D2C7-IT + 2141-V11 for Brain Cancer

Recruiting in Palo Alto (17 mi)

Overseen by Annick Desjardins, MD,FRCPC

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Annick Desjardins, MD

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

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

No Placebo Group

Trial Summary

What is the purpose of this trial?

This is a phase 1 study of an anti-CD40 monoclonal antibody (2141-V11) in combination with D2C7-IT for patients with recurrent World Health Organization (WHO) grade III or 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 taking your current medications. However, you cannot have received chemotherapy, immunotherapy, or certain other treatments within specific time frames before starting the study drug. It's best to discuss your current medications with the study team.

What data supports the effectiveness of the treatment D2C7-IT + 2141-V11 for brain cancer?

Research shows that combining D2C7-IT, which targets specific proteins on tumor cells, with an anti-CD40 antibody can activate the immune system and lead to long-term tumor control in brain cancer models. This combination treatment has shown promising results in mice, leading to cures and increased immune activity against tumors. ^{1 2 3 4 5}

Is the D2C7-IT + 2141-V11 treatment generally safe for humans?

The D2C7-IT treatment has shown promising results in preclinical studies, and a rat toxicity study helped determine safe dosage levels, leading to FDA approval for human trials. The Fc-engineered anti-CD40 antibody, part of the treatment, has shown potential toxicity in systemic use, but this can be reduced with direct tumor injection, which is part of the current approach. ^{1 2 6 7 8}

What makes the D2C7-IT + 2141-V11 treatment unique for brain cancer?

The D2C7-IT + 2141-V11 treatment is unique because it combines a targeted immunotoxin that attacks specific proteins on brain cancer cells with an immune-boosting component that helps the body's immune system fight the tumor. This dual approach not only directly kills cancer cells but also stimulates a long-lasting immune response, which is different from standard treatments like surgery, radiation, and chemotherapy. ^{1 6 8 9 10}

Research Team

Annick Desjardins, MD,FRCPC

Principal Investigator

Duke University

Eligibility Criteria

Adults over 18 with recurrent high-grade malignant glioma confirmed by biopsy, able to undergo MRI, and not pregnant or breastfeeding. They must have a good performance status (able to care for themselves), adequate blood counts, normal liver function tests, and agree to use effective contraception if of childbearing potential. Excluded are those with severe medical conditions like active infections or heart disease, recent chemotherapy or immunotherapy within specific time frames, certain prior cancers, autoimmune diseases requiring treatment in the past 3 months, and excessive steroid use.

Inclusion Criteria

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

My recent biopsy confirmed the recurrence of my tumor.

My blood clotting tests are normal, and if I'm on blood thinners, they're managed as per guidelines.

Exclusion Criteria

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

I haven't had immunotherapy in the last 4 weeks or have recovered from its side effects.

I have severe lung disease or my diabetes is not under control.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

D2C7-IT and 2141-V11 are delivered sequentially directly into the tumor by Convection Enhanced Delivery (CED) using an intracerebral catheter. TMD placement may occur approximately 14 days prior to D2C7-IT infusion for eligible patients.

1 year

Every 3 weeks for 1 year

Follow-up

Participants are monitored for safety and effectiveness after treatment, including monitoring for unacceptable toxicity and adverse events.

4 weeks

Extension

Patients who benefit from the therapy and desire to continue will receive CPL subcutaneous injections of 2141-V11 at 2.0 mg every 4-6 weeks.

Long-term

Treatment Details

Interventions

• 2141-V11 (Monoclonal Antibodies)
• D2C7-IT (Virus Therapy)

Trial Overview This phase 1 trial is testing a combination of an anti-CD40 monoclonal antibody called 2141-V11 and D2C7-IT in patients who have had their brain tumor come back after initial treatment. The study aims to evaluate the safety of this combo therapy at Duke's Brain Tumor Center.

Participant Groups

Group I: D2C7-IT + 2141-V11 and TMD Placement Experimental Treatment 2 Interventions

Patients who meet eligibility and agree with TMD placement will have the TMD implanted approximately 14 days prior to D2C7-IT infusion. Intraoperative CT will be performed post implant to ensure device location accuracy and check for hemorrhage. Prior to catheter insertion for D2C7-IT infusion, the first tumor/fluid sampling through the TMD will occur. Repeated tumor/fluid sampling via the TMD will occur prior to every 2141-V11 perilymphatic infusion, i.e., approximately 2 weeks (+ 1 week) after D2C7-IT and then every 3 weeks for 1 year.

Group II: D2C7-IT + 2141-V11 Experimental Treatment 2 Interventions

Single D2C7-IT intratumoral infusion (4613.2 ng/mL in 36 mL) over 72 hours followed by single 2141-V11 (3.0 mg, RP2D established prior to V5.0) infusion (5 dose levels) over 7 hours. This will be followed 2 weeks later by initiation of CPL subcutaneous injections of 2141-V11 at 2.0 mg, which will be repeated again 2 weeks later and then every 3 weeks for 1 year.

Who Is Running the Clinical Trial?

Annick Desjardins, MD

Lead Sponsor

Trials

3

Recruited

150+

Darell Bigner

Lead Sponsor

Trials

8

Recruited

380+

Rockefeller University

Collaborator

Trials

162

Recruited

16,700+

Richard P. Lifton

Rockefeller University

Chief Executive Officer since 2016

MD, PhD

Barry S. Coller

Rockefeller University

Chief Medical Officer since 2016

MD

Findings from Research

Using a mouse model that mimics human immune responses, researchers found that anti-CD40 antibodies can cause significant toxicity, similar to what is observed in patients, which helps predict potential side effects in clinical settings.

However, by delivering an Fc-engineered anti-CD40 antibody directly into tumors, the study demonstrated that it is possible to achieve strong antitumor immunity while avoiding the systemic toxicities associated with traditional methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicity of an Fc-engineered anti-CD40 antibody is abrogated by intratumoral injection and results in durable antitumor immunity. Knorr, DA., Dahan, R., Ravetch, JV.[2019]

Anti-CD40 monoclonal antibodies can be engineered to switch from antagonists, which are used for autoimmune diseases, to potent agonists that effectively target cancer, particularly by changing to the hIgG2 isotype.

This conversion results in significantly enhanced antitumor activity, with one antagonist becoming a super-agonist that outperforms previously known highly effective anti-CD40 mAbs, showcasing the potential of Fc engineering in therapeutic applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Isotype Switching Converts Anti-CD40 Antagonism to Agonism to Elicit Potent Antitumor Activity. Yu, X., Chan, HTC., Fisher, H., et al.[2023]

The engineered anti-CD40 antibody XmAbCD40 showed up to 150-fold increased antibody-dependent cell-mediated cytotoxicity (ADCC) compared to a native IgG1 anti-CD40 antibody, indicating its enhanced ability to target and kill cancer cells in various B-lineage malignancies.

XmAbCD40 was more effective than both the native IgG1 analog and the anti-CD20 antibody rituximab in inhibiting tumor growth in mouse models, suggesting its potential as a powerful immunotherapy for treating CD40(+) cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fc-engineered anti-CD40 antibody enhances multiple effector functions and exhibits potent in vitro and in vivo antitumor activity against hematologic malignancies. Horton, HM., Bernett, MJ., Peipp, M., et al.[2021]

Modified Fc regions of agonistic anti-human CD40 monoclonal antibodies (mAbs) significantly enhance their effectiveness in a mouse model that expresses human CD40 and IgG receptors.

The study emphasizes the importance of balancing increased treatment efficacy with the potential for secondary side effects, indicating that while modifications can improve outcomes, they may also introduce risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhibitory IgG Receptor-Expressing Cells: The Must-Have Accessory for Anti-CD40 Immunomodulatory mAb Efficacy. Bruhns, P., Teillaud, JL.[2018]

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]

ADC-1013, a fully human agonistic CD40 antibody, effectively activates dendritic cells, leading to enhanced immune responses such as increased secretion of IL12 and upregulation of costimulatory molecules, which are crucial for T-cell activation.

In preclinical models, ADC-1013 demonstrated significant antitumor effects and the ability to induce long-term tumor-specific immunity, suggesting its potential as a novel local immunotherapy for cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The human agonistic CD40 antibody ADC-1013 eradicates bladder tumors and generates T-cell-dependent tumor immunity. Mangsbo, SM., Broos, S., Fletcher, E., et al.[2021]

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 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]

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]

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

Toxicity of an Fc-engineered anti-CD40 antibody is abrogated by intratumoral injection and results in durable antitumor immunity. [2019]

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

Isotype Switching Converts Anti-CD40 Antagonism to Agonism to Elicit Potent Antitumor Activity. [2023]

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

Fc-engineered anti-CD40 antibody enhances multiple effector functions and exhibits potent in vitro and in vivo antitumor activity against hematologic malignancies. [2021]

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

Inhibitory IgG Receptor-Expressing Cells: The Must-Have Accessory for Anti-CD40 Immunomodulatory mAb Efficacy. [2018]

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

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

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

The human agonistic CD40 antibody ADC-1013 eradicates bladder tumors and generates T-cell-dependent tumor immunity. [2021]

8. England pubmed.ncbi.nlm.nih.gov

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

9. 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]

10. 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]