Virus-Based Gene Therapy (AdV-HSV1-TK and AdV-Flt3L) in Combination With Valacyclovir for the Treatment of Pediatric and Young Adult Patients With Resectable, Recurrent Primary Malignant Brain Tumors

University of Michigan Rogel Cancer Center

Status and phase

Not yet enrolling

Phase 1

Conditions

Resectable Brain Neoplasm

Recurrent Malignant Brain Neoplasm

Recurrent Diffuse Hemispheric Glioma, H3 G34-Mutant

Treatments

Procedure: Magnetic Resonance Imaging

Procedure: Tumor Resection

Other: Survey Administration

Procedure: Biospecimen Collection

Drug: Valacyclovir

Genetic: Ad-hCMV-Flt3L

Genetic: Ad-hCMV-TK

Study type

Interventional

Funder types

Other

Identifiers

NCT06914479

HUM00252291 (Other Identifier)

NCI-2025-01951 (Registry Identifier)

UMCC 2024.064

Details and patient eligibility

About

This phase I trial tests the safety, side effects and best dose of AdV-HSV1-TK and AdV-Flt3L in combination with valacyclovir for the treatment of patients with primary cancerous (malignant) brain tumors that can be removed by surgery (resectable) and that have come back after a period of improvement (recurrent). AdV-HSV1-TK and AdV-Flt3L use a virus modified in the laboratory to kill tumor cells and stimulate the immune system to recognize the tumor cells as "invaders" which can lead to tumor shrinkage. For this process to work, an oral anti-herpes medication called valacyclovir is also needed. Giving AdV-HSV1-TK, AdV-Flt3L and valacyclovir may be safe, tolerable and/or effective in treating patients with resectable, recurrent primary malignant brain tumors.

Enrollment

11 estimated patients

Sex

All

Ages

3 to 39 years old

Volunteers

No Healthy Volunteers

Inclusion criteria

Age 3 to 25 years with:
- Diagnosis of malignant primary brain tumor after tumor recurrence, relapse, or progression who have completed up-front, standard-of-care therapy
Age 26 to 39 years with:
- Diagnosis of diffuse hemispheric glioma, H3 G34-mutant, per 2021 World Health Organization (WHO) classification, after tumor recurrence, relapse, or progression who have completed up-front, standard-of-care therapy
At least 10 kg (and body surface area [BSA] > 0.5 m^2)
Participants who are receiving corticosteroids must be on a stable or decreasing dose for at least 3 days prior to baseline MRI
Surgical resection of the tumor recurrence/relapse/progression is clinically indicated at the time of enrollment
A legal parent/guardian or patient must be able to understand, and willing to sign, a written informed consent and assent document, as appropriate
Participant must be willing to provide archival formalin-fixed embedded (FFPE) and/or frozen tissue specimens, if available
Participant must have recovered from all acute side effects of prior therapy.
- From the projected start of scheduled study treatment, the following time periods must have elapsed: At least 7 days after last dose of a biologic agent or beyond time during which adverse events are known to occur for a biologic agent, 5 half-lives from any investigational agent, 4 weeks from cytotoxic therapy (except 23 days for temozolomide and 6 weeks from nitrosoureas), 6 weeks from antibody therapy (21 days for bevacizumab,.6 weeks from cellular therapy (i.e. modified T cells, natural killer [NK] cells, dendritic cells, etc.), or 4 weeks (or 5 half-lives, whichever is shorter) from other antitumor therapies
For participants who have received radiotherapy previously, participants must be at least 28 days from focal radiation therapy, at least 150 days from craniospinal irradiation therapy.
- The use of bevacizumab to control radiation therapy-induced edema is allowed prior to or during study therapy (if used for tumor-directed therapy, please see required washout period above).
  - Dosing limitations are as follows:
    - Bevacizumab (or bioequivalent) for up to a maximum of 5 doses, dosing per institutional standard. There is no required washout period
Prior use of temozolomide during radiation at maximum of the standard pediatric dosing (defined as 90 mg/m^2/dose continuously during radiation therapy) or dexamethasone is allowed
Peripheral absolute neutrophil count (ANC) ≥ 1000/mm^3 (1.0g/l)
Platelet count ≥ 100,000/mm^3 (100x10^9/l) (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
Creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 70mL/min/1.73 m^2 or a serum creatinine within the normal limits for age
Bilirubin (sum of conjugated + unconjugated) ≤ 2 x upper limit of normal (ULN) for age
Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 3 x ULN
Serum albumin ≤ 2 g/dL
Performance score ≥ 60 (Karnofsky for participants > 16 years of age, Lansky for participants ≤ 16 years of age.)
- Participants who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
The effects of the study drugs on the developing human fetus are unknown. For this reason, females of child-bearing potential (FOCBP) and males must agree to use adequate contraception for the duration of study participation and 30 days after last dose of AdV-HSV1-TK/AdV-Flt3L or valacyclovir, whichever is later.
- Adequate methods include hormonal or barrier method of birth control, or abstinence at the time of study entry and for the duration of study participation.
- Should a participant become pregnant or suspects she is pregnant while participating in this study, she should inform her treating physician immediately.
- Males treated on this study must also agree to use adequate contraception as of the time of enrollment onto the study and for the duration of study participation. Male participants must notify the treating physician immediately if his partner becomes pregnant while he is receiving study therapy

Exclusion criteria

Patient deemed not clinically appropriate to undergo tumor tissue resection by a neurosurgeon
Evidence of disseminated disease, including diffuse leptomeningeal disease or evidence of cerebrospinal fluid (CSF) dissemination
Patient with primary brainstem or primary spinal tumors
History of prior gene therapy
Ongoing therapy with valacyclovir that is unable to be stopped due to a medical condition
Known allergy to valacyclovir
Concurrent use of other investigational agents.
- Participants who are currently receiving another investigational drug. Investigational imaging agents or agents used to enhance tumor visibility on imaging or during tumor biopsy/resection should be discussed with the study chairs
Participants who are currently receiving anti-cancer agents
Participants with a known disorder that affects their immune system, such as HIV or hepatitis B or C, or an auto-immune disorder requiring systemic cytotoxic or immunosuppressive therapy
Presence of uncontrolled infection or other uncontrolled systemic illness
Current diagnosis of bipolar disorder or major depressive disorder
Presence of a congenital immune deficiency syndrome or acquired autoimmune disease
Female participants of childbearing potential must not be pregnant or breast-feeding. Female participants of childbearing potential must have a negative serum or urine or serum pregnancy test prior to the start of therapy (as clinically indicated)
Active illicit drug use or diagnosis of alcoholism
History of kidney transplant
History of allogeneic stem cell transplantation
Known additional malignancy that is progressing or requires active treatment within 3 years of start of study drug

Trial design

Primary purpose

Treatment

Allocation

N/A

Interventional model

Single Group Assignment

Masking

None (Open label)

11 participants in 1 patient group

Treatment (AdV-HSV1-TK , AdV-Flt3L and valacyclovir)

Experimental group

Description:

Patients undergo standard of care tumor resection and receive AdV-HSV1-TK and AdV-Flt3L via multiple injections over 3-5 minutes each to areas around the tumor. One to three days after surgery, patients receive valacyclovir PO TID on days 1-14 of each cycle. Cycles repeat every 12 weeks for 5 cycles in the absence of disease progression or unacceptable toxicity. Patients may also receive standard of care radiation therapy starting on day 21. Patients undergo MRI and blood sample collection throughout the study.