Virus-Based Drug Therapy for Brain Tumor

(rQNestin Trial)

Recruiting at 4 trial locations

Overseen By E. Antonio Chiocca, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Dana-Farber Cancer Institute

Must not be taking: Antivirals, Immunosuppressants, Anti-VEGF

Disqualifiers: Systemic malignancy, Chronic infections, others

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

Compensation: Varies

Number of Visits: 8

Duration: Approximately 4 months

62 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new virus-based drug, rQNestin34.5v.2, for treating brain tumors that have recurred or worsened. The main goal is to determine the drug's safety and identify the optimal dose for treatment. Participants will receive the drug directly into the tumor, possibly with additional medication to enhance the body's response. Suitable candidates for this trial have previously been diagnosed with certain brain tumors, such as glioblastoma, and have undergone treatments like surgery or radiation. As a Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the chance to be among the first to receive this new therapy.

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

The trial protocol does not specify if you need to stop all current medications, but certain medications must be stopped before participating. For example, you must stop taking dexamethasone at least 14 days before the first treatment and antiviral medications like valacyclovir, acyclovir, or ganciclovir at least 7 days before surgery.

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

Research shows that the investigational drug rQNestin34.5v.2 is undergoing safety testing in people with recurring brain tumors. In earlier studies, this oncolytic virus, which targets and kills cancer cells, infected tumor cells and activated the body's immune response against them. However, detailed safety information from human trials is not yet available. As a Phase 1 study, the main goal is to assess how well people tolerate the drug and to determine the right dose, so some safety information is still being collected. In contrast, cyclophosphamide, used with rQNestin34.5v.2 in one part of the study, is a well-known chemotherapy drug with established side effects, such as nausea and decreased blood cell counts. While rQNestin34.5v.2 is still under investigation, cyclophosphamide has a more established safety record. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for recurrent malignant glioma, which often involve surgery, radiation, and chemotherapy, rQNestin34.5v.2 offers a unique virus-based approach. This experimental therapy uses a genetically modified virus to specifically target and destroy cancer cells while sparing healthy ones. Additionally, it is directly injected into the tumor, which could enhance its effectiveness by concentrating the treatment at the cancer site. Researchers are also testing an arm of the treatment with cyclophosphamide pre-treatment, which might enhance the virus's ability to attack the tumor. These innovative methods have the potential to improve outcomes for patients with this aggressive type of brain tumor.

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

Research has shown that rQNestin34.5v.2, a virus targeting cancer cells, might help treat brain tumors. This virus is designed to destroy tumor cells while sparing normal cells. Early studies have shown promise in fighting gliomas, a type of brain tumor. In this trial, participants in Arm A will receive rQNestin34.5v.2 alone, while those in Arm B will receive rQNestin34.5v.2 with cyclophosphamide, a drug that can weaken the tumor's defenses and potentially enhance the virus's effectiveness. Arm C will explore multiple doses of rQNestin34.5v.2. Researchers aim to offer new hope for people with recurring brain tumors through this method. ^{1 2 6 7 8}

Who Is on the Research Team?

E. Antonio Chiocca, MD, PhD

Principal Investigator

Brigham and Women's Hospital

Are You a Good Fit for This Trial?

Adults over 18 with recurrent brain tumors who've had prior radiation and chemotherapy, have a Karnofsky Performance Score ≥70, and can tolerate multiple biopsies. They must not be pregnant or breastfeeding, agree to use contraception, and have no severe infections or immune disorders. Tumors must meet specific size/location criteria.

Inclusion Criteria

For use of other investigational drug or other anti-tumor treatment, specific time periods must have elapsed from the projected start of scheduled study treatment

My first surgery biopsy confirmed I have glioma.

I have been diagnosed with a specific type of brain tumor that is not IDH mutant.

Exclusion Criteria

I have a chronic infection with HIV, hepatitis B, or C.

I am currently being treated for an active infection.

I have had cancer that needed treatment beyond surgery in the last 2 years.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive intratumoral administration of rQNestin34.5v.2, with or without Cyclophosphamide pre-treatment, following a dose escalation design

Approximately 4 months

6 visits (in-person) on days 0, 15, 30, 60, 90, and 120

Follow-up

Participants are monitored for safety and effectiveness after treatment, including MRI evaluations and assessments of HSV1 viremia and antibody response

1 year

Evaluations every 2 months

What Are the Treatments Tested in This Trial?

Interventions

• rQNestin34.5v.2

Trial Overview The trial is testing rQNestin34.5v.2, an investigational oncolytic virus for safety and proper dosage against recurrent malignant glioma. It includes cyclophosphamide treatment and stereotactic biopsy in a Phase I clinical setting.

How Is the Trial Designed?

Group I: Arm C- Multiple Dose rQNestin Experimental Treatment 2 Interventions

Arm C includes up to 6 intratumoral repeated doses of rQNestin34.5v.2, first in a cohort receiving 10\^8 pfus per time point, followed by a cohort receiving 10\^9 or 10\^7 pfus per time point. * Arm C adds 2 cohorts of 12 subjects in an open-label clinical trial of rQNestin34.5v.2 administered at two dose levels * The injections are planned for days 0, 15, 30, 60, 90, and 120 * Subjects with presumed radiologic evidence of recurrent malignant glioma will undergo stereotactic biopsy under monitored general or local anesthesia. Evidence of recurrent high grade or malignant must be found on frozen section for the person to receive administration of the agent.

Group II: Arm B- rQNestin+CPA Experimental Treatment 3 Interventions

Arm B is rQNestin34.5v.2 treatment with Cyclophosphamide (CPA) pre-treatment This study follows a standard 3+3 dose escalation design. Participants will not enroll to Arm B until the MTD or HTD has been met for Arm A. * Cyclophosphamide one intravenous injection 2 days prior to procedure. * Subjects with presumed radiologic evidence of recurrent malignant glioma will undergo stereotactic biopsy under monitored general or local anesthesia. Evidence of recurrent high grade or malignant must be found on frozen section for the person to receive administration of the agent. * rQNestin34.5v.2 Indicated dose as per cohort, Intratumor administration during surgery, single dose

Group III: Arm A- rQNestin Experimental Treatment 2 Interventions

Arm A is rQNestin34.5v.2 treatment This study follows a standard 3+3 dose escalation design. Participants will not enroll to Arm B until the MTD or HTD has been met for Arm A. * Subjects with presumed radiologic evidence of recurrent malignant glioma will undergo stereotactic biopsy under monitored general or local anesthesia. Evidence of recurrent high grade or malignant must be found on frozen section for the person to receive administration of the agent. * rQNestin34.5v.2 Indicated dose as per cohort, Intratumor administration during surgery, single dose

Who Is Running the Clinical Trial?

Dana-Farber Cancer Institute

Lead Sponsor

Trials

1,128

Recruited

382,000+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

Candel Therapeutics, Inc.

Industry Sponsor

Trials

12

Recruited

1,300+

Published Research Related to This Trial

Oncolytic viruses (OVs) show promise as a novel treatment for malignant gliomas, which are difficult to treat with conventional therapies, as they can selectively target and kill cancer cells.

Clinical trials have demonstrated the safety of various OVs, such as herpes simplex virus and adenovirus, while also indicating their potential effectiveness against malignant gliomas, suggesting a new avenue for improving treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

EXPLORING THE ANTITUMOR EFFECT OF VIRUS IN MALIGNANT GLIOMA. Saha, D., Ahmed, SS., Rabkin, SD.[2020]

The study developed three mathematical models to analyze the effects of Vesicular Stomatitis Virus (VSV) on glioblastoma (GBM) cells, showing that a more complex model incorporating time-delay effects accurately predicts the virus's dynamics in vitro.

The findings suggest that the delay time is a critical factor in modeling the lytic action of VSV on GBM, providing a foundation for future simulations of in vivo treatments for various cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A mathematical approach to virus therapy of glioblastomas. de Rioja, VL., Isern, N., Fort, J.[2019]

Glioblastoma multiforme (GBM) is a highly challenging cancer due to its aggressive nature and the difficulty in treating it effectively with current methods, which have only shown modest improvements in patient outcomes.

Oncolytic virotherapy, which uses genetically engineered viruses to target and destroy cancer cells, shows promise as a new treatment approach for GBM, with various viral vectors like herpes simplex and poliovirus currently in different stages of clinical development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunovirotherapy for the Treatment of Glioblastoma and Other Malignant Gliomas. Estevez-Ordonez, D., Chagoya, G., Salehani, A., et al.[2023]

Gene therapy using replication-competent viruses, like engineered herpes simplex-1 virus mutants G207 and HSV1716, shows promise in selectively targeting and destroying primary brain tumors while sparing healthy neurons, as demonstrated in Phase I trials for recurrent high-grade glioma.

The review also highlights ongoing research into other viral therapies, such as Newcastle disease virus and adenovirus mutant ONYX-015, which may offer additional strategies for treating malignant gliomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oncolytic viruses: clinical applications as vectors for the treatment of malignant gliomas. Shah, AC., Benos, D., Gillespie, GY., et al.[2023]

Viruses are being explored as innovative therapies for malignant gliomas, serving both as vectors for delivering therapeutic genes and as agents that can selectively destroy tumor cells.

Current clinical trials have utilized retroviral and adenoviral vectors to enhance tumor susceptibility to treatments, as well as conditionally replicating HSV viruses, showing promise but indicating a need for further research into additional viral options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Viruses in the treatment of brain tumors. Fecci, PE., Gromeier, M., Sampson, JH.[2019]

Oncolytic viruses have shown promise as a safe treatment option for malignant brain tumors, particularly glial tumors, with some patients experiencing impressive results from viral therapy.

The effectiveness of oncolytic virotherapy varies among patients due to the high genetic heterogeneity of tumor cells, highlighting the need for further advancements in treatment methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Oncolytic viruses for therapy of malignant glioma]. Sosnovtceva, AO., Grinenko, NF., Lipatova, AV., et al.[2018]

The study found that the oncolytic viruses VSV-ΔM51 and vvDD can effectively infect and kill temozolomide (TMZ) resistant brain tumor stem cells (BTSCs) and their differentiated cells, indicating a potential new treatment option for patients who do not respond to standard chemotherapy.

Both viruses were shown to inhibit the self-renewal activity of TMZ resistant BTSCs in vitro, suggesting they could serve as a promising supplement to existing GBM therapies, especially for those with resistance to TMZ.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide resistant human brain tumor stem cells are susceptible to recombinant vesicular stomatitis virus and double-deleted Vaccinia virus in vitro. Jiang, B., Lun, X., Hao, X., et al.[2018]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7195500/

Preclinical Toxicology of rQNestin34.5v.2 - PubMed Central rQNestin34.5v.2 is an oncolytic herpes simplex virus 1 (oHSV) that retains expression of the neurovirulent ICP34.5 gene under glioma-selective transcriptional ...

2. clinicaltrial.be clinicaltrial.be/en/details/8898?per_page=100&recruiting=1&enrolling_by_invitation=1&active_not_recruiting=1&not_yet_recruiting=0&completed=0&only_recruiting=0&only_eligible=0

A Study of the Treatment of Recurrent Malignant Glioma Wi... The purpose of this research study is to test if rQnestin34.5v.2 is safe to use in humans, and if it is effective in treating malignant glioma.

3. mskcc.org mskcc.org/cancer-care/clinical-trials/23-257

A Phase 1 Study of rQNestin34.5v.2 in People With Glioma Researchers are assessing a drug called rQNestin34.5v.2, for people with brain cancer that came back after treatment.

4. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT03152318/

Clinical Trial: NCT03152318 - Malignant Glioma The purpose of this research study is to test if rQnestin34.5v.2 is safe to use in humans, and if it is effective in treating malignant glioma.

5. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs003378.v1.p1

dbGaP Study - NCBI - NIH This study is a first-in-human phase 1 trial of recurrent, IDH wild-type glioblastoma (rGBM) patients treated with CAN-3110 (aka rQNestin34.5v.2)

6. trialx.com trialx.com/clinical-trials/listings/272669/a-study-of-the-treatment-of-recurrent-malignant-glioma-with-rqnestin345v2/

A Study of the Treatment of Recurrent Malignant Glioma ... This research study is a Phase I clinical trial, which tests the safety of an investigational drug and also tries to define the appropriate dose ...

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.TPS2097

omic” analyses in recurrent glioblastoma (GBM). A multi-institutional phase 1 clinical trial was started in recurrent GBM (rGBM) patients treated with up to 6 stereotactic administrations of the oncolytic ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8310195/

Oncolytic Viruses for Malignant Glioma - PubMed Central - NIH Several oncolytic viruses have demonstrated the ability to infect tumors and trigger anti-tumor immune responses in malignant glioma patients.