Melanoma Treatment With White Blood Cells That Destroy MART Expressing Tumor Cells

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier:
NCT01495572
First received: December 16, 2011
Last updated: March 14, 2014
Last verified: November 2013
  Purpose

Background:

- Some cancer treatments collect a patient s own blood cells to use as specialized cancer-fighting cells. Collected white blood cells known as PBL (peripheral blood lymphocytes) can use to isolate special cells that can fight tumors. Before treatment with PBL, chemotherapy is given to destroy existing white blood cells so that the new cells can survive and attack the tumors. After PBL treatment, aldesleukin is given to help the new cells grow. Researchers want to see if special white blood cells that recognize a specific protein that is present in melanoma cells (MART) can cause tumors to shrink. These white blood cells will be tested with and without aldesleukin.

Objectives:

  • To test the safety and effectiveness of white blood cells that target MART in the treatment of melanoma.
  • To test white blood cells that target MART with and without aldesleukin.

Eligibility:

- Individuals at least 18 years of age who have melanoma that has not responded to standard treatments.

Design:

  • Participants will be screened with a medical history and physical exam. Blood and urine samples will be taken. Imaging studies such as x-rays or magnetic resonance imaging scans will be performed.
  • Participants will provide white blood cells through leukapheresis. Researchers will attempt to isolate white blood cells that recognize MART
  • Seven days before the start of treatment, participants will have chemotherapy.
  • After the last dose of chemotherapy, participants will receive the MART reactive PBL cells. Filgrastim doses will also be given to help white blood cell counts return to normal. Participants will have frequent blood tests.
  • Participants who are able to have aldesleukin treatment will start within 24 hours after receiving the MART reactuve PBL cells. Treatment will continue for up to 5 days.
  • Participants may have an optional tumor or lymph node biopsy to study the effects of treatment.
  • If the tumor continues to grow after MART PBL treatment, participants may have one more round of cell collection and treatment.
  • Participants will have followup visits for up to 6 months after receiving the MART reactive PBL treatment.

Condition Intervention Phase
Mestatic Melanoma
Skin Cancer
Drug: Fludarabine
Drug: Cycolphosphamide
Drug: Aldesleukin
Drug: MART-1 Reactive CD8+ PBL
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase II Study in Patients With Metastatic Melanoma Using a Non-Myeloablative Lymphocyte Depleting Regimen of Chemotherapy Followed by Infusion of MART-1 Reactive Peripheral Blood Lymphocytes (PBL) With or Without High Dose Aldesleukin

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Determine whether autologous MART-1:27-35 reactive PBL infused with or without the administration of high-dose aldesleukin may result in clinical tumor regression. [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  • Determine the toxicity of this treatment regimen. [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • To determine the survival in patients, of infused cells following the administration of the non-myeloablative regimen, using analysis of the sequence of the variable region of the T cell receptor or flow cytometry (FACS). [ Time Frame: 3 years ] [ Designated as safety issue: No ]

Enrollment: 5
Study Start Date: December 2011
Study Completion Date: February 2014
Primary Completion Date: February 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: HD
Pts receiving high dose aldesleukin: Cyclophosphamide 60 mg/kg IV for days -7 and -6, Fludarabine 25 mg/m2 IV for days -5 to -1, plus MART-127-35 reactive CD8+ PBL up to 3x1011 IV over 20-30 minutes on day 0, plus aldesleukin 720,000 IU/kg IV over 15 minutes, every 8 hrs for up to 5 days.
Drug: Fludarabine
25 mg/m2 IV (in the vein) for 5 days(day -5 to -1)
Drug: Cycolphosphamide
60 mg/kg IV (in the vein) for days -7 and -6
Drug: Aldesleukin
Only given to patients assigned to Arm HD - 720,000 IU/kg IV over 15 minutes, every 8 hrs (+/- 1 hr) for up to 5 days (max 15 doses).-6
Drug: MART-1 Reactive CD8+ PBL
IV over 30 minutes on day 0
Experimental: PBL
Cyclophosphamide 60 mg/kg IV for days -7 and -6, Fludarabine 25 mg/m2 IV for days -5 to -1, plus MART-127-35 reactive CD8+ PBL up to 3x1011 IV over 20-30 minutes on day 0
Drug: Fludarabine
25 mg/m2 IV (in the vein) for 5 days(day -5 to -1)
Drug: Cycolphosphamide
60 mg/kg IV (in the vein) for days -7 and -6
Drug: MART-1 Reactive CD8+ PBL
IV over 30 minutes on day 0

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

-INCLUSION CRITERIA:

  1. Measurable metastatic melanoma.
  2. Confirmation of diagnosis of metastatic melanoma and positivity for MART confirmed by the Laboratory of Pathology of the NCI.
  3. Patients with 3 or less brain metastases are eligible. Note: If lesions are symptomatic or greater than or equal to 1 cm each, these lesions must have been treated and stable for 3 months for the patient to be eligible.
  4. Patients must be refractory to high dose aldesleukin treatment.

    NOTE: This is not required for patients with non-cutaneous melanoma, patients for whom high dose aldesleukin is medically contraindicated or for patients who are unwilling to receive high dose aldesleukin.

  5. MART-1:27-35 reactive peripheral blood lymphocytes derived from a leukapheresis.
  6. HLA-A 0201 positive.
  7. Greater than or equal to 18 years of age and less than or equal to age 70.
  8. Both genders must be willing to practice birth control during treatment and for four months after receiving the preparative regimen.
  9. Life expectancy of greater than three months.
  10. Willing to sign a durable power of attorney.
  11. Able to understand and sign the Informed Consent Document.
  12. Clinical performance status of ECOG 0 or 1 for the high-dose aldesleukin cohort or ECOG 0, 1 or 2 for no aldesleukin cohort.
  13. Hematology:

    • Absolute neutrophil count greater than 1000/mm(3) without support of filgrastim
    • Normal WBC (> 3000/mm(3)).
    • Hemoglobin greater than 8.0 g/dl
    • Platelet count greater than 100,000/mm(3).
  14. 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 or hepatitis C. If hepatitis C antibody test is positive, the patients must be tested for the presence of antigen by RT-PCR and be HCV RNA negative
  15. Chemistry:

    • Serum ALT/AST less than less or equal to 3 times the upper limit of normal.
    • Serum creatinine less than or equal to 1.6 mg/dl.
    • Total bilirubin less than or equal to 2.0 mg/dl, except in patients with Gilbert s Syndrome who must have a total bilirubin less than 3 mg/dl.
  16. More than four weeks must have elapsed since any prior systemic therapy, including chemotherapy, immunotherapy, and/or other targeted therapies, 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 may have undergone minor surgical procedures within the past 3 weeks, as long as patients meet eligibility criteria
  17. Six weeks must have elapsed from the time of any antibody therapy that could affect an anti cancer immune response, including anti-CTLA4 antibody therapy, so at the time the patient receives the preparative regimen to allow antibody levels to decline.
  18. Patients who have previously received ipilimumab and have documented GI toxicity must have a normal colonoscopy with normal colonic biopsies.

NOTE: this is only required for patients who will receive high dose aldesleukin.

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. Systemic steroid therapy required.
  3. Active systemic infections, coagulation disorders or other active major medical illnesses of the cardiovascular, respiratory or immune system, as evidenced by a positive stress thallium or comparable test, myocardial infarction, cardiac arrhythmias, obstructive or restrictive pulmonary disease.
  4. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
  5. 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.)
  6. History of severe immediate hypersensitivity reaction to any of the agents used in this study.
  7. The following patients will be excluded from the high-dose aldesleukin arm (but may be eligible for cells alone arm):

    1. History of coronary revascularization or ischemic symptoms
    2. Any patient known to have an LVEF less than or equal to 45 percent.
    3. Documented LVEF of less than or equal to 45 percent tested in patients with:

      • Clinically significant atrial and/or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, second or third degree heart block
      • Age greater than or equal to 60 years old
    4. Documented FEV1 less than or equal to 60 percent predicted tested in patients with:

      • A prolonged history of cigarette smoking (20 pk/yrs of smoking within the past 2 years)
      • Symptoms of respiratory dysfunction
    5. Clinically significant patient history which in the judgment of the Principal Investigator would compromise the patient s ability to tolerate aldesleukin
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01495572

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
Investigators
Principal Investigator: Udai S Kammula, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier: NCT01495572     History of Changes
Other Study ID Numbers: 120045, 12-C-0045
Study First Received: December 16, 2011
Last Updated: March 14, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Malignant Melanoma
Immunotherapy
Cell Therapy
HLA-A2 Positive
Skin Cancer

Additional relevant MeSH terms:
Skin Neoplasms
Melanoma
Neoplasms by Site
Neoplasms
Skin Diseases
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Nevi and Melanomas
Fludarabine
Fludarabine monophosphate
Aldesleukin
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents

ClinicalTrials.gov processed this record on April 17, 2014