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S-Gboxin (lyophilized form of S-Gboxin) for the treatment diffuse midline glioma with H3 K27M / H3 K28M mutation

S-Gboxin

Andrey Petrov, Dr

Oliever Parteny

F. 50y.o. 77kg, DS confirmed 18 Nov. 2022 Received treatment: 11 courses of TMZ (240mg) Radiotherapy 30 courses of 1.8Gr (total 54 Gr, TMZ 140 mg on RT). Bevacizumab intravenously -400 mg -0-14-28-42 (December-February 2023). Severe side effects. The attending physician discontinued bevacizumab after 4 courses. In remission for 11 months. According to the results of the MRI dated April 28, 2024, continued growth.

Neurological status is good. Reflexes are not impaired. To date, treatment options have been exhausted. Participation of the patient in Clinical Trials is impossible. As of April 2024, negative dynamics. The patient signed an informed consent agreement. Information on taking L-S-Gboxin (Lyophilisate) as part of a compassionate program - explained.

Written consent of the attending physician for the patient's participation in the Compassion Program (TRIANGLE) with L-S-Gboxi (Lyophilisate) - received.

(medical documentation will be available on clinicaltrials.gov within a month from the date of publication - patient's consent to publish the medical history and examination results has been obtained)

TREATMENT PLAN

Оn days 1 to 3 of treatment, the patient will receive a sublingual form of the lyophilized form of L-S-Gboxin at a dose of 5 mg/kg.

If there is no toxicity, on days 4 to 14 the patient will receive a sublingual form of the lyophilized form of S-Gboxin at a dose of 10 mg/kg.

The first course of treatment is 14 days. On day 20, MRI + PET-CT monitoring is carried out to assess the dynamics of tumor growth. Based on the results of the examination plan, the attending physician and the main investigator make a decision on the continuation of treatment and the duration of the second course of therapy.

A Single Patient Compassionate Use Clinical Trial for the Use of L-S-Gboxin (Lyophilized Form of S-Gboxin) for the Treatment Diffuse Midline Glioma, H3 K27/28-altered (DMG), Including Diffuse Intrinsic Pontine Glioma (DIPG)

Petrov, Andrey

Medulloblastoma

Antineoplastic Agents

Temozolomide

The trial consisted of two phases: dose climbing phase and extension phase. At least 15 patients with malignant brain glioma (WHO Grade IV) were enrolled in the climbing phase. According to the 3+3 design, the amount of cells suitable for implantable Ommaya capsules for cell transfusion was increased according to the dose of 1x107, 3x107, 1x108 and 3x108 per dose, so as to observe its tolerability and safety. In the expansion phase, 10 patients with malignant brain glioma (WHO Grade IV) were enrolled, and dose expansion therapy was performed according to the optimal dose obtained in the climbing phase to observe its tolerability and safety. One course of treatment every 4 weeks, a total of 3 courses. Vγ9Vδ2 T cells were injected into the ventricle or ventricle once a week for the first three weeks and observed at the fourth week. In some patients, radiotherapy or other chemotherapy drugs (such as temozolomide) may be combined at week 4.

Vγ9Vδ2 T cell

Tao Sun

Yi Wang

Primary brain malignant tumor has become the first lethal tumor in children and young adults, and the treatment is limited, and the prognosis of patients is poor. According to the classification of the World Health Organization, glioblastoma is divided into grade II, III and IV gliomas; The higher the degree of malignancy, the worse the clinical outcome. Among them, the most malignant, most lethal, and most common types of tumors include supratentorial glioblastoma, diffuse endopontine glioma (DIPG), medulloblastoma, and ependymoma. Its high malignancy is mainly manifested in three aspects: extremely rapid growth and obvious invasion; The operation is not easy to remove all; The tumor has a tendency of recurrence and disseminated implantation. It can occur with children and adults of all ages. At present, surgery combined with chemoradiotherapy is the main treatment, but the therapeutic effect is not good. Studies have shown that glioblastoma, as the most common primary brain malignant tumor in adults, after standard surgery, radiotherapy and chemotherapy, the median survival time is less than 15 months, and the overall five-year survival rate is only 5.4%. Even after receiving new and expensive Tumor-treating fields, the median survival time is less than 21 months. The median survival time of DIPG patients is generally less than 1 year, and the 5-year survival rate is less than 5%. The average 5-year survival rate of medulloblastoma and anaplastic ependymoma is 40%\~60%. Innovative treatments are urgently needed. Immunotherapy based on Vγ9Vδ2 T cells has become a promising research direction in recent years. Its unique phosphine antigen recognition does not depend on major histocompatibility complex (MHC), easy to allograft and other advantages. Making it one of the most promising cell therapies. Brain glioma has abnormal cholesterol metabolism and phosphine antigen accumulation, which is easily sensed by Vγ9Vδ2 T cells. Therefore, the clinical exploration of Vγ9Vδ2 T cells for glioma is of great significance to both the scientific and clinical communities.

Research purpose

1. Main purpose:

   To evaluate the safety and feasibility of allogeneic Vγ9Vδ2 T cell therapy.
2. Secondary Purpose:

   To evaluate the therapeutic effect of allogeneic Vγ9Vδ2 T cells on brain malignant glioma (WHO IV).
3. Explore goals:

To investigate the expansion, infiltration and persistence of Vγ9Vδ2 T cells after reinfusion. To investigate the immunological dynamics of Vγ9Vδ2 T cells after reinfusion. To explore biomarkers that might predict the clinical efficacy of Vγ9Vδ2 T cell therapy.

Research design types, principles and test steps

1. Research design This is an exploratory clinical trial. It is planned to enroll 50 patients with malignant glioma (WHO Grade IV) in the Department of Neurosurgery of Beijing Tiantan Hospital to conduct a single-center, single-arm open phase I clinical trial. To evaluate the safety, feasibility, and efficacy of allogeneic Vγ9Vδ2 T cell infusion regimen in the treatment of malignant brain gliomas (WHO Grade IV).

   The trial consisted of two phases: dose climbing phase and extension phase. At least 15 patients with malignant brain glioma (WHO Grade IV) were enrolled in the climbing phase. According to the 3+3 design, the cell transfusion volume was successively increased according to the doses of 1x107, 3x107, 1x108 and 3x108 per dose to observe its tolerability and safety. In the expansion phase, 10 patients with malignant brain glioma (WHO Grade IV) were enrolled, and dose expansion therapy was performed according to the optimal dose obtained in the climbing phase to observe its tolerability and safety. One course of treatment every 4 weeks, a total of 3 courses. At the same time, patients who failed to complete at least one course of precision treatment for any reason after enrollment were included in the internal control group, and patients who met the admission criteria of this study but did not participate in this study were included in the external control group, with a total of 25 cases.
2. Sample size and research plan After signing the informed consent form (ICF), subjects will complete the screening period assessment according to the trial plan process sheet. Patients can be combined with the chemotherapy drug temozolomide according to the specific condition.

Recruit 20 healthy donors to provide peripheral blood. After the donors sign the informed consent, they will complete the evaluation and collection of peripheral blood according to the procedure table of the trial plan.

After screening qualified donors, it is necessary to arrange monopexing as soon as possible. The full name of mononuclear cell collection is peripheral blood mononuclear cell collection. In this study, blood cell separation will be used for mononuclear cell collection.

Monofrequency: ECG monitoring was performed before and during monofrequency, and was recorded once an hour from the beginning until the end of monofrequency. The collection time must record the circulation amount, collection volume, and collection time in a timely manner. Information on the preparation of single samples and Vγ9Vδ2 T cells was collected and recorded. If the donor does not consent to the continued use of its Vγ9Vδ2 T cells in this study, the study will be destroyed in accordance with the standard procedures prescribed by national law.

At least 15 patients with malignant brain glioma (WHO Grade IV) were initially planned to be enrolled using a staggered dosing strategy. Subject 1 and 2, and subject 2 and 3 must be monitored at least 2 weeks apart. The number of allogeneic Vγ9Vδ2 T cells was increased at each dose of 1×107, 3×107, 1×108, and 3x108 to observe their tolerance and safety. Short-term safety evaluation was performed 2-3 days after each course of cell infusion. After the treatment, according to the number of successfully prepared allogeneic Vγ9Vδ2 T cells, the study doctor can choose to continue to give cell transfusion for multiple courses according to the clinical condition of the subjects.

Further enrollment of 10 patients with malignant brain glioma (WHO Grade IV) is planned for dose-extension therapy at the optimal dose obtained above to observe tolerability and safety. One course of treatment every 4 weeks, a total of 3 courses. Short-term safety evaluation was performed 2-3 days after each course of cell infusion. After the end of 3 courses, the number of successfully prepared Vγ9Vδ2 T cells can also be selected by the research doctor according to the clinical condition of the subjects to continue to give cell transfusion for multiple courses. Patients who failed to complete at least one course of precision treatment for any reason after enrollment were included in the internal control group, and patients who met the admission criteria of this study but did not participate in this study were included in the external control group, with a total of 25 cases.

Follow-up was performed at 30 days, 2 months, 3 months, 6 months, 9 months, and 12 months after the first cell reinfusion, or early withdrawal from the study, and efficacy was assessed at each follow-up.

The end of the trial was defined as withdrawal of informed consent by the last subject, termination of treatment or withdrawal from the trial, loss of follow-up or death, completion of 1 year of follow-up, or early termination of the study, whichever occurred first.

The trial may be terminated prematurely at any time for any reason attributable to the Sponsor. If necessary, the subject should have an end-of-treatment visit as soon as possible.

4. Research methods Vγ9Vδ2 T cell therapy program

This is an exploratory clinical trial. It is planned to enroll 50 patients with malignant glioma (WHO Grade IV) in the Department of Neurosurgery of Beijing Tiantan Hospital to conduct a single-center, single-arm open phase I clinical trial. To evaluate the safety, feasibility, and efficacy of allogeneic Vγ9Vδ2 T cell infusion regimen in the treatment of malignant brain gliomas (WHO Grade IV).

The trial consisted of two phases: dose climbing phase and extension phase. At least 15 patients with malignant brain glioma (WHO Grade IV) were enrolled in the climbing phase. According to the 3+3 design, the amount of cells suitable for implantable Ommaya capsules for cell transfusion was increased according to the dose of 1x107, 3x107, 1x108 and 3x108 per dose, so as to observe its tolerability and safety. In the expansion phase, 10 patients with malignant brain glioma (WHO Grade IV) were enrolled, and dose expansion therapy was performed according to the optimal dose obtained in the climbing phase to observe its tolerability and safety. One course of treatment every 4 weeks, a total of 3 courses. Vγ9Vδ2 T cells were injected into the ventricle or ventricle once a week for the first three weeks and observed at the fourth week. In some patients, radiotherapy or other chemotherapy drugs (such as temozolomide) may be combined at week 4.

The study was a single-arm, single-center intervention Phase I clinical study. The overall study was carried out in two steps:

1. Uphill phase: At least 15 patients with malignant glioma (WHO Grade IV) were initially planned to be enrolled. According to the 3+3 design, the amount of cell transfusion was increased successively according to the doses of 1x107, 3x107, 1x108 and 3x108 per dose to observe the tolerance and safety of the cells.
2. Expansion stage: 10 patients with malignant brain glioma (WHO Grade IV) are planned to be enrolled for dose expansion therapy according to the optimal dose obtained in the climbing stage, so as to observe its tolerability and safety. One course of treatment every 4 weeks, a total of 3 courses.

Clinical Study of Allogeneic Vγ9Vδ2 T Cells in the Treatment of Brain Malignant Glioma

The study will collect all adverse events that occurred after participants initiated leukocyte monopexy to Vγ9Vδ2 T cell therapy for a specified period of time or until disease progression. Safety assessment tests include: blood oxygen saturation should not be lower than 80mmHg; The ECG results of heart rate and ECG should be normal sinus rhythm. Blood biochemical examination of white blood cells should be maintained at 4000-10000/μL level; IL6 should be less than 200pg/mL. Safety assessment was performed according to the study protocol one day before each infusion of Vγ9Vδ2 T cells and one week after each infusion. Safety assessment tests include: blood oxygen saturation should not be lower than 80mmHg; The ECG results of heart rate, PR interval, RR interval, QRS, QT interval, QTcF and ECG should be normal sinus rhythm. Blood biochemical examination of white blood cells should be maintained at 4000-10000/μL level; IL6 should be less than 200pg/mL.

Primary endpoints typically included MRI measurements of enhanced lesions in the lumen before and each week after reinfusion using RANO criteria: complete response (disappearance of enhanced lesions), partial response (reduction \> 30%), disease stabilization (reduction \<30% or increase \< 20%), or disease progression (lesions \> 20% or emergence of new lesions).

Survival analysis: Overall survival (OS), which measures the time from the start of treatment to death from any cause, is measured in months, compared to historical controls, and has an effect of 14 months.

Beijing Tiantan Hospital

Glioblastoma

Astrocytoma

Oligodendroglioma

Anaplastic Astrocytoma

Bevacizumab

Cetuximab

Antineoplastic Agents, Immunological

Angiogenesis Inhibitors

Growth Inhibitors

Participants in this group will receive Cetuximab and Bevacizumab infusion into an artery each month for up to approximately one year.

Subjects will receive monthly dosing of bevacizumab (15 mg/kg) and cetuximab (200mg/m2)

SIACI of cetuximab and bevacizumab

Heather McCrea, MD

This study assesses the safety and efficacy of repeat monthly dosing of super-selective intra-arterial cerebral infusion (SIACI) of cetuximab and bevacizumab in patients \< 22 years of age.

Treatment of Relapsed/Refractory Intracranial Glioma in Patients Under 22 Years of Age

Phase I/II Trial of Repeat Dosing of Super-Selective Intraarterial Infusion of Erbitux (Cetuximab) and Avastin (Bevacizumab) for Treatment of Relapsed/Refractory Intracranial Glioma in Patients Under 22 Years of Age

The number of treatment-related adverse events will be assessed and graded according to the NCI Common Toxicity Criteria, version 5.0.

The overall response proportion along with a 95% confidence interval will be estimated via binomial proportions. We will define "evaluable" patients as patients who met eligibility requirements and have initiated therapy.

PFS will be measured from the date of the first dose of SIACI Cetuximab/Avastin to the date of progression.

OS will be measured from the date of diagnosis to the date of death

University of Miami

Assistant Professor

Patients with DIPG for whom CAR T cells will be delivered into the ventricular system

Interventions:

Biological: Autologous B7H3-specific chimeric antigen receptor (CAR) T cell with additional of IL-7Ra signaling domain Dose level: 1x10e7 CAR T cell, 3x10e7 CAR T cell, 10x10e7 CAR T cell

Autologous T cells lentivirally transduced to express a B7H3 specific chimeric antigen receptor (CAR) with additional of IL-7 receptor alpha signalingdomain given via indwelling central nervous system (CNS) catheter

B7H3 specific CAR T cell with IL-7Ra signaling domain

Piti Techavichit Associate Professor, MD

Koramit Suppipat, MD

Kanhatai Chiengthong, MD

Supannikar Tawinwung, PhD

A Phase 1 clinical trial to evaluate the safety and early efficacy of CAR T-cell with IL-7Ra signal targeting B7H3 in children with diffuse intrinsic pontine glioma (DIPG) patients after complete standard treatments.

The brain tumor known as Diffuse Intrinsic Pontine Glioma is commonly found in children aged between 5 to 10 years. This type of tumor is aggressive and infiltrates the structures of the brain stem. Treatment options are limited due to the location of the tumor, making it impossible to surgically remove the mass like other brain cancers. The standard treatment for this type of tumor is radiation therapy, as this type of cancer does not respond to chemotherapy or currently available targeted drugs. However, radiation therapy has been found to be ineffective and does not improve survival rates.

Currently, there is development in cancer treatment using immunotherapy, where the patient's immune cells are genetically modified to target the cancer, also known as CAR T cells, for the treatment of recurrent or refractory cancers in solid tumors and brain cancers. The research project aims to study the efficacy and safety of treating patients with pontine glioma using T cells that are antigen-specific and have signals from the interleukin-7 receptor alpha and are specific to the B7H3 antigen on the tumor surface. This research is the first of its kind in Thai patients. The research project expects that this treatment will be highly safe and effective in controlling diffuse pontine glioma.

Safety and Efficacy of Loco-regional B7H3 IL-7Ra CAR T Cell in DIPG

Safety and Efficacy of Intraventricular Infusion of B7H3 With IL-7 Receptor Alpha Signaling Chimeric Antigen Receptor T Cell in Diffuse Intrinsic Pontine Glioma

The persistence and distribution of B7H3-IL7Ra CAR T cells in the CSF and peripheral blood of diffuse intrinsic pontine glioma patients will be measured by flow cytometry.

Serum cytokine level measurement before and after B7-H3-IL7Ra CAR T-cell infusion.

The incidence of adverse events assessed by the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0

The overall response rate will be assessed using radiologic response criteria that use the standard sum of the two longest 2D perpendicular diameters to distinguish stable disease, progressive disease (\>25% increase), partial response (\>50% decrease), and complete response (no evaluable or measurable disease).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Single Patient Compassionate Use Clinical Trial for the Use of L-S-Gboxin (Lyophilized Form of S-Gboxin) for the Treatment Diffuse Midline Glioma, H3 K27/28-altered (DMG), Including Diffuse Intrinsic Pontine Glioma (DIPG)	NCT06439849	DIPG Brain Tumo... Diffuse Brainst... H3 K27M H3 K28M GBM	S-Gboxin	-	Petrov, Andrey
Clinical Study of Allogeneic Vγ9Vδ2 T Cells in the Treatment of Brain Malignant Glioma	NCT06396481	GBM DIPG Brain Tumo... Medulloblastoma	Vγ9Vδ2 T cell	4 Years -	Beijing Tiantan Hospital
Treatment of Relapsed/Refractory Intracranial Glioma in Patients Under 22 Years of Age	NCT05956821	Glioblastoma Mu... Anaplastic Astr... Fibrillary Astr... Oligodendroglio... Diffuse Intrins... Diffuse Intrins... DIPG Brain Tumo... H3 K27M	SIACI of cetuxi...	1 Year - 21 Years	University of Miami
Treatment of Relapsed/Refractory Intracranial Glioma in Patients Under 22 Years of Age	NCT05956821	Glioblastoma Mu... Anaplastic Astr... Fibrillary Astr... Oligodendroglio... Diffuse Intrins... Diffuse Intrins... DIPG Brain Tumo... H3 K27M	SIACI of cetuxi...	1 Year - 21 Years	University of Miami
Clinical Study of Allogeneic Vγ9Vδ2 T Cells in the Treatment of Brain Malignant Glioma	NCT06396481	GBM DIPG Brain Tumo... Medulloblastoma	Vγ9Vδ2 T cell	4 Years -	Beijing Tiantan Hospital
Safety and Efficacy of Loco-regional B7H3 IL-7Ra CAR T Cell in DIPG	NCT06221553	DIPG Brain Tumo... Diffuse Intrins...	B7H3 specific C...	1 Year - 18 Years	Chulalongkorn University

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