GFRα4 CAR T Cells in MTC Patients

Phase I Trial of GFRα4 CAR T Cells in Adult Patients With Recurrent or Metastatic Medullary Thyroid Cancer

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).

Study Overview

• Status: Recruiting
• Conditions: Metastatic Medullary Thyroid Cancer
• Intervention / Treatment: Drug: single dose of CART-GFRa4 cells; Drug: Fludarabine; Drug: Cyclophosphamide

• Study Type: Interventional
• Enrollment (Estimated): 18
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Abramson Cancer Center Clinical Trials Service; Phone Number: 855-216-0098; Email: PennCancerTrials@careboxhealth.com

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • University of Pennsylvania
      • Contact: Abramson Cancer Center Clinical Trials Service; Phone Number: 855-216-0098; Email: PennCancerTrials@careboxhealth.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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. Evidence of 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 - Retired with Protocol Version 3.
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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Health Services Research
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Incidence of Treatment-Emergent Adverse Events as assessed by CTCAE v5.0.	15 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Percentage of manufacturing products that meet release criteria.	3 months
Number of subjects who have a response	12 months
Best Overall Response (BOR)	12 months
Duration of Response (DOR)	12 months
Overall survival (OS)	12 months
Progression-free survival (PFS)	12 months

Collaborators and Investigators

• Sponsor: University of Pennsylvania
• Investigators: Principal Investigator: Roger Cohen, MD, University of Pennsylvania

Study record dates

Study Major Dates

• Study Start (Actual): August 19, 2021
• Primary Completion (Estimated): June 1, 2039
• Study Completion (Estimated): June 1, 2039

Study Registration Dates

• First Submitted: May 3, 2021
• First Submitted That Met QC Criteria: May 3, 2021
• First Posted (Actual): May 7, 2021

Study Record Updates

• Last Update Posted (Actual): June 22, 2023
• Last Update Submitted That Met QC Criteria: June 20, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Endocrine System Diseases; Endocrine Gland Neoplasms; Thyroid Diseases; Head and Neck Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Thyroid Neoplasms; Carcinoma, Neuroendocrine; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Cyclophosphamide; Fludarabine
• Other Study ID Numbers: IRB# 848848; UPCC# 12320

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No