Description:
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).
Title
- 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
Clinical Trial IDs
- ORG STUDY ID:
IRB# 848848; UPCC# 12320
- NCT ID:
NCT04877613
Conditions
- Metastatic Medullary Thyroid Cancer
Interventions
Drug | Synonyms | Arms |
---|
single dose of CART-GFRa4 cells | | Cohort -1: single dose of 2x10^7 CART-GFRa4 cells via intravenous infusion |
Fludarabine | | Cohort -1: single dose of 2x10^7 CART-GFRa4 cells via intravenous infusion |
Cyclophosphamide | | Cohort -1: single dose of 2x10^7 CART-GFRa4 cells via intravenous infusion |
Purpose
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).
Trial Arms
Name | Type | Description | Interventions |
---|
Cohort 1: single dose of 5x10^7 CART-GFRa4 cells via intravenous infusion | Experimental | | - single dose of CART-GFRa4 cells
- Fludarabine
- Cyclophosphamide
|
Cohort -1: single dose of 2x10^7 CART-GFRa4 cells via intravenous infusion | Experimental | | - single dose of CART-GFRa4 cells
- Fludarabine
- Cyclophosphamide
|
Cohort 2: single dose of 1x10^8 CART-GFRa4 cells via intravenous infusion | Experimental | | - single dose of CART-GFRa4 cells
- Fludarabine
- Cyclophosphamide
|
Cohort 3: single fixed dose of 3x10^8 CART-GFRa4 cells via intravenous infusion | Experimental | | - single dose of CART-GFRa4 cells
- Fludarabine
- Cyclophosphamide
|
Eligibility 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).
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Incidence of Treatment-Emergent Adverse Events as assessed by CTCAE v5.0. |
Time Frame: | 15 years |
Safety Issue: | |
Description: | |
Secondary Outcome Measures
Measure: | Percentage of manufacturing products that meet release criteria. |
Time Frame: | 3 months |
Safety Issue: | |
Description: | |
Measure: | Number of subjects who have a response |
Time Frame: | 12 months |
Safety Issue: | |
Description: | |
Measure: | Best Overall Response (BOR) |
Time Frame: | 12 months |
Safety Issue: | |
Description: | |
Measure: | Duration of Response (DOR) |
Time Frame: | 12 months |
Safety Issue: | |
Description: | |
Measure: | Overall survival (OS) |
Time Frame: | 12 months |
Safety Issue: | |
Description: | |
Measure: | Progression-free survival (PFS) |
Time Frame: | 12 months |
Safety Issue: | |
Description: | |
Details
Phase: | Phase 1 |
Primary Purpose: | Interventional |
Overall Status: | Recruiting |
Lead Sponsor: | University of Pennsylvania |
Last Updated
August 25, 2021