Genetically Engineered Cells (Autologous Anti-HER2 CAR-CD28 T Cells) in Combination with Immune Checkpoint Inhibitors for the Treatment of Advanced Sarcoma
This phase I trial tests the safety and side effects of autologous anti-HER2 chimeric antigen receptor (CAR)-CD28 T cells in combination with immune checkpoint inhibitors in treating patients with sarcoma that has spread to other places in the body (advanced). Antibodies are types of proteins that protect the body from bacterial and other diseases. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells including tumor cells. The T cells given in this study will come from the patient and will have a new gene put in them that makes them able to recognize HER2, a protein on the surface of tumor cells. In addition, it contains CD28, which stimulated T cells and make them last longer. These HER2-specific T cells may help the body's immune system identify and kill HER2 positive sarcoma cells. After this new gene is put into the T cell, the T cell becomes known as a chimeric antigen receptor T cell or CAR T cell. Immune checkpoint inhibitors are drugs that remove the brakes on the immune system to allow it to act against cancer. Giving immune checkpoint inhibitors with autologous anti-HER2 CAR-CD28 T cells may help autologous anti-HER2 CAR-CD28 T cells work better in treating patients with sarcoma.
Inclusion Criteria
- PROCUREMENT ELIGIBILITY: Diagnosis of a HER2-positive sarcoma. Immunohistochemistry (IHC) will be used to determine HER2 expression. Standard HER2 positive breast cancer density gradient tissue microarrays will be used as positive controls. HER2 expression will be graded for percent positive tumor cells (grade 0: no staining; grade 1: 1–25%; grade 2: 26–50%; grade 3: 51–75%; and grade 4: 76- 100%) and intensity of staining (negative; 1+; 2+; and 3+). For the patient to meet eligibility, tumors are required to have at least >= grade 1 and >= 1+ intensity score for HER2 staining
- PROCUREMENT ELIGIBILITY: Age between 1 to 25 years
- PROCUREMENT ELIGIBILITY: Karnofsky or Lansky performance score of >= 60
- PROCUREMENT ELIGIBILITY: Informed consent explained to, understood by, and signed by patient/guardian. Patient or guardian given copy of informed consent
- TREATMENT ELIGIBILITY: Diagnosis of a HER2 positive sarcoma with disease progression or recurrence after at least one prior systemic therapy
- TREATMENT ELIGIBILITY: At least 4 weeks from and having recovered from acute toxic effects of all prior cytotoxic chemotherapy. Those receiving targeted (non-cytotoxic) drugs must be at least 7 days or 3 drug half-lives, whichever is greater, from last receipt of said drug and must have recovered from all acute toxic effects of that drug
- TREATMENT ELIGIBILITY: Normal cardiac left ventricular end diastolic function (LVEF) as measured by echocardiogram (normal per institutional limits)
- TREATMENT ELIGIBILITY: Karnofsky or Lansky performance score of >= 60
- TREATMENT ELIGIBILITY: Total bilirubin =< 1.5 x upper limit of normal (ULN) for age AND direct bilirubin =< ULN for age
- TREATMENT ELIGIBILITY: Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN
- TREATMENT ELIGIBILITY: Serum creatinine =< 1.5 x ULN for age
- TREATMENT ELIGIBILITY: Hemoglobin (Hgb) >= 7.0 g/dL (transfusion allowed)
- TREATMENT ELIGIBILITY: White blood cell count (WBC) > 2,000/ul
- TREATMENT ELIGIBILITY: Absolute neutrophil count (ANC) > 1,000/ul
- TREATMENT ELIGIBILITY: Platelets > 75,000/ul (not transfused)
- TREATMENT ELIGIBILITY: Pulse oximetry of >= 90% on room air
- TREATMENT ELIGIBILITY: Sexually active males and females of childbearing potential must agree to use a form of contraception considered effective and medically acceptable by the investigator. Non-childbearing potential is defined as pre-menarche, greater than 1-year postmenopausal, or surgically sterilized
- TREATMENT ELIGIBILITY: Available autologous transduced cytotoxic T lymphocytes with >= 15% expression of HER2 CAR and killing of HER2-postiive targets >= 20% in cytotoxicity assay
- TREATMENT ELIGIBILITY: Informed consent explained to, understood by, and signed by patient or guardian. Patient or guardian given copy of informed consent
Exclusion Criteria
- PROCUREMENT ELIGIBILITY: Known human immunodeficiency virus (HIV) positivity
- PROCUREMENT ELIGIBILITY: Severe previous toxicity from cyclophosphamide including, but not limited to, decreased heart function, abnormal heart rhythms, severe allergic reaction, or grade 4 hemorrhagic cystitis
- PROCUREMENT ELIGIBILITY: Severe previous toxicity from fludarabine including, but not limited to, neurotoxicity, coma, renal injury requiring dialysis, development of hemolytic anemia, or development of a secondary malignancy
- PROCUREMENT ELIGIBILITY: Severe hypersensitivity (>= grade 3) to pembrolizumab or nivolumab or any of their excipients
- PROCUREMENT ELIGIBILITY: History of allergic reactions attributed to murine protein containing products, dimethyl sulfoxide (DMSO) or dextran 40
- PROCUREMENT ELIGIBILITY: Cardiac disorder defined as left ventricular ejection fraction below the institution normal as determined by echocardiogram or New York Heart Association (NYHA) functional class III or IV or clinically significant cardiac arrhythmia
- PROCUREMENT ELIGIBILITY: Active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
- PROCUREMENT ELIGIBILITY: History of non-infectious pneumonitis that required steroids or current pneumonitis
- PROCUREMENT ELIGIBILITY: Known history of active tuberculosis
- PROCUREMENT ELIGIBILITY: Has undergone solid organ transplantation at any time
- PROCUREMENT ELIGIBILITY: Has a diagnosis of immunodeficiency or is receiving any other form of immunosuppressive therapy aside from cytotoxic chemotherapy
- PROCUREMENT ELIGIBILITY: Presence of bulky tumor at the primary or metastatic site
- PROCUREMENT ELIGIBILITY: Has a history or current evidence of any condition, therapy, or laboratory or radiologic abnormality that is not in the best interest of the subject to participate, as determined by the treating investigator
- TREATMENT ELIGIBILITY: Known HIV positivity
- TREATMENT ELIGIBILITY: Intercurrent infection
- TREATMENT ELIGIBILITY: Pregnant or lactating
- TREATMENT ELIGIBILITY: History of hypersensitivity to murine protein-containing products, DMSO or dextran 40
- TREATMENT ELIGIBILITY: Severe previous toxicity from cyclophosphamide including, but not limited to, decreased heart function, abnormal heart rhythms, severe allergic reaction, or grade 4 hemorrhagic cystitis
- TREATMENT ELIGIBILITY: Severe previous toxicity from fludarabine including, but not limited to, neurotoxicity, coma, renal injury requiring dialysis, development of hemolytic anemia, or development of a secondary malignancy
- TREATMENT ELIGIBILITY: Severe hypersensitivity (>= grade 3) to pembrolizumab or nivolumab or any of their excipients
- TREATMENT ELIGIBILITY: Cardiac disorder defined as left ventricular ejection fraction below the institution normal as determined by echocardiogram or New York Heart Association (NYHA) functional class III or IV or clinically significant cardiac arrhythmia
- TREATMENT ELIGIBILITY: Active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
- TREATMENT ELIGIBILITY: History of non-infectious pneumonitis that required steroids or current pneumonitis
- TREATMENT ELIGIBILITY: Known history of active tuberculosis
- TREATMENT ELIGIBILITY: Has received a live virus vaccine within previous 30 days
- TREATMENT ELIGIBILITY: Has undergone solid organ transplantation at any time
- TREATMENT ELIGIBILITY: Has a diagnosis of immunodeficiency or is receiving any other form of immunosuppressive therapy
- TREATMENT ELIGIBILITY: Presence of bulky tumor at the primary or metastatic site
- TREATMENT ELIGIBILITY: Has received radiotherapy within 14 days of start of trial treatment with the exception that those who have received palliative radiation (=< 2 weeks of radiotherapy) to non-central nervous system disease within 7 days are permitted. Subjects must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis
- TREATMENT ELIGIBILITY: Has a history or current evidence of any condition, therapy, or laboratory or radiologic abnormality that is not in the best interest of the subject to participate, as determined by the treating investigator
Additional locations may be listed on ClinicalTrials.gov for NCT04995003.
Locations matching your search criteria
United States
Texas
Houston
PRIMARY OBJECTIVE:
I. To determine the safety of administering one dose of autologous anti-HER2 CAR-CD28 T cells (autologous T cells expressing a HER2 CD28zeta CAR) following lymphodepletion chemotherapy and in combination with PD-1 antibody in patients with HER2 positive recurrent or progressive sarcoma.
SECONDARY OBJECTIVE:
I. To assess the anti-tumor effects of HER2 CAR T cells infused in combination with lymphodepletion and PD-1 antibody.
EXPLORATORY OBJECTIVES:
I. To assess the in vivo kinetics of HER2 CAR T cells infused in combination with lymphodepletion and PD-1 antibody.
II. To evaluate the endogenous immune response following infusion of HER2 CAR T cells given in combination with lymphodepletion and PD-1 antibody.
III. To characterize the peripheral blood immune cells following infusion of HER2 CAR T cells.
IV. To evaluate the effect of HER2 CAR T cells given in combination with lymphodepletion and PD-1 antibody on the tumor and/or circulating tumor deoxyribonucleic acid (ctDNA) over time when feasible.
V. To evaluate changes to the gut microbiome following infusions of HER2 CAR T cells and PD-1 antibody.
OUTLINE: Patients are assigned to 1 of 2 arms.
ARM A: Patients receive cyclophosphamide intravenously (IV) over 1 hour on days -7 and -6, fludarabine IV over 30 minutes on days -5 to -1, and autologous anti-HER2 CAR-CD28 T cells IV over 1-10 minutes on day 0. Beginning 7 days after CAR T cell infusion, patients receive pembrolizumab IV over 30 minutes every 3 weeks for up to 12 weeks from date of last T-cell infusion or until the start of the subsequent treatment cycle on the study, whichever is earlier. Cycles of HER2 CD28zeta CAR T cells may repeat every 6 to 12 weeks in the absence of disease progression or unacceptable toxicity.
ARM B: Patients receive cyclophosphamide IV over 1 hour on days -7 and -6, fludarabine IV over 30 minutes on days -5 to -1, and autologous anti-HER2 CAR-CD28 T cells IV over 1-10 minutes on day 0. Beginning 7 days after CAR T cell infusion, patients receive nivolumab IV over 30 minutes every 2 weeks for up to 12 weeks from date of last T-cell infusion or until the start of the subsequent treatment cycle on the study, whichever is earlier. Cycles of HER2 CD28zeta CAR T cells may repeat every 6 to 12 weeks in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 3, 6, 9, and 12 months, every 6 months for 4 years, and then annually for up to 15 years.
Trial PhasePhase I
Trial Typetreatment
Lead OrganizationBaylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
Principal InvestigatorMeenakshi Hegde
- Primary IDHEROS 3.0
- Secondary IDsNCI-2021-14265, H-49271
- ClinicalTrials.gov IDNCT04995003