Genetically Modified Cells (KIND T Cells) for the Treatment of HLA-A*0201-Positive Patients With H3.3K27M-Mutated Glioma

Study Overview
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Brief Summary
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This phase I, first-in-human trial tests the safety, side effects, and best dose of genetically modified cells called KIND T cells after lymphodepletion (a short dose of chemotherapy) in treating patients who are HLA-A*0201-positive and have H3.3K27M-mutated diffuse midline glioma. KIND T cells are a type of treatment in which a patient's T cells (a type of immune system cell) are changed in the laboratory into KIND T cells so they will recognize certain markers found in tumor cells. Drugs such as cyclophosphamide and fludarabine are chemotherapy drugs used to decrease the number of T cells in the body to make room for KIND T cells. Giving KIND T cells after cyclophosphamide and fludarabine may be more useful against cancer compared to the usual treatment for patients with H3.3K27M-mutated diffuse midline glioma (DMG).

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) of a single intravenous (IV) infusion of autologous anti-H3.3K27M T-cell receptor (TCR) -expressing T-cells (KIND T cells) in HLA-A*0201+ participants with H3.3K27M+ diffuse midline gliomas. II. To determine the safety profile of a single intravenous (IV) infusion of KIND T cells in HLA-A*0201+ participants with H3.3K27M+ diffuse midline gliomas. SECONDARY OBJECTIVES: I. To evaluate manufacturing feasibility of KIND T cells. II. To characterize KIND T cells with respect to their expansion and persistence. EXPLORATORY OBJECTIVES: I. To assess Health-Related Quality of Life (HRQoL) in patients newly diagnosed with HLA-A*0201+ H3.3K27M+ DMG. II. To assess patient and/or proxy satisfaction with study participation via patient-reported outcome (PRO) measures in the context of race ethnicity and other health related social risks. III To assess on therapy toxicity in the context of race, ethnicity and other health related social risks. OUTLINE: This is a dose-escalation study of KIND T cells. CONDITIONING REGIMEN: Patients receive fludarabine intravenously (IV) on days -4, -3, and -2 and cyclophosphamide IV on day -2 in the absence of disease progression or unacceptable toxicity. T CELL THERAPY: Patients receive KIND T cells IV over 10 minutes on day 0. After completion of study treatment, patients are followed up at day 1, 3, 7, 10, 14, 21, and 28, weeks 8-24 and 28-92, months 24-36, and then yearly until year 15.

Official Title
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PNOC018 A Phase 1 Clinical Trial of Autologous T Cells Expressing a TCR Specific for H3.3K27M With Inhibition of Endogenous TCR (KIND T Cells) in HLA-A*0201-positive Participants With Newly Diagnosed H3.3K27M-positive Diffuse Midline Gliomas

Conditions
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Diffuse Midline Glioma, H3 K27M-Mutant

Intervention / Treatment
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* Drug: Cyclophosphamide
* Drug: Fludarabine
* Biological: Autologous Anti-H3.3K27M TCR-expressing T-cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants 3 to 25 years of age inclusive, at the time of signing the informed consent. The first two participants will be 12 years of age or older. Male participants of impregnate potential must agree to use contraception, during the study and for at least 6 months after the last study intervention and refrain from donating sperm during this period. Female participants of childbearing potential must agree to follow the contraceptive guidance, during the study and for at least 6 months after the last study intervention. Females of childbearing potential must have a negative serum or urine pregnancy test within 14 days of receiving study interventions. Central nervous system (CNS) reservoir such as Ommaya catheter must be in place. Newly diagnosed participants with intracranial diffuse midline gliomas (DMG) who are positive for the H3.3K27M mutation (positive testing from a Clinical Laboratory Improvement Amendments (CLIA) laboratory required or equivalent) and who completed standard radiation therapy. Participants that have received any tumor directed therapy other than radiation must be discussed with study chairs. All participants must t test positive for HLA-A*0201 (positive testing from a CLIA or equivalent laboratory required). Other HLA-A2 subtypes are excluded. All participants must consent for tumor tissue (fresh or archival) for biomarker analysis. All participants must have measurable disease at the time of consent. All participants must be either off systemic steroids or be on a stable dose of dexamethasone (maximum dose of 0.1 mg/kg/day or 4 mg/day) at the time of enrollment. All participants must be off systemic steroids for 7 days or more prior to leukapheresis. Participants must not have received any bone marrow transplants for the treatment of their tumor. All participants must have started standard radiation therapy within 6 weeks of diagnosis by either imaging or tissue confirmation whichever was completed last (biopsy or surgery). Peripheral absolute neutrophil account 1000/mm^3 Platelet count 100,000/mm^3 (transfusion dependent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment) Absolute lymphocyte count >= 500/microliter (uL) or cluster of differentiation 3 (CD3) count of >= 150/uL Creatinine clearance or radioisotope glomerular filtration rate >= 70 mL/min/1.73 m^2 or maximum serum creatinine based on age/gender as follows: 3 to < 6 years =< 0.8 mg/dL (male and female) 6 to < 10 years =< 1.0 mg/dL (male and female) 10 to < 13 years =< 1.2 mg/dL (male and female) 13 to < 16 years =< 1.5 mg/dL (male) and 1.4 mg/dL (female) >= 16 years =< 1.7 mg/dL (male) and 1.4 mg/dL (female) Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN Serum albumin >= 2 g/dL Corrected QT interval (QTc) =< 480 ms Shortening fraction >= 27% by echocardiogram No evidence of dyspnea at rest No exercise intolerance due to pulmonary insufficiency Pulse oximetry > 92% while breathing room air A well-controlled seizure disorder Performance status (Lansky < 16 years and Karnofsky >= 16 years) that is at least 70 Capable of giving signed informed consent or assent depending on participant age as appropriate which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Assent will be obtained when appropriate based on the subjects age. Exclusion Criteria: Participants with magnetic resonance imaging (MRI) or clinical evidence of uncontrolled tumor mass effect; the assessment of mass effect should be made by the study investigators prior to any planned KIND T cell treatment. Pre-infusions MRI will need to be reviewed by the study investigators prior to dosing. Participant with an assessment score >= 3 will be excluded Participants with DMG located in the spinal cord Participants with a known disorder that affects their immune system such as human immunodeficiency virus (HIV) or hepatitis B or C, or an autoimmune disorder requiring systemic cytotoxic or immunosuppressive therapy. Participants who are currently using inhaled, intranasal, ocular, topical, or other non-oral or non-IV steroids are not necessarily excluded from the study. Participants who have received prior solid organ or bone marrow transplantation. Participants with uncontrolled infection. Female participants of childbearing potential must not be pregnant or breast-feeding. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection,symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Untreated symptomatic hydrocephalus determined by treating physician. Participants who are unable to return for follow-up visits or obtain follow-up studies required to assess toxicity to therapy. Participants who are currently receiving another investigational drug. Participants who are currently receiving other anticancer agents (bevacizumab used to treat tumor mass effect will not constitute an exclusion; at time of enrollment participants need to be off bevacizumab and will need to be discussed with the study team).

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 25 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (KIND T cells, cyclophosphamide, fludarabine)<br>Patients receive fludarabine IV on days -4, -3, and -2 and cyclophosphamide IV on day -2 in the absence of disease progression or unacceptable toxicity for the conditioning regimen. Patients also receive KIND T cells IV at dose level 1 (2 x 106 dextramer®+ CD8+ cells/kg) on day 0. If no DLTs are reported, newly enrolling participants may receive dose level 2 of KIND T cells on day 0. | Drug: Cyclophosphamide<br>* Given IV<br>* Other names: Cycloblastin;Drug: Fludarabine<br>* Given IV<br>* Other names: Fludara;Biological: Autologous Anti-H3.3K27M TCR-expressing T-cells<br>* Given IV<br>* Other names: KIND T cells;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) | MTD is defined as the dose at which fewer than one-third of participants experience a dose limiting toxicity (DLT) for all participants who received at least one study intervention. | Up to 28 days following infusion of autologous anti-H3.3K27M TCR-expressing T-cells (KIND T cells) | 
| Number of participants with treatment-emergent adverse events | Treatment-emergent adverse events will be graded according to severity, and their incidence will be summarized by dose level. | Up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants who receive KIND T cells | The percentage of participants who received KIND T cell infusions will be reported. If the manufacturing of T-cell product is not successful because it does not meet release criteria, the participant will have the choice of a second apheresis for a second manufacturing process | Up to 12 months | 
| Duration of KIND T cells in-vivo persistence | The duration of KIND T cells in-vivo persistence will be estimated using Kaplan-Meier techniques. In addition, the persistence of KIND T cells will be evaluated for each participant for up to 12 months or until any 2 sequential negative tests documenting loss of KIND T cells in blood. | Up to 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Autologous T Cells, KIND T Cells, HLA-A*0201-Positive