Study of Gene Modified Immune Cells in Patients With Advanced Melanoma
Condition: Metastatic Melanoma
MeSH terms: Melanoma
Intervention: F5 TCR transgenic cells and MART-1 peptide pulsed dendritic cells; non-myeloablative conditioning chemotherapy
Intervention description: After chemotherapy, patients receive up to 1 x 10(9) MART-1 F5 TCR transgenic T cells infused i.v., 1 x 10(7) MART-1 peptide pulsed dendritic cells intradermally, and low dose IL-2 500,000 IU/m2 s.c. twice daily for 14 days.; Patients receive non-myeloablative conditioning chemotherapy with Cyclophosphamide 60 mg/kg/day x 2 days and Fludarabine 25 mg/m2/day i.v. over 30 minutes for 4 days
Intervention MeSH terms: Aldesleukin; Interleukin-2
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 14.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Adoptive transfer therapy; Dendritic cell vaccines

Summary:

      The purpose of this phase 2 study is to find the best way to give this new experimental
      regimen and determine if it can treat metastatic melanoma in humans. In this phase 2 study,
      the experimental products are given initially to a group of 8 people. If safe and found to
      have significant anti-tumor activity, it will be given to up to 14 other people, for a total
      of 22 people in this study. Physicians watch subjects carefully for any harmful side effects.
      Although the experimental regimen has been well tested in laboratory and animal studies, and
      a similar regimen has been given to a group of patients at the National Cancer Institute in
      Bethesda, MD, the side effects in people cannot be completely known ahead of time. This
      protocol is offered only to people whose condition cannot be helped by other known
      treatments.

      The study procedures will start with the collection of white blood cells through apheresis (a
      procedure in which blood is drawn from a patient and separated into its components, some of
      which are retained, such as white blood cells, and the remainder returned by transfusion to
      the patient).

      Subjects will be asked to undergo two aphereses, one to make the gene-modified MART-1 TCR
      CTLs (cytolytic T lymphocyte) and the dendritic cell vaccines, and a second one after the
      subject receives the gene modified cells to later study them in the blood.

      On the day of the first apheresis, subjects will be admitted to the hospital and will receive
      chemotherapy over the next five days which decreases the risk of rejection of the transferred
      cells by the subject's immune system and facilitates their expansion and attack of the
      melanoma lesions. During this time, the gene-modified MART-1 TCR CTLs and the dendritic cells
      will be manufactured in the laboratory from the apheresis product and will be extensively
      tested to assure that they express the appropriate TCR and that they do not contain any
      contaminating bacteria or virus. Then the gene-modified MART-1 TCR CTLs will be given back to
      the subject through a vein in the arm. It will be followed by vaccination with the dendritic
      cells under the skin. During the next fourteen days, subjects will also receive interleukin 2
      (IL-2), which is a standard treatment for patients with metastatic melanoma. During the next
      2 to 3 weeks, subjects will stay in the hospital until the study investigators determine that
      the subject has fully recovered from all of the procedures, and it is safe for the subject to
      go home. Chemotherapy frequently causes a decrease in the platelet or red blood cells, and
      therefore subjects may require platelet and/or red blood cell transfusions.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Histologically confirmed melanoma that is considered surgically incurable with either:

               -  Stage IIIc melanoma including locally relapsed, satellite, in-transit lesions or
                  bulky draining node metastasis.

               -  Stage IV melanoma (M1a, M1b or M1c). At least 1 lesion amenable for outpatient
                  biopsies; this should be a cutaneous or palpable metastatic site or a deeper site
                  accessible by image-guided biopsy that is deemed safe to access by the treating
                  physicians and interventional radiologists. Patients without accessible lesions
                  for biopsy but with prior tissue available from metastatic disease would be
                  eligible at the investigator's discretion.

          -  MART-1 positive melanoma by RT-PCR or Immuno-histochemical (IHC).

          -  HLA-A*0201 (HLA-A2.1) positivity by molecular subtyping*.

          -  Age greater than or equal to 18 years old.

          -  Life expectancy greater than 3 months assessed by a study physician.

          -  A minimum of one measurable lesion defined as:

               -  Meeting the criteria for measurable disease according to Response Evaluation
                  Criteria in Solid Tumors (RECIST).

               -  Skin lesion(s) selected as non-completely biopsied target lesion(s) that can be
                  accurately measured and recorded by color photography with a ruler to document
                  the size of the target lesion(s).

          -  No restriction based on prior treatments.

          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.

          -  Adequate bone marrow and hepatic function determined within 30-60 days prior to
             enrollment, defined as:

               -  Absolute neutrophil count >= 1.5 x 109 cells/L.

               -  Platelets >= 100 x 109/L.

               -  Hemoglobin >= 10 g/dL.

               -  Aspartate and alanine aminotransferases (AST, ALT) =< 2.5 x ULN (=< 5 x ULN, if
                  documented liver metastases are present).

               -  Total bilirubin =< 2 x Upper Limit of Normal (ULN) (except patients with
                  documented Gilbert's syndrome).

               -  Creatinine < 2 mg/dl (or a glomerular filtration rate > 60).

               -  Must be willing and able to accept at least two leukapheresis procedures.

               -  Must be willing and able to accept at least two tumor biopsies.

               -  Must be willing and able to provide written informed consent.

          -  Patients with HLA-A*0205 (HLA-A2.5) positivity by molecular subtyping may be eligible
             if there is demonstration that they can correctly present the MART-126-35 epitope as
             stimulators for IFN-gamma production by MART-1 F5 TCR transgenic cells.

        Exclusion Criteria

          -  Previously known hypersensitivity to any of the agents used in this study.

          -  Received systemic treatment for cancer, including immunotherapy, within one month
             prior to initiation of dosing within this protocol. However, cell harvesting by
             leukapheresis may be performed before one month from prior therapy if the study
             investigators consider that it will not have a detrimental impact on the generation of
             the two cell therapies in this protocol.

          -  History of, or significant evidence of risk for, chronic inflammatory or autoimmune
             disease (eg, Addison's disease, multiple sclerosis, Graves disease, Hashimoto's
             thyroiditis, inflammatory bowel disease, psoriasis, rheumatoid arthritis, systemic
             lupus erythematosus, hypophysitis, pituitary disorders, etc.). Patients will be
             eligible if prior autoimmune disease is not deemed to be active (e.g. fibrotic damage
             of the thyroid after thyroiditis or its treatment, with stable thyroid hormone
             replacement therapy). Vitiligo will not be a basis for exclusion.

          -  History of inflammatory bowel disease, celiac disease, or other chronic
             gastrointestinal conditions associated with diarrhea or bleeding, or current acute
             colitis of any origin.

          -  Potential requirement for systemic corticosteroids or concurrent immunosuppressive
             drugs based on prior history or received systemic steroids within the last 4 weeks
             prior to enrollment (inhaled or topical steroids at standard doses are allowed).

          -  HIV seropositivity or other congenital or acquired immune deficiency state, which
             would increase the risk of opportunistic infections and other complications during
             chemotherapy-induced lymphodepletion. If there is a positive result in the infectious
             disease testing that was not previously known, the patient will be referred to their
             primary physician and/or infectious disease specialist.

          -  Hepatitis B or C seropositivity with evidence of ongoing liver damage, which would
             increase the likelihood of hepatic toxicities from the chemotherapy conditioning
             regimen and supportive treatments. If there is a positive result in the infectious
             disease testing that was not previously known, the patient will be referred to their
             primary physician and/or infectious disease specialist.

          -  Dementia or significantly altered mental status that would prohibit the understanding
             or rendering of informed consent and compliance with the requirements of this
             protocol.

          -  Clinically active brain metastases. Radiological documentation of absence of active
             brain metastases at screening is required for all patients. Prior evidence of brain
             metastasis successfully treated with surgery or radiation therapy will not be
             exclusion for participation as long as they are deemed under control at the time of
             study enrollment.

          -  Pregnancy or breast-feeding. Female patients must be surgically sterile or be
             postmenopausal for two years, or must agree to use effective contraception during the
             period of treatment and 6 months after. All female patients with reproductive
             potential must have a negative pregnancy test (serum/urine) within 14 days from
             starting the conditioning chemotherapy. The definition of effective contraception will
             be based on the judgment of the study investigators.

          -  Since IL-2 is administered following cell infusion:

               -  Patients will be excluded if they have a history of clinically significant ECG
                  abnormalities, symptoms of cardiac ischemia or arrhythmias and have a left
                  ventricular ejection fraction (LVEF) < 45% on a cardiac stress test (stress
                  thallium, stress MUGA, dobutamine echocardiogram, or other stress test).

               -  Similarly, patients who are 50 years old with a baseline LVEF < 45% will be
                  excluded.

               -  Patients with ECG results of any conduction delays (PR interval >200ms, QTC >
                  480ms), sinus bradycardia (resting heart rate <50 beats per minute), sinus
                  tachycardia (HR>120 beats per minute) will be evaluated by a cardiologist prior
                  to starting the trial. Patients with any arrhythmias, including atrial
                  fibrillation/atrial flutter, excessive ectopy (defined as >20 PVCs per minute),
                  ventricular tachycardia, 3rd degree heart block will be excluded from the study
                  unless cleared by a cardiologist.

               -  Patients with pulmonary function test abnormalities as evidenced by a forced
                  expiratory volume at one second/forced vital capacity (FEV1/FVC)< 70% of
                  predicted for normality will be excluded.