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

NCT04995003 | Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: H-49271 HEROS 3.0R01CA276684
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Sarcoma; HER-2 Protein Overexpression; Osteosarcoma; Rhabdomyosarcoma; Ewing Sarcoma; Synovial Sarcoma; Soft Tissue Sarcoma; Undifferentiated Sarcoma

Keywords

Sarcoma; Her-2 Positive Sarcoma; autologous T cells; HER2 positive recurrent or progressive sarcoma; HER2 CAR T cells; Osteosarcoma; Rhabdomyosarcoma; Ewing sarcoma; Synovial sarcoma; Soft tissue sarcoma; Undifferentiated sarcoma

Outcome Measures

Primary Outcomes (2)

• ARM A: Dose-limiting toxicity (DLT) rate by CTCAE v5.0. Neurotoxicity and cytokine release syndrome (CRS) will be graded according to ASTCT Consensus Grading System.

  Any grade 5 event, Grade 3 and 4 cytokine release syndrome (CRS) or neurological toxicities that fail to return to grade 2 within 5 days of T cell infusion , and all other grade 3 or 4 toxicities (including allergic reactions to T cell infusions) that fail to return to grade 2 within 72 hours. In the event that the combination treatment potentiates expected, severe toxicities attributable to PD-1 antibody, investigators will employ an additional stopping rule which will be applied to each arm separately. If (1) two within the initial six patients treated or (2) greater than 33% of all patients thereafter develop greater than or equal to grade 3 non-hematologic, non-dermatologic toxicity attributable to PD-1 antibody but not attributable to HER2 CAR T cells during the DLT window, investigators will pause enrollment to that study arm. Toxicity will be evaluated according to the CTCAE v5.0 except for CRS and neurotoxicity.

  By day 42 or 14 days after second dose of Pembrolizumab (whichever is longer)

• ARM B: Dose-limiting toxicity (DLT) rate by CTCAE v5.0. Neurotoxicity and cytokine release syndrome (CRS) will be graded according to ASTCT Consensus Grading System.

  Any grade 5 event, Grade 3 and 4 cytokine release syndrome (CRS) or neurological toxicities that fail to return to grade 2 within 5 days of T cell infusion , and all other grade 3 or 4 toxicities (including allergic reactions to T cell infusions) that fail to return to grade 2 within 72 hours. In the event that the combination treatment potentiates expected, severe toxicities attributable to PD-1 antibody, investigators will employ an additional stopping rule which will be applied to each arm separately. If (1) two within the initial six patients treated or (2) greater than 33% of all patients thereafter develop greater than or equal to grade 3 non-hematologic, non-dermatologic toxicity attributable to PD-1 antibody but not attributable to HER2 CAR T cells during the DLT window, investigators will pause enrollment to that study arm. Toxicity will be evaluated according to the CTCAE v5.0 except for CRS and neurotoxicity.

  By day 42 or 7 days after third dose of Nivolumab (whichever is longer)

Secondary Outcomes (1)

• Overall Response rate according to RECIST 1.1 Criteria SD, PR and CR are considered responders.

  42 plus/minus 7 days

Study Arms (2)

Arm A

EXPERIMENTAL

autologous HER2 CAR T cells infused in combination with lymphodepletion chemotherapy and the PD-1 antibody pembrolizumab

Genetic: T cells or CAR T cells; Drug: Pembrolizumab Injectable Product

Arm 2

EXPERIMENTAL

autologous HER2 CAR T cells infused in combination with lymphodepletion chemotherapy and the PD-1 antibody nivolumab

Genetic: T cells or CAR T cells; Drug: Nivolumab Injectable Product

Interventions

T cells or CAR T cells GENETIC

There are 2 dose levels: Dose Level 1 (1x10\^8 cells/m2) and Dose Level -1 (5x10\^7 cells/m2). In the event that Dose Level 1 is not tolerable, de-escalation to Dose Level -1 will occur.

Also known as: HER2 CAR T cells

Arm 2; Arm A

Pembrolizumab Injectable Product DRUG

2 mg/kg/dose (max 200 mg/dose) every 3 weeks

Also known as: immune checkpoint inhibitor

Arm A

Nivolumab Injectable Product DRUG

3 mg/kg/dose (\<40kg) or 124 mg (≥40 kg) every 2 weeks

Also known as: immune checkpoint inhibitor

Arm 2

Eligibility Criteria

• Age: 1 Year - 25 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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% 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.
• Diagnosis of a HER2 positive sarcoma with active 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)

You may not qualify if:

• 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
• Known, active 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.
• Note: A new echocardiogram or EKG is not required to make this determination.
• 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
• Known HIV positivity

Sponsors & Collaborators

• Baylor College of Medicine: lead
• The Faris Foundation USA: collaborator
• Center for Cell and Gene Therapy, Baylor College of Medicine: collaborator
• Stand Up To Cancer: collaborator
• Triumph Over Kid Cancer Foundation: collaborator
• St. Baldrick's Foundation: collaborator
• National Cancer Institute (NCI): collaborator

Study Sites (1)

Texas Children's Hospital

Houston, Texas, 77030, United States

RECRUITING

Related Links

• The Genetic and Rare Diseases (GARD) Information Center

MeSH Terms

Conditions

Sarcoma; Osteosarcoma; Rhabdomyosarcoma; Sarcoma, Ewing; Sarcoma, Synovial

Interventions

Immunotherapy, Adoptive; Immune Checkpoint Inhibitors

Condition Hierarchy (Ancestors)

Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Myosarcoma; Neoplasms, Muscle Tissue

Intervention Hierarchy (Ancestors)

Adoptive Transfer; Immunization, Passive; Immunization; Immunotherapy; Immunomodulation; Biological Therapy; Therapeutics; Immunologic Techniques; Investigative Techniques; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Antineoplastic Agents, Immunological; Antineoplastic Agents; Therapeutic Uses

Study Officials

• Meenakshi Hegde, MD

  Baylor College of Medicine

  PRINCIPAL INVESTIGATOR

• Shoba Navai, MD

  Baylor College of Medicine

  PRINCIPAL INVESTIGATOR

• Nabil Ahmed, MD

  Baylor College of Medicine

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Meenakshi Hegde, MD

CONTACT

832-824-4840; mghegde@bcm.edu

Brandon Garner

CONTACT

832-824-4594; bjgarner@texaschildrens.org

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Model Details: Patients will be non-randomly assigned to one of two arms, Arm A or Arm B. Dose de-escalation will occur independently in each arm. Arm A treatment will consist of autologous HER2 CAR T cells infused in combination with lymphodepletion and the PD-1 antibody pembrolizumab. Accrual will start at Dose Level 1. In the event that Dose Level 1 is not tolerable, de-escalation to Dose Level -1 will occur. Arm B treatment will consist of autologous HER2 CAR T cells infused in combination with lymphodepletion and the PD-1 antibody nivolumab. Accrual will start at Dose Level 1. In the event that Dose Level 1 is not tolerable, de-escalation to Dose Level -1 will occur.

Study Record Dates

• First Submitted: August 2, 2021
• First Posted: August 6, 2021
• Study Start: December 7, 2021
• Primary Completion (Estimated): June 30, 2028
• Study Completion (Estimated): June 30, 2043
• Last Updated: January 22, 2026

Record last verified: 2026-01

Locations

US (1)