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History of Changes for Study: NCT00924001
Chemotherapy Followed by Infusion of DMF5 Cells to Treat Metastatic Melanoma
Latest version (submitted October 18, 2012) on ClinicalTrials.gov
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Study Record Versions
Version A B Submitted Date Changes
1 June 17, 2009 None (earliest Version on record)
2 July 22, 2009 Eligibility and Study Status
3 August 24, 2009 Study Status
4 September 2, 2009 Study Description and Study Status
5 September 9, 2009 Study Status
6 September 16, 2009 Sponsor/Collaborators and Study Status
7 November 25, 2009 Study Design and Study Status
8 February 3, 2010 Study Status and Study Description
9 May 25, 2010 Study Status
10 June 8, 2010 Study Status and Study Description
11 June 16, 2010 Study Status
12 July 7, 2010 Study Status
13 September 17, 2010 References and Study Status
14 October 27, 2010 Recruitment Status, Study Status, Contacts/Locations, Study Design and References
15 May 7, 2012 Recruitment Status, Study Status, Outcome Measures, Arms and Interventions, Study Description, Oversight, Results, Contacts/Locations, Eligibility and Study Design
16 October 18, 2012 Study Status and Arms and Interventions
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Study NCT00924001
Submitted Date:  June 17, 2009 (v1)

Open or close this module Study Identification
Unique Protocol ID: 070210
Brief Title: Chemotherapy Followed by Infusion of DMF5 Cells to Treat Metastatic Melanoma
Official Title: Phase I/II Study Using a Non-Myeloablative Lymphocyte Depleting Regimen of Chemotherapy Followed by Infusion of Allogeneic Tumor-Reactive Lymphocyte Cell Line DMF5 in Metastatic Melanoma
Secondary IDs: 07-C-0210
Open or close this module Study Status
Record Verification: March 2009
Overall Status: Recruiting
Study Start: August 2007
Primary Completion: May 2009 [Anticipated]
Study Completion: May 2009 [Anticipated]
First Submitted: June 17, 2009
First Submitted that
Met QC Criteria:
June 17, 2009
First Posted: June 18, 2009 [Estimate]
Last Update Submitted that
Met QC Criteria:
June 17, 2009
Last Update Posted: June 18, 2009 [Estimate]
Open or close this module Sponsor/Collaborators
Sponsor: National Cancer Institute (NCI)
Responsible Party:
Collaborators:
Open or close this module Oversight
U.S. FDA-regulated Drug:
U.S. FDA-regulated Device:
Data Monitoring:
Open or close this module Study Description
Brief Summary:

Background:

  • This study will use cells called DMF5 to treat patients with metastatic melanoma (melanoma that has spread beyond the primary tumor site).
  • The DMF5 cells were first obtained from a tumor of a patient with melanoma with HLA-A201 tissue type. The tumor cells were grown in the laboratory, and when the laboratory-grown cells were given back to the patient, the patient's tumors shrank dramatically. In laboratory tests, DMF5 cells were also shown to shrink mouse melanoma tumors.

Objectives:

-To determine whether preparatory chemotherapy followed by infusion of DMF5 cells is a safe and effective for shrinking melanoma tumors.

Eligibility:

-Patients with metastatic melanoma and tissue type HLA-A201who are 18 years of age or older.

Design:

  • Patients have a preparatory regimen of chemotherapy with cyclophosphamide and fludarabine followed by infusion of DMF5 cells and then high-dose interleukin. The chemotherapy, interleukin and cells are given intravenously (through a vein).
  • Patients have frequent blood tests to look for the side effects and response to treatment.
  • Patients may be asked to have a tumor biopsy (surgical removal of a small piece of tumor tissue) to examine the effects of treatment on the immune cells in the tumor.
  • Patients have a physical examination, CT of the chest, abdomen and pelvis and laboratory tests 4 to 6 weeks after treatment and then monthly to evaluate the tumor.
  • The first group of patients participates in the Phase I portion of the study, called the dose escalation phase. This phase will determine the highest safe dose of DMF5 cells. There will be three dose levels of DMF5 cells, with the first patients enrolled getting the smallest dose and then increasing the dose when the preceding level has been shown to be safe.
  • Patients in the Phase II portion of the study receive DMF5 cells at the highest dose found to be safe in Phase I, to test the effectiveness of the treatment....
Detailed Description:

Background:

In previous trials in the Surgery Branch, a 51 percent objective response rate has been observed in heavily pre-treated patients with metastatic melanoma undergoing adoptive cell transfer therapy utilizing a non-myeloablative preparative regimen followed by administration of autologous tumor-reactive lymphocytes and subsequent treatment with high-dose aldesleukin.

However, in patients with metastatic melanoma undergoing metastasectomy, recovery of adequate numbers of tumor specific T lymphocytes from surgical specimens is possible in approximately half of all patients, thus limiting the application of adoptive cell transfer therapy.

Murine models performed in the Surgery Branch have demonstrated solid tumor regression in mice treated with allogeneic tumor specific T cells combined with a preinfusion lymphodepleting regimen.

We have identified a tumor specific lymphocyte cell line (DMF5) used previously in an autologous adoptive cell transfer protocol that was associated with an objective clinical response in that patient.

In subsequent preclinical testing of this lymphocyte population, we have demonstrated high specificity against HLA-A 0201 positive melanoma cell lines as well as the common shared melanocyte differentiation antigen MART-1:27-35. We have expanded this lymphocyte population to provide up to 30 individual allogeneic cell transfers to HLAA 0201 positive patients with metastatic melanoma.

In this trial we want to test our hypothesis that objective tumor regression can be achieved with the DMF5 allogeneic T-cell product using a non-myeloablative regimen followed by cell transfer and high-dose aldesleukin.

It should be emphasized that this protocol is designed to test whether highly melanoma reactive allogeneic lymphocytes can mediate cancer regresssion. The DMF5 cell line is a limited reagent only available for the treatment of up to 30 patients. However, if this treatment results in cancer regression, it will represent an important step in our development of an allogeneic T-cell recepter engineered universal effector cell line for the treatment of patients with cancer.

Objectives:

To evaluate the safety of the administration of the DMF5 allogeneic T-cell product in patients receiving the non- myeloablative conditioning regimen, and aldesleukin.

To determine whether this allogeneic tumor-specific lymphocyte cell line, hereafter referred to as DMF5, infused in conjunction with the administration of high-dose aldesleukin may result in objective clinical tumor regression in eligible HLA-A 0201 positive patients with metastatic melanoma receiving a non-myeloablative lymphoid depleting preparative regimen.

To determine the in vivo survival of the infused cells following the non-myeloablative regimen, via analysis of the sequence of the variable region of the T cell receptor or flow cytometry (FACS).

Eligibility:

Patients with metastatic melanoma who are greater than or equal to 18 years of age, HLA-A 0201 positive, do not have suitable autologous tumor reactive TIL cells available, and are able to tolerate high-dose aldesleukin.

Design:

Patients will receive a non-myeloablative lymphocyte depleting preparative regiment consisting of cyclophosphamide (60 mg/kg/day x 2 days IV) and fludarabine (25 mg/m2/day IV x 5 days).

Patients will receive intravenous adoptive transfer of the tumor reactive lymphocyte cell line DMF5 (after its expansion in interleukin-2 and OKT3) followed by high-dose intravenous (IV) aldesleukin (720,000 IU/kg/dose every 8 hours for up to 15 doses).

Patients will undergo complete evaluation of tumor with physical examination, CT of the chest, abdomen, and pelvis and clinical laboratory evaluation four to six weeks after treatment and then monthly for approximately 3 to 4 months or until off study criteria are met. The study will be conducted using a Phase I/II optimal design. The protocol will proceed in a phase 1 dose escalation design, with three cohorts. Should a single patient experience a dose limiting toxicity at a particular dose level, three more patients would be treated at that dose to confirm that no greater than 1/6 patients have a DLT prior to proceeding to the next higher level. If a level with 2 or more DLTs in 3-6 patients has been identified, three additional patients will be accrued at the next lowest dose, for a total of 6, in order to further characterize the safety of the maximum tolerated dose prior to starting the phase II portion. If a dose limiting toxicity occurs in the first cohort, that cohort will be expanded to 6 patients. If 2 DLTs are encountered in this cohort, the study will be terminated.

Open or close this module Conditions
Conditions: Melanoma
Malignant Melanoma
Melanoma, Experimental
Keywords: Clinical Response
Immunotherapy
Cancer
Cytokines
Adoptive Cell Therapy
Melanoma
Metastatic Melanoma
Open or close this module Study Design
Study Type: Interventional
Primary Purpose: Treatment
Study Phase: Phase 1/Phase 2
Interventional Study Model: Single Group Assignment
Number of Arms:
Masking: None (Open Label)
Allocation: Non-Randomized
Enrollment: 30
Open or close this module Arms and Interventions
Intervention Details:
Drug: DMF5 Melanoma Reactive TIL
Drug: Cyclophosphamide
Drug: Fludarabine
Drug: Aldesleukin
Open or close this module Outcome Measures
Primary Outcome Measures:
1. Clinical response according to RECIST criteria and toxicity.
Secondary Outcome Measures:
1. Determine the rate of repopulation of young TIL cells and establish correlates that predict in vivo persistence and clinical response.
Open or close this module Eligibility
Minimum Age: 18 Years
Maximum Age:
Sex: All
Gender Based:
Accepts Healthy Volunteers: No
Criteria:

-INCLUSION CRITERIA:

  1. Measurable metastatic melanoma that is refractory to standard treatment including high dose aldesleukin.
  2. Unsuitable autologous cells for IRB approved Surgery Branch adoptive cell therapy studies.
  3. Greater than or equal to 18 years of age.
  4. Life expectancy of greater than three months.
  5. Willing to sign a durable power of attorney.
  6. Able to understand and sign the Informed Consent Document.
  7. HLA-A 0201 positive.
  8. Willing to practice birth control during treatment and for four months after receiving the preparative regimen.
  9. Clinical performance status of ECOG 0 or 1.
  10. Hematology:
    • Absolute neutrophil count greater than 1000/mm(3) without support of filgrastim.
    • WBC greater than 3000/mm(3).
    • Hemoglobin greater than 8.0 g/dl.
    • Platelet count greater than 100,000/mm(3).
  11. 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 hepatitis C antibody unless antigen negative.
    • Women of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the preparative chemotherapy on the fetus.
  12. Chemistry:
    • Serum ALT/AST less than three 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 3.0 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).
  14. Six weeks must have elapsed since prior MDX-010 therapy to allow antibody levels to decline.
  15. Patients who have previously received MDX-010 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 preparative chemotherapy on the fetus or infant.
  2. Active systemic infections, coagulation disorders or other major medical illnesses of the cardiovascular, respiratory or immune system, myocardial infarction, cardiac arrhythmias, obstructive or restrictive pulmonary disease.
  3. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
  4. Opportunistic infections (The experimental treatment being evaluated in his 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. Symptomatic CNS lesions (Patients maybe eligible after treatment of their symptomatic lesions.)
  6. Systemic steroid therapy.
  7. History of severe immediate hypersensitivity reaction to any of the agents used in this study.
  8. History of coronary revascularization or ischemic symptoms.
  9. Patients with a prolonged (greater than 20 pk/yrs) history of cigarette smoking or symptoms of respiratory dysfunction with PFT's indicating an FEV1 less than 60 percent predicted for age.
  10. Patients with a history of clinically significant atrial and/or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, heart block or greater than or equal to age 60 with an LEVF of less than 45 percent on cardiac evaluation (echocardiogram, MUGA, etc.) will be excluded.
  11. Positive allo-specific reactivity of the DMF5 cells to the patient's PBMC.
  12. Documented penicillin allergy.
Open or close this module Contacts/Locations
Central Contact Person: Recruitment Center - SB
Telephone: (866) 820-4505
Email: ncisbirc@mail.nih.gov
Locations: United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
[Recruiting]
Bethesda, Maryland, United States, 20892
Open or close this module IPDSharing
Plan to Share IPD:
Open or close this module References
Citations: Mills CD, North RJ. Expression of passively transferred immunity against an established tumor depends on generation of cytolytic T cells in recipient. Inhibition by suppressor T cells. J Exp Med. 1983 May 1;157(5):1448-60. PubMed 6189937
Fernandez-Cruz E, Woda BA, Feldman JD. Elimination of syngeneic sarcomas in rats by a subset of T lymphocytes. J Exp Med. 1980 Oct 1;152(4):823-41. PubMed 6968337
Greenberg PD, Kern DE, Cheever MA. Therapy of disseminated murine leukemia with cyclophosphamide and immune Lyt-1+,2- T cells. Tumor eradication does not require participation of cytotoxic T cells. J Exp Med. 1985 May 1;161(5):1122-34. PubMed 3921652
Links: Description: NIH Clinical Center Detailed Web Page
Available IPD/Information:

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