DB107-RRV + DB107-FC for Brain Tumors

Recruiting at 3 trial locations

Overseen By Noriyuki Kasahara, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Nicholas Butowski

Must be taking: Temozolomide

Must not be taking: Anticoagulants, Antiplatelets, NSAIDs

Disqualifiers: HIV, Hepatitis B, Hepatitis C, others

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

Compensation: Varies

Number of Visits: 6

70 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment combination for individuals with newly diagnosed High Grade Glioma (HGG), an aggressive brain tumor. The researchers aim to determine if adding two experimental drugs, DB107-RRV (vocimagene amiretrorepvec) and DB107-FC (Flucytosine Extended-Release Tablets), to the standard treatment can improve outcomes. Participants will receive either the experimental drugs plus radiation and chemotherapy or just radiation, depending on their specific tumor characteristics. This trial targets those recently diagnosed with HGG who plan to undergo surgery to remove most of the tumor. As a Phase 1, Phase 2 trial, it seeks to understand how the treatment works in people and measure its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking research.

Do I need to stop my current medications for the trial?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial team or your doctor to get specific guidance based on your situation.

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

In previous studies, DB107-RRV, formerly known as Toca 511, demonstrated good safety results. Patients tolerated it well, experiencing no severe side effects. Some even had long-lasting responses, with effects lasting about three years on average. DB107-RRV targets cancer cells while avoiding normal brain tissue, enhancing its safety profile.

DB107-FC, previously called Toca FC, is also undergoing safety testing. It is a modified version of the drug 5-fluorocytosine (5-FC), used in other cancer treatments. Past trials in patients with aggressive brain tumors reported manageable side effects, suggesting it is generally safe for human use.

These treatments are in the early stages of human testing, so they are still being evaluated for safety and effectiveness. However, the available data provides a positive outlook on their safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for brain tumors, which often rely on chemotherapy and radiation, DB107-RRV and DB107-FC offer a unique approach. These investigational treatments use a novel mechanism involving a recombinant replicating virus (DB107-RRV) that specifically targets tumor cells, potentially improving precision and minimizing damage to healthy cells. Additionally, DB107-FC is administered orally, providing a more convenient delivery method compared to intravenous chemotherapy. Researchers are excited because these treatments aim to enhance the effectiveness of radiation therapy and offer a targeted attack on tumor cells, which could lead to better outcomes and fewer side effects for patients.

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

Research shows that combining DB107-RRV and DB107-FC might benefit patients with high-grade gliomas, a type of brain tumor. In this trial, participants will receive either DB107-RRV and DB107-FC with Temozolomide and Radiation Therapy or DB107-RRV and DB107-FC with Radiation Therapy alone, based on their MGMT methylation status. Studies with similar treatments have shown that patients lived between about 13 months to nearly 4 years, depending on their specific tumor. For some, the cancer stopped growing or spreading temporarily, with a disease control rate of 61%. This treatment delivers high doses of medicine directly to the brain, which could be especially useful for hard-to-treat brain tumors like gliomas. While the results are promising, further research is needed to confirm these benefits. ^{2 4 5 6 7}

Who Is on the Research Team?

Nicholas Butowski, MD

Principal Investigator

University of California, San Francisco

Noriyuki Kasahara, MD, PhD

Principal Investigator

University of California, San Francisco

Are You a Good Fit for This Trial?

This trial is for newly diagnosed High Grade Glioma patients who have undergone maximum surgical resection. It's suitable for those with MGMT methylated tumors receiving radiation and Temozolomide per the Stupp Protocol, or just radiation therapy if unmethylated.

Inclusion Criteria

I agree to use birth control or abstain from sex as required.

I am willing to give a blood sample for DGM7 status testing.

Participants must not be breastfeeding

Exclusion Criteria

I can swallow and absorb medications properly.

I have a severe illness that makes surgery too risky.

I have received treatment for a high-grade brain tumor before.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Surgical Resection and Initial Treatment

Participants receive DB107-RRV intracranially at resection and intravenously within 8 hours following surgery

Up to 6 weeks for surgical recovery

1 visit (in-person) for surgery

Radiation and Chemotherapy

Participants receive radiation therapy and chemotherapy (DB107-FC and Temozolomide for methylated MGMT) following surgical recovery

6 weeks

5 visits per week (in-person) for radiation

Adjuvant Therapy

Participants receive adjuvant DB107-FC and Temozolomide for up to 6 cycles or until progression

Up to 6 months

Monthly visits (in-person) for each cycle

Follow-up

Participants are monitored for safety and survival status

Up to 15 years

What Are the Treatments Tested in This Trial?

Interventions

• DB107-FC
• DB107-RRV
• Radiation Therapy
• Temozolomide

Trial Overview The study tests DB107-RRV and DB107-FC after surgery in comparison to historical data. Patients will receive these treatments along with standard care, which includes radiation and possibly Temozolomide, depending on their tumor type.

How Is the Trial Designed?

Group I: No MGMT Methylation (DB107-RRV, DB107-FC, Radiation therapy) Experimental Treatment 6 Interventions

Participants receive a 4.0 x 10\^8 transduction units per milliliter (TU/mL)) dose of DB107-RRV intracranially (IC) at resection and a 1.4 x 10\^9 TU/mL dose IV prior to leaving surgery room. Participants have up to 6 weeks for surgical recovery. Unmethylated MGMT participants receive 300 mg/kg/day DB107-FC PO during RT over 5 days during weeks 1-2, \& 5-6. 2 gray (Gy)/day standard of care (SOC) RT will be given for 5 consecutive days for 6 weeks. After RT, participants receive 1.4 x 10\^9 TU/mL of DB107-RRV IV on days 7 and 14 and continue during a 4-week rest period between RT and adjuvant therapy. Participants who begin adjuvant therapy receive 300 mg/kg/day DB107-FC PO on days 1-5 of a 28-day cycle up to 6 cycles or until PD. Participants with no PD during adjuvant treatment may receive additional cycles of DB107-FC until PD, withdrawal, death or study closure. Participants will be followed up for safety and survival status for up to 15 years.

Group II: Low to High MGMT Methylation (DB107-RRV, DB107-FC, Temozolomide (TMZ), Radiation therapy) Experimental Treatment 6 Interventions

Participants receive a 4.0 x 10\^8 TU/mL dose of DB107-RRV IC at resection and a 1.4 x 10\^9 TU/mL dose IV prior to prior to leaving surgery room. Participants have up to 6 weeks for surgical recovery. Low to high MGMT methylation participants receive 75 mg/m\^2 TMZ per SOC and 300mg/kg/day DB107-FC PO concurrent with 2 Gy/day over 5 consecutive days during weeks 1-2, \& 5-6. After RT, participants receive 1.4 x 10\^9 TU/mL DB107-RRV IV on days 7 and 14. IV DB107-RRV occurs during a 4-week rest period between RT and adjuvant portions of the protocol. Participants who begin adjuvant therapy receive 300 mg/kg/day DB107-FC PO on days 1-5 of a 28-day cycle for up to 6 cycles or until PD with 150-200 mg/m\^2 adjuvant TMZ per SOC on days 1-5 of each cycle for up to 6 cycles. Participants with no PD may continue to receive additional cycles of DB107-FC PD, withdrawal, death or study closure. Participants will be followed up for safety and survival status for up to 15 years.

DB107-FC is already approved in United States, European Union for the following indications:

Approved in United States as DB107-FC for:

• None approved yet; Investigational for high-grade glioma (HGG) including glioblastoma (GBM)

Approved in European Union as DB107-FC for:

• None approved yet; Investigational for high-grade glioma (HGG) including glioblastoma (GBM); Orphan Drug Designation granted

Who Is Running the Clinical Trial?

Nicholas Butowski

Lead Sponsor

Trials

3

Recruited

130+

University of California, San Francisco

Lead Sponsor

Trials

2,636

Recruited

19,080,000+

California Institute for Regenerative Medicine (CIRM)

Collaborator

Trials

70

Recruited

3,300+

Denovo Biopharma LLC

Industry Sponsor

Trials

19

Recruited

3,200+

Anova Enterprises, Inc

Industry Sponsor

Trials

2

Recruited

100,000+

Published Research Related to This Trial

FLASH radiotherapy (FL-RT) delivers radiation at a very high dosage rate, showing similar antitumor efficacy to standard radiation while significantly reducing damage to normal tissues, thanks to the 'FLASH effect'.

Recent animal studies suggest that FL-RT enhances anticancer potency and minimizes radiation-induced tissue damage, indicating its potential as a safer and more effective treatment option in future clinical applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Flash Therapy for Cancer: A Potentially New Radiotherapy Methodology. Polevoy, GG., Kumar, DS., Daripelli, S., et al.[2023]

FLASH radiotherapy (RT) significantly spares circulating immune cells, reducing their killing from 90-100% at conventional dose rates to only 5-10% at ultra-high dose rates, which may enhance its therapeutic effects.

The study identified a threshold FLASH dose rate of approximately 40 Gy/s for mice, suggesting that this technology could be adapted for human use with a lower dose rate, potentially improving treatment outcomes while minimizing damage to the immune system.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ultra-high dose rate effect on circulating immune cells: A potential mechanism for FLASH effect? Jin, JY., Gu, A., Wang, W., et al.[2021]

FMdC, a novel ribonucleotide reductase inhibitor, demonstrated a dose-dependent antitumor effect in nude mice with cervix cancer and glioblastoma, with a maximum tolerated dose of 10 mg/kg over 12 days.

When combined with radiotherapy, FMdC significantly enhanced the effectiveness of radiation treatment, reducing the required radiation dose for tumor control and increasing long-term remission rates, particularly in glioblastoma models.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

(E)-2'-deoxy-2'-(fluoromethylene) cytidine potentiates radioresponse of two human solid tumor xenografts. Sun, LQ., Li, YX., Guillou, L., et al.[2013]

FLASH radiotherapy (FLASH-RT) delivers radiation at ultra-high dose rates, showing a unique 'FLASH effect' that spares normal tissues while maintaining similar anti-tumor activity compared to conventional radiation treatments.

The review highlights the potential of combining FLASH-RT with immunotherapy, as FLASH-RT may positively influence the immune landscape, making it a promising approach for enhancing clinical outcomes in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Can Rational Combination of Ultra-high Dose Rate FLASH Radiotherapy with Immunotherapy Provide a Novel Approach to Cancer Treatment? Zhang, Y., Ding, Z., Perentesis, JP., et al.[2021]

The combination of radiotherapy and anti-CD137 antibody treatment led to complete tumor eradication in 67% of mice with established brain tumors, indicating a promising efficacy for this approach in treating high-grade glioma.

This treatment not only prolonged survival but also generated antitumor immunity in long-term survivors, as evidenced by increased tumor-infiltrating lymphocytes and tumor-specific gammaIFN production, suggesting a potential mechanism for sustained anti-tumor effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiotherapy enhances antitumor effect of anti-CD137 therapy in a mouse Glioma model. Newcomb, EW., Lukyanov, Y., Kawashima, N., et al.[2022]

In a phase I clinical trial involving patients with recurrent high-grade gliomas, treatment with vocimagene amiretrorepvec (Toca 511) and Toca FC showed improved survival rates compared to historical controls, with some patients achieving durable complete responses.

The study identified potential molecular and immunologic indicators, such as specific genetic mutations and cytokine levels, that may predict clinical outcomes and support the immune-related mechanism of action of this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular and Immunologic Signatures are Related to Clinical Benefit from Treatment with Vocimagene Amiretrorepvec (Toca 511) and 5-Fluorocytosine (Toca FC) in Patients with Glioma. Accomando, WP., Rao, AR., Hogan, DJ., et al.[2021]

Toca 511, a tumor-selective retroviral vector, effectively delivers the cytosine deaminase gene to glioma cells, enabling the conversion of the prodrug 5-fluorocytosine (5-FC) into the active anti-cancer drug 5-fluorouracil (5-FU) within the tumor cells.

The study found that 5-FU not only has direct cytotoxic effects but also enhances the effectiveness of radiation therapy, making it a promising strategy for treating aggressive brain tumors like glioblastoma in ongoing clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiosensitization of gliomas by intracellular generation of 5-fluorouracil potentiates prodrug activator gene therapy with a retroviral replicating vector. Takahashi, M., Valdes, G., Hiraoka, K., et al.[2021]

In a phase I trial involving 56 patients with recurrent high-grade glioma, the combination of vocimagene amiretrorepvec (Toca 511) and extended-release 5-fluorocytosine (Toca FC) resulted in durable complete responses in 21.7% of patients, with a median follow-up of 35.7 months for responders.

All patients who achieved a durable response remained alive and in response for over 33.9 months, indicating a potential link between durable responses and improved overall survival, particularly in those with IDH1 mutant tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durable complete responses in some recurrent high-grade glioma patients treated with Toca 511 + Toca FC. Cloughesy, TF., Landolfi, J., Vogelbaum, MA., et al.[2020]

Radiation therapy can significantly influence the immune response in tumors, potentially making the tumor environment more favorable for immune attack, depending on factors like dose and delivery method.

New techniques like FLASH and spatially fractionated radiotherapies (SFRT) show promise in enhancing the immune response while protecting healthy tissues, suggesting they could be effective when combined with immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiation-induced immune response in novel radiotherapy approaches FLASH and spatially fractionated radiotherapies. Bertho, A., Iturri, L., Prezado, Y.[2023]

The combination of anti-GITR monoclonal antibody (mAb) and stereotactic radiosurgery (SRS) significantly improved survival rates in a mouse model of glioblastoma, with a cure rate of 24% compared to 0% for either treatment alone, indicating a strong immune-mediated effect.

The treatment with anti-GITR (1) and SRS led to increased infiltration of CD4+ effector T-cells and enhanced production of immune signaling molecules like IFNγ and IL-2, suggesting that this combination effectively shifts the immune response against the tumor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Agonist anti-GITR monoclonal antibody and stereotactic radiation induce immune-mediated survival advantage in murine intracranial glioma. Patel, MA., Kim, JE., Theodros, D., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06504381

Study Details | NCT06504381 | DB107-RRV, ... This is a multicenter, open-label study of DB107-RRV (formerly Toca 511) and DB107-FC (formerly Toca FC) when administered following surgical resection in ...

2. synapse.patsnap.com synapse.patsnap.com/article/anova-begins-phase-12a-study-of-db107-for-high-grade-gliomas-with-first-patient-enrolled

Anova Begins Phase 1/2a Study of DB107 for High-Grade ... This trial is focused on evaluating DB107 as a potential treatment for brain tumors, particularly high-grade gliomas (HGG). The study, a Phase 1 ...

3. biospace.com biospace.com/press-releases/anova-announces-first-patient-enrolled-to-phase-1-2a-study-of-db107-for-the-treatment-of-high-grade-gliomas

Anova Announces First Patient Enrolled to Phase 1/2a ... DB107 is an investigational gene therapy being developed by Denovo Biopharma for the treatment of HGG, including glioblastoma multiforme (GBM).

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11878440/

An Update on the Clinical Status, Challenges, and Future ... Oncolytic virotherapy for malignant gliomas has come a long way from where it started but widespread clinical efficacy has not yet been achieved.

5. withpower.com withpower.com/trial/phase-2-glioma-8-2024-2f776

DB107-RRV + DB107-FC for Brain Tumors The study is designed to evaluate whether treatment with DB107-RRV in combination with DB107-FC when added to standard of care provides clinical benefit to ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4246057/

Radio-sensitization of gliomas by intracellular generation ... ... extended-release formulation of 5-fluorocytosine (5-FC), Toca FC, are currently being evaluated in clinical trials in patients with recurrent high-grade glioma

7. clinicaltrials.gov clinicaltrials.gov/study/NCT06504381?cond=Gene+Therapy&aggFilters=status%3Arec

DB107-RRV, DB107-FC, and Radiation Therapy With or ... The study is designed to evaluate whether treatment with DB107-RRV in combination with DB107-FC when added to standard of care provides clinical benefit to ...