Drosophila-generated CTL

Phase II Study of Metastatic Melanoma Using a Nonmyeloablative Lymphodepleting Regimen Followed by Melanoma-Reactive T-Cells Sensitized in Vitro With Peptide-Pulsed Drosophila Cells

Background:

• Recent cancer treatment studies have shown that altering a cancer patient's own white blood cells may help the immune system fight the cancer. In all of these studies, participants donate their own white blood cells through a procedure called leukapheresis, and the cells are altered in the laboratory and given back to the participants. After the cells are given, the patients receive aldesleukin (IL-2) to help the tumor fighting cells stay alive longer. For individuals with metastatic melanoma, pieces of melanoma proteins may be added to the collected white blood cells to help the immune system recognize and attack the cancer cells.
• Researchers are interested in testing a new process in which cells from fruit flies (Drosophila) are used to help the melanoma proteins attach to the white blood cells. The fruit fly cells die off shortly after the proteins are introduced to the white blood cells. Researchers are also interested in determining whether IL-2 treatment is necessary after this new cancer treatment process.

Objectives:

• To test the safety and effectiveness of modified white blood cells (Drosophila-generated CTL) as a treatment for metastatic melanoma that has not responded to standard treatments.
• To determine whether IL-2 treatment improves the effectiveness of Drosophila-generated cytolytic T lymphocytes (CTL).

Eligibility:

- Individuals at least 18 years of age who have been diagnosed with metastatic melanoma that has not responded to previous IL-2 treatment.

Design:

• Participants will be screened with a physical examination and medical history, tumor imaging studies, and heart and lung function tests.
• Prior to treatment, participants will have an intravenous catheter inserted into the chest to administer the study drugs.
• Participants will have leukapheresis to provide white blood cells for laboratory modification.
• Seven days before the start of the treatment, participants will be admitted to the hospital to have chemotherapy with cyclophosphamide and fludarabine. These drugs will suppress the immune system to improve the effects of the treatment.
• One to four days after the last dose of chemotherapy, participants will receive the modified cells. Participants in the group that will receive IL-2 will begin to receive the treatment 24 hours after the cell infusion, every day for 5 days. All participants will receive filgrastim injections to help the body produce more white blood cells.
• Participants will recover in the hospital for about 7 to 12 days after the cell infusion or the last dose of IL-2. Participants will continue to receive medications and provide blood and tumor samples for testing.
• Participants will have regular followup visits to assess the effects of the treatment.

Study Overview

• Status: Terminated
• Conditions: Metastatic Cutaneous Melanoma
• Intervention / Treatment: Drug: fludarabine; Drug: cyclophosphamide; Drug: Drosophila-peptide pulsed Melanoma-reactive autologous CD8+ PBL; Drug: Aldesleukin

Detailed Description

Background:

• Adoptive transfer studies in patients with metastatic melanoma following lymphodepletion have resulted in up to 50% objective response rates with a 10-15% rate of complete responses.
• A novel method involves the use of insect cell lines which do not express any native major histocompatibility complex (MHC) molecules.
• When stably transfected with human MHC molecules and appropriate adhesion and costimulatory molecules, a Drosophila cell line can potently stimulate tumor-reactivity in vitro from human peripheral blood lymphocytes (PBL).
• The current proposed transfer of Drosophila-cell stimulated autologous cluster of differentiation 8 (CD8) plus PBL administered in conjunction with a lymphodepleting preparative regimen, with or without low-dose aldesleukin would represent a significantly novel approach to adoptive immunotherapy.

Objectives:

• To determine whether infusion of CD8+ autologous PBL sensitized in vitro with peptide pulsed HLA-A2-expressing Drosophila cells (CTL-05) and administered in combination with a lymphodepleting preparative regimen and supportive systemic aldesleukin can result in clinical tumor regression in human leukocyte antigen serotype within HLA-A A serotype group (HLA-A2+) patients with metastatic melanoma.
• To determine the safety of the above regimen.
• To investigate the contribution of low-dose systemic aldesleukin to cell efficacy.

Eligibility:

Patients who are HLA-A*0201 positive and 18 years of age or older must have

• metastatic melanoma with measurable disease
• been previously treated with aldesleukin for melanoma;
• normal basic laboratory values.

Patients may not have:

• concurrent major medical illnesses;
• any form of primary or secondary immunodeficiency;
• requirement for systemic steroid therapy

Design:

• The first 20 patients enrolled (cohort 0) will receive a non-myeloablative lymphocyte depleting preparative regimen followed by administration of intravenous CTL-05 and low-dose subcutaneous aldesleukin (daily for 5 days).
• If 3 or more of the 20 patients respond, subsequent patients will be randomized between two cohorts. Patients in cohort 1 will receive a non-myeloablative lymphocyte depleting preparative regimen followed by administration of CTL-05 and low-dose subcutaneous aldesleukin (daily for 5 days). Patients in Cohort 2 will receive a non-myeloablative lymphocyte depleting preparative regimen followed by administration of CTL-05 and NO subsequent aldesleukin.
• A complete evaluation will be conducted 8 weeks (plus or minus 2 weeks) after the initiation of chemotherapy. The trial will be conducted using a small Simon MinMax Phase II design in the initial phase and a Simon optimal design in the second phase. A maximum of 35 patients may be accrued to each of cohorts 1 and 2. If no responses are seen in the first 13 patients receiving no systemic aldesleukin, then accrual to that cohort will cease. Total enrollment may be up to 90 patients.

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center, 9000 Rockville Pike

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

• INCLUSION CRITERIA:

  1. Metastatic cutaneous melanoma with measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria
  2. Previously received high dose-aldesleukin and have been either non-responders (progressive disease) or have recurred.
  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. Greater than or equal to 18 years of age.
  5. Able to understand and sign the Informed Consent Document
  6. Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1.
  7. Life expectancy of greater than three months.
  8. Patients of both genders must be willing to practice a highly effective method of birth control during and for four months following treatment
  9. Patients must be HLA-A*0201 positive

  10. Serology:

      1. 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.)
      2. Seronegative for hepatitis B antigen and hepatitis C antibody unless antigen negative.

  11. Hematology:

      1. Absolute neutrophil count greater than 1000/mm^3 without the support of filgrastim.
      2. White blood cell (WBC) (> 3000/mm^3).
      3. Platelet count greater than 100,000/mm^3.
      4. Hemoglobin greater than 8.0 g/dl.

  12. Chemistry:

      1. Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) less or equal to 2.5 times the upper limit of normal.
      2. Serum creatinine less than or equal to 1.6 mg/dl.
      3. 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.
  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 hypothyroidism, alopecia, or vitiligo).
  14. Six weeks must have elapsed since prior anti-CTLA4 antibody therapy to allow antibody levels to decline.
  15. Patients who have previously received anti-CTLA4 antibody must have a normal colonoscopy with normal colonic biopsies.

EXCLUSION CRITERIA:

1. Active systemic infections, coagulation disorders or other active major medical illnesses.
2. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
3. 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).
4. Requirement for systemic steroid therapy
5. History of severe immediate hypersensitivity reaction to any of the agents used in this study.
6. History of coronary revascularization or ischemic symptoms
7. Any patient known to have an left ventricular ejection fraction (LVEF) less than or equal to 45%.

8. Documented LVEF of less than or equal to 45% tested in patients with:

   1. Clinically significant atrial and/or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, second or third degree heart block
   2. Age greater than or equal to 60 years old

9. Documented forced expiratory volume 1 (FEV1) less than or equal to 60% predicted tested in patients with:

   1. A prolonged history of cigarette smoking (20 pk/yrs of smoking)
   2. Symptoms of respiratory dysfunction
10. Pregnant or nursing women

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 0; Drosophila generated CTL + SQ IL-2 Drug: 1 fludarabine, cyclophosphamide, Drosophila-peptide pulsed Melanoma-reactive autologous CD8+ peripheral blood lymphocytes (PBL) (CTL-05), aldesleukin Fludarabine 25 mg/m^2 x 5 days Cyclophosphamide 60 mg/kg intravenous (IV) x2 days, Up to 1x10e10 CTL-05 cells Aldesleukin 125,000 IU/kg/dose as a daily subcutaneous injection	Drug: fludarabine; Fludarabine 25 mg/m^2 x 5 days; Other Names: Fludara; Drug: cyclophosphamide; Cyclophosphamide 60 mg/kg intravenous (IV) x 2 days; Other Names: Cytoxan; Drug: Drosophila-peptide pulsed Melanoma-reactive autologous CD8+ PBL; Up to 1x10e10 CTL-05 cells; Drug: Aldesleukin; Aldesleukin 125,000 IU/kg/dose as a daily subcutaneous injection; Other Names: IL-2
Experimental: Cohort 1; 2 Experimental Lymphodepleting regimen +Cells+Low dose IL-2 Drug: 2 fludarabine, cyclophosphamide, Drosophila-peptide pulsed Melanoma-reactive autologous CD8+ peripheral blood lymphocytes (PBL), aldesleukin Fludarabine 25 mg/m^2 x 5 days Cyclophosphamide 60 mg/kg intravenous (IV) x2 days, Up to 1x10e10 CTL-05 cells Aldesleukin 125,000 IU/kg/dose as a daily subcutaneous injection	Drug: fludarabine; Fludarabine 25 mg/m^2 x 5 days; Other Names: Fludara; Drug: cyclophosphamide; Cyclophosphamide 60 mg/kg intravenous (IV) x 2 days; Other Names: Cytoxan; Drug: Drosophila-peptide pulsed Melanoma-reactive autologous CD8+ PBL; Up to 1x10e10 CTL-05 cells; Drug: Aldesleukin; Aldesleukin 125,000 IU/kg/dose as a daily subcutaneous injection; Other Names: IL-2
Experimental: Cohort 2; 1 Experimental Lymphodepleting regimen +Cells Drug: 3 fludarabine, cyclophosphamide, Drosophila-peptide pulsed Melanoma-reactive autologous CD8+ peripheral blood lymphocytes (PBL) Fludarabine 25 mg/m^2 x 5 days Cyclophosphamide 60 mg/kg intravenous (IV) x2 days, Up to 1x10e10 CTL-05 cells	Drug: fludarabine; Fludarabine 25 mg/m^2 x 5 days; Other Names: Fludara; Drug: cyclophosphamide; Cyclophosphamide 60 mg/kg intravenous (IV) x 2 days; Other Names: Cytoxan; Drug: Drosophila-peptide pulsed Melanoma-reactive autologous CD8+ PBL; Up to 1x10e10 CTL-05 cells; Drug: Aldesleukin; Aldesleukin 125,000 IU/kg/dose as a daily subcutaneous injection; Other Names: IL-2

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Response	Clinical response is assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Complete response (CR) is a disappearance of all target lesions. Partial response (PR) is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD. Progression disease (PD) is at least a 20 % increase in the sum of the LD of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more lesions. Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as references the smallest sum LD.	7 months
Safety of Drosophila Generated PBL Administered in Combination With a Lymphodepleting Preparative Regimen and Supportive Systemic Aldesleukin	Here is the number of participants with adverse events. For a detailed list of adverse events see the adverse event module.	7 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Investigate Low-dose Systemic Aldesleukin to Cell Efficacy	Low-dose systemic aldesleukin will be evaluated to determine cell activity in metastatic melanoma.	7 months

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: James Yang, M.D., National Cancer Institute (NCI)

Publications and helpful links

General Publications

• Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, Royal RE, Kammula U, White DE, Mavroukakis SA, Rogers LJ, Gracia GJ, Jones SA, Mangiameli DP, Pelletier MM, Gea-Banacloche J, Robinson MR, Berman DM, Filie AC, Abati A, Rosenberg SA. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol. 2005 Apr 1;23(10):2346-57. doi: 10.1200/JCO.2005.00.240.
• Balch CM, Soong SJ, Gershenwald JE, Thompson JF, Reintgen DS, Cascinelli N, Urist M, McMasters KM, Ross MI, Kirkwood JM, Atkins MB, Thompson JA, Coit DG, Byrd D, Desmond R, Zhang Y, Liu PY, Lyman GH, Morabito A. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol. 2001 Aug 15;19(16):3622-34. doi: 10.1200/JCO.2001.19.16.3622.
• Smith FO, Downey SG, Klapper JA, Yang JC, Sherry RM, Royal RE, Kammula US, Hughes MS, Restifo NP, Levy CL, White DE, Steinberg SM, Rosenberg SA. Treatment of metastatic melanoma using interleukin-2 alone or in conjunction with vaccines. Clin Cancer Res. 2008 Sep 1;14(17):5610-8. doi: 10.1158/1078-0432.CCR-08-0116.

Study record dates

Study Major Dates

• Study Start (Actual): April 15, 2011
• Primary Completion (Actual): December 8, 2011
• Study Completion (Actual): December 8, 2011

Study Registration Dates

• First Submitted: January 6, 2011
• First Submitted That Met QC Criteria: January 6, 2011
• First Posted (Estimate): January 7, 2011

Study Record Updates

• Last Update Posted (Actual): August 1, 2017
• Last Update Submitted That Met QC Criteria: July 3, 2017
• Last Verified: July 1, 2017

More Information

Terms related to this study

• Keywords: Immunotherapy; Skin Cancer; Melanoma; Malignancy; Metastatic Melanoma; Melanoma Peptides
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Anti-HIV Agents; Anti-Retroviral Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Aldesleukin; Cyclophosphamide; Fludarabine
• Other Study ID Numbers: 110052; 11-C-0052

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No