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GFRα4 CAR T Cells in MTC Patients

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ClinicalTrials.gov Identifier: NCT04877613
Recruitment Status : Recruiting
First Posted : May 7, 2021
Last Update Posted : August 25, 2021
Sponsor:
Information provided by (Responsible Party):
University of Pennsylvania

Brief Summary:
This is an open-label phase 1 study to assess the safety and feasibility of autologous T cells expressing a single-chain scFv targeting GFRα4 with tandem TCR/CD3ζ and 4-1BB (TCRζ/4-1BB) co-stimulatory domains (referred to as "CART-GFRa4 cells") in patients with incurable medullary thyroid cancer (MTC).

Condition or disease Intervention/treatment Phase
Metastatic Medullary Thyroid Cancer Drug: single dose of CART-GFRa4 cells Drug: Fludarabine Drug: Cyclophosphamide Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 18 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: The is a Phase I dose finding study to determine the safety of CART-GFRa4 cells. Dose escalation and determination of maximum tolerated dose (MTD) will be based on the standard 3+3 design to explore 3 possible dose levels.
Masking: None (Open Label)
Primary Purpose: Health Services Research
Official Title: Phase I Trial of GFRα4 CAR T Cells in Adult Patients With Recurrent or Metastatic Medullary Thyroid Cancer
Actual Study Start Date : August 19, 2021
Estimated Primary Completion Date : June 1, 2039
Estimated Study Completion Date : June 1, 2039


Arm Intervention/treatment
Experimental: Cohort 1: single dose of 5x10^7 CART-GFRa4 cells via intravenous infusion Drug: single dose of CART-GFRa4 cells
Intravenous infusion of lentiviral transduced autologous T cells that have been engineered to express an extracellular single chain antibody (scFv) with specificity towards GFRa4 with fludarabine and cyclophosphamide.

Drug: Fludarabine
Lyphodepletion

Drug: Cyclophosphamide
Lyphodepletion

Experimental: Cohort -1: single dose of 2x10^7 CART-GFRa4 cells via intravenous infusion Drug: single dose of CART-GFRa4 cells
Intravenous infusion of lentiviral transduced autologous T cells that have been engineered to express an extracellular single chain antibody (scFv) with specificity towards GFRa4 with fludarabine and cyclophosphamide.

Drug: Fludarabine
Lyphodepletion

Drug: Cyclophosphamide
Lyphodepletion

Experimental: Cohort 2: single dose of 1x10^8 CART-GFRa4 cells via intravenous infusion Drug: single dose of CART-GFRa4 cells
Intravenous infusion of lentiviral transduced autologous T cells that have been engineered to express an extracellular single chain antibody (scFv) with specificity towards GFRa4 with fludarabine and cyclophosphamide.

Drug: Fludarabine
Lyphodepletion

Drug: Cyclophosphamide
Lyphodepletion

Experimental: Cohort 3: single fixed dose of 3x10^8 CART-GFRa4 cells via intravenous infusion Drug: single dose of CART-GFRa4 cells
Intravenous infusion of lentiviral transduced autologous T cells that have been engineered to express an extracellular single chain antibody (scFv) with specificity towards GFRa4 with fludarabine and cyclophosphamide.

Drug: Fludarabine
Lyphodepletion

Drug: Cyclophosphamide
Lyphodepletion




Primary Outcome Measures :
  1. Incidence of Treatment-Emergent Adverse Events as assessed by CTCAE v5.0. [ Time Frame: 15 years ]

Secondary Outcome Measures :
  1. Percentage of manufacturing products that meet release criteria. [ Time Frame: 3 months ]
  2. Number of subjects who have a response [ Time Frame: 12 months ]
  3. Best Overall Response (BOR) [ Time Frame: 12 months ]
  4. Duration of Response (DOR) [ Time Frame: 12 months ]
  5. Overall survival (OS) [ Time Frame: 12 months ]
  6. Progression-free survival (PFS) [ Time Frame: 12 months ]


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Signed, written informed consent
  2. Male or female age ≥ 18 years
  3. Histologically or cytologically confirmed diagnosis of medullary thyroid cancer (MTC).
  4. Incurable recurrent/metastatic disease that is progressive after at least 1 prior tyrosine kinase inhibitor (TKI) containing regimen, or the patient was intolerant of or declined such therapy.
  5. Adequate organ function defined as:

    1. Serum creatinine ≤ 2.5 mg/dl or estimated creatinine clearance ≥ 30 ml/min and not on dialysis.
    2. AST ≤ 5x upper limit of normal range and total bilirubin ≤ 2.0 mg/dl; except for patients in whom hyperbilirubinemia is attributed to Gilbert's syndrome.
    3. Left Ventricular Ejection Fraction (LVEF) ≥ 45% confirmed by ECHO/MUGA
    4. Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and pulse oxygen > 92% on room air
  6. ECOG Performance Status that is either 0 or 1.
  7. Toxicities from prior therapies must have recovered to grade ≤ 2 according to the CTCAE 5.0 criteria or to the patient's prior baseline.
  8. Patients must have evaluable disease as defined by RECIST 1.1.
  9. Subjects of reproductive potential must agree to use acceptable birth control methods.

Exclusion Criteria:

  1. Active hepatitis B or hepatitis C infection.
  2. Any other active, uncontrolled infection.
  3. Any prior history of moderate to severe (Grade 2 or higher) pneumonitis.
  4. Subjects with chronic kidney disease with Grade 2 or higher renal impairment (eGFR or CrCl 59-30 ml/min/1.73 m2).
  5. Class III/IV cardiovascular disability according to the New York Heart Association Classification.
  6. Clinically apparent arrhythmia or arrhythmias that are not stable on medical management within two weeks of physician-investigator confirmation of eligibility.
  7. Planned concurrent treatment with systemic high dose corticosteroids. Patients may be on a stable low dose of steroids (≤10mg equivalent of prednisone). Use of inhaled steroids is allowable. Corticosteroid treatment as anti-emetic prophylaxis on the day of lymphodepleting chemotherapy administration is allowed per institutional practice.
  8. Any moderate to severe skin rash or allergies requiring systemic treatment.
  9. Receipt of immune checkpoint inhibitors within 2 months prior to physician-investigator confirmation of eligibility.
  10. Pregnant or nursing (lactating) women.
  11. Active autoimmune disease requiring systemic immunosuppressive treatment equivalent to ≥ 10mg daily of prednisone. Patients with autoimmune neurological diseases (such as MS or Parkinson's) will be excluded.
  12. Have any history of prior or active central nervous system (CNS) involvement (e.g., leptomeningeal disease, parenchymal masses) with MTC. Screening for this (e.g., with lumbar puncture and/or brain MRI) is not required unless suspicious symptoms and/or radiographic findings are present. Subjects with calvarial metastatic disease that extends intracranially and involves the dura will be excluded, even if CSF is negative for MTC.
  13. Known seizure disorder or history of prior seizures requiring medication.
  14. History of allergy or hypersensitivity to study product excipients (human serum albumin, DMSO, and Dextran 40).

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): NCT04877613


Contacts
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Contact: Abramson Cancer Center Clinical Trials Service 855-216-0098 PennCancerTrials@emergingmed.com

Locations
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United States, Pennsylvania
University of Pennsylvania Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Abramson Cancer Center Clinical Trials Service    855-216-0098    PennCancerTrials@emergingmed.com   
Sponsors and Collaborators
University of Pennsylvania
Investigators
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Principal Investigator: Roger Cohen, MD University of Pennsylvania
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Responsible Party: University of Pennsylvania
ClinicalTrials.gov Identifier: NCT04877613    
Other Study ID Numbers: IRB# 848848; UPCC# 12320
First Posted: May 7, 2021    Key Record Dates
Last Update Posted: August 25, 2021
Last Verified: August 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Thyroid Neoplasms
Carcinoma, Neuroendocrine
Thyroid Diseases
Endocrine System Diseases
Endocrine Gland Neoplasms
Neoplasms by Site
Neoplasms
Head and Neck Neoplasms
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Cyclophosphamide
Fludarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists