D2C7-IT for Brain Cancer

Overseen By Stevie Threatt

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Darell Bigner

Must not be taking: Immunotherapeutics, Antiangiogenics, Alkylating agents

Disqualifiers: Pregnancy, Unstable systemic disease, others

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

Compensation: Varies

Number of Visits: 8

Duration: 72 hours

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called D2C7-IT (an immunotoxin) for individuals with a specific type of recurring brain cancer known as malignant glioma. The researchers aim to find the safest dose for future studies by administering the treatment directly into the tumor. It targets those diagnosed with recurrent grade III or IV malignant glioma who have completed initial treatments like surgery and radiation. Participants will stay in the hospital for a 72-hour treatment period. This study seeks to identify the right dose for this promising treatment. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive it.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, certain treatments like immunotherapeutic agents, antiangiogenic agents, and some chemotherapies must be stopped a few weeks before enrollment. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that D2C7-IT is likely to be safe for humans?

Research shows that D2C7-IT targets specific proteins in brain cancer cells, aiming to attack cancer cells while sparing healthy ones. Earlier studies have demonstrated its effectiveness against glioblastoma cells, a type of brain cancer.

Regarding safety, current studies primarily focus on determining the maximum dose that can be administered without causing excessive side effects. Some patients have responded well, living for several months after treatment. However, as this trial is in an early phase, the main goal is to establish a safe dose, so long-term safety information remains limited.

In summary, D2C7-IT appears promising, but further research is necessary to fully understand its safety in humans. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about D2C7-IT for brain cancer because it targets malignant gliomas directly at the tumor site, using a method called convection-enhanced delivery (CED). Unlike traditional treatments like surgery, radiation, or chemotherapy, D2C7-IT is delivered intratumorally, meaning it's placed directly into the tumor. This approach allows for a more concentrated and localized treatment, potentially minimizing damage to healthy brain tissue and enhancing effectiveness. Additionally, D2C7-IT uses a unique antibody that specifically targets tumor cells, offering a more precise attack on the cancer, which could lead to better outcomes for patients with recurrent malignant gliomas.

What evidence suggests that D2C7-IT might be an effective treatment for brain cancer?

Research has shown that D2C7-IT, the treatment under study in this trial, may help treat brain tumors. This treatment targets specific proteins, such as EGFRwt and EGFRvIII, often present in aggressive brain cancers. In earlier studies, some patients experienced a reduction in tumor size and lived for several months after receiving D2C7-IT. Early results suggest that D2C7-IT could help fight aggressive brain tumors by directly attacking the tumor cells. Although more research is needed, these initial findings offer hope for its potential effectiveness. ^{3 4 6 7 8}

Who Is on the Research Team?

Dan Landi, MD

Principal Investigator

Preston Robert Tisch Brain Tumor Center at Duke University Medical Center

Are You a Good Fit for This Trial?

Adults over 18 with recurrent high-grade brain tumors (WHO grade III or IV malignant glioma) who've had prior treatment, can undergo MRI scans, and agree to use contraception. They must have good performance status and adequate organ function. Excluded are those with certain medical conditions, recent treatments, or severe allergies.

Inclusion Criteria

You have a type of brain tumor called grade III or IV malignant glioma that has come back after treatment.

You have been diagnosed with a high-grade malignant brain tumor in the top part of the brain.

Before getting the treatment, a biopsy must confirm that the tumor has come back.

Exclusion Criteria

You have a serious brain condition that needs urgent treatment.

You have been taking more than 4mg of dexamethasone per day in the 2 weeks before starting the treatment.

You have received certain types of chemotherapy within a specific time period before enrolling in the study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

1 visit (in-person)

Treatment

Participants receive D2C7-IT administered intratumorally via convection-enhanced delivery following confirmatory diagnostic biopsy

72 hours

Continuous hospital stay

Initial Follow-up

Participants are evaluated for adverse events and monitored for safety

2 weeks

1 visit (in-person)

Extended Follow-up

Participants are monitored every 8 weeks for safety and effectiveness until 48 weeks

48 weeks

6 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• D2C7-IT

Trial Overview The trial is testing D2C7-IT delivered directly into the tumor in the brain to find the safest dose for future studies. Patients will receive a biopsy followed by catheter placement for infusion if recurrent glioma is confirmed.

How Is the Trial Designed?

Group I: D2C7-IT Experimental Treatment 1 Intervention

Recurrent malignant glioma patients will receive D2C7-IT, delivered intratumorally by CED following confirmatory diagnostic biopsy.

Who Is Running the Clinical Trial?

Darell Bigner

Lead Sponsor

Trials

8

Recruited

380+

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]

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]

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]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2020.38.15_suppl.2566

Phase I trial of D2C7 immunotoxin (D2C7-IT) administered ... We report the results of a phase I trial evaluating D2C7-IT delivered intratumorally by CED. Methods: Eligible patients were adults with recurrent ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6216151/

ATIM-36. DOSE ESCALATION TRIAL OF D2C7 ... Fifteen patients are alive. Two patients have partial response and are alive ≥8.2 months and ≥34 months after infusion. CONCLUSION: DL17 is above the maximal ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT02303678

D2C7 for Adult Patients With Recurrent Malignant Glioma This is a Phase I study to determine the maximum tolerated dose (MTD) and/or recommended phase II dose of D2C7-IT (D2C7 Immunotoxin) when delivered ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3766439/

Construction of an immunotoxin, D2C7-(scdsFv)-PE38KDEL ... The D2C7-(scdsFv)-PE38KDEL immunotoxin exhibited significant potential for treating brain tumors expressing EGFRwt, EGFRvIII, and both EGFRwt and EGFRvIII.

5. jitc.bmj.com jitc.bmj.com/content/7/1/142

Improved efficacy against malignant brain tumors with ... D2C7-IT is currently being evaluated in a dose-escalation phase I clinical trial for recurrent WHO grade III and IV malignant glioma patients ( ...

6. acir.org acir.org/weekly-digests/2023/february/improving-d2c7-immunotoxin-therapy-with-agonist-cd40

Improving D2C7-immunotoxin therapy with agonist CD40 In this setting, the combination therapy induced tumor regression in more mice, reduced tumor burdens, and improved survival over either ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4788550/

Preclinical Toxicity Evaluation of a Novel Immunotoxin, D2C7 ... D2C7-IT has high affinity and specificity for both the EGFRwt and EGFRvIII proteins, it exhibits robust cytotoxic activities against glioblastoma cells ...

8. 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 ...