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

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ClinicalTrials.gov Identifier: NCT04995003
Recruitment Status : Recruiting
First Posted : August 6, 2021
Last Update Posted : December 29, 2021
Sponsor:
Collaborators:
Center for Cell and Gene Therapy, Baylor College of Medicine
The Faris Foundation USA
Stand Up To Cancer
Triumph Over Kid Cancer Foundation
St. Baldrick's Foundation
Information provided by (Responsible Party):
Meenakshi Hegde, M.D., Baylor College of Medicine

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.


Condition or disease Intervention/treatment Phase
Sarcoma HER-2 Protein Overexpression Genetic: cells Drug: Pembrolizumab Injectable Product Drug: Nivolumab Injectable Product Drug: Lymphodepletion Chemotherapy Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 25 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

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.

Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Study of HER2 Chimeric Antigen Receptor (CAR) T Cells in Combination With Checkpoint Blockade in Patients With Advanced Sarcoma (HEROS 3.0)
Actual Study Start Date : December 7, 2021
Estimated Primary Completion Date : February 1, 2025
Estimated Study Completion Date : February 1, 2040

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Arm A
autologous HER2 CAR T cells infused in combination with lymphodepletion chemotherapy and the PD-1 antibody pembrolizumab
Genetic: cells
HER2 CAR T cells infused in combination with lymphodepletion chemotherapy
Other Name: HER2 CAR T cells

Drug: Pembrolizumab Injectable Product
2 mg/kg/dose (max 200 mg/dose) every 3 weeks
Other Name: immune checkpoint inhibitor

Drug: Lymphodepletion Chemotherapy
Fludarabine plus Cyclophosphamide
Other Name: Fludarabine and Cyclophosphamide

Experimental: Arm 2
autologous HER2 CAR T cells infused in combination with lymphodepletion chemotherapy and the PD-1 antibody nivolumab
Genetic: cells
HER2 CAR T cells infused in combination with lymphodepletion chemotherapy
Other Name: HER2 CAR T cells

Drug: Nivolumab Injectable Product
3 mg/kg/dose (<40kg) or 124 mg (≥40 kg) every 2 weeks
Other Name: immune checkpoint inhibitor

Drug: Lymphodepletion Chemotherapy
Fludarabine plus Cyclophosphamide
Other Name: Fludarabine and Cyclophosphamide




Primary Outcome Measures :
  1. 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. [ Time Frame: By day 42 or 14 days after second dose of Pembrolizumab (whichever is longer) ]

    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.


  2. 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. [ Time Frame: By day 42 or 7 days after third dose of Nivolumab (whichever is longer) ]

    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.



Secondary Outcome Measures :
  1. Overall Response rate according to RECIST 1.1 Criteria SD, PR and CR are considered responders. [ Time Frame: 42 plus/minus 7 days ]

    Subjects who receive at least one dose of HER2 CAR T cells and two doses of PD-1 antibody are evaluable.

    Response in patients with disease measurable by imaging will be determined by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1




Information from the National Library of Medicine

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Ages Eligible for Study:   1 Year to 25 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

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): NCT04995003


Contacts
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Contact: Meenakshi Hegde, MD 832-824-4840 mghegde@bcm.edu
Contact: Shoba Navai, MD 832-824-7482 Shoba.Navai@Bcm.Edu

Locations
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United States, Texas
Texas Children's Hospital Recruiting
Houston, Texas, United States, 77030
Sponsors and Collaborators
Baylor College of Medicine
Center for Cell and Gene Therapy, Baylor College of Medicine
The Faris Foundation USA
Stand Up To Cancer
Triumph Over Kid Cancer Foundation
St. Baldrick's Foundation
Investigators
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Principal Investigator: 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
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Responsible Party: Meenakshi Hegde, M.D., Assistant Professor, Baylor College of Medicine
ClinicalTrials.gov Identifier: NCT04995003    
Other Study ID Numbers: H-49271 HEROS 3.0
First Posted: August 6, 2021    Key Record Dates
Last Update Posted: December 29, 2021
Last Verified: December 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 Meenakshi Hegde, M.D., Baylor College of Medicine:
Sarcoma
Her-2 Positive Sarcoma
autologous T cells
HER2 positive recurrent or progressive sarcoma
HER2 CAR T cells
Additional relevant MeSH terms:
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Sarcoma
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Cyclophosphamide
Pembrolizumab
Nivolumab
Fludarabine
Immune Checkpoint Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antineoplastic Agents, Immunological