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Interleukin-15 and -21 Armored Glypican-3-specific Chimeric Antigen Receptor Expressed in T Cells for Pediatric Solid Tumors

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ClinicalTrials.gov Identifier: NCT04715191
Recruitment Status : Not yet recruiting
First Posted : January 20, 2021
Last Update Posted : January 20, 2021
Sponsor:
Collaborator:
Center for Cell and Gene Therapy, Baylor College of Medicine
Information provided by (Responsible Party):
Andras Heczey, Baylor College of Medicine

Brief Summary:

Patients may be considered if the cancer has come back, has not gone away after standard treatment or the patient cannot receive standard treatment. This research study uses special immune system cells called CARE T cells, a new experimental treatment.

The body has different ways of fighting infection and disease. No single way seems perfect for fighting cancers. This research study combines two different ways of fighting cancer: antibodies and T cells. Antibodies are types of proteins that protect the body from infectious diseases and possibly cancer. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells, including cells infected with viruses and tumor cells. Both antibodies and T cells have been used to treat patients with cancers. They have shown promise, but have not been strong enough to cure most patients.

Investigators have found from previous research that they can put a new gene (a tiny part of what makes-up DNA and carries a person's traits) into T cells that will make them recognize cancer cells and kill them. In the lab, investigators made several genes called a chimeric antigen receptor (CAR), from an antibody called GPC3. The antibody GPC3 recognizes a protein found solid tumors including pediatric liver cancers. This CAR is called GPC3-CAR. To make this CAR more effective, investigators also added two genes that includes IL15 and IL21, which are protein that helps CAR T cells grow better and stay in the blood longer so that they may kill tumors better. The mixture of GPC3-CAR and IL15 plus IL21 killed tumor cells better in the laboratory when compared with CAR T cells that did not have IL15 plus IL21 .This study will test T cells that investigators made (called genetic engineering) with GPC3-CAR and the IL15 plus IL21 (CARE T cells) in patients with GPC3-positive solid tumors.

T cells made to carry a gene called iCasp9 can be killed when they encounter a specific drug called AP1903. The investigators will insert the iCasp9 and IL15 plus IL21 together into the T cells using a virus that has been made for this study. The drug (AP1903) is an experimental drug that has been tested in humans with no bad side-effects. The investigators will use this drug to kill the T cells if necessary due to side effects.

This study will test T cells genetically engineered with a GPC3-CAR and IL15 plus IL21 (CARE T cells) in patients with GPC3-positive solid tumors.

The CARE T cells are an investigational product not approved by the Food and Drug Administration.

The purpose of this study is to find the biggest dose of CARE T cells that is safe, to see how long they last in the body, to learn what the side effects are and to see if the CARE T cells will help people with GPC3-positive solid tumors.


Condition or disease Intervention/treatment Phase
Liver Cancer Rhabdomyosarcoma Malignant Rhabdoid Tumor Liposarcoma Wilms Tumor Yolk Sac Tumor Genetic: CARE T cells Drug: Cytoxan Drug: Fludara Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Interleukin-15 and -21 Armored Glypican-3-specific Chimeric Antigen Receptor Expressing Autologous T Cells as an Immunotherapy for Children With Solid Tumors (CARE)
Estimated Study Start Date : July 2022
Estimated Primary Completion Date : August 2025
Estimated Study Completion Date : July 2040


Arm Intervention/treatment
Experimental: CARE T cells + Fludarabine and Cytoxan
GPC3-CAR and the IL15 plus IL21 (CARE T cells) along with lymphodepleting chemotherapy (Cytoxan and Fludarabine) will be administered to patients with GPC3-positive solid tumors.
Genetic: CARE T cells

Three different dosing schedules will be evaluated. The following dose levels will be evaluated:

DL1: 1x10^8/m2 DL2: 3x10^8/m2 DL3: 1x10^9/m2

The doses are calculated according to the actual number of GPC3-CAR transduced T cells.

Other Name: 15.21.GPC3-CAR T cells

Drug: Cytoxan
Cyclophosphamide will be given at a dose of 500 mg/m2/day for 3 days given intravenously.
Other Name: Cyclophosphamide

Drug: Fludara
Fludarabine will be given at a dose of 30 mg/m2/day for 3 days given intravenously.
Other Name: Fludarabine




Primary Outcome Measures :
  1. Number of Patients with Dose Limiting Toxicity [ Time Frame: 4 weeks ]
    A dose limiting toxicity is defined as any toxicity that is considered to be primarily related to the GPC3-CAR T cells. Specifically those which are Grade 5; non-hematologic Grade 3-4 not returning to Grade 2 within 72 hours; Grade 2-4 allergic reaction; Hematologic Grade 4 that fails to return to Grade 2 or baseline (whichever is more severe) within 14 days; all grade 4 CRS and neurologic toxicities and grade 3 CRS and neurologic toxicities that fail to return to Grade 1 within 7 days.


Secondary Outcome Measures :
  1. Percent of Patients with best response as either complete remission or partial remission [ Time Frame: 4 weeks ]
    Response rates will be estimated as the percent of patients whose best response is either complete remission or partial remission by combining the data from the two patients. To compare with historical data, a 95% confidence interval will be calculated for the response rate

  2. Median T cell persistence [ Time Frame: 15 years ]
    T cell persistence will be measured by PCR



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   1 Year to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Procurement Eligibility

Inclusion Criteria:

  • Relapsed or refractory GPC3-positive* solid tumors (as determined by immunohistochemistry with an extent score of >=Grade 2 [>25% positive tumor cells] and an intensity score of >= 2 [scale 0-4]).
  • Age ≥1 year and ≤ 21 years
  • Lansky or Karnofsky score ≥60%
  • Life expectancy ≥16 weeks
  • Barcelona Clinic Liver Cancer Stage A, B or C (for patients with hepatocellular carcinoma only)
  • Child-Pugh-Turcotte score <7 (for patients with hepatocellular carcinoma only)
  • Informed consent explained to, understood by and signed by patient/guardian. Patient/guardian given copy of informed consent

Exclusion Criteria:

  • History of hypersensitivity reactions to murine protein-containing products OR presence of human anti-mouse antibody (HAMA) prior to enrollment (only patients who have received prior therapy with murine antibodies).
  • History of organ transplantation
  • Known HIV positivity
  • Active bacterial, fungal or viral infection (except Hepatitis B or Hepatitis C virus infections)

Treatment Eligibility

Inclusion Criteria:

  • Age ≥ 1 year and ≤ 21 years
  • Barcelona Clinic Liver Cancer Stage A, B or C (for patients with hepatocellular carcinoma only)
  • Life expectancy of ≥ 12 weeks
  • Lansky or Karnofsky score ≥ 60%
  • Child-Pugh-Turcotte score < 7 (for patients with hepatocellular carcinoma only)
  • Adequate organ function:
  • Creatinine clearance as estimated by Cockcroft Gault or Schwartz ≥ 60 ml/min
  • serum AST< 5 times ULN
  • total bilirubin < 3 times ULN for age
  • INR ≤1.7 (for patients with hepatocellular carcinoma only)
  • absolute neutrophil count > 500/µl
  • platelet count > 25,000/µl (can be transfused)
  • Hgb ≥ 7.0 g/dl (can be transfused)
  • Pulse oximetry >90% on room air
  • Refractory or relapsed disease after treatment with up- front therapy and at least one salvage treatment cycle
  • Recovered from acute toxic effects of all prior chemotherapy and investigational agents before entering this study
  • Sexually active patients must be willing to utilize one of the more effective birth control methods for 3 months after the T-cell infusion.
  • Informed consent explained to, understood by and signed by patient/guardian. Patient/guardian given copy of informed consent

Exclusion Criteria:

  • Pregnancy or lactation
  • Uncontrolled infection
  • Systemic steroid treatment (greater than or equal to 0.5 mg prednisone equivalent/kg/day, dose adjustment or discontinuation of medication must occur at least 24 hours prior to CAR T cell infusion)
  • Known HIV positivity
  • Active bacterial, fungal or viral infection (except Hepatitis B or Hepatitis C virus infections)
  • History of organ transplantation
  • History of hypersensitivity reactions to murine protein-containing products OR presence of human anti-mouse antibody (HAMA) prior to enrollment (only patients who have received prior therapy with murine antibodies)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04715191


Contacts
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Contact: Andras Heczey (832) 824-4233 axheczey@txch.org
Contact: David Steffin (832) 824-4233 dhsteffi@texaschildrens.org

Locations
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United States, Texas
Texas Children's Hospital
Houston, Texas, United States, 77030
Sponsors and Collaborators
Baylor College of Medicine
Center for Cell and Gene Therapy, Baylor College of Medicine
Investigators
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Principal Investigator: Andras Heczey, MD Baylor College of Medicine
Principal Investigator: David Steffin, MD Baylor College of Medicine
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Responsible Party: Andras Heczey, Assistant Professor, Baylor College of Medicine
ClinicalTrials.gov Identifier: NCT04715191    
Other Study ID Numbers: CARE
First Posted: January 20, 2021    Key Record Dates
Last Update Posted: January 20, 2021
Last Verified: January 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Andras Heczey, Baylor College of Medicine:
15.21.GPC3-CAR T cells
GPC3
Glypican
Additional relevant MeSH terms:
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Neoplasms
Rhabdomyosarcoma
Wilms Tumor
Liposarcoma
Endodermal Sinus Tumor
Rhabdoid Tumor
Neoplasms by Site
Myosarcoma
Neoplasms, Muscle Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Sarcoma
Neoplasms, Complex and Mixed
Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplastic Syndromes, Hereditary
Kidney Diseases
Urologic Diseases
Genetic Diseases, Inborn
Neoplasms, Adipose Tissue
Mesonephroma
Neoplasms, Germ Cell and Embryonal
Cyclophosphamide
Fludarabine
Fludarabine phosphate
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents