Administration of Autologous T-Cells Genetically Engineered to Express T-Cell Receptors Reactive Against Mutated or Viral Neoantigens in a Patient With Metastatic Cancer Plus the Administration of Pembrolizumab

NCT04536922 | Withdrawn Phase 2 FDA Drug

• 2 other identifiers: 10000163000163-C
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

Background: A cancer treatment has been developed called "gene transfer" or "gene therapy." It involves taking white blood cells from a person (called apheresis), genetically modifying the cells in a lab to recognize cancer, and then giving the cells back to the person. Researchers want to see if this treatment can help people with metastatic squamous cell anal cancer. Objective: To see if treating cancer with a person s own white blood cells that have been genetically modified can cause tumors to shrink. Eligibility: People who have metastatic squamous cell anal cancer for which standard treatments have not worked. Design: Participants will have had a tumor biopsy and apheresis to collect white blood cells under a separate protocol. Participants will stay at the hospital for 3 to 4 weeks. They will have an intravenous (IV) catheter placed in a large vein in the upper chest. Participants will get chemotherapy drugs (fludarabine and cyclophosphamide), the cell infusion, and aldesleukin through the IV. Pembrolizumab is given before and for three doses given every three weeks after the cell infusion. Aldesleukin will help the cells grow. Participants will take an antibiotic, antiviral, and antifungal by mouth. They will get an injection of filgrastim. It will stimulate the formation of white blood cells. Participants will have blood and urine tests. They will have physical exams. Their symptoms will be reviewed. They will have imaging scans. About 6 and 12 weeks after they finish treatment, participants will have safety follow-up visits. These visits will take 1 to 2 days. Participants will return to the Clinical Center every 3 to 6 months for 3 years, and then as determined by their doctor. They will be followed long term for up to 15 years on a separate study.

Conditions

Metastatic HPV-16 Positive Squamous Cell Anal Cancer

Keywords

Gene Therapy; Immunotherapy; Cell Therapy; Adoptive Cell Therapy

Outcome Measures

Primary Outcomes (1)

• Treatment

  Under a single-patient IND, to treat a patient with metastatic HPV-16 positive squamous cell anal cancer with autologous peripheral blood lymphocytes (PBL) that have been transduced with genes encoding T-cell receptors that recognize mutated or viral neoantigens in the autologous cancer.

  6 and 12 weeks after cell infusion, then every 3 months x3, then every 6 months x 2 years, then per PI discretion

Study Arms (1)

iTCR + Pembro

EXPERIMENTAL

Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + Individual Patient TCR-Transduced PBL + high- or low-dose aldesleukin + pembrolizumab prior to cell administration and 3 additional doses every 3 weeks following cell infusion

Drug: Cyclophosphamide; Drug: Fludarabine; Drug: Aldesleukin; Drug: Pembrolizumab (KEYTRUDA(R)); Biological: Individual Patient TCR-Transduced PBL

Interventions

Cyclophosphamide DRUG

Days -7 and -6: Cyclophosphamide 60 mg/kg/day x 2 days IV in 250 mL D5W infused simultaneously with mesna 15 mg/kg /day over 1 hour x 2 days.

iTCR + Pembro

Fludarabine DRUG

Days -7 to -3: Fludarabine 25 mg /m2/day IVPB daily over 30 minutes for 5 days.

iTCR + Pembro

Aldesleukin DRUG

Aldesleukin 720,000 IU/kg IV (based on total body weight) over 15 minutes approximately every 8 hours beginning within 24 hours of cell infusion and continuing for up to 4 days (maximum 10 doses).

iTCR + Pembro

Pembrolizumab (KEYTRUDA(R)) DRUG

Pembrolizumab 2 mg /kg IV over approximately 30 minutes on Days -2, 21, 42, and 63.

iTCR + Pembro

Individual Patient TCR-Transduced PBL BIOLOGICAL

Day 0: Cells will be infused at a dose not to exceed 1.5e11 in 400 mL intravenously on the Patient Care Unit over 20-30 minutes (2-4 days after the last dose of fludarabine).

iTCR + Pembro

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Measurable (per RECIST v1.1 criteria), metastatic squamous cell anal cancer.
• Refractory to approved standard systemic therapy.
• Clinical performance status of ECOG 0 or 1
• Willing to practice birth control from the time of enrollment on this study and for four months after treatment.
• Must have a negative pregnancy test because of the potentially dangerous effects of the treatment on the fetus.
• Serology
• Seronegative for HIV antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive may have decreased immune-competence and thus be less responsive to the experimental treatment and more susceptible to its toxicities.)
• Seronegative for hepatitis B antigen, and seronegative for hepatitis C antibody. If hepatitis C antibody test is positive, then patient must be tested for the presence of antigen by RT-PCR and be HCV RNA negative.
• Hematology
• ANC \> 1000/mm\^3 without the support of filgrastim
• WBC \>= 3000/mm\^3
• Platelet count \>= 100,000/mm\^3
• Hemoglobin \> 8.0 g/dL. Subject may be transfused to reach this cut-off.
• Chemistry
• Serum ALT/AST \<= 5.0 x ULN

You may not qualify if:

• Patient is pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant.
• Concurrent systemic steroid therapy.
• Active systemic infections requiring anti-infective treatment, coagulation disorders, or any other active or uncompensated major medical illnesses.
• Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease and AIDS).
• History of major organ autoimmune disease.
• Grade 3 or 4 major organ irAEs following treatment with anti-PD-1/PD-L1, including but not limited to myocarditis and pneumonitis.
• Concurrent opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immunecompetence may be less responsive to the experimental treatment and more susceptible to its toxicities.)
• History of severe immediate hypersensitivity reaction to cyclophosphamide, fludarabine, or aldesleukin.
• History of coronary revascularization or ischemic symptoms.
• Patient is known to have an LVEF \<= 45%.
• Patient is receiving any other investigational agents.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Interventions

Cyclophosphamide; fludarabine; aldesleukin; pembrolizumab

Intervention Hierarchy (Ancestors)

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

Study Officials

• Steven A Rosenberg, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 2, 2020
• First Posted: September 3, 2020
• Study Start: January 27, 2021
• Primary Completion: January 27, 2021
• Study Completion: January 27, 2021
• Last Updated: February 1, 2021

Record last verified: 2021-01

Locations

US (1)