B7-H3-Specific Chimeric Antigen Receptor Autologous T-Cell Therapy for Pediatric Patients With Solid Tumors (3CAR)

Overview

3CAR is being done to investigate an immunotherapy for patients with solid tumors. It is a Phase I clinical trial evaluating the use of autologous T cells genetically engineered to express B7-H3-CARs for patients ≤ 21 years old, with relapsed/refractory B7-H3+ solid tumors. This study will evaluate the safety and maximum tolerated dose of B7-H3-CAR T cells.The purpose of this study is to find the maximum (highest) dose of B7-H3-CAR T cells that are safe to give to patients with B7-H3-positive solid tumors. Primary objective To determine the safety of one intravenous infusion of autologous, B7-H3-CAR T cells in patients (≤ 21 years) with recurrent/refractory B7-H3+ solid tumors after lymphodepleting chemotherapy Secondary objective To evaluate the antitumor activity of B7-H3-CAR T cells Exploratory objectives * To evaluate the tumor environment after treatment with B7-H3-CAR T cells * To assess the immunophenotype, clonal structure and endogenous repertoire of B7-H3-CAR T cells and unmodified T cells * To characterize the cytokine profile in the peripheral blood after treatment with B7-H3-CAR T cells

Detailed description

Treatment will include a single infusion of B7-H3-CAR T cells after lymphodepleting chemotherapy, with dosing based on the number of CAR+ T cells and patient weight. The study will evaluate the safety and maximum tolerated dose (MTD) of B7-H3-CAR T cells, using a standard 3+3 study design and a 6-week evaluation period. The total study duration will be 1 year, at which point patients will enroll on our existing institutional long-term follow-up protocol.

Interventions

• Drug Fludarabine
  Fludarabine phosphate is a synthetic purine nucleoside analog. It acts by inhibiting DNA polymerase, ribonucleotide reductase and DNA primase by competing with the physiologic substrate, deoxyadenosine triphosphate, resulting in inhibition of DNA synthesis. Intravenous
• Drug Cyclophosphamide
  Cyclophosphamide is a nitrogen mustard derivative. It acts as an alkylating agent that causes cross-linking of DNA strands by binding with nucleic acids and other intracellular structures, thus interfering with the normal function of DNA. Intravenous
• Drug MESNA
  Mesna is a synthetic sulfhydryl (thiol) compound. Mesna contains free sulfhydryl groups that interact chemically with urotoxic metabolites of oxaza-phosphorine derivatives such as cyclophosphamide and ifosfamide
• Drug B7-H3 CAR T cells
  The study participant will receive B7-H3-CAR T cells by vein, through either an IV or a central line.

Primary outcome measures

• Safety of B7-H3-CAR T cells [Time frame: 6 weeks after B7-H3-CAR T cell infusion]

Secondary outcome measures (1)

• Clinical Response [Time frame: 6 weeks after B7-H3-CAR T cell infusion]

Eligibility criteria

Inclusion criteria

Procurement and T-cell production eligibility\*

\*a previously collected, autologous leukapheresis product can be used for T-cell production

• Age ≤21 years old
• B7-H3+ solid tumor with measurable disease; B7-H3 expression will be evaluated by standard immunohistochemistry (IHC) using a previously obtained biopsy; a tumor is considered B7-H3 positive with an H-score ≥100
• Estimated life expectancy of >12 weeks
• Karnofsky or Lansky (age-dependent) performance score ≥50
• For females of child bearing age:
• Not pregnant with negative serum pregnancy test within 7 days prior to enrollment
• Not lactating with intent to breastfeed
• Meets eligibility criteria to undergo autologous apheresis, or have previously undergone autologous apheresis

Exclusion criteria

• Known primary immunodeficiency
• Known HIV positivity
• Severe intercurrent bacterial, viral or fungal infection (e.g. active hepatitis B or C infection or adenovirus infection)
• History of hypersensitivity reactions to murine protein-containing products
• Rapidly progressive disease (in the opinion of the study PIs)

Inclusion criteria

Treatment eligibility

• Age ≤21 years old
• B7-H3+ solid tumor with measurable disease
• Evidence of relapsed or refractory disease after standard first-line therapy
• Estimated life expectancy of >8 weeks
• Karnofsky or Lansky (age-dependent) performance score≥50
• Echocardiogram with a ventricular ejection fraction
• >40%; or shortening fraction ≥25%
• Adequate renal function defined as creatinine clearance or radioisotope GFR 50 ml/min/1.73m2 (GFR 40 ml/min/1.73m2 if < 2 years of age)
• Adequate pulmonary function defined as pulse oximetry ≥92% on room air or forced vital capacity (FVC) ≥50% of predicted value
• Total Bilirubin ≤3 times the upper limit of normal for age, except in subjects with Gilbert's syndrome
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤5 times the upper limit of normal for age
• Hemoglobin≥ 7g/dL (can be transfused)
• Platelet count >50,000/uL (can be transfused)
• Absolute neutrophil count (ANC) ≥ 1000/uL
• Has recovered from all NCI CTAE grade III-IV, non-hematologic acute toxicities from prior therapy
• For females of child bearing age:
• Not pregnant with negative serum pregnancy test within 7 days prior to enrollment
• Not lactating with intent to breastfeed
• If sexually active, agreement to use birth control until 3 months after T-cell infusion. Male partners should use a condom.
• Available autologous transduced T-cell product that has met GMP release criteria
• Agreement to participate in long-term follow-up protocol for patients, who have received genetically modified cell products

Exclusion criteria

• Known primary immunodeficiency
• History of HIV infection
• Severe, uncontrolled intercurrent bacterial, viral or fungal infection
• History of hypersensitivity reactions to murine protein-containing products
• Receiving systemic steroid therapy exceeding the equivalent of 0.5 mg/kg/day of methylprednisolone, in the 7 days prior to B7-H3-CAR T-cell infusion
• Receiving systemic therapy in the 14 days prior to CAR T-cell infusion, which will interfere with the activity of the B7-H3-CAR product (in the opinion of the study PIs).
• Rapidly progressing disease (in the opinion of the study PIs)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• St. Jude Children's Research Hospital — Memphis

Identifiers

NCT: NCT04897321 · 3CAR · NCI-2021-10933

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗