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

NCT02153905

Description:

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.

Related Conditions:
  • Cancer
Recruiting Status:

Terminated

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: T Cell Receptor Immunotherapy Targeting MAGE-A3 for Patients With Metastatic Cancer Who Are HLA-A*01 Positive
  • Official Title: A Phase I-II Study of the Treatment of Metastatic Cancer That Expresses MAGE-A3 Using Lymphodepleting Conditioning Followed by Infusion of Anti-MAGE-A3 HLA-A*01 Restricted TCR-Gene Engineered Lymphocytes and Aldesleukin

Clinical Trial IDs

  • ORG STUDY ID: 140110
  • SECONDARY ID: 14-C-0110
  • NCT ID: NCT02153905

Conditions

  • Breast Cancer
  • Cervical Cancer
  • Renal Cancer
  • Melanoma
  • Bladder Cancer

Interventions

DrugSynonymsArms
AldesleukinInterleukin-2Phase 1 - Dose Escalation/De-Escalation
FludarabineFludaraPhase 1 - Dose Escalation/De-Escalation
CyclophosphamideCytoxanPhase 1 - Dose Escalation/De-Escalation
Anti-MAGE-A3 human leukocyte antigen serotype within HLA-A A serotype group (HLA-A* 01)-restricted T-cell receptor (TCR)Phase 1 - Dose Escalation/De-Escalation

Purpose

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.

Detailed Description

      Background:

        -  We have constructed a single retroviral vector that contains both alpha and beta chains
           of a T cell receptor (TCR) that recognizes the human leukocyte antigen serotype within
           HLA-A "A" serotype group (HLA-A 01) restricted MAGE-A3 tumor antigen, which can be used
           to mediate genetic transfer of this TCR with high efficiency.

        -  In co-cultures with human leukocyte antigen serotype within HLA-A A serotype group
           (HLA-A 01) and MAGE-A3 double positive tumors, the anti-MAGE-A3- A 01 restricted
           (anti-MAGE-A3-01) TCR transduced T cells secreted significant amounts of Interferon
           (IFN)- >= with high specificity.

      Objectives:

      Primary objectives:

        -  Determine a safe dose of administration of autologous T cells transduced with an anti-
           MAGE-A3 HLA-A 01-restricted TCR (MAGE-A3-01) 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.

        -  Determine the toxicity profile of this treatment regimen.

      Eligibility:

      Patients who are HLA-A 01 positive and 18 years of age or older must have

        -  Metastatic cancer whose tumors express the MAGE-A3 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:

        -  Peripheral blood mononuclear cells (PBMC) obtained by leukapheresis will be transduced
           with the retroviral vector supernatant encoding the anti-MAGE-A3 HLA-A 01-restricted
           TCR.

        -  The study will begin with a phase I dose escalation. After the maximum tolerated dose
           (MTD) cell dose has been determined, patients will be enrolled into the phase II portion
           of the trial at the MTD established during the phase I portion of the study. In the
           phase II portion, patients will be entered into two cohorts: cohort 2a will include
           patients with metastatic melanoma; cohort 2b 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 intravenous (IV) aldesleukin.

        -  Patients will undergo complete evaluation of tumor response every 1-6 months until off
           study criteria are met.

        -  For each of the two 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
           modes 20% partial response (PR) + complete response (CR) rate (p1=0.20).

        -  In order to complete the dose escalation phase and both phase II cohorts, a total of up
           to 20+82=102 patients may be required (20 + 2 strata with a maximum of 41 apiece). Up to
           6 patients enrolled at the MTD will count towards the accrual in the appropriate phase
           II strata if they are evaluable for response and if they would be fully eligible for
           enrollment in the phase II portion of the trial. Provided that about 4-5 patients per
           month will be able to be enrolled onto this trial, approximately 2 to 3 years may be
           needed to accrue the maximum number of required patients.
    

Trial Arms

NameTypeDescriptionInterventions
Phase 1 - Dose Escalation/De-EscalationExperimentalNon-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + MAGE-A3- A1 transduced peripheral blood lymphocytes (PBL) + high-dose aldesleukin
  • Aldesleukin
  • Fludarabine
  • Cyclophosphamide
  • 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 DoseExperimentalNon-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + MAGE-A3- A1 transduced peripheral blood lymphocytes (PBL) + high-dose aldesleukin
  • Aldesleukin
  • Fludarabine
  • Cyclophosphamide
  • Anti-MAGE-A3 human leukocyte antigen serotype within HLA-A A serotype group (HLA-A* 01)-restricted T-cell receptor (TCR)

Eligibility Criteria

        -  INCLUSION CRITERIA:

               1. 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).

               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 human leukocyte antigen serotype within HLA-A A serotype group
                  (HLA-A*01) positive.

               4. Greater than or equal to 18 years of age and less than or equal to age 70.

               5. Ability of subject to understand and the willingness to sign the Informed Consent
                  Document

               6. Willing to sign a durable power of attorney

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

               8. 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.

               9. 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.

              10. Women of child-bearing potential must have a negative pregnancy test because of
                  the potentially dangerous effects of the treatment on the fetus.

              11. 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

                    -  Platelet count greater than or equal to 100,000/mm^3

                    -  Hemoglobin > 8.0 g/dl

              12. Chemistry:

                    -  Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) less
                       than or equal to to 2.5 times the upper limit of normal

                    -  Serum creatinine less than or equal to to 1.6 mg/dl

                    -  Total bilirubin less than or equal to to 1.5 mg/dl, except in patients with
                       Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dl.

              13. 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
                  gastrointestinal (GI) toxicity must have a normal colonoscopy with normal colonic
                  biopsies

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

        Note: Patients who have previously received ipilimumab and have documented gastrointestinal
        (GI) toxicity must have a normal colonoscopy with normal colonic biopsies.

        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 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.

          9. Patients with central nervous system (CNS) metastases or symptomatic CNS involvement
             (including cranial neuropathies or mass lesions).

         10. Patients presenting with lesions that may harbor an occult infectious source.

         11. 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

         12. Patients who are receiving any other investigational agents.
      
Maximum Eligible Age:70 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Cell Dose (MTD)
Time Frame:Within 30 days of study cell infusion, before progression to next-higher dose level
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:In Vivo Survival of T-Cell Receptor (TCR) Cells
Time Frame:Up to 3 years after study cell infusion
Safety Issue:
Description:In vivo survival of gene-engineered lymphocytes derived from the infused cells will be analyzed by tetramer analysis and staining for the T-cell receptor (TCR). Tetramer analysis is measured by % of peripheral blood.
Measure:Number of Participants With Dose-Limiting Toxicity (DLT)
Time Frame:Within 30 days of study cell infusion
Safety Issue:
Description: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.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Terminated
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

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

Last Updated

June 17, 2019