D2C7-IT + 2141-V11 for Glioblastoma

Overseen By Daniel Landi, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Darell Bigner

Must be taking: Temozolomide

Must not be taking: Immunosuppressants, Steroids

Disqualifiers: Pregnancy, Severe heart disease, others

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

Compensation: Varies

Number of Visits: Unknown

50 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and effectiveness of two investigational drugs, D2C7-IT and 2141-V11, for glioblastoma, a type of brain cancer. After surgery, participants receive a dose of D2C7-IT (an immunotoxin) directly into the brain, followed by multiple doses of 2141-V11 (an Fc-engineered anti-CD40 agonist monoclonal antibody) under the skin near the head and neck. The trial seeks adults recently diagnosed with glioblastoma, particularly if standard treatment has left a reachable tumor by catheter.

As a Phase 1/Phase 2 trial, this research focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking cancer treatment development.

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.

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

Research shows that D2C7-IT is generally safe when injected directly into tumors. In studies with people, it has been used without major safety problems. This treatment targets specific proteins in tumors, preventing them from producing the proteins needed for growth.

For 2141-V11, research indicates it can safely activate the body's immune system to fight cancer. In trials with people who have various types of cancer, 2141-V11 was safe and even helped shrink tumors in some cases. Most participants did not experience severe side effects from this treatment.

Both treatments are still being tested, but current studies suggest they hold promise for safety in people with cancer. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the treatment combination of D2C7-IT and 2141-V11 for glioblastoma because it offers a novel approach by directly targeting the tumor in multiple ways. D2C7-IT is administered as an intratumoral infusion, which allows it to directly attack cancer cells within the tumor itself, potentially increasing its effectiveness. Additionally, 2141-V11 is given through both infusion and injections in the cervical perilymphatic subcutaneous area, a method that could enhance the immune system's ability to recognize and fight the tumor. This multi-pronged and targeted strategy could offer advantages over standard treatments like surgery, radiation, and chemotherapy, which often affect both cancerous and healthy cells.

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

Research has shown that D2C7-IT, one of the treatments in this trial, strongly affects tumors in mice with glioma, a type of brain cancer, when delivered directly into the brain. In some patients, this treatment has partially reduced tumors, with some remaining in this improved state for over two years. D2C7-IT targets specific proteins on cancer cells, aiding in their destruction.

Meanwhile, 2141-V11, another treatment in this trial, is an antibody that helps the immune system attack the tumor. It has demonstrated the ability to eliminate tumors and create a long-lasting immune response in some cancer patients. Together, these treatments aim to fight glioblastoma by both directly attacking cancer cells and boosting the body's immune system. ^{1 2 3 4 6}

Who Is on the Research Team?

Daniel Landi, MD

Principal Investigator

Duke University

Are You a Good Fit for This Trial?

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.

Hemoglobin ≥ 9 g/dl prior to catheter placement

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• 2141-V11
• D2C7-IT

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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 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]

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]

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]

Citations

1. sciencedirect.com sciencedirect.com/science/article/pii/S1535610825003198

Fc-optimized CD40 agonistic antibody elicits tertiary ... The resulting local immune responses by 2141-V11 mediated abscopal antitumor effects and sustained immune memory. These findings demonstrate ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11177954/

Intratumoral Fc-optimized agonistic CD40 antibody induces ... Intratumoral Fc-optimized agonistic CD40 antibody induces tumor rejection and systemic antitumor immunity in patients with metastatic cancer.

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.e14015

A phase 1 trial of D2C7-it in combination with an Fc- ... We are conducting a first in human trial of the combination of D2C7-IT + 2141-V11 administered via CED in recurrent MG patients.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10639447/

CTIM-09. PHASE 1/1B TRIAL OF FC-ENGINEERED ANTI- ... We initiated a phase 1 trial of D2C7-IT+2141-V11 (Fc-engineered anti-CD40 agonist) administered via CED in rMG patients. METHODS. Eligibility includes adult ...

5. synapse.patsnap.com synapse.patsnap.com/drug/9f1ff50fb3524530a70f20b3e8c1f475

2141-V11 - Drug Targets, Indications, Patents Here, we present a phase 1 study (NCT04059588) of intratumoral (i.t.) 2141-V11, an Fc-engineered anti-CD40 agonistic antibody with enhanced binding to the ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04059588

NCT04059588 | A Study Investigating the Safety and ... The purpose of this study is to test the safety and tolerability of 2141-V11 in people who have cancer that does not respond to standard treatment and who have ...