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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and effectiveness of a new treatment combination for recurrent glioblastoma, an aggressive brain cancer. The treatment uses two drugs: D2C7-IT (an immunotoxin) and 2141-V11 (an Fc-engineered anti-CD40 agonist monoclonal antibody), administered directly to the brain and through subcutaneous injections. It targets individuals who have previously undergone surgery to remove part of their tumor. Participants must have a confirmed glioblastoma diagnosis and be able to undergo brain MRI scans. 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 innovative therapy.

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.

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

Research has shown that the combination of D2C7-IT and 2141-V11 is safe when delivered directly into the brain tumor using convection enhanced delivery (CED). This method applies the treatment right at the tumor site. In earlier studies, the treatment showed promising results without major safety concerns.

The D2C7-IT and 2141-V11 combination has been tested in patients with recurring brain cancer, and results suggest it is generally well-tolerated. Most patients managed the treatment without significant problems. However, like all treatments, some side effects could occur, but studies have not consistently reported severe adverse events.

Anyone considering joining a clinical trial should know that this treatment is still in the early testing stages. Researchers are still learning about its complete safety profile. However, studies conducted so far indicate that the treatment might be safe for people with this type of brain cancer. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for brain cancer, which typically involve surgery, radiation, and chemotherapy, the combination of D2C7-IT and 2141-V11 offers a novel approach. D2C7-IT is delivered directly into the tumor through an intratumoral infusion, potentially targeting the cancer cells more precisely and reducing damage to surrounding healthy tissue. Additionally, 2141-V11 is administered via the cervical perilymphatic subcutaneous area, which is less common and could enhance immune response directly against the tumor. Researchers are excited about this treatment because it combines targeted delivery with a potential immune system boost, offering hope for more effective and less invasive therapy options.

What evidence suggests that the combination of D2C7-IT and 2141-V11 could be effective for brain cancer?

Research has shown that D2C7-IT might help treat glioblastoma, a type of brain cancer. In lab studies, it found and destroyed cancer cells by stopping them from making certain proteins. Early results also suggest that 2141-V11, a specially designed antibody, can help the immune system fight tumors more effectively. In this trial, participants will receive a combination of D2C7-IT and 2141-V11, potentially offering a new way to tackle brain cancer by combining a direct attack on cancer cells with a stronger immune response. While more research is needed, these early findings offer hope for those dealing with recurrent glioblastoma. ^{5 6 7 8 9}

Who Is on the Research Team?

Annick Desjardins, MD

Principal Investigator

Duke University

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

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]

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]

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 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]

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]

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]

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. 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.

5. 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 ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9661116/

CTIM-23. DOSE ESCALATION TRIAL OF FC ... Intratumoral administration of D2C7-IT+2141-V11 via CED is safe, encouraging efficacy results are observed.

7. clinicaltrials.gov clinicaltrials.gov/study/NCT04547777

Phase 1 Trial of D2C7-IT in Combination With 2141-V11 for ... 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 ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10440725/

Immunotoxin-αCD40 therapy activates innate and adaptive ... D2C7-IT+αCD40 treatment stimulated intratumoral CD8+ T cell proliferation and generated cures in glioma-bearing mice despite FTY720-induced ...

9. researchgate.net researchgate.net/publication/361121878_A_phase_1_trial_of_D2C7-it_in_combination_with_an_Fc-engineered_anti-CD40_monoclonal_antibody_2141-V11_administered_intratumorally_via_convection-enhanced_delivery_for_adult_patients_with_recurrent_ma

A phase 1 trial of D2C7-it in combination with an Fc ... A phase 1 trial of D2C7-it in combination with an Fc-engineered anti-CD40 monoclonal antibody (2141-V11) administered intratumorally via ...