D2C7-IT + Atezolizumab for Glioma

Overseen By Daniel Landi, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Darell Bigner

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 3

Duration: Up to 2 years

18 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a phase 1 study of atezolizumab in combination with D2C7-IT, a dual-specific monoclonal antibody (mAB) with a high affinity for both EGFRwt- and EGFRvIII-expressing cells, in patients with recurrent World Health Organization (WHO) grade IV malignant glioma at the Preston Robert Tisch Brain Tumor Center (PRTBTC) at Duke.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop all current medications, but you cannot have received chemotherapy or certain other treatments within specific time frames before starting the study. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

What data supports the effectiveness of the treatment D2C7-IT + Atezolizumab for glioma?

Research shows that D2C7-IT, a targeted therapy, can effectively kill glioblastoma cells by targeting specific proteins on the tumor, and it has shown promising results in animal models. Atezolizumab, an immune checkpoint inhibitor, has demonstrated activity in various cancers, including glioblastoma, by helping the immune system attack cancer cells. ^{1 2 3 4 5}

What safety data exists for D2C7-IT and Atezolizumab in humans?

Atezolizumab has been tested in patients with glioblastoma and other cancers, showing some clinical activity and safety in humans. D2C7-IT has been tested in rats, where high doses caused some brain-related side effects, but lower doses were found to be safe, leading to approval for human trials. ^{3 4 5 6 7}

How is the drug D2C7-IT + Atezolizumab unique for treating glioma?

D2C7-IT + Atezolizumab is unique because it combines an immunotoxin that targets specific proteins (EGFRwt and EGFRvIII) on glioblastoma cells with a checkpoint inhibitor to enhance the immune response. This approach aims to overcome the immune suppression typically seen in glioblastoma, potentially leading to more effective and durable treatment outcomes. ^{1 3 4 7 8}

Research Team

Daniel Landi, MD

Principal Investigator

Duke University

Eligibility Criteria

Adults with recurrent grade IV malignant glioma who have adequate organ function, are not pregnant or breastfeeding, and can undergo MRI. They must be able to sign informed consent, have a Karnofsky Performance Score of at least 70%, and meet specific blood count criteria. Excluded are those with immunodeficiency, severe lung or diabetes issues, certain allergies, recent immunotherapy or radiation unless showing progression, active infections or heart disease.

Inclusion Criteria

Hemoglobin ≥ 9 g/dl prior to biopsy

Neutrophil count ≥ 1000 cells/mm3 prior to biopsy

I am able to care for myself but may not be able to do active work.

Exclusion Criteria

My tumor has or might have a specific genetic feature, and I've had chemotherapy before.

Patients with an impending, life-threatening cerebral herniation syndrome, based on the assessment of the study neurosurgeons or their designate

I have worsening muscle weakness and muscle loss in my arms and legs.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single D2C7-IT infusion and atezolizumab infusions every three weeks

Up to 2 years

Every 3 weeks (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, with particular interest in adverse events and inflammatory events

1 year

Treatment Details

Interventions

• Atezolizumab
• D2C7-IT

Trial Overview The trial is testing the combination of Atezolizumab (an immune checkpoint inhibitor) with two different concentrations of D2C7-IT (a monoclonal antibody targeting cancer cells) in patients with recurring brain tumors. It's a phase 1 study focusing on safety and how well these treatments work together.

Participant Groups

Group I: D2C7-IT (6920 ng/mL) + Atezolizumab Experimental Treatment 2 Interventions

Single D2C7-IT convection-enhanced delivery (CED) infusion (6920 ng/mL) plus atezolizumab (1200 mg) intravenous (IV) infusions every three weeks for up to two years

Group II: D2C7-IT (4613.2 ng/mL) + Atezolizumab Experimental Treatment 2 Interventions

Single D2C7-IT convection-enhanced delivery (CED) infusion (4613.2 ng/mL) plus atezolizumab (1200 mg) intravenous (IV) infusions every three weeks for up to two years

Atezolizumab is already approved in United States, European Union for the following indications:

Approved in United States as Tecentriq for:

• Melanoma
• Hepatocellular carcinoma
• Small cell lung cancer
• Non-small cell lung cancer
• Urothelial carcinoma

Approved in European Union as Tecentriq for:

• Melanoma
• Hepatocellular carcinoma
• Small cell lung cancer
• Non-small cell lung cancer
• Urothelial carcinoma

Who Is Running the Clinical Trial?

Darell Bigner

Lead Sponsor

Trials

8

Recruited

380+

Annick Desjardins, MD

Lead Sponsor

Trials

3

Recruited

150+

Istari Oncology, Inc.

Industry Sponsor

Trials

13

Recruited

400+

Genentech, Inc.

Industry Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

The combination of D2C7-immunotoxin (IT) and αCD40 costimulation significantly enhances anti-tumor immunity in glioblastoma models, leading to long-term tumor-specific CD8+ T cell responses and even cures in mice.

This promising preclinical success has led to the initiation of a phase 1 clinical trial (NCT04547777) to evaluate the safety and efficacy of the D2C7-IT+αhCD40 treatment in human patients with malignant glioma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunotoxin-αCD40 therapy activates innate and adaptive immunity and generates a durable antitumor response in glioblastoma models. Parker, S., McDowall, C., Sanchez-Perez, L., et al.[2023]

The novel immunotoxin D2C7-(scdsFv)-PE38KDEL effectively targets both the wild-type epidermal growth factor receptor (EGFR) and the EGFR deletion mutant (EGFRvIII), which are commonly found in glioblastoma.

This immunotoxin has shown strong anti-cancer effects in established murine glioma models, indicating its potential as a therapeutic option for treating this aggressive brain tumor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel recombinant immunotoxin-based therapy targeting wild-type and mutant EGFR improves survival in murine models of glioblastoma. Chandramohan, V., Bigner, DD.[2022]

A novel tumor-targeted immunotoxin, D2C7-IT, has been developed to specifically target and kill glioblastoma cells expressing the EGFRwt and EGFRvIII proteins, showing effective cytotoxicity in various glioblastoma cell lines and xenograft models.

D2C7-IT has demonstrated robust anti-tumor efficacy in mouse models and has passed preclinical toxicity studies, leading to FDA approval for a Phase I/II clinical trial, indicating its potential as a new treatment option for glioblastoma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

EGFR/EGFRvIII-targeted immunotoxin therapy for the treatment of glioblastomas via convection-enhanced delivery. Bao, X., Pastan, I., Bigner, DD., et al.[2020]

D2C7-IT, an immunotoxin targeting specific EGFR proteins, demonstrated significant tumor-killing ability in glioblastoma cells, with effective in vitro IC50 values of 0.47 ng/mL and 1.05 ng/mL for CT-2A and SMA560 cells, respectively.

Combining D2C7-IT with immune checkpoint inhibitors (αCTLA-4 and αPD-1) not only prolonged survival in murine models of glioma but also led to complete tumor regressions in some cases, indicating a promising strategy for enhancing antitumor immune responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved efficacy against malignant brain tumors with EGFRwt/EGFRvIII targeting immunotoxin and checkpoint inhibitor combinations. Chandramohan, V., Bao, X., Yu, X., et al.[2023]

Atezolizumab, an immune checkpoint inhibitor, was found to be safe and well tolerated in a phase 1a clinical trial involving 16 patients with recurrent glioblastoma, with no severe treatment-related side effects reported.

The treatment showed some efficacy, with one patient achieving a partial response and three others stabilizing their disease, while median overall survival was 4.2 months, suggesting that certain biomarkers like peripheral CD4+ T cells may help identify patients who could benefit most from this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical activity and safety of atezolizumab in patients with recurrent glioblastoma. Lukas, RV., Rodon, J., Becker, K., et al.[2020]

References

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

Immunotoxin-αCD40 therapy activates innate and adaptive immunity and generates a durable antitumor response in glioblastoma models. [2023]

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

A novel recombinant immunotoxin-based therapy targeting wild-type and mutant EGFR improves survival in murine models of glioblastoma. [2022]

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

EGFR/EGFRvIII-targeted immunotoxin therapy for the treatment of glioblastomas via convection-enhanced delivery. [2020]

4. England pubmed.ncbi.nlm.nih.gov

Improved efficacy against malignant brain tumors with EGFRwt/EGFRvIII targeting immunotoxin and checkpoint inhibitor combinations. [2023]

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

Clinical activity and safety of atezolizumab in patients with recurrent glioblastoma. [2020]

6. Ireland pubmed.ncbi.nlm.nih.gov

Atezolizumab in patients with advanced non-small cell lung cancer and history of asymptomatic, treated brain metastases: Exploratory analyses of the phase III OAK study. [2019]

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

Preclinical toxicity evaluation of a novel immunotoxin, D2C7-(scdsFv)-PE38KDEL, administered via intracerebral convection-enhanced delivery in rats. [2018]

8. Germany pubmed.ncbi.nlm.nih.gov

Production and quality control assessment of a GLP-grade immunotoxin, D2C7-(scdsFv)-PE38KDEL, for a phase I/II clinical trial. [2023]