Summary

Eligibility
for people ages 3-21 (full criteria)
Location
at UCSF
Dates
study started
estimated completion
Principal Investigator
by Sabine Mueller, MD, PhD, MAS (ucsf)Hideho Okada, MD, PhD (ucsf)
Headshot of Sabine Mueller
Sabine Mueller
Headshot of Hideho Okada
Hideho Okada

Description

Summary

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).

Official Title

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

Details

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-A0201+ 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-A0201+ 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 describe anti-tumor responses and survival after infusion of KIND T cells. II. To explore the association of tumor and immune biomarkers including but not limited to characterization of KIND T cells in blood and tumor samples with clinical endpoints and/or adverse events (AEs). 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.

Keywords

Diffuse Midline Glioma, H3 K27M-Mutant Autologous T Cells KIND T Cells HLA-A*0201-Positive Glioma Cyclophosphamide Fludarabine Autologous Anti-H3.3K27M TCR-expressing T-cells

Eligibility

You can join if…

Open to people ages 3-21

  • Participants 3 to 21 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.
  • All participants must 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 prior chemotherapy, immunotherapy, or bone marrow transplant 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/mm3

  • Platelet count 100,000/mm3 (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 m2 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.

You CAN'T join if...

  • 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 or who have previously received another investigational drug for the purposes of treating their tumor.
  • 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).

Location

  • University of California, San Francisco
    San Francisco California 94143 United States

Lead Scientists at University of California Health

  • Sabine Mueller, MD, PhD, MAS (ucsf)
    Professor, Neurology, School of Medicine
  • Hideho Okada, MD, PhD (ucsf)
    Dr. Okada is a creative physician-scientist who has developed therapeutic modalities in the laboratory, translated them into clinical protocols, and used his expertise as both scientist and clinician to assess the clinical data from ongoing trials. Dr. Okada's work has consistently focused on immunotherapeutic strategies aimed at a daunting challenge in oncology – malignant brain tumors.

Details

Status
not yet accepting patients
Start Date
Completion Date
(estimated)
Sponsor
University of California, San Francisco
ID
NCT05478837
Phase
Phase 1 Glioma Research Study
Study Type
Interventional
Participants
Expecting 12 study participants
Last Updated