GFRα4 CAR T Cells in MTC Patients
Primary Purpose
Metastatic Medullary Thyroid Cancer
Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
single dose of CART-GFRa4 cells
Fludarabine
Cyclophosphamide
Sponsored by
About this trial
This is an interventional health services research trial for Metastatic Medullary Thyroid Cancer
Eligibility Criteria
Inclusion Criteria:
- Signed, written informed consent
- Male or female age ≥ 18 years
- Histologically or cytologically confirmed diagnosis of medullary thyroid cancer (MTC).
- 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.
Adequate organ function defined as:
- Serum creatinine ≤ 2.5 mg/dl or estimated creatinine clearance ≥ 30 ml/min and not on dialysis.
- 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.
- Left Ventricular Ejection Fraction (LVEF) ≥ 45% confirmed by ECHO/MUGA
- Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and pulse oxygen > 92% on room air
- ECOG Performance Status that is either 0 or 1.
- Toxicities from prior therapies must have recovered to grade ≤ 2 according to the CTCAE 5.0 criteria or to the patient's prior baseline.
- Patients must have evaluable disease as defined by RECIST 1.1.
- Subjects of reproductive potential must agree to use acceptable birth control methods.
Exclusion Criteria:
- Evidence of active hepatitis B or hepatitis C infection.
- Any other active, uncontrolled infection.
- Any prior history of moderate to severe (Grade 2 or higher) pneumonitis.
- Subjects with chronic kidney disease with Grade 2 or higher renal impairment (eGFR or CrCl 59-30 ml/min/1.73 m2).
- Class III/IV cardiovascular disability according to the New York Heart Association Classification.
- Clinically apparent arrhythmia or arrhythmias that are not stable on medical management within two weeks of physician-investigator confirmation of eligibility.
- 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.
- Any moderate to severe skin rash or allergies requiring systemic treatment.
- Receipt of immune checkpoint inhibitors within 2 months prior to physician-investigator confirmation of eligibility - Retired with Protocol Version 3.
- Pregnant or nursing (lactating) women.
- 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.
- 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.
- Known seizure disorder or history of prior seizures requiring medication.
- History of allergy or hypersensitivity to study product excipients (human serum albumin, DMSO, and Dextran 40).
Sites / Locations
- University of PennsylvaniaRecruiting
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm Type
Experimental
Experimental
Experimental
Experimental
Arm Label
Cohort 1: single dose of 5x10^7 CART-GFRa4 cells via intravenous infusion
Cohort -1: single dose of 2x10^7 CART-GFRa4 cells via intravenous infusion
Cohort 2: single dose of 1x10^8 CART-GFRa4 cells via intravenous infusion
Cohort 3: single fixed dose of 3x10^8 CART-GFRa4 cells via intravenous infusion
Arm Description
Outcomes
Primary Outcome Measures
Incidence of Treatment-Emergent Adverse Events as assessed by CTCAE v5.0.
Secondary Outcome Measures
Percentage of manufacturing products that meet release criteria.
Number of subjects who have a response
Best Overall Response (BOR)
Duration of Response (DOR)
Overall survival (OS)
Progression-free survival (PFS)
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT04877613
Brief Title
GFRα4 CAR T Cells in MTC Patients
Official Title
Phase I Trial of GFRα4 CAR T Cells in Adult Patients With Recurrent or Metastatic Medullary Thyroid Cancer
Study Type
Interventional
2. Study Status
Record Verification Date
June 2023
Overall Recruitment Status
Recruiting
Study Start Date
August 19, 2021 (Actual)
Primary Completion Date
June 1, 2039 (Anticipated)
Study Completion Date
June 1, 2039 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Pennsylvania
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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).
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Metastatic Medullary Thyroid Cancer
7. Study Design
Primary Purpose
Health Services Research
Study Phase
Phase 1
Interventional Study Model
Sequential Assignment
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)
Allocation
Non-Randomized
Enrollment
18 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Cohort 1: single dose of 5x10^7 CART-GFRa4 cells via intravenous infusion
Arm Type
Experimental
Arm Title
Cohort -1: single dose of 2x10^7 CART-GFRa4 cells via intravenous infusion
Arm Type
Experimental
Arm Title
Cohort 2: single dose of 1x10^8 CART-GFRa4 cells via intravenous infusion
Arm Type
Experimental
Arm Title
Cohort 3: single fixed dose of 3x10^8 CART-GFRa4 cells via intravenous infusion
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
single dose of CART-GFRa4 cells
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Fludarabine
Intervention Description
Lyphodepletion
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Intervention Description
Lyphodepletion
Primary Outcome Measure Information:
Title
Incidence of Treatment-Emergent Adverse Events as assessed by CTCAE v5.0.
Time Frame
15 years
Secondary Outcome Measure Information:
Title
Percentage of manufacturing products that meet release criteria.
Time Frame
3 months
Title
Number of subjects who have a response
Time Frame
12 months
Title
Best Overall Response (BOR)
Time Frame
12 months
Title
Duration of Response (DOR)
Time Frame
12 months
Title
Overall survival (OS)
Time Frame
12 months
Title
Progression-free survival (PFS)
Time Frame
12 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Signed, written informed consent
Male or female age ≥ 18 years
Histologically or cytologically confirmed diagnosis of medullary thyroid cancer (MTC).
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.
Adequate organ function defined as:
Serum creatinine ≤ 2.5 mg/dl or estimated creatinine clearance ≥ 30 ml/min and not on dialysis.
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.
Left Ventricular Ejection Fraction (LVEF) ≥ 45% confirmed by ECHO/MUGA
Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and pulse oxygen > 92% on room air
ECOG Performance Status that is either 0 or 1.
Toxicities from prior therapies must have recovered to grade ≤ 2 according to the CTCAE 5.0 criteria or to the patient's prior baseline.
Patients must have evaluable disease as defined by RECIST 1.1.
Subjects of reproductive potential must agree to use acceptable birth control methods.
Exclusion Criteria:
Evidence of active hepatitis B or hepatitis C infection.
Any other active, uncontrolled infection.
Any prior history of moderate to severe (Grade 2 or higher) pneumonitis.
Subjects with chronic kidney disease with Grade 2 or higher renal impairment (eGFR or CrCl 59-30 ml/min/1.73 m2).
Class III/IV cardiovascular disability according to the New York Heart Association Classification.
Clinically apparent arrhythmia or arrhythmias that are not stable on medical management within two weeks of physician-investigator confirmation of eligibility.
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.
Any moderate to severe skin rash or allergies requiring systemic treatment.
Receipt of immune checkpoint inhibitors within 2 months prior to physician-investigator confirmation of eligibility - Retired with Protocol Version 3.
Pregnant or nursing (lactating) women.
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.
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.
Known seizure disorder or history of prior seizures requiring medication.
History of allergy or hypersensitivity to study product excipients (human serum albumin, DMSO, and Dextran 40).
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Abramson Cancer Center Clinical Trials Service
Phone
855-216-0098
Email
PennCancerTrials@careboxhealth.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Roger Cohen, MD
Organizational Affiliation
University of Pennsylvania
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Pennsylvania
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Abramson Cancer Center Clinical Trials Service
Phone
855-216-0098
Email
PennCancerTrials@careboxhealth.com
12. IPD Sharing Statement
Plan to Share IPD
No
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GFRα4 CAR T Cells in MTC Patients
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