial of chemoradiotherapy with temozolomide plus nivolumab or placebo for newly diagnosed glioblastoma with methylated MGMT promoter. [2023]

8. United States pubmed.ncbi.nlm.nih.gov

Randomized Phase II and Biomarker Study of Pembrolizumab plus Bevacizumab versus Pembrolizumab Alone for Patients with Recurrent Glioblastoma. [2022]

9. Switzerland 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. [2021]