MAGE-A3/12 Metastatic Cancer Treatment With Anti-MAGE-A3/12 TCR-Gene Engineered Lymphocytes

This study has been terminated.
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier:
NCT01273181
First received: January 7, 2011
Last updated: March 27, 2013
Last verified: March 2013
  Purpose

Background:

- MAGE-A3/12 is a type of protein commonly found on certain types of cancer cells, particularly in metastatic cancer. Researchers have developed a process to take lymphocytes (white blood cells) from cancer patients, modify them in the laboratory to target cancer cells that contain MAGE-A3/12, and return them to the patient to help attack and kill the cancer cells. These modified white blood cells are an experimental treatment, but researchers are interested in determining their safety and effectiveness as a possible treatment for cancers that involve MAGE-A3/12.

Objectives:

- To evaluate the safety and effectiveness of anti-MAGE-A3/12 lymphocytes as a treatment for metastatic cancers that have not responded to standard treatment.

Eligibility:

- Individuals at least 18 years of age who have been diagnosed with metastatic melanoma, renal cell cancer, or another type of metastatic cancer that has not responded to standard treatment.

Design:

  • Participants will be screened with a full medical history and physical examination, as well as blood and urine tests, tumor samples, and imaging studies.
  • Participants will have leukapheresis to collect enough white blood cells for modification in the laboratory.
  • Seven days before the start of anti-MAGE-A3/12 treatment, participants will have chemotherapy with cyclophosphamide and fludarabine to suppress the immune system in preparation for the treatment.
  • After the last dose of chemotherapy, participants will receive the anti-MAGE-A3/12 cells as an infusion for 20 to 30 minutes, followed by a dose of interleukin-2 to keep the anti-MAGE-A3/12 cells alive and active as long as possible. Participants will also receive filgrastim to encourage the production of blood cells.
  • Participants will remain in the hospital to be monitored for possible side effects, and after release from the hospital will have regular followup exams with blood samples and imaging studies to evaluate the effectiveness of the treatment....

Condition Intervention Phase
Metastatic Cancer
Metastatic Renal Cancer
Metastatic Melanoma
Biological: PG13-MAGE-A3 TCR9W11 (anti-MAGE-A3/12 TCR) Transduced Autologous Peripheral Blood Lymphocytes
Drug: Aldesleukin
Drug: Cyclophosphamide
Drug: Fludarabine
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I/II Study of Metastatic Cancer That Expresses MAGE-A3/12 Using Lymphodepleting Conditioning Followed by Infusion of Anti-MAGE-A3/12 TCR-Gene Engineered Lymphocytes

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Toxicity Profile [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
    Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.

  • Clinical Tumor Regression (Complete Response (CR) + Partial Response (PR)) in Patients With Metastatic Cancer [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    Tumor regression response is assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response (CR) is a disappearance of all target lesions. Partial response (PR) is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD.


Enrollment: 9
Study Start Date: December 2010
Study Completion Date: December 2012
Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Ph I:Anti-MAGE A3/12 TCR PBL 5x10e9

Cyclophosphamide : 60 mg/kg/day x 2 days intravenous (IV)

Aldesleukin : 720,000 IU/kg every 8 hours for a maximum of 15 doses

PG13-MAGE-A3 TCR9W11 (anti-MAGE-A3/12 TCR) Transduced Autologous Peripheral Blood Lymphocytes :

Fludarabine : 25 mg/m^2/day intravenous piggy back (IVPB) daily over 30 minutes for 5 days.

Note for phase I: The study will begin by evaluating the safety of two ranges of cells, 5x10^9-3x10^10, and greater than 3x10^10-1x10^11 in a standard phase I dose escalation fashion using a 3+3 design.

Biological: PG13-MAGE-A3 TCR9W11 (anti-MAGE-A3/12 TCR) Transduced Autologous Peripheral Blood Lymphocytes
N/A
Drug: Aldesleukin
720,000 IU/kg every 8 hours for a maximum of 15 doses
Other Name: IL-2
Drug: Cyclophosphamide
60 mg/kg/day x 2 days intravenous (IV)over 1 hour.
Drug: Fludarabine
25 mg/m^2/day intravenous piggy back (IVPB) daily over 30 minutes for 5 days.
Experimental: Ph I:Anti-MAGE A3/12 TCR PBL 3x10e10

Cyclophosphamide : 60 mg/kg/day x 2 days intravenous (IV)

Aldesleukin : 720,000 IU/kg every 8 hours for a maximum of 15 doses

PG13-MAGE-A3 TCR9W11 (anti-MAGE-A3/12 TCR) Transduced Autologous Peripheral Blood Lymphocytes :

Fludarabine : 25 mg/m^2/day intravenous piggy back (IVPB) daily over 30 minutes for 5 days.

Note for phase I: The study will begin by evaluating the safety of two ranges of cells, 5x10^9-3x10^10, and greater than 3x10^10-1x10^11 in a standard phase I dose escalation fashion using a 3+3 design.

Biological: PG13-MAGE-A3 TCR9W11 (anti-MAGE-A3/12 TCR) Transduced Autologous Peripheral Blood Lymphocytes
N/A
Drug: Aldesleukin
720,000 IU/kg every 8 hours for a maximum of 15 doses
Other Name: IL-2
Drug: Cyclophosphamide
60 mg/kg/day x 2 days intravenous (IV)over 1 hour.
Drug: Fludarabine
25 mg/m^2/day intravenous piggy back (IVPB) daily over 30 minutes for 5 days.
Experimental: Ph II:Anti-MAGE TCR PBL MTD+HD IL-2

Phase II:Anti-MAGE A3/12 TCR PBL MTD + HD IL-2, Melanoma, RCC

Cyclophosphamide : 60 mg/kg/day x 2 days intravenous (IV)

Aldesleukin : 720,000 IU/kg every 8 hours for a maximum of 15 doses

PG13-MAGE-A3 TCR9W11 (anti-MAGE-A3/12 TCR) Transduced Autologous Peripheral Blood Lymphocytes :

Fludarabine : 25 mg/m^2/day intravenous piggy back (IVPB) daily over 30 minutes for 5 days.

Note for phase II:patients will be entered into two cohorts based on histology:cohort 1 will include patients with metastatic melanoma or renal cell cancer; cohort 2 will include patients with other types of metastatic cancer.

Biological: PG13-MAGE-A3 TCR9W11 (anti-MAGE-A3/12 TCR) Transduced Autologous Peripheral Blood Lymphocytes
N/A
Drug: Aldesleukin
720,000 IU/kg every 8 hours for a maximum of 15 doses
Other Name: IL-2
Drug: Cyclophosphamide
60 mg/kg/day x 2 days intravenous (IV)over 1 hour.
Drug: Fludarabine
25 mg/m^2/day intravenous piggy back (IVPB) daily over 30 minutes for 5 days.
Experimental: Ph II:Anti-MAGE A3/12 TCR PBL MTD

Phase II: Anti-MAGE A3/12 TCR PBL MTD + HD-IL2 Other Cancer

Cyclophosphamide : 60 mg/kg/day x 2 days intravenous (IV)

Aldesleukin : 720,000 IU/kg every 8 hours for a maximum of 15 doses

PG13-MAGE-A3 TCR9W11 (anti-MAGE-A3/12 TCR) Transduced Autologous Peripheral Blood Lymphocytes :

Fludarabine : 25 mg/m^2/day intravenous piggy back (IVPB) daily over 30 minutes for 5 days.

Note for phase II:patients will be entered into two cohorts based on histology:cohort 1 will include patients with metastatic melanoma or renal cell cancer; cohort 2 will include patients with other types of metastatic cancer.

Biological: PG13-MAGE-A3 TCR9W11 (anti-MAGE-A3/12 TCR) Transduced Autologous Peripheral Blood Lymphocytes
N/A
Drug: Aldesleukin
720,000 IU/kg every 8 hours for a maximum of 15 doses
Other Name: IL-2
Drug: Cyclophosphamide
60 mg/kg/day x 2 days intravenous (IV)over 1 hour.
Drug: Fludarabine
25 mg/m^2/day intravenous piggy back (IVPB) daily over 30 minutes for 5 days.

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

Metastatic cancer that expresses MAGE-A3/12 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-A3/12 per 106 GAPDH copies, or by immunohistochemistry of resected tissue defined as 10% or greater of cells being 2-3+, or serum antibody reactive with MAGE-A3/12. Metastatic cancer diagnosis will be confirmed by the Laboratory of Pathology at the National Cancer Institute (NCI).

Patients with melanoma or renal cell cancer must have previously received high dose aldesleukin and have been either non-responders (progressive disease) or have recurred. Patients with other histologies, must have previously received at least one systemic standard care (or effective salvage chemotherapy regimens) for metastatic disease, if known to be effective for that disease, and have been either non-responders (progressive disease) or have recurred.

Greater than or equal to 18 years of age.

Willing to sign a durable power of attorney

Able to understand and sign the Informed Consent Document

Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1.

Life expectancy of greater than three months.

Patients of both genders must be willing to practice birth control for four months after receiving the preparative regimen.

Patients must be human leukocyte antigen (HLA)-A*0201 positive

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 hepatitis C antibody unless antigen negative.

Hematology:

  • Absolute neutrophil count greater than 1000/mm^3 without the support of filgrastim.
  • White blood cell (WBC) (> 3000/mm^3).
  • Platelet count greater than 100,000/mm^3.
  • Hemoglobin greater than 8.0 g/dl.

Chemistry:

  • Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) less or equal to 2.5 times the upper limit of normal.
  • Serum creatinine less than or equal to 1.6 mg/dl.
  • Total bilirubin less than or equal to 1.5 mg/dl, except in patients with Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dl.

More than four weeks must have elapsed since any prior systemic therapy at the time the patient receives the preparative regimen, and patients' toxicities must have recovered to a grade 1 or less (except for toxicities such as alopecia or vitiligo).

EXCLUSION CRITERIA:

Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the preparative chemotherapy on the fetus or infant.

Active systemic infections, coagulation disorders or other major medical illnesses of the cardiovascular, respiratory or immune system, myocardial infarction, cardiac arrhythmias, obstructive or restrictive pulmonary disease.

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 coronary revascularization or ischemic symptoms

Any patient known to have an left ventricular ejection fraction (LVEF) less than or equal to 45%.

Documented LVEF of less than or equal to 45% tested in patients with:

  • History of ischemic heart disease, chest pain, or clinically significant atrial and/or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, second or third degree heart block
  • Age greater than or equal to 60 years old

Documented forced expiratory volume 1 (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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01273181

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
Investigators
Principal Investigator: Steven A Rosenberg, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier: NCT01273181     History of Changes
Other Study ID Numbers: 110062, 11-C-0062
Study First Received: January 7, 2011
Results First Received: February 14, 2013
Last Updated: March 27, 2013
Health Authority: United States: Federal Government
United States: Food and Drug Administration

Keywords provided by National Institutes of Health Clinical Center (CC):
Immunotherapy
Gene Therapy
Metastatic Cancer
Clinical Response
Metastatic Melanoma
Metastatic Renal Cell Cancer

Additional relevant MeSH terms:
Carcinoma, Renal Cell
Kidney Neoplasms
Melanoma
Neoplasm Metastasis
Neoplasms
Neoplasms, Second Primary
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Kidney Diseases
Urologic Diseases
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms, Nerve Tissue
Nevi and Melanomas
Neoplastic Processes
Pathologic Processes
Cyclophosphamide
Fludarabine phosphate
Fludarabine
Aldesleukin
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on August 28, 2014