D2C7-IT + 2141-V11 for Glioblastoma

Overseen by Daniel Landi, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Darell Bigner

Must be taking: Temozolomide

Must not be taking: Immunosuppressants, Steroids

Disqualifiers: Pregnancy, Severe heart disease, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

The purpose of this research study is to determine the safety and efficacy of administering a single intracerebral (within the brain) dose of investigational compounds called D2C7-immunotoxin (IT) and 2141-V11 in residual disease (within tumor margins) after surgery, followed by later repeated injections of 2141-V11 in the subcutaneous area (under the skin) around the lymph nodes of the head and neck for adults newly diagnosed with a type of cancerous brain tumor called glioblastoma. The word "investigational" means the study drugs are still being tested in research studies and are not approved by the U.S. Food and Drug Administration (FDA).

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on anticoagulation therapy, it may be held during the perioperative period (around the time of surgery) as per the neurosurgical team's recommendations.

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

Research shows that the combination of D2C7-IT and an anti-CD40 antibody can activate the immune system and lead to long-term tumor-specific immune responses in glioblastoma models, resulting in cures in mice. This suggests potential effectiveness in treating glioblastoma by enhancing the body's immune response against the tumor. ^{1 2 3 4 5}

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

Preclinical studies in mice and rats have shown promising results for the safety of D2C7-IT and Fc-engineered anti-CD40 antibodies, with toxicity being manageable when delivered directly into tumors. Early human trials are underway to further evaluate safety, but results are not yet conclusive. ^{1 6 7 8 9}

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

The D2C7-IT + 2141-V11 treatment is unique because it combines a targeted immunotoxin that attacks specific proteins on glioblastoma cells with an engineered antibody that stimulates the immune system, potentially overcoming the tumor's ability to suppress immune responses. This approach aims to enhance the body's natural defenses against the tumor, offering a novel strategy compared to traditional treatments like surgery, radiation, and chemotherapy. ^{1 7 8 9 10}

Research Team

Daniel Landi, MD

Principal Investigator

Duke University

Eligibility Criteria

Adults over 18 with newly diagnosed glioblastoma, a type of brain tumor, who've had surgery to remove it but still have some remaining disease. They must be in good health otherwise, with proper organ function and blood counts, not on high doses of steroids or anticoagulants that can't be paused for surgery. Participants should not be pregnant or breastfeeding and must agree to use birth control if they can have children.

Inclusion Criteria

Total bilirubin ≤ 1.5 x ULN prior to catheter placement

I have a specific type of brain tumor (glioblastoma) that has been surgically removed but still shows signs on scans.

My platelet count is high enough for tests and procedures.

Exclusion Criteria

I do not have severe health issues that could interfere with the treatment.

I am not pregnant or breastfeeding.

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

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Intratumoral Infusion

Single infusion of D2C7-IT over 3 days followed by a single infusion of 2141-V11 over 7 hours delivered to the tumor margins through a catheter placed in the brain

3 days

Subcutaneous Injection and Radiation

First subcutaneous injection of 2141-V11 around the lymph nodes of the head and neck, followed by standard radiation therapy lasting 3 to 6 weeks

3-6 weeks

Post-Radiation Injections

Resumption of 2141-V11 injections around the lymph nodes of the head and neck, starting 1 week after radiation and continuing every 3 weeks for up to a year

up to 1 year

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• 2141-V11 (Cancer Vaccine)
• D2C7-IT (Immunotoxin)

Trial Overview The trial is testing two investigational drugs: D2C7-IT given once inside the brain after surgery and 2141-V11 injected multiple times under the skin near lymph nodes. The study aims to see how safe these treatments are and how well they work against glioblastoma when combined with standard radiation therapy.

Participant Groups

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

Single D2C7-IT intratumoral infusion (6920 ng/mL in 36 mL) over 72 hours followed by single 2141-V11 infusion (5 dose levels) over 7 hours followed by an injection of 2141-V11 in the cervical perilymphatic subcutaneous area ipsilateral to the tumor at week 2, radiation, and further injections of 2141-V11 in the cervical perilymphatic subcutaneous area ipsilateral to the tumor.

Who Is Running the Clinical Trial?

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

Higher levels of CD40/CD40L expression in grade III gliomas are associated with better prognoses in patients with glioblastoma, suggesting it could serve as a useful biomarker for treatment outcomes.

The use of FGK45, an agonistic antibody targeting CD40, in combination with OX86 significantly prolonged survival in glioma models, indicating a promising immunotherapeutic strategy for treating gliomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD40/CD40L expression correlates with the survival of patients with glioblastomas and an augmentation in CD40 signaling enhances the efficacy of vaccinations against glioma models. Chonan, M., Saito, R., Shoji, T., et al.[2018]

Systemic delivery of αCD40 antibodies in preclinical glioma models leads to the formation of tertiary lymphoid structures (TLS), which are associated with increased T cell infiltration in treatment-naïve glioma patients.

Despite promoting TLS formation, αCD40 treatment results in hypofunctional T cells and impairs the effectiveness of immune checkpoint inhibitors, likely due to the accumulation of suppressive CD11b+ B cells in the tumor microenvironment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Agonistic CD40 therapy induces tertiary lymphoid structures but impairs responses to checkpoint blockade in glioma. van Hooren, L., Vaccaro, A., Ramachandran, M., et al.[2021]

The study identified folate receptor beta (FR beta) on tumor-associated macrophages (TAMs) in glioblastomas, suggesting a potential target for therapy.

A recombinant immunotoxin designed to target FR beta-expressing TAMs significantly depleted these macrophages and reduced tumor growth in a rat glioma model, indicating its potential as a therapeutic tool for treating glioblastomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting tumor-associated macrophages in an experimental glioma model with a recombinant immunotoxin to folate receptor beta. Nagai, T., Tanaka, M., Tsuneyoshi, Y., et al.[2023]

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]

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]

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]

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]

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]

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]

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. England pubmed.ncbi.nlm.nih.gov

CD40/CD40L expression correlates with the survival of patients with glioblastomas and an augmentation in CD40 signaling enhances the efficacy of vaccinations against glioma models. [2018]

3. England pubmed.ncbi.nlm.nih.gov

Agonistic CD40 therapy induces tertiary lymphoid structures but impairs responses to checkpoint blockade in glioma. [2021]

4. Germany pubmed.ncbi.nlm.nih.gov

Targeting tumor-associated macrophages in an experimental glioma model with a recombinant immunotoxin to folate receptor beta. [2023]

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

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

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

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

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

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

10. 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]