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

This study is currently recruiting participants.
Verified September 28, 2017 by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
Sponsor:
ClinicalTrials.gov Identifier:
NCT02111850
First Posted: April 11, 2014
Last Update Posted: October 19, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
  Purpose

Background:

The 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-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:

- Adults age 18-70 with metastatic cancer expressing the MAGE-A3 molecule.

Design:

  • Work up stage: Patients will be seen as an outpatient at the 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.

Condition Intervention Phase
Cervical Cancer Renal Cancer Urothelial Cancer Melanoma Breast Cancer Biological: Anti-MAGE-A3-DP4 TCR Drug: Cyclophosphamide Drug: Fludarabine Drug: Aldesleukin Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/II Study of the Treatment of Metastatic Cancer That Expresses MAGE-A3 Using Lymphodepleting Conditioning Followed by Infusion of HLA-DP0401/0402 Restricted Anti-MAGE-A3 TCR-Gene Engineered Lymphocytes and Aldesleukin

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Frequency of treatment related adverse events [ Time Frame: 30 days after end of treatment ]
  • Response Rate [ Time Frame: 6 and 12 weeks after cell infusion, then every 3 months x3, then every 6 months x2 years. ]

Secondary Outcome Measures:
  • Measure Persistence [ Time Frame: 2-4 years after cell infusion ]

Estimated Enrollment: 107
Study Start Date: April 9, 2014
Estimated Study Completion Date: December 27, 2024
Estimated Primary Completion Date: December 29, 2023 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Renal and Other types of Metstatic Cancer
Patients will receive the standard NCI Surgery Branch non-myeloablative, lymphodepleting preparative regimen consisting of cyclophosphamide andfludarabine followed by IV infusion of anti-MAGE-A3-DP4 TCR engineered PBL and aldesleukin.
Biological: Anti-MAGE-A3-DP4 TCR
On day 0 (one to four days after the last dose of fludarabine) cells will be infused intravenously (i.v.) on the Patient Care Unit over 20 to 30 minutes
Drug: Cyclophosphamide
On days -7 and -6, Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml D5W over 1 hr.
Drug: Fludarabine
On days -5 to -1, Fludarabine 25 mg/m2/day IVPB daily over 30 minutes for 5 days.
Drug: Aldesleukin
Aldesleukin 720,000 IU/kg IV (based on total body weight) over 15 minutes approximately every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum of 15 doses).
Experimental: Melanoma
Patients will receive the standard NCI Surgery Branch non-myeloablative, lymphodepleting preparative regimen consisting of cyclophosphamide andfludarabine followed by IV infusion of anti-MAGE-A3-DP4 TCR engineered PBL and aldesleukin.
Biological: Anti-MAGE-A3-DP4 TCR
On day 0 (one to four days after the last dose of fludarabine) cells will be infused intravenously (i.v.) on the Patient Care Unit over 20 to 30 minutes
Drug: Cyclophosphamide
On days -7 and -6, Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml D5W over 1 hr.
Drug: Fludarabine
On days -5 to -1, Fludarabine 25 mg/m2/day IVPB daily over 30 minutes for 5 days.
Drug: Aldesleukin
Aldesleukin 720,000 IU/kg IV (based on total body weight) over 15 minutes approximately every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum of 15 doses).

Detailed Description:

Background:

  • We have constructed a single retroviral vector that contains both and $ <= chains of a T cell receptor (TCR) that recognizes the DP0401/0402 restricted MAGE-A3 tumor antigen, which can be used to mediate genetic transfer of this TCR with high efficiency.
  • In co-cultures with HLA-DP0401/0402 and MAGE-A3 double positive tumors, the anti- MAGE-A3- DP0401/0402 restricted (anti-MAGE-A3-DP4) TCR transduced T cells secreted significant amounts of IFN-y with high specificity.

Objectives:

Primary objectives:

  • Determine a safe dose of the administration of autologous CD4 cells transduced with an anti- MAGE-A3-DP0401/0402 restricted (MAGE-A3-DP4) TCR and aldesleukin to patients following a nonmyeloablative but lymphoid depleting preparative regimen.
  • Determine if this approach will result in objective tumor regression in patients with metastatic cancer expressing MAGE-A3-DP4.
  • Determine the toxicity profile of this treatment regimen.

Eligibility:

Patients who are HLA-DP0401/0402 positive and 18 years of age or older must have

  • Metastatic cancer whose tumors express the MAGE-A3-DP4 antigen;
  • Previously received and have been a non-responder to or recurred following at least one first line treatment for metastatic disease;

Patients may not have:

- Contraindications for high dose aldesleukin administration.

Design:

  • PBMC obtained by leukapheresis will be enriched for CD4 cells and transduced with the retroviral vector supernatant encoding the anti-MAGE-A3-DP4 TCR.
  • The study will begin in a standard phase I dose escalation. After the MTD cell dose has been determined, patients will be enrolled into the phase 2 portion of the trial at the MTD established during the phase I portion of the study. In the phase 2 portion, patients will be entered into two cohorts: cohort 1 will include patients with metastatic melanoma; cohort 2 will include patients with renal cancer and other types of metastatic cancer.
  • Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of ex vivo tumor reactive, TCR gene-transduced PBMC plus IV aldesleukin.
  • Patients will undergo complete evaluation of tumor response every 1-6 months until off study criteria are met.
  • For each of the 2 strata evaluated in the phase 2 portion, the study will be conducted using a phase II optimal design where initially 21 evaluable patients will be enrolled. For each of these two arms of the trial, if 0 or 1 of the 21 patients experiences a clinical response, then no further patients will be enrolled but if 2 or more of the first 21 evaluable patients enrolled have a clinical response, then accrual will continue until a total of 41 evaluable patients have been enrolled in that stratum.
  • For both strata, the objective will be to determine if the treatment regimen is able to be associated with a clinical response rate that can rule out 5% (p0=0.05) in favor of a modest 20% PR + CR rate (p1=0.20).
  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

-INCLUSION CRITERIA:

  1. Metastatic or locally advanced refractory/recurrent cancer that expresses MAGE-A3 as assessed by one of the following methods: RT-PCR on tumor tissue defined as 30,000 copies of MAGE-A3 per 10^6 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 NCI.
  2. 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.
  3. Patients must be HLA-DP4 positive.
  4. Patients with 3 or fewer brain metastases that are less than 1 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.
  5. Greater than or equal to 18 years of age and less than or equal to age 70.
  6. Ability of subject to understand and the willingness to sign the Informed Consent Document.
  7. Willing to sign a durable power of attorney
  8. Clinical performance status of ECOG 0 or 1
  9. 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.
  10. Serology:

    • Seronegative for 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 HCV RNA negative.
  11. Women of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the treatment on the fetus.
  12. Hematology

    • Absolute neutrophil count greater than 1000/mm^3 without the support of filgrastim
    • WBC greater than or equal to 3000/mm^3
    • Platelet count greater than or equal to 100,000/mm^3
    • Hemoglobin > 8.0 g/dl
  13. Chemistry:

    • Serum ALT/AST less than 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.
  14. 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). Patients must have

    progressing disease after prior treatment. Note: Patients who have previously received ipilimumab and have documented GI toxicity must have a normal colonoscopy with normal colonic biopsies.

  15. Subjects must be co-enrolled in protocol 03-C-0277.

EXCLUSION CRITERIA:

  1. Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant.
  2. Active systemic infections, (e.g.: requiring anti-infective treatment), coagulation disorders or any other active major medical illnesses
  3. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
  4. 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).
  5. Concurrent systemic steroid therapy.
  6. History of severe immediate hypersensitivity reaction to any of the agents used in this study.
  7. History of any cardiac events including coronary revascularization or ischemic symptoms.
  8. Documented 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.
  9. Documented 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
  10. Patients who are receiving any other investigational agents.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02111850


Contacts
Contact: Abigail R Johnson, R.N. (866) 820-4505 ncisbirc@mail.nih.gov
Contact: Steven A Rosenberg, M.D. (866) 820-4505 sar@mail.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact NCI/Surgery Branch Recruitment Center    866-820-4505    ncisbirc@mail.nih.gov   
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Steven A Rosenberg, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02111850     History of Changes
Other Study ID Numbers: 140052
14-C-0052
First Submitted: April 9, 2014
First Posted: April 11, 2014
Last Update Posted: October 19, 2017
Last Verified: September 28, 2017

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
Gene Therapy
Tumor Regression
Immunotherapy
Adoptive Cell Therapy

Additional relevant MeSH terms:
Uterine Cervical Neoplasms
Neoplasm Metastasis
Kidney Neoplasms
Carcinoma, Renal Cell
Uterine Neoplasms
Genital Neoplasms, Female
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Uterine Cervical Diseases
Uterine Diseases
Genital Diseases, Female
Neoplastic Processes
Pathologic Processes
Urologic Neoplasms
Kidney Diseases
Urologic Diseases
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Cyclophosphamide
Fludarabine phosphate
Fludarabine
Aldesleukin
Interleukin-2
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents