DB107-RRV + DB107-FC for Brain Tumors
Recruiting in Palo Alto (17 mi)
+2 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Nicholas Butowski
Must be taking: Temozolomide
Must not be taking: Anticoagulants, Antiplatelets, NSAIDs
Disqualifiers: HIV, Hepatitis B, Hepatitis C, others
No Placebo Group
Trial Summary
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.
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.12345
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.678910
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.
I am between 18 and 75 years old.
See 8 more
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.
See 10 more
Trial 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 (Virus Therapy)
- DB107-RRV (Virus Therapy)
- Radiation Therapy (Radiation)
- Temozolomide (Chemotherapy)
Trial OverviewThe 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
2Treatment groups
Experimental Treatment
Group I: No MGMT Methylation (DB107-RRV, DB107-FC, Radiation therapy)Experimental Treatment6 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 Treatment6 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of Southern CaliforniaLos Angeles, CA
University of California, San DiegoSan Diego, CA
University of CaliforniaSan Francisco, CA
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Who Is Running the Clinical Trial?
Nicholas ButowskiLead Sponsor
University of California, San FranciscoLead Sponsor
California Institute for Regenerative Medicine (CIRM)Collaborator
Denovo Biopharma LLCIndustry Sponsor
Anova Enterprises, IncIndustry Sponsor
References
Flash Therapy for Cancer: A Potentially New Radiotherapy Methodology. [2023]In traditional treatment modalities and standard clinical practices, FLASH radiotherapy (FL-RT) administers radiation therapy at an exceptionally high dosage rate. When compared to standard dose rate radiation therapy, numerous preclinical investigations have demonstrated that FL-RT provides similar benefits in conserving normal tissue while maintaining equal antitumor efficacy, a phenomenon possible due to the 'FLASH effect' (FE) of FL-RT. The methodologies involve proton radiotherapy, intensity-modulated radiation treatment, and managing high-throughput damage by radiation to solid tissues. Recent results from animal studies indicate that FL-RT can reduce radiation-induced tissue damage, significantly enhancing anticancer potency. Focusing on the potential benefits of FL proton beam treatment in the years to come, this review details the FL-RT research that has been done so far and the existing theories illuminating the FL effects. This subject remains of interest, with many issues still needing to be answered. We offer a brief review to emphasize a few of the key efforts and difficulties in moving FL radiation research forward. The existing research state of FL-RT, its affecting variables, and its different specific impacts are presented in this current review. Key topics discussed include the biochemical mechanism during FL therapy, beam sources for FL therapy, the FL effect on immunity, clinical and preclinical studies on the protective effect of FL therapy, and parameters for effective FL therapy.
Radiation-induced immune response in novel radiotherapy approaches FLASH and spatially fractionated radiotherapies. [2023]The last several years have revealed increasing evidence of the immunomodulatory role of radiation therapy. Radiotherapy reshapes the tumoral microenvironment can shift the balance toward a more immunostimulatory or immunosuppressive microenvironment. The immune response to radiation therapy appears to depend on the irradiation configuration (dose, particle, fractionation) and delivery modes (dose rate, spatial distributions). Although an optimal irradiation configuration (dose, temporal fractionation, spatial dose distribution, etc.) has not yet been determined, temporal schemes employing high doses per fraction appear to favor radiation-induced immune response through immunogenic cell death. Through the release of damage-associated molecular patterns and the sensing of double-stranded DNA and RNA breaks, immunogenic cell death activates the innate and adaptive immune response, leading to tumor infiltration by effector T cells and the abscopal effect. Novel radiotherapy approaches such as FLASH and spatially fractionated radiotherapies (SFRT) strongly modulate the dose delivery method. FLASH-RT and SFRT have the potential to trigger the immune system effectively while preserving healthy surrounding tissues. This manuscript reviews the current state of knowledge on the immunomodulation effects of these two new radiotherapy techniques in the tumor, healthy immune cells and non-targeted regions, as well as their therapeutic potential in combination with immunotherapy.
Can Rational Combination of Ultra-high Dose Rate FLASH Radiotherapy with Immunotherapy Provide a Novel Approach to Cancer Treatment? [2021]FLASH radiotherapy (FLASH-RT) delivers radiation treatment at an ultra-high dose rate that is several orders of magnitude higher than current clinical practice. In multiple preclinical studies, FLASH-RT has shown consistent normal tissue sparing effects while preserving equivalent antitumour activity in comparison with conventional dose rate radiation treatment. This is known as the 'FLASH effect'. Given the recent research interest in combining hypofractionated radiotherapy with immunotherapy to try to improve clinical outcomes, there is an intriguing clinical question as to whether FLASH irradiation may be a rational partner to combine with immune modulating drugs? To better predict the synergistic effect of both modalities, here we review the biological mechanisms of how FLASH differentially impacts the immune landscape, including circulating immune cells, tumour microenvironment and the inflammatory response. In order to make recommendations for future research, we summarise all published studies that investigated the immune modulatory effects of FLASH-RT and further explore the scientific reasons for combining FLASH with immunotherapy for potential clinical applications.
Ultra-high dose rate effect on circulating immune cells: A potential mechanism for FLASH effect? [2021]"FLASH" radiotherapy (RT) is a potential paradigm-changing RT technology with marked tumor killing and normal tissue sparing. However, the mechanism of the FLASH effect is not well understood. We hypothesize that the ultra-high dose rate FLASH-RT significantly reduces the killing of circulating immune cells which may partially contribute to the reported FLASH effect.
Radiotherapy enhances antitumor effect of anti-CD137 therapy in a mouse Glioma model. [2022]Previously, we reported that peripheral vaccination of mice with modified autologous tumor cells secreting granulocyte-macrophage colony-stimulating factor (GM-CSF) combined with ionizing radiation to the whole brain cured 50% of mice using a syngeneic, intracranial model of murine high-grade glioma. Here, we tested the combination of radiotherapy (4 Gy x 2) with an immunotherapeutic approach using an anti-CD137 antibody directed to the co-stimulatory molecule CD137. The CD137 antibody has shown promise in generating effective antitumor responses in several animal models and has demonstrated a favorable toxicity profile in the clinic. The combination of radiation and anti-CD137 therapy resulted in complete tumor eradication and prolonged survival in six of nine (67%) mice with established brain tumors (P = 0.0009). Five of six (83%) long-term survivors in the combination group demonstrated antitumor immunity by rejecting challenge tumors. Antitumor immunity was associated with an increased number of tumor-infiltrating lymphocytes (TILs) in brain tumors and increased tumor-specific production of gammaIFN. In view of the finding that radiation enhanced the antitumor effect of anti-CD137 therapy, this approach should be studied further for clinical translation.
(E)-2'-deoxy-2'-(fluoromethylene) cytidine potentiates radioresponse of two human solid tumor xenografts. [2013]Antitumor and radiosensitizing effects of (E)-2'-deoxy-2'-(fluoromethylene) cytidine (FMdC), a novel inhibitor of ribonucleotide reductase, were evaluated on nude mice bearing s.c. human C33-A cervix cancer and U-87 MG glioblastoma xenografts. FMdC given once daily has a dose-dependent antitumor effect. The maximum tolerated dose in the mice was reached with 10 daily i.p. administrations of 10 mg/kg over 12 days. In the case of radiotherapy (RT) alone (10 fractions over 12 days), the radiation dose required to produce local tumor control in 50% of the treated C33-A xenografts was 51.0 Gy. When combined with FMdC, the radiation dose required to produce local tumor control was reduced to 41.4 and 38.2 Gy, at respective doses of 5 and 10 mg/kg given i.p. 1 h before each irradiation. The corresponding enhancement ratios (ERs) were 1.2 and 1.3, respectively. In U-87 MG xenografts, when 5-20 mg/kg FMdC combined with 30 or 40 Gy of RT, the combination treatment produced a significantly increased growth delay as compared with RT alone (P
Agonist anti-GITR monoclonal antibody and stereotactic radiation induce immune-mediated survival advantage in murine intracranial glioma. [2022]Glioblastoma (GBM) is a poorly immunogenic neoplasm treated with focused radiation. Immunotherapy has demonstrated synergistic survival effects with stereotactic radiosurgery (SRS) in murine GBM. GITR is a co-stimulatory molecule expressed constitutively on regulatory T-cells and by effector T-cells upon activation. We tested the hypothesis that anti-GITR monoclonal antibody (mAb) and SRS together would confer an immune-mediated survival benefit in glioma using the orthotopic GL261 glioma model.
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]High-grade gliomas (HGGs) are central nervous system tumors with poor prognoses and limited treatment options. Vocimagene amiretrorepvec (Toca 511) is a retroviral replicating vector encoding cytosine deaminase, which converts extended release 5-fluorocytosine (Toca FC) into the anticancer agent, 5-fluorouracil. According to preclinical studies, this therapy kills cancer cells and immunosuppressive myeloid cells in the tumor microenvironment, leading to T-cell-mediated antitumor immune activity. Therefore, we sought to elucidate this immune-related mechanism of action in humans, and to investigate potential molecular and immunologic indicators of clinical benefit from therapy.
Radiosensitization of gliomas by intracellular generation of 5-fluorouracil potentiates prodrug activator gene therapy with a retroviral replicating vector. [2021]A tumor-selective non-lytic retroviral replicating vector (RRV), Toca 511, and an extended-release formulation of 5-fluorocytosine (5-FC), Toca FC, are currently being evaluated in clinical trials in patients with recurrent high-grade glioma (NCT01156584, NCT01470794 and NCT01985256). Tumor-selective propagation of this RRV enables highly efficient transduction of glioma cells with cytosine deaminase (CD), which serves as a prodrug activator for conversion of the anti-fungal prodrug 5-FC to the anti-cancer drug 5-fluorouracil (5-FU) directly within the infected cells. We investigated whether, in addition to its direct cytotoxic effects, 5-FU generated intracellularly by RRV-mediated CD/5-FC prodrug activator gene therapy could also act as a radiosensitizing agent. Efficient transduction by RRV and expression of CD were confirmed in the highly aggressive, radioresistant human glioblastoma cell line U87EGFRvIII and its parental cell line U87MG (U87). RRV-transduced cells showed significant radiosensitization even after transient exposure to 5-FC. This was confirmed both in vitro by a clonogenic colony survival assay and in vivo by bioluminescence imaging analysis. These results provide a convincing rationale for development of tumor-targeted radiosensitization strategies utilizing the tumor-selective replicative capability of RRV, and incorporation of radiation therapy into future clinical trials evaluating Toca 511 and Toca FC in brain tumor patients.
Durable complete responses in some recurrent high-grade glioma patients treated with Toca 511 + Toca FC. [2020]Vocimagene amiretrorepvec (Toca 511) is an investigational gamma-retroviral replicating vector encoding cytosine deaminase that, when used in combination with extended-release 5-fluorocytosine (Toca FC), results preclinically in local production of 5-fluorouracil, depletion of immune-suppressive myeloid cells, and subsequent induction of antitumor immunity. Recurrent high-grade glioma (rHGG) patients have a high unmet need for effective therapies that produce durable responses lasting more than 6 months. In this setting, relapse is nearly universal and most responses are transient.