T Cell Receptor Immunotherapy Targeting MAGE-A3 for Patients With Metastatic Cancer Who Are HLA-A*01 Positive

NCT02153905 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: 14011014-C-0110
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 1

Brief Summary

Background: The National Cancer Institute (NCI) Surgery Branch has developed an experimental therapy for treating patients with 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 patients white blood cells with a retrovirus that has the gene for anti-MAGE-A3 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 cells) cause tumors to shrink and to be certain the treatment is safe Eligibility: \- Adults age 18-66 with 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 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 cells and aldesleukin. They will stay in the hospital for about 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. Follow up visits take up to 2 days.

Conditions

Breast Cancer; Cervical Cancer; Renal Cancer; Melanoma; Bladder Cancer

Keywords

Melanoma; Immunotherapy; Metastatic Cancer; Gene Therapy; T Cells

Outcome Measures

Primary Outcomes (4)

• Maximum Tolerated Cell Dose (MTD)

  Highest dose at which less than or equal to 1 of 6 patients experienced a dose limiting toxicity (DLT) or the highest dose level studied if DLTs are not observed at any of the dose levels. DLT is defined as follows: Grade 3-5 allergic reactions related to the study cell infusion. Grade 3 and greater autoimmune reactions. Grades 3 and greater organ toxicity (cardiac, dermatologic, gastrointestinal, hepatic, pulmonary, renal/genitourinary, or neurologic) not pre-existing or due to the underlying malignancy and occurring within 30 days of study cell infusion and does not resolve within 72 hours. Treatment-related death within 8 weeks of the study cell infusion.

  Within 30 days of study cell infusion, before progression to next-higher dose level

• Number of Patients With Objective Tumor Regression

  Objective tumor regression is defined as the number of participants with a complete or partial response per 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 (LD) of target lesions, taking as reference the baseline sum LD.

  6 and 12 weeks after cell infusion on up to 2 years

• Number of Treatment Related Adverse Events Related to T-Cell Receptor (TCR) Gene-Engineered Cells

  Aggregate of all Grade ≥3 adverse events and their frequency possibly, probably or definitely related to the research. Adverse Events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v.4.0. Grade 3 is severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living (ADL). Grade 4 is life-threatening consequences; urgent intervention indicated. Grade 5 is death related to adverse event.

  Date treatment consent signed to end of treatment, approximately 30 days

• Number of Participants With Serious and Non-Serious Adverse Events

  Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

  Date treatment consent signed to date off study, approximately 53 days for the Anti-MAGE-A3 A1 TCR PBL 1x10^9 Cells + Interleukin-2 (IL-2) Arm/Group, and 1 year and 4 months for the Anti-MAGE-A3 A1 TCR PBL 1x10^8 Cells + Interleukin-2 (IL-2) Arm/Group.

Secondary Outcomes (2)

• In Vivo Survival of T-Cell Receptor (TCR) Cells

  Up to 3 years after study cell infusion

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

  Within 30 days of study cell infusion

Study Arms (2)

Phase 1 - Dose Escalation/De-Escalation

EXPERIMENTAL

Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + MAGE-A3- A1 transduced peripheral blood lymphocytes (PBL) + high-dose aldesleukin

Drug: Aldesleukin; Drug: Fludarabine; Drug: Cyclophosphamide; Biological: Anti-MAGE-A3 human leukocyte antigen serotype within HLA-A A serotype group (HLA-A* 01)-restricted T-cell receptor (TCR)

Phase II - Maximum Tolerated Dose

EXPERIMENTAL

Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + MAGE-A3- A1 transduced peripheral blood lymphocytes (PBL) + high-dose aldesleukin

Drug: Aldesleukin; Drug: Fludarabine; Drug: Cyclophosphamide; Biological: Anti-MAGE-A3 human leukocyte antigen serotype within HLA-A A serotype group (HLA-A* 01)-restricted T-cell receptor (TCR)

Interventions

Aldesleukin DRUG

Aldeskeukin 720,000 IU/kg (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: Interleukin-2

Phase 1 - Dose Escalation/De-Escalation; Phase II - Maximum Tolerated Dose

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

Phase 1 - Dose Escalation/De-Escalation; Phase II - Maximum Tolerated Dose

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 hr.

Also known as: Cytoxan

Phase 1 - Dose Escalation/De-Escalation; Phase II - Maximum Tolerated Dose

Anti-MAGE-A3 human leukocyte antigen serotype within HLA-A A serotype group (HLA-A* 01)-restricted T-cell receptor (TCR) BIOLOGICAL

Day 0: MAGE-A3-A1 transduced peripheral blood lymphocytes (PBL) will be infused intravenously on the Patient Care Unit over 20-30 minutes.

Phase 1 - Dose Escalation/De-Escalation; Phase II - Maximum Tolerated Dose

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 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 106 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 leukocyte antigen serotype within HLA-A A serotype group (HLA-A\*01) positive.
• 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 virus ribonucleic acid (HCV 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
• White blood cell (WBC) greater than or equal to 3000/mm\^3

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:
• Age 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.
• Patients with central nervous system (CNS) metastases or symptomatic CNS involvement (including cranial neuropathies or mass lesions).
• Patients presenting with lesions that may harbor an occult infectious source.
• 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

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

• Johnson LA, Morgan RA, Dudley ME, Cassard L, Yang JC, Hughes MS, Kammula US, Royal RE, Sherry RM, Wunderlich JR, Lee CC, Restifo NP, Schwarz SL, Cogdill AP, Bishop RJ, Kim H, Brewer CC, Rudy SF, VanWaes C, Davis JL, Mathur A, Ripley RT, Nathan DA, Laurencot CM, Rosenberg SA. Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood. 2009 Jul 16;114(3):535-46. doi: 10.1182/blood-2009-03-211714. Epub 2009 May 18.

  PMID: 19451549 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

MeSH Terms

Conditions

Breast Neoplasms; Uterine Cervical Neoplasms; Kidney Neoplasms; Melanoma; Urinary Bladder Neoplasms; Neoplasm Metastasis

Interventions

aldesleukin; Interleukin-2; fludarabine; fludarabine phosphate; Cyclophosphamide

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Uterine Neoplasms; Genital Neoplasms, Female; Urogenital 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; Urinary Bladder Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Interleukins; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Lymphokines; Proteins; Biological Factors; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Results Point of Contact

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

sr78a@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: May 31, 2014
• First Posted: June 3, 2014
• Study Start: July 3, 2014
• Primary Completion: September 10, 2018
• Study Completion: September 10, 2018
• Last Updated: June 17, 2019
• Results First Posted: June 5, 2019

Record last verified: 2019-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)