T Cell Receptor Immunotherapy Targeting MAGE-A3 for Patients With Metastatic Cancer Who Are HLA-DP0401 Positive

NCT02111850 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: 14005214-C-0052
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 1

Brief Summary

Background: The National Cancer Institute (NCI) Surgery Branch has developed an experimental therapy for treating patients with metastatic cancer that involves taking white blood cells from the patient, growing them in the laboratory in large numbers, genetically modifying these specific cells with a type of virus (retrovirus) to attack only the tumor cells, and then giving the cells back to the patient. This type of therapy is called gene transfer. In this protocol, we are modifying the patient s white blood cells with a retrovirus that has the gene for anti-Melanoma antigen family A, 3 (MAGE-A3)-DP0401/0402 incorporated in the retrovirus. Objective: The purpose of this study is to determine a safe number of these cells to infuse and to see if these particular tumor-fighting cells (anti-MAGE-A3-DP0401/0402 cells) cause tumors to shrink and to be certain the treatment is safe. Eligibility: \- Adult's age 18-70 with metastatic cancer expressing the MAGE-A3 molecule. Design:

• Work up stage: Patients will be seen as an outpatient at the National Institutes of Health (NIH) clinical Center and undergo a history and physical examination, scans, x-rays, lab tests, and other tests as needed
• Leukapheresis: If the patients meet all of the requirements for the study, they will undergo leukapheresis to obtain white blood cells to make the anti-MAGE-A3-DP0401/0402 cells. {Leukapheresis is a common procedure, which removes only the white blood cells from the patient.}
• Treatment: Once their cells have grown, the patients will be admitted to the hospital for the conditioning chemotherapy, the anti-MAGE-A3-DP0401/0402 cells and aldesleukin. They will stay in the hospital for approximately 4 weeks for the treatment.
• Follow up: Patients will return to the clinic for a physical exam, review of side effects, lab tests, and scans about every 1-3 months for the first year, and then every 6 months to 1 year as long as their tumors are shrinking.

Conditions

Cervical Cancer; Renal Cancer; Urothelial Cancer; Melanoma; Breast Cancer

Keywords

Gene Therapy; Tumor Regression; Immunotherapy; Adoptive Cell Therapy

Outcome Measures

Primary Outcomes (3)

• Maximum Tolerated Cell Dose (MTD) of Cluster of Differentiation 4 (CD4) Cells Transduced With an Anti-MAGE-A3-DP0401/0402 Restricted (MAGE-A3-DP4) T Cell Receptor and Aldesleukin

  Highest dose at which less than or equal to 1 of 6 patients experienced a dose-limiting toxicity (DLT) (all grade 3 and greater toxicities with the exception of myelosuppression and grade 3 fever, for example) or the highest dose level studied if DLTs are not observed at any of the dose levels.

  Before progression to next-higher dose level, at least two weeks

• Percentage of Participants Who Have a Clinical Response to Treatment (Objective Tumor Regression)

  Percentage of participants who have a clinical response to treatment (objective tumor regression) measured by the Response Evaluation Criteria in Solid Tumors (RECIST)v1.0. Complete response is disappearance of all target lesions. Partial response is at least a 30% decrease in the sum of the longest diameter of target lesions. Progression is at least a 20% increase in the sum of longest diameter of target lesions or the appearance of one or more new lesions. And stable disease is neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease.

  6 and 12 weeks after cell infusion, then every 3 months x3, then every 6 months x2 years, then per principal investigator discretion, approximately 6 years

• Number of Adverse Events With Grades ≥1 That Are Possibly, Probably, and/or Definitely Related to Treatment

  Aggregate of all adverse events with Grades ≥1 that are possibly, probably, and/or definitely related to treatment. Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening, and Grade 5 is death related to adverse events.

  6 weeks after cell infusion

Secondary Outcomes (1)

• Number of Engineered T Cell Receptor (TCR) Cells That Survived at 4 Weeks

  4 weeks

Other Outcomes (2)

• Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0).

  Date treatment consent signed to date off study, an average of 17 months

• Number of Participants With Dose-limiting Toxicity (DLT)

  Before progression to next-higher dose level, approximately 2 weeks

Study Arms (2)

1/Phase I Experimental Therapy

EXPERIMENTAL

Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + Anti-Melanoma antigen family A, 3 (MAGE-A3)-DP4 T cell receptor (TCR) peripheral blood lymphocytes (PBL) + high-dose aldesleukin

Biological: Anti-MAGE-A3-DP4 T Cell Receptor (TCR) Peripheral Blood Lymphocytes (PBL); Drug: Cyclophosphamide; Drug: Fludarabine; Drug: Aldesleukin

2/Phase II Experimental Therapy

EXPERIMENTAL

Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + Anti-Melanoma antigen family A, 3 (MAGE-A3)-DP4 T cell receptor (TCR) peripheral blood lymphocytes (PBL) + high-dose aldesleukin

Biological: Anti-MAGE-A3-DP4 T Cell Receptor (TCR) Peripheral Blood Lymphocytes (PBL); Drug: Cyclophosphamide; Drug: Fludarabine; Drug: Aldesleukin

Interventions

Anti-MAGE-A3-DP4 T Cell Receptor (TCR) Peripheral Blood Lymphocytes (PBL) BIOLOGICAL

Day 0: cells will be infused intravenously (i.v.) on the Patient Care Unit over 20 to 30 minutes

1/Phase I Experimental Therapy; 2/Phase II Experimental Therapy

Cyclophosphamide DRUG

Days -7 and -6: Cyclophosphamide 60 mg/kg/day X 2 days intravenous (IV) in 250 ml dextrose 5 % in water (D5W) with Mesna 15 mg/kg /day X 2 days over 1 hour.

Also known as: Cytoxan

1/Phase I Experimental Therapy; 2/Phase II Experimental Therapy

Fludarabine DRUG

Days -7 to -3: Fludarabine 25 mg/m\^2 /day intravenous piggy-back (IVPB) daily over 30 minutes for 5 days.

Also known as: Fludara

1/Phase I Experimental Therapy; 2/Phase II Experimental Therapy

Aldesleukin DRUG

Aldesleukin 720,000 IU/kg intravenous (IV) (based on total body weight) over 15 minutes every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum 15 doses).

Also known as: Proleukin

1/Phase I Experimental Therapy; 2/Phase II Experimental Therapy

Eligibility Criteria

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

You may qualify if:

• Metastatic or locally advanced refractory/recurrent cancer that expresses Melanoma antigen family A, 3 (MAGE-A3) as assessed by one of the following methods: Reverse transcription polymerase chain reaction (RT-PCR) on tumor tissue defined as 30,000 copies of MAGE-A3 per 10\^6 glyceraldehyde 3-phosphate dehydrogenase (GAPDH) copies, or by immunohistochemistry of resected tissue defined as 10% or greater of tumor cells being 2-3+ for MAGE-A3, or serum antibody reactive with MAGE-A3. Metastatic cancer diagnosis will be confirmed by the Laboratory of Pathology at the National Cancer Institute (NCI).
• Patients must have previously received prior first line standard therapy (or effective salvage chemotherapy regimens) for their disease, if known to be effective for that disease, and have been either non-responders (progressive disease) or have recurred.
• Patients must be human leucocyte antigen (HLA)-DP4 positive.
• Patients with 3 or fewer brain metastases that are less than 1 centimeter (cm) in diameter and asymptomatic are eligible. Lesions that have been treated with stereotactic radiosurgery must be clinically stable for 1 month after treatment for the patient to be eligible. Patients with surgically resected brain metastases are eligible.
• Greater than or equal to 18 years of age and less than or equal to age 70.
• Ability of subject to understand and the willingness to sign the Informed Consent Document.
• Willing to sign a durable power of attorney
• Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1
• Patients of both genders must be willing to practice birth control from the time of enrollment on this study and for up to four months after treatment.
• Serology:
• Seronegative for human immunodeficiency virus (HIV) antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive can 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 hepatitis C hepatitis C virus (HCV) ribonucleic acid (RNA) negative.
• Women of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the treatment on the fetus.
• Hematology
• Absolute neutrophil count greater than 1000/mm\^3 without the support of filgrastim

You may not qualify if:

• Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant.
• Active systemic infections, (e.g.: requiring anti-infective treatment), coagulation disorders or any other active major medical illnesses
• Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
• Concurrent opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immune competence may be less responsive to the experimental treatment and more susceptible to its toxicities).
• Concurrent systemic steroid therapy.
• History of severe immediate hypersensitivity reaction to any of the agents used in this study.
• History of any cardiac events including coronary revascularization or ischemic symptoms.
• Documented left ventricular ejection fraction (LVEF) of less than or equal to 45% testing is required in patients who are
• greater than or equal to 65 years old
• Clinically significant atrial and or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, second or third degree heart block or have a history of ischemic heart disease, or chest pain.
• Documented forced expiratory volume (FEV1) less than or equal to 60% predicted tested in patients with:
• A prolonged history of cigarette smoking (20 pk/year of smoking within the past 2 years).
• Symptoms of respiratory dysfunction
• Patients who are receiving any other investigational agents.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• Morgan RA, Dudley ME, Yu YY, Zheng Z, Robbins PF, Theoret MR, Wunderlich JR, Hughes MS, Restifo NP, Rosenberg SA. High efficiency TCR gene transfer into primary human lymphocytes affords avid recognition of melanoma tumor antigen glycoprotein 100 and does not alter the recognition of autologous melanoma antigens. J Immunol. 2003 Sep 15;171(6):3287-95. doi: 10.4049/jimmunol.171.6.3287.

  PMID: 12960359 BACKGROUND

• Suri A. Cancer testis antigens--their importance in immunotherapy and in the early detection of cancer. Expert Opin Biol Ther. 2006 Apr;6(4):379-89. doi: 10.1517/14712598.6.4.379.

  PMID: 16548764 BACKGROUND

• Robbins PF, Morgan RA, Feldman SA, Yang JC, Sherry RM, Dudley ME, Wunderlich JR, Nahvi AV, Helman LJ, Mackall CL, Kammula US, Hughes MS, Restifo NP, Raffeld M, Lee CC, Levy CL, Li YF, El-Gamil M, Schwarz SL, Laurencot C, Rosenberg SA. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol. 2011 Mar 1;29(7):917-24. doi: 10.1200/JCO.2010.32.2537. Epub 2011 Jan 31.

  PMID: 21282551 BACKGROUND

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Uterine Cervical Neoplasms; Kidney Neoplasms; Melanoma; Breast Neoplasms

Interventions

Cyclophosphamide; fludarabine; fludarabine phosphate; aldesleukin

Condition Hierarchy (Ancestors)

Uterine Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Uterine Cervical Diseases; Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Urologic Neoplasms; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Skin Diseases; Skin and Connective Tissue Diseases; Breast Diseases

Intervention Hierarchy (Ancestors)

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

Results Point of Contact

• Title: Dr. Steven A. Rosenberg
• Organization: National Cancer Institute

sar@mail.nih.gov

240-858-3080

Study Officials

• Steven A Rosenberg, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: April 9, 2014
• First Posted: April 11, 2014
• Study Start: February 7, 2014
• Primary Completion: March 24, 2021
• Study Completion: March 24, 2021
• Last Updated: March 29, 2022
• Results First Posted: March 29, 2022

Record last verified: 2022-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)