Overview

HER2 Chimeric Antigen Receptor (CAR) T Cells in Combination With Checkpoint Blockade in Patients With Advanced Sarcoma

Status:
Not yet recruiting
Trial end date:
2040-02-01
Target enrollment:
0
Participant gender:
All
Summary
The purpose of this study is to learn whether it is safe to give HER2-CAR T cells in combination with an immune checkpoint inhibitor drug (pembrolizumab or nivolumab), to learn what the side effects are, and to see whether this therapy might help patients with sarcoma. Another goal of this study is to study the bacteria found in the stool of patients with sarcoma who are being treated with HER2 CAR T cells and immune checkpoint inhibitor drugs to see if the types of bacteria influence how well the treatment works. The investigators have found from previous research that they can put a new gene into T cells that will make them recognize cancer cells and kill them. They now want to see if they can put a new gene in these cells that will let the T cells recognize and kill sarcoma cells. The new gene that the investigators will put in makes an antibody specific for HER2 (Human Epidermal Growth Factor Receptor 2) that binds to sarcoma cells. In addition, it contains CD28, which stimulated T cells and make them last longer. 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. In another clinical study using these CAR T cells targeting HER2 as well as other studies using CAR T cells, investigators found that giving chemotherapy before the T cell infusion can improve the effect the T cells can have. Giving chemotherapy before a T cell infusion is called lymphodepletion since the chemotherapy is specifically chosen to decrease the number of lymphocytes in the body. Decreasing the number of the patient's lymphocytes first should allow the infused T cells to expand in the body, and potentially kill cancer cells more effectively. The chemotherapy used for lymphodepletion is a combination of cyclophosphamide and fludarabine. After the patient receives the lymphodepletion chemotherapy and CAR T cells during treatment on the study, they will receive an antibody drug called an immune checkpoint inhibitor, pembrolizumab or nivolumab. Immune checkpoint inhibitors are drugs that remove the brakes on the immune system to allow it to act against cancer.
Phase:
Phase 1
Accepts Healthy Volunteers?
No
Details
Lead Sponsor:
Baylor College of Medicine
Collaborators:
Center for Cell and Gene Therapy, Baylor College of Medicine
St. Baldrick's Foundation
Stand Up To Cancer
The Faris Foundation USA
Triumph Over Kid Cancer Foundation
Treatments:
Cyclophosphamide
Fludarabine
Immune Checkpoint Inhibitors
Nivolumab
Pembrolizumab
Criteria
Procurement Inclusion Criteria:

- Diagnosis of a HER2-positive sarcoma. Immunohistochemistry (IHC) will be used to
determine HER2 expression.45,138 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% and Grade 3: 51-100%) 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.

- Age between 1 to 25 years

- Karnofsky or Lansky performance score of ≥ 60

- Informed consent explained to, understood by, and signed by patient/guardian. Patient
or guardian given copy of informed consent.

Treatment Inclusion Criteria:

- Diagnosis of a HER2 positive sarcoma with disease progression or recurrence after at
least one prior systemic therapy

- 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.

- Normal cardiac left ventricular end diastolic function (LVEF) as measured by
echocardiogram (normal per institutional limits)

- Karnofsky or Lansky performance score of ≥60

- Total bilirubin ≤1.5x upper limit of normal (ULN) for age AND direct bilirubin ≤ULN
for age

- AST/ALT ≤ 2.5x ULN

- Serum creatinine ≤1.5x ULN for age

- Hgb ≥ 7.0 g/dL (transfusion allowed)

- WBC > 2,000/µl

- ANC >1,000/ul

- Platelets >75,000/ul (not transfused)

- Pulse oximetry of ≥ 90% on room air

- 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
post-menopausal, or surgically sterilized.

- Available autologous transduced cytotoxic T lymphocytes with ≥ 15% expression of HER2
CAR and killing of HER2-positive targets ≥ 20% in cytotoxicity assay

- Informed consent explained to, understood by, and signed by patient or guardian.
Patient or guardian given copy of informed consent.

Procurement Exclusion Criteria:

- Known HIV positivity

- Severe previous toxicity from cyclophosphamide including, but not limited to,
decreased heart function, abnormal heart rhythms, severe allergic reaction, or grade 4
hemorrhagic cystitis

- 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

- Severe hypersensitivity (≥Grade 3) to pembrolizumab or nivolumab or any of their
excipients

- History of allergic reactions attributed to murine protein containing products, DMSO
or dextran 40

- 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

- 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

- History of non-infectious pneumonitis that required steroids or current pneumonitis

- Known history of active tuberculosis

- Has undergone solid organ transplantation at any time

- Has a diagnosis of immunodeficiency or is receiving any other form of
immunosuppressive therapy aside from cytotoxic chemotherapy

- Presence of bulky tumor at the primary or metastatic site

- 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 Exclusion Criteria:

- Known HIV positivity

- Intercurrent infection

- Pregnant or lactating

- History of hypersensitivity to murine protein-containing products, DMSO or dextran 40

- Severe previous toxicity from cyclophosphamide including, but not limited to,
decreased heart function, abnormal heart rhythms, severe allergic reaction, or grade 4
hemorrhagic cystitis

- 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

- Severe hypersensitivity (≥Grade 3) to pembrolizumab or nivolumab or any of their
excipients

- 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

- 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.

- History of non-infectious pneumonitis that required steroids or current pneumonitis

- Known history of active tuberculosis

- Has received a live virus vaccine within previous 30 days

- Has undergone solid organ transplantation at any time

- Has a diagnosis of immunodeficiency or is receiving any other form of
immunosuppressive therapy

- Presence of bulky tumor at the primary or metastatic site

- 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.

- 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