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

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

Study Overview

• Status: Recruiting
• Conditions: Melanoma; Soft Tissue Sarcoma; Carcinoma; Osteosarcoma; Ewing Sarcoma; Rhabdoid Tumor; Neuroblastoma; Rhabdomyosarcoma; Wilms Tumor; Hepatoblastoma; Desmoplastic Small Round Cell Tumor; Pediatric Solid Tumor; Clear Cell Sarcoma; Malignant Peripheral Nerve Sheath Tumors; Adrenocortical Cancer; Germ Cell Cancer
• Intervention / Treatment: Drug: Fludarabine; Drug: Cyclophosphamide; Drug: MESNA; Drug: 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.

• Study Type: Interventional
• Enrollment (Estimated): 32
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Chris DeRenzo, MD; Phone Number: 866-278-5833; Email: referralinfo@stjude.org

Study Locations

• United States
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • Recruiting
      • St. Jude Children'S Research Hospital
      • Contact: Chris DeRenzo, MD; Phone Number: 866-278-5833; Email: referralinfo@stjude.org
      • Principal Investigator: Chris DeRenzo, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 21 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Other: Treatment Phase; During the treatment phase, the participant receives an infusion of the B7-H3-CAR T cells that were made in the Collection and Manufacturing Phase. Chemotherapy is given for several days prior to the cellular infusion. Patients are then monitored for possible side effects, as well as effects of the treatment on their cancer.

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; Other Names: Fludara; 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; Other Names: Cytoxan; 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; Other Names: Mesnex; 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.; Other Names: CAR T- cell infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety of B7-H3-CAR T cells	A phase I design to determine the maximum tolerated dose (MTD) of autologous, B7-H3-CAR T cells. Four dose levels (3x10^5/kg, 1x10^6/kg, 3x10^6/kg, and 1x10^7/kg) will be evaluated.	6 weeks after B7-H3-CAR T cell infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Response	The number of patients with objective responses (complete response (CR) + partial response (PR)) determined by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.	6 weeks after B7-H3-CAR T cell infusion

Collaborators and Investigators

• Sponsor: St. Jude Children's Research Hospital
• Investigators: Principal Investigator: Chris DeRenzo, MD, St. Jude Children'S Research Hospital

Publications and helpful links

Helpful Links

• St. Jude Children's Research Hospital
• Clinical Trials Open at St. Jude

Study record dates

Study Major Dates

• Study Start (Actual): July 6, 2022
• Primary Completion (Estimated): March 1, 2026
• Study Completion (Estimated): March 1, 2027

Study Registration Dates

• First Submitted: May 11, 2021
• First Submitted That Met QC Criteria: May 18, 2021
• First Posted (Actual): May 21, 2021

Study Record Updates

• Last Update Posted (Actual): August 8, 2023
• Last Update Submitted That Met QC Criteria: August 7, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Endocrine System Diseases; Endocrine Gland Neoplasms; Genetic Diseases, Inborn; Neuromuscular Diseases; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Nerve Tissue; Peripheral Nervous System Diseases; Kidney Neoplasms; Nervous System Neoplasms; Neoplastic Syndromes, Hereditary; Neoplasms, Complex and Mixed; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Neuroectodermal Tumors, Primitive; Neoplasms, Muscle Tissue; Peripheral Nervous System Neoplasms; Neuroectodermal Tumors, Primitive, Peripheral; Adrenal Gland Diseases; Myosarcoma; Neoplasms, Fibrous Tissue; Fibrosarcoma; Neurofibroma; Adrenal Gland Neoplasms; Adrenal Cortex Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Neoplasms; Sarcoma; Neoplasms, Germ Cell and Embryonal; Sarcoma, Ewing; Rhabdoid Tumor; Osteosarcoma; Neuroblastoma; Nerve Sheath Neoplasms; Rhabdomyosarcoma; Wilms Tumor; Hepatoblastoma; Neurofibrosarcoma; Adrenocortical Carcinoma; Sarcoma, Clear Cell; Desmoplastic Small Round Cell Tumor; Adrenal Cortex Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Cyclophosphamide; Fludarabine
• Other Study ID Numbers: 3CAR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes