DB107-RRV + DB107-FC for Brain Tumors

Recruiting at 2 trial locations

Overseen By Neuro-Oncology New Patient Coordinator

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

Trial Summary

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.

What evidence supports the effectiveness of the treatment DB107-RRV + DB107-FC for brain tumors?

Research on FLASH radiotherapy, a component of the treatment, shows it can effectively kill tumors while sparing healthy tissue, potentially enhancing the overall anticancer effect. Additionally, combining radiotherapy with immunotherapy has shown promise in preclinical studies, suggesting a potential benefit for brain tumor treatment. ^{1 2 3 4 5}

What makes the treatment DB107-RRV + DB107-FC unique for brain tumors?

This treatment is unique because it uses a virus to deliver a gene into tumor cells, which then converts a harmless drug into a powerful cancer-fighting agent directly inside the tumor. This approach not only targets cancer cells but also helps the immune system fight the tumor, offering a new way to treat brain tumors that are hard to manage with standard therapies. ^{6 7 8 9 10}

What is the purpose of this trial?

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 newly diagnosed High Grade Glioma (HGG) patients. 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 newly diagnosed HGG when compared to historical performance previously determined in well controlled clinical trials published in the peer reviewed literature. This study is going to be conducted in newly diagnosed HGG patients receiving with maximum surgical resection treatment followed by radiation and temozolomide treatment using the established Stupp Protocol for O6-methylguanine-DNA methyl-transferase (MGMT) methylated patients or radiation therapy for MGMT unmethylated patients.

Research Team

Nicholas Butowski, MD

Principal Investigator

University of California, San Francisco

Noriyuki Kasahara, MD, PhD

Principal Investigator

University of California, San Francisco

Eligibility Criteria

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.

My primary tumor can be tested for specific genetic changes.

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Flash Therapy for Cancer: A Potentially New Radiotherapy Methodology. [2023]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Radiation-induced immune response in novel radiotherapy approaches FLASH and spatially fractionated radiotherapies. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Can Rational Combination of Ultra-high Dose Rate FLASH Radiotherapy with Immunotherapy Provide a Novel Approach to Cancer Treatment? [2021]

4. Ireland pubmed.ncbi.nlm.nih.gov

Ultra-high dose rate effect on circulating immune cells: A potential mechanism for FLASH effect? [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Radiotherapy enhances antitumor effect of anti-CD137 therapy in a mouse Glioma model. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

(E)-2'-deoxy-2'-(fluoromethylene) cytidine potentiates radioresponse of two human solid tumor xenografts. [2013]

7. England pubmed.ncbi.nlm.nih.gov

Agonist anti-GITR monoclonal antibody and stereotactic radiation induce immune-mediated survival advantage in murine intracranial glioma. [2022]

8. United States 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. [2021]

9. England pubmed.ncbi.nlm.nih.gov

Radiosensitization of gliomas by intracellular generation of 5-fluorouracil potentiates prodrug activator gene therapy with a retroviral replicating vector. [2021]

10. England pubmed.ncbi.nlm.nih.gov

Durable complete responses in some recurrent high-grade glioma patients treated with Toca 511 + Toca FC. [2020]