D2C7-IT + Atezolizumab for Glioma

Overseen By Daniel Landi, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Darell Bigner

Must not be taking: Chemotherapy, Immunotherapy, Bevacizumab, others

Disqualifiers: Pregnancy, Severe heart disease, Uncontrolled diabetes, others

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination treatment for individuals with grade IV malignant glioma, an aggressive brain tumor. The study tests the effects of two drugs, atezolizumab (an immunotherapy drug) and D2C7-IT (an experimental treatment), to determine if they can work together to better target and treat this cancer. Participants will receive these treatments to help researchers assess their safety and effectiveness. Suitable candidates for this trial have a confirmed recurrence of this brain tumor and can undergo an MRI scan. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

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.

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

Previous studies have tested atezolizumab in patients with glioblastoma and other cancers. These studies found it to be generally safe and somewhat effective, indicating it worked and was well-tolerated. D2C7-IT, a type of monoclonal antibody, is a lab-made protein that can attach to specific targets in the body and has also been tested in humans. It specifically targets cells in brain tumors.

As this is a phase 1 study, the primary focus is on assessing the safety of using D2C7-IT with atezolizumab together. Phase 1 studies represent the early stages of research, aiming to determine if treatments are safe and how the body reacts to them. Early findings from other trials suggest that both atezolizumab and D2C7-IT have been safe, indicating that the combination should be reasonably well-tolerated. However, the complete safety profile is still being explored in this study. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about D2C7-IT combined with atezolizumab for glioma because it introduces a unique approach to treatment. Unlike standard options like temozolomide and radiation therapy, which focus on damaging cancer DNA or killing cancer cells directly, D2C7-IT uses convection-enhanced delivery to target a specific receptor on tumor cells, potentially offering a more direct attack on the cancer. This method, combined with atezolizumab, an immunotherapy drug that boosts the body's immune response against tumors, could enhance the effectiveness and precision of treatment. By integrating these innovative approaches, this combination has the potential to improve outcomes for patients with glioma.

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

Research has shown that combining D2C7-IT and atezolizumab may help treat glioblastoma, a type of brain cancer. In this trial, participants will receive one of two different dosages of D2C7-IT alongside atezolizumab. D2C7-IT is a special protein that targets and kills cancer cells with specific changes in their surface proteins called EGFR. Lab studies demonstrated that D2C7-IT effectively kills glioblastoma cells. Atezolizumab is a drug that helps the immune system find and attack cancer cells. Using these two treatments together might enhance their effectiveness, as atezolizumab could help the immune system attack the cancer cells that D2C7-IT targets. ^{1 2 3 4 5}

Who Is on the Research Team?

Daniel Landi, MD

Principal Investigator

Duke University

Are You a Good Fit for This Trial?

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.

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

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04160494

D2C7-IT With Atezolizumab for Recurrent Gliomas 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 ...

2. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2020-01526

D2C7-IT and Atezolizumab for the Treatment of Recurrent ... Combining D2C7-IT with a checkpoint inhibitor, such as atezolizumab, may be effective against glioblastoma. Eligibility Criteria ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7650440/

CTIM-23. A PHASE 1 TRIAL OF D2C7-IT IN ... D2C7 immunotoxin (D2C7-IT) is a dual-specific recombinant immunotoxin comprising an EGFR-wt and mutant-specific (EGFRvIII) monoclonal antibody fragment and a ...

4. withpower.com withpower.com/trial/phase-1-glioma-2-2020-12e08

D2C7-IT + Atezolizumab for Glioma · Info for Participants D2C7-IT, an immunotoxin targeting specific EGFR proteins, demonstrated significant tumor-killing ability in glioblastoma cells, with effective in vitro IC50 ...

5. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/94/NCT04160494/ICF_000.pdf

This consent form template does not contain HIPAA language The purpose of this research study is to determine the safety of administering a single dose of an investigational compound called ...