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 H3.3K27M-positive Diffuse Midline Gliomas

Status: Recruiting
Location: See location...
Intervention Type: Drug, Biological
Study Type: Interventional
Study Phase: Phase 1
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).

Eligibility
Participation Requirements
Sex: All
Minimum Age: 2
Maximum Age: 25
Healthy Volunteers: f
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• Participants 2 to 25 years of age inclusive, at the time of signing the informed consent. The first two participants will be 12-25 years of age.

• 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.

• CNS reservoir such as Ommaya catheter must be in place.

• Patients must be enrolled on PNOC COMP prior to enrollment on PNOC018 if PNOC COMP is open to accrual at the enrolling institution.

• Participants with 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 at least 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 if available.

• All participants must have evaluable or measurable disease at the time of consent.

• All participants must be either off systemic steroids or be on a stable or declining dose of dexamethasone (maximum dose of 0.1 mg/kg/day or 4 mg/day) at the time of enrollment.

• Participants must not have received any bone marrow transplants for the treatment of their tumor.

• Participants must discontinue all anti-cancer agents and radiotherapy and, must have recovered from significant acute toxic effects of prior therapies.

‣ Chemotherapy/biologic therapy: All cytotoxic chemotherapy/biologic therapy must be discontinued ≥ 7 days prior to enrollment.

⁃ Immunotherapy: The last dose of anti-tumor antibody therapy must be at least 3 half-lives or 30 days, whichever is shorter, from the time of enrollment.

• All participants must have adequate organ function.

• Adequate bone marrow function is defined as:

‣ Peripheral absolute neutrophil account 1000/mm\^3 and

⁃ 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/µL or CD3 count of \>= 150/µL

• Adequate renal function is defined as:

• 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)

⁃ 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)

• Adequate liver function is defined as:

‣ Bilirubin (sum of conjugated + unconjugated) =\< 1.5 x upper limit of normal (ULN) for age and

⁃ Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =\< 2.5 x ULN and

⁃ Serum albumin \>= 2 g/dL

• Participants with a history of congestive heart failure at risk because of underlying cardiovascular disease or exposure to cardiotoxic drugs must have adequate cardiac function as clinically indicated. Only order ECHO and EKG for patients with history of cardiac toxicity.

‣ (QTc) =\< 480 ms

⁃ Injection fraction \>= 45% by echocardiogram

• Adequate pulmonary function is defined as no evidence of dyspnea at rest, no exercise intolerance due to pulmonary insufficiency, and pulse oximetry \> 92% while breathing room air

• Adequate neurologic function is defined as a well-controlled seizure disorder and performance status (Lansky \< 16 years and Karnofsky \>= 16 years) that is at least 60.

• Informed consent: 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.

Locations
United States
California
University of California, San Francisco
RECRUITING
San Francisco
Contact Information
Primary
PNOC Operations
PNOC018@ucsf.edu
415-502-1600
Time Frame
Start Date: 2023-07-20
Estimated Completion Date: 2029-08-31
Participants
Target number of participants: 12
Treatments
Experimental: Treatment (KIND T cells, cyclophosphamide, fludarabine)
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.
Related Therapeutic Areas
Sponsors
Collaborators: The V Foundation, Parker Institute for Cancer Immunotherapy, Alliance for Cancer Gene Therapy
Leads: University of California, San Francisco

This content was sourced from clinicaltrials.gov

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