GFRα4 CAR T Cells in MTC Patients

NCT04877613 | Active Not Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: IRB# 848848; UPCC# 12320
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

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).

Conditions

Metastatic Medullary Thyroid Cancer; Recurrent Thyroid Gland Medullary Carcinoma

Outcome Measures

Primary Outcomes (1)

• Incidence of Treatment-Emergent Adverse Events as assessed by CTCAE v5.0.

  15 years

Secondary Outcomes (6)

• Percentage of manufacturing products that meet release criteria.

  3 months

• Number of subjects who have a response (ORR)

  12 months

• Best Overall Response (BOR)

  12 months

• Duration of Response (DOR)

  12 months

• Overall survival (OS)

  12 months

Study Arms (4)

Cohort 1: single dose of 5x10^7 CART-GFRa4 cells via intravenous infusion

EXPERIMENTAL

Drug: single dose of CART-GFRa4 cells; Drug: Fludarabine; Drug: Cyclophosphamide

Cohort -1: single dose of 2x10^7 CART-GFRa4 cells via intravenous infusion

EXPERIMENTAL

Drug: single dose of CART-GFRa4 cells; Drug: Fludarabine; Drug: Cyclophosphamide

Cohort 2: single dose of 1x10^8 CART-GFRa4 cells via intravenous infusion

EXPERIMENTAL

Drug: single dose of CART-GFRa4 cells; Drug: Fludarabine; Drug: Cyclophosphamide

Cohort 3: single fixed dose of 3x10^8 CART-GFRa4 cells via intravenous infusion

EXPERIMENTAL

Drug: single dose of CART-GFRa4 cells; Drug: Fludarabine; Drug: Cyclophosphamide

Interventions

single dose of CART-GFRa4 cells DRUG

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.

Cohort -1: single dose of 2x10^7 CART-GFRa4 cells via intravenous infusion; Cohort 1: single dose of 5x10^7 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

Fludarabine DRUG

Lymphodepletion

Cohort -1: single dose of 2x10^7 CART-GFRa4 cells via intravenous infusion; Cohort 1: single dose of 5x10^7 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

Cyclophosphamide DRUG

Lymphodepletion

Cohort -1: single dose of 2x10^7 CART-GFRa4 cells via intravenous infusion; Cohort 1: single dose of 5x10^7 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

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 greater than 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.

You may not qualify if:

• Evidence of active hepatitis B or hepatitis C infection. The following would not qualify as an active infection, thus would not exclude the subject from participating
• Positive HBV serology with undetectable viral load and ongoing antiviral prophylaxis for potential HBV reactivation.
• Positive HCV serology with quantitative PCR for plasma HCV RNA below the lower limit of detection, with or without concurrent antiviral HCV treatment.
• 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.

Sponsors & Collaborators

• University of Pennsylvania: lead

Study Sites (1)

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

MeSH Terms

Conditions

Carcinoma, Medullary

Interventions

fludarabine; Cyclophosphamide

Condition Hierarchy (Ancestors)

Carcinoma, Neuroendocrine; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms, Ductal, Lobular, and Medullary; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Study Officials

• Roger Cohen, MD

  University of Pennsylvania

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: HEALTH SERVICES RESEARCH
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: May 3, 2021
• First Posted: May 7, 2021
• Study Start: August 19, 2021
• Primary Completion (Estimated): June 1, 2039
• Study Completion (Estimated): June 1, 2039
• Last Updated: July 3, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)