D2C7-IT + 2141-V11 for Brain Cancer

Overseen By Daniel Landi, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Annick Desjardins, MD

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: 3

Duration: 1 year

90 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment combination for aggressive brain cancer known as malignant glioma. The study examines the effectiveness of a drug called 2141-V11 (an Fc-engineered anti-CD40 agonist monoclonal antibody) when combined with another treatment, D2C7-IT (a D2C7 immunotoxin), in combating recurrent cancer. One group of participants will also have a Tumor Monorail Device (TMD) implanted to aid in treatment delivery. Individuals with recurring WHO grade III or IV malignant glioma may be suitable candidates for this study. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the chance to be among the first to receive this new treatment.

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.

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

Studies have shown that D2C7-IT, a treatment for brain cancer, can cause some side effects. Common risks include the death of tumor cells, effects on healthy brain tissue, and issues related to the delivery tube. These effects occur due to the treatment's action on tumor cells.

Research on 2141-V11's safety in cancer patients found it to be generally well-tolerated, with most people not experiencing severe side effects. However, like many treatments, some risks exist. Potential participants should discuss expectations with the trial team. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike standard treatments for brain cancer, which typically involve surgery, radiation, and chemotherapy, the combination of D2C7-IT and 2141-V11 offers a novel approach. Researchers are excited because D2C7-IT is delivered directly into the tumor, potentially enhancing precision and minimizing damage to healthy brain tissue. Additionally, 2141-V11 is administered perilymphatically, which is a unique delivery method that could improve drug distribution within the brain. This combination aims to target cancer cells more effectively, offering hope for a more efficient and targeted treatment option.

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

Research has shown that D2C7-IT, a special type of treatment, effectively targets certain proteins on cancer cells in lab studies, stopping their growth. Studies also indicate that 2141-V11, a treatment that boosts the immune system, has shown positive results in fighting other types of cancer. In this trial, participants will receive a combination of D2C7-IT and 2141-V11, designed to directly attack the tumor and strengthen the body's natural defenses. Early results suggest this method could benefit patients with aggressive brain tumors. ^{2 3 4 6 7}

Who Is on the Research Team?

Annick Desjardins, MD,FRCPC

Principal Investigator

Duke University

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• 2141-V11
• D2C7-IT

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.

How Is the Trial Designed?

Group I: D2C7-IT + 2141-V11 and Tumor Monorail Device (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+

Published Research Related to This Trial

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]

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 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]

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 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 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]

Citations

1. 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 ...

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

Fc-optimized CD40 agonistic antibody elicits tertiary ... Here, we present a phase 1 study (NCT04059588 ) of intratumoral (i.t.) 2141-V11, an Fc-engineered anti-CD40 agonistic antibody with enhanced ...

3. academic.oup.com academic.oup.com/neuro-oncology/article/25/Supplement_5/v62/7405724

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.

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

Intratumoral Fc-optimized agonistic CD40 antibody induces ... Here, we present the results of a phase 1 study on intratumoral administration of an anti-CD40 agonistic antibody (2141-V11) Fc-engineered to enhance FcγRIIB ...

5. withpower.com withpower.com/trial/phase-2-glioblastoma-8-2024-6f3bd

D2C7-IT + 2141-V11 for Brain Cancer Additionally, Fc-engineered anti-CD40 antibodies have shown strong antitumor activity in other cancer types, suggesting potential effectiveness in brain cancer.

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 ...

7. cancer.gov cancer.gov/clinicaltrials/NCI-2022-04330

Intratumoral 2141-V11 and D2C7-IT for the Treatment of ... This phase I trial tests the safety, side effects, and best dose of 2141-V11 in combination with D2C7-immunotoxin (IT) given intratumorally via ...