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

NCT02111850

Description:

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.

Related Conditions:
  • Cancer
Recruiting Status:

Recruiting

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-DP0401 Positive
  • 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

Clinical Trial IDs

  • ORG STUDY ID: 140052
  • SECONDARY ID: 14-C-0052
  • NCT ID: NCT02111850

Conditions

  • Cervical Cancer
  • Renal Cancer
  • Urothelial Cancer
  • Melanoma
  • Breast Cancer

Interventions

DrugSynonymsArms
Anti-MAGE-A3-DP4 TCR PBL1/Phase I Experimental Therapy
Cyclophosphamide1/Phase I Experimental Therapy
Fludarabine1/Phase I Experimental Therapy
high dose Aldesleukin1/Phase I Experimental Therapy

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.

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 1 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 1 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 2 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).
    

Trial Arms

NameTypeDescriptionInterventions
1/Phase I Experimental TherapyExperimentalNon-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + Anti-MAGE-A3-DP4 TCR PBL + high-dose aldeskin
  • Anti-MAGE-A3-DP4 TCR PBL
  • Cyclophosphamide
  • Fludarabine
  • high dose Aldesleukin
2/Phase II Experimental TherapyExperimentalNon-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + Anti-MAGE-A3-DP4 TCR PBL + high-dose aldeskin
  • Anti-MAGE-A3-DP4 TCR PBL
  • Cyclophosphamide
  • Fludarabine
  • high dose Aldesleukin

Eligibility 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.
      
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: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 DLT or the highest dose level studied if DLTs are not observed at any of the dose levels.

Secondary Outcome Measures

Measure:Engineered cell survival
Time Frame:2-4 years after cell infusion
Safety Issue:
Description:TCR and vector presence will be quantitated in PBMC samples using established PCR techniques

Details

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

Trial Keywords

  • Gene Therapy
  • Tumor Regression
  • Immunotherapy
  • Adoptive Cell Therapy

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