D2C7-IT + 2141-V11 for Brain Cancer

Overseen By Stevie Threatt

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)

Compensation: Varies

Number of Visits: 2

Duration: 49 weeks

46 Participants Needed

Trial Summary

Do I need to stop taking my current medications to join the trial?

The trial protocol does not specify if you need to 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 trial team.

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

Research shows that combining D2C7-IT with an anti-CD40 antibody activates the immune system and leads to long-term tumor-specific immune responses in brain cancer models, resulting in cures in mice. Additionally, Fc-engineered anti-CD40 antibodies have shown strong antitumor activity in other cancer types, suggesting potential effectiveness in brain cancer. ^{1 2 3 4 5}

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

The D2C7-IT treatment has been tested in animal models and early human trials, showing promising results with manageable safety profiles. The Fc-engineered anti-CD40 antibody, part of the treatment, has shown potential toxicities in systemic use, but these can be reduced with direct tumor injections, suggesting a safer approach for human use. ^{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 more effectively. This 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 7 9 10}

What is the purpose of this trial?

The purpose of this study is to assess the safety and efficacy of the combination of D2C7-IT+2141-V11 administered in the non-enhancing tumor of patients with resected recurrent glioblastoma (rGBM) via convection enhanced delivery (CED), followed by subcutaneous cervical perilymphatic injections (CPLIs) of 2141-V11 2 and 4 weeks post infusion, then every 3 weeks for a year, and every 4-6 weeks thereafter if patients benefit from therapy.

Research Team

Annick Desjardins, MD

Principal Investigator

Duke University

Eligibility Criteria

This trial is for adults over 18 with a specific brain cancer called WHO grade 4 IDHwt GBM. They must have had surgery recently, be able to undergo MRI scans, and not be pregnant or breastfeeding. Participants need normal blood counts and organ function tests, agree to use birth control, and can't have certain medical conditions or recent treatments with other cancer therapies.

Inclusion Criteria

My brain tumor is a confirmed grade 4 and not IDH mutant.

Hemoglobin ≥ 9 g/dl prior to biopsy

Neutrophil count ≥ 1000 prior to biopsy

Exclusion Criteria

Patients with albumin allergy

I am not pregnant or breastfeeding.

I am at risk of a severe brain condition due to pressure increase.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive D2C7-IT and 2141-V11 infused in the residual disease via CED, followed by repeated injections of 2141-V11 in the cervical perilymphatic subcutaneous area

49 weeks

Injections at weeks 2, 4, 7, 10, and every 3 weeks until week 49

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Open-label extension (optional)

Participants who benefit from the therapy may continue receiving CPLI of 2141-V11 every 4-6 weeks

Long-term

Treatment Details

Interventions

• 2141-V11
• D2C7-IT

Trial Overview The study tests D2C7-IT combined with 2141-V11 in patients who've had brain surgery for recurrent glioblastoma. The treatment involves direct infusion into the brain followed by injections near lymph nodes over several weeks to see if it's safe and effective against the tumor.

Participant Groups

Group I: 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 an 2141-V11 infusion over 7 hours. This is followed by injections of 2141-V11 (2mg) in the cervical perilymphatic (CPLI) subcutaneous area ipsilateral to the tumor at weeks 2, 4, 7, 10 and then every 3 weeks until week 49. After week 49 (equivalent of 1 year of every 3 weeks CPLI of 2141-V11), patients who have completed 1 year of CPL subcutaneous injections of 2141-V11 at 2 mg every 3 weeks, who benefit from the therapy, and desire to continue on therapy, will receive CPLI of 2141-V11 at 2 mg every 4-6 weeks.

Who Is Running the Clinical Trial?

Darell Bigner

Lead Sponsor

Trials

8

Recruited

380+

Rockefeller University

Collaborator

Trials

162

Recruited

16,700+

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]

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]

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]

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]

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. England pubmed.ncbi.nlm.nih.gov

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

8. 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]

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]