Lymphodepletion Plus Adoptive Cell Transfer With or Without Dendritic Cell Immunization in Patients With Metastatic Melanoma

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2016 by M.D. Anderson Cancer Center
Sponsor:
Collaborators:
Prometheus Laboratories
Key Biologics, LLC
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier:
NCT00338377
First received: February 10, 2006
Last updated: February 10, 2016
Last verified: February 2016
  Purpose

Objectives:

The primary objective will be to determine whether patients receiving the combination of dendritic cells and high dose IL-2 have sustained persistence of infused T cells compared to patients treated with T cells and high dose IL-2 alone.

Secondary endpoints will include evaluations for tumor response and studies to determine whether dendritic cells enhance the infused T cells in anti-tumor activity and their ability to migrate to the tumor site. In addition, we will evaluate the characteristics of the infused T cells that correspond with effectiveness in vivo.

Cohort C:

The primary endpoint will be the overall response rate of TIL treatment for patients who have not achieved PR or CR or have progressive disease from treatment of the BRAF inhibitor alone.

Cohort D:

The primary objective of Cohort D is to confirm the safety of adoptively transferred, TIL into the CSF. The secondary objective is the evaluation of clinical imaging and CSF response. Correlative s objectives will assess if the intrathecally-infused T cells persist in the CSF, assess circulating tumor cells in the CSF, and assess various cytokine and other analyses, as feasible.


Condition Intervention Phase
Melanoma
Biological: Dendritic Cell Immunization
Drug: Cyclophosphamide
Drug: Fludarabine
Biological: T-Cells
Biological: Interleukin-2
Drug: Mesna
Biological: Intrathecal T-Cells
Biological: Intrathecal Interleukin-2
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Lymphodepletion Plus Adoptive Cell Transfer With or Without Dendritic Cell Immunization in Patients With Metastatic Melanoma

Resource links provided by NLM:


Further study details as provided by M.D. Anderson Cancer Center:

Primary Outcome Measures:
  • Objective Response (OR) [ Time Frame: Clinical Evaluation during first 70 Days, CT Scan at 6-8 weeks (+/- 7 days) after cell infusion. ] [ Designated as safety issue: No ]
    Objective response (OR) defined as immune-related Best Overall Response (irBOR). irBOR is best confirmed immune-related response criteria (irRC) overall response over the study as a whole, recorded between the date of first dose until the last tumor assessment before subsequent therapy (except for local palliative radiotherapy for painful bone lesions) for the individual subjects in the study.

  • Longitudinal Immune Response [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
    Longitudinal immune response defined as: Conversion of positive to negative cytology. Any perceptible improvement of the MRI findings confirmed by radiologist and/or the investigator confirmed by 2 successive MRIs 4 weeks apart. Any clinical improvement in terms of neurological symptoms.


Estimated Enrollment: 189
Study Start Date: February 2006
Estimated Primary Completion Date: February 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Group A: Chemotherapy + IL-2 plus T-cells
Cyclophosphamide 60 mg/kg/d by vein (IV) over 2 hours Days -7 and -6 (with Mesna) and Fludarabine 25 mg/m^2 IV daily Days -5 to -1 before T cell infusion. On Day 0, up to 1.5 x 10^11 T cells IV infusion over 30-60 minutes. Interleukin-2 12-16 hours after T cell infusion at standard dose of 720,000 IU/kg as intravenous bolus over 15 minute period every 8-16 hours for up to 15 doses on Days 1-5 and 22-26.
Drug: Cyclophosphamide
60 mg/kg/d by vein over 2 hours on Days -7 and -6 before T cell infusion
Other Names:
  • Cytoxan
  • Neosar
Drug: Fludarabine
25 mg/m^2 by vein daily over 30 minutes on Days -5 to -1 before T cell infusion.
Other Names:
  • Fludarabine Phosphate
  • Fludara
Biological: T-Cells
On Days 0, up to 1.5 x 10^11 T-cells by vein infusion over 30-60 minutes.
Biological: Interleukin-2
12-16 hours after completing the T cell infusion, all will receive high dose IL-2 on an inpatient basis at the standard dose of 720,000 IU/kg as an intravenous bolus over approximately a 15 minute period every 8-16 hours for up to 15 doses on Days 1-5 and 22-26 (+/- 7 days), as tolerated.
Other Names:
  • IL-2
  • Proleukin
Drug: Mesna
60 mg/kg with D5W or NS at 125 ml/hr infused intravenously over 24 hours on Day -7 and -6.
Other Names:
  • Sodium 2-mercaptoethanesulfonate
  • Mesnum
  • Mesnex
  • NSC-113891
Experimental: Group B: Chemotherapy + IL-2 plus T-Cells + Vaccine
Chemotherapy and IL-2 plus T-cells and the vaccine of dendritic cells received by vein (IV) about 4 hours after T-cells and again on Day 21 (+/- 7 days). Cyclophosphamide 60 mg/kg/d IV over 2 hours Days -7 and -6 (with Mesna) and Fludarabine 25 mg/m^2 IV daily Days -5 to -1 before T cell infusion. On Day 0, up to 1.5 x 10^11 T cells IV infusion over 30-60 minutes. Interleukin-2 12-16 hours after T cell infusion at standard dose of 720,000 IU/kg as intravenous bolus over 15 minute period every 8-16 hours for up to 15 doses on Days 1-5 and 22-26.
Biological: Dendritic Cell Immunization
1x10^7 to 2.5x10^8 MART-1 peptide-pulsed Dendritic Cells given by vein over 20-30 minutes approximately 4 hrs after receiving T cells.
Drug: Cyclophosphamide
60 mg/kg/d by vein over 2 hours on Days -7 and -6 before T cell infusion
Other Names:
  • Cytoxan
  • Neosar
Drug: Fludarabine
25 mg/m^2 by vein daily over 30 minutes on Days -5 to -1 before T cell infusion.
Other Names:
  • Fludarabine Phosphate
  • Fludara
Biological: T-Cells
On Days 0, up to 1.5 x 10^11 T-cells by vein infusion over 30-60 minutes.
Biological: Interleukin-2
12-16 hours after completing the T cell infusion, all will receive high dose IL-2 on an inpatient basis at the standard dose of 720,000 IU/kg as an intravenous bolus over approximately a 15 minute period every 8-16 hours for up to 15 doses on Days 1-5 and 22-26 (+/- 7 days), as tolerated.
Other Names:
  • IL-2
  • Proleukin
Drug: Mesna
60 mg/kg with D5W or NS at 125 ml/hr infused intravenously over 24 hours on Day -7 and -6.
Other Names:
  • Sodium 2-mercaptoethanesulfonate
  • Mesnum
  • Mesnex
  • NSC-113891
Experimental: Group C: Prior Treatment with BRAF Inhibitor
Chemotherapy and IL-2 plus T-cells and the vaccine of dendritic cells received by vein (IV) about 4 hours after T-cells and again on Day 21 (+/- 7 days). Cyclophosphamide 60 mg/kg/d IV over 2 hours Days -7 and -6 (with Mesna) and Fludarabine 25 mg/m^2 IV daily Days -5 to -1 before T cell infusion. On Day 0, up to 1.5 x 10^11 T cells IV infusion over 30-60 minutes. Interleukin-2 12-16 hours after T cell infusion at standard dose of 720,000 IU/kg as intravenous bolus over 15 minute period every 8-16 hours for up to 15 doses on Days 1-5 and 22-26.
Biological: Dendritic Cell Immunization
1x10^7 to 2.5x10^8 MART-1 peptide-pulsed Dendritic Cells given by vein over 20-30 minutes approximately 4 hrs after receiving T cells.
Drug: Cyclophosphamide
60 mg/kg/d by vein over 2 hours on Days -7 and -6 before T cell infusion
Other Names:
  • Cytoxan
  • Neosar
Drug: Fludarabine
25 mg/m^2 by vein daily over 30 minutes on Days -5 to -1 before T cell infusion.
Other Names:
  • Fludarabine Phosphate
  • Fludara
Biological: T-Cells
On Days 0, up to 1.5 x 10^11 T-cells by vein infusion over 30-60 minutes.
Biological: Interleukin-2
12-16 hours after completing the T cell infusion, all will receive high dose IL-2 on an inpatient basis at the standard dose of 720,000 IU/kg as an intravenous bolus over approximately a 15 minute period every 8-16 hours for up to 15 doses on Days 1-5 and 22-26 (+/- 7 days), as tolerated.
Other Names:
  • IL-2
  • Proleukin
Drug: Mesna
60 mg/kg with D5W or NS at 125 ml/hr infused intravenously over 24 hours on Day -7 and -6.
Other Names:
  • Sodium 2-mercaptoethanesulfonate
  • Mesnum
  • Mesnex
  • NSC-113891
Experimental: Group D: Leptomeningeal Disease

T-cells: 5.0x109 TIL administered on Day 1 and 10x109 TIL on Day 15.

IL-2: 1.2 MIU of IL- 2 on Days 2, 4, 9, 11, 16 and 18 as tolerated. After this period, patient receives twice weekly IL-2 that will be gradually changed to weekly IL-2. After 4-6 weeks, patients switched to IL-2.

Biological: Intrathecal T-Cells
5.0x109 T-cells administered on Day 1, and 10x109 T-cells on Day 15. 1.2 MIU of IL- 2 on Day 2, 4, 9, 11, 16 and 18 as tolerated.
Biological: Intrathecal Interleukin-2
1.2 MIU of IL- 2 on Day 2, 4, 9, 11, 16 and 18 as tolerated. Then, patient receives twice weekly IL-2 that will be gradually changed to weekly IL-2. After 4-6 weeks patients switched to IL-2 maintenance.
Other Name: IL-2

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   12 Years and older   (Child, Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Patients must have metastatic melanoma or stage III in-transit or regional nodal disease. (Turnstile I)
  2. Patients must receive an MRI/CT of the brain or PET/CT within 6 months of consenting. If new lesions are present, PI or his designee should make final determination regarding enrollment. (Turnstile I)
  3. Age greater than or equal to 12 years. (Turnstile I)
  4. Clinical performance status of ECOG 0-2. (Turnstile I)
  5. Patients previously treated with immunotherapy, targeted therapy, or no therapy will be eligible. Patients receiving cytotoxic agents will be evaluated by the PI or his designee as to suitable eligibility. (Turnstile I)
  6. Patients must be HLA-A2 for cohort A. (Turnstile II-Chemotherapy/Cell Infusion-Inclusion Criteria)
  7. Patients must have adequate TIL available. (Turnstile II)
  8. Patients must have measurable metastatic melanoma. (Turnstile II - Chemotherapy/Cell Infusion -Inclusion Criteria).
  9. Patients may have brain lesions which measure </= 1cm each. Lesions that are >1 cm that have been treated with SRS and in the opinion of the PI or his designee no longer represents active disease will also be allowed. (Turnstile II - Chemotherapy/Cell Infusion- Inclusion Criteria).
  10. Patients of both genders must practice birth control for four months after receiving the preparative regimen. (Turnstile II - Chemotherapy/Cell Infusion- Inclusion Criteria).
  11. Patients must have a documented negative pregnancy test (urine or serum) for women who have menstruation in the past 12 months and without sterilization surgery.
  12. Unless surgically sterile by bilateral tubal ligation or vasectomy of partner(s), the patient agrees to continue to use a barrier method of contraception throughout the study such as: condom, diaphragm, hormonal, IUD, or sponge plus spermicide. Abstinence is an acceptable form of birth control. (Turnstile II)
  13. Pregnancy testing will be performed within 7 days prior to treatment. (Turnstile II)
  14. Clinical performance status of ECOG 0 - 2 at the time of chemotherapy infusion. (Turnstile II - Chemotherapy/Cell Infusion-Inclusion Criteria).
  15. Absolute neutrophil count greater than or equal to 750/mm3. (Turnstile II - Chemotherapy/Cell Infusion- Inclusion Criteria).
  16. Platelet count greater than or equal to 75,000/mm3. (Turnstile II - Chemotherapy/Cell Infusion- Inclusion Criteria).
  17. Hemoglobin greater than or equal to 8.0 g/dl. (Turnstile II - Chemotherapy/Cell Infusion).
  18. Serum ALT less than three times the upper limit of normal. (Turnstile II - Chemotherapy/Cell Infusion- Inclusion Criteria).
  19. Serum creatinine less than or equal to 1.6 mg/dl. (Turnstile II - Chemotherapy/Cell Infusion-Inclusion Criteria).
  20. 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. (Turnstile II - Chemotherapy/Cell Infusion - Inclusion Criteria).
  21. Patients in Cohort A will be randomized to receive either TIL alone or TIL plus Dendritic cells.
  22. A stress cardiac test (stress thallium, stress MUGA, dobutamine echocardiogram or other stress test that will rule out cardiac ischemia) within 6 months of lymphodepletion. (Turnstile II - Chemotherapy/Cell Infusion-Inclusion Criteria).
  23. Pulmonary function tests (FEV1>65% or FVC>65%of predicted) within 6 months of lymphodepletion. (Turnstile II - Chemotherapy/Cell Infusion - Inclusion Criteria).
  24. MRI/CT of the brain within 42 days of lymphodepletion. CT scan of chest/abdomen/pelvis or PET/CT within 30 days of lymphodepletion. Exception: Patients randomized to receive dendritic cells may have an MRI of the brain within 30 days of lymphodepletion. (Turnstile II-Chemotherapy/Cell Infusion-Inclusion Criteria)
  25. Patients must be receiving a B-RAF inhibitor and failed to achieve PR or CR or have progressive disease in response to B-RAF treatment (Cohort C).
  26. i. Patients with MRI evidence of LMD, with or without evidence of malignant cells in CSF ("positive cytology"), or ii. Patients with evidence of malignant cells in the CSF (positive cytology), with or without MRI evidence of LMD, or iii. Patients with surgically-proven LMD (leptomeningeal involvement on pathology review) +/- MRI or CSF evidence by MRI or CSF cytology (Cohort D)
  27. a. Many patients present with concomitant systemic disease outside of the central nervous system. Extra-CNS disease status should meet the following criteria: i. Patients with concomitant systemic disease under control with current or prior systemic treatment, as per primary treating physician ii. Patients without any evidence of systemic disease, either receiving systemic treatment or on active observation (Cohort D)
  28. c. Previous Therapies i. Patients who are currently being treated with IT IL-2 for LMD are eligible. No wash out period is required. ii. Patients who have been previously treated with other IT therapies are eligible, as long as there is at least a 2 week wash out period iii. Patients who have previously received therapy with systemic TIL therapy are eligible.
  29. (contd #28) iv. Patients with VP shunts must have VP shunts with on/off valves and must be expected to tolerate VP shunt valve off for more than 6 hours Patients who have received CNS irradiation, including whole brain radiation or stereotactic radiosurgery, are eligible, if they are at least 1 weeks post CNS-irradiation (Cohort D)Patients who are currently being treated with IT IL-2 for LMD are eligible. No wash out period is required. (Cohort D)
  30. d. Other Requirements i. Patients must be able to give informed consent ii. Patients must have ECOG performance status 0, 1 or 2 and/or KPS > 50 iii. Patients must be able to swallow iv. Patients must be able to sit up with or without assistance v. Patients must be able to undergo contrast-enhanced MRI. (Cohort D)

Exclusion Criteria:

  1. Has had prior systemic cancer cytotoxic chemotherapy within the past four weeks at the time of the start of the lymphodepletion regimen.
  2. Has had prior B-RAF or MEK targeted therapy within 7 days prior to the start of the lymphodepletion regimen (Cohort A and Cohort B).
  3. Is not receiving B-RAF treatment (Cohort C) (Turnstile II - Chemotherapy/Cell Infusion Exclusion Criteria)
  4. Achieves PR or CR in response to B-RAF treatment (Cohort C).
  5. Women who are pregnant or nursing will be excluded because of the potentially dangerous effects of the preparative chemotherapy on the fetus. (Turnstile II - Chemotherapy/Cell Infusion Exclusion Criteria)
  6. Any active systemic infections requiring intravenous antibiotics, coagulation disorders or other major medical illnesses of the cardiovascular, respiratory or immune system, such as abnormal stress test and/or abnormal PFT. PI or his designee shall make the final determination regarding appropriateness of enrollment.(Turnstile II - Chemotherapy/Cell Infusion Exclusion Criteria)
  7. Any form of primary or secondary immunodeficiency. Must have recovered immune competence after chemotherapy or radiation therapy as evidenced by lymphocyte counts (> 500/mm3), WBC (> 3,000/mm3) or absence of opportunistic infections. (Turnstile II - Chemotherapy/Cell Infusion Exclusion Criteria)
  8. Require steroid therapy or steroid-containing compounds, or have used systemic steroids in the past 30 days, or have used topical or inhalational steroids in the past 2 weeks prior to lymphodepletion. Exception: Patients on physiologic dose of steroid (Turnstile II - Chemotherapy/Cell Infusion Exclusion Criteria)
  9. Presence of a significant psychiatric disease, which in the opinion of the principal investigator or his designee, would prevent adequate informed consent or render immunotherapy unsafe or contraindicated. (Turnstile II - Chemotherapy/Cell Infusion Exclusion Criteria)
  10. Patients with rapidly advancing systemic disease, especially those without good options of systemic treatment for their disease outside the CNS. (Cohort D)
  11. Patients with rapidly advancing parenchymal brain metastases (Cohort D)
  12. Pregnant patients (Cohort D)
  13. Patients with rapid decline in neurological function as documented on exam and/or as per clinical judgment of treating physician (Cohort D)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00338377

Contacts
Contact: Patrick Hwu, MD 713-792-2921 phwu@mdanderson.org
Contact: Ralph Freedman, MD 713-792-2933 rfreedman@mdanerson.org

Locations
United States, Texas
The University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Patrick Hwu, MD    713-792-2921    phwu@mdanderson.org   
Principal Investigator: Patrick Hwu, MD         
Sponsors and Collaborators
M.D. Anderson Cancer Center
Prometheus Laboratories
Key Biologics, LLC
National Cancer Institute (NCI)
Investigators
Principal Investigator: Patrick Hwu, MD M.D. Anderson Cancer Center
  More Information

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT00338377     History of Changes
Other Study ID Numbers: 2004-0069  NCI-2012-01368  5R01CA187076-02 
Study First Received: February 10, 2006
Last Updated: February 10, 2016
Health Authority: United States: Food and Drug Administration
United States: Federal Government

Keywords provided by M.D. Anderson Cancer Center:
Melanoma
Regional nodal disease
Dendritic Cell Immunization
Lymphodepletion
Adoptive Cell Transfer
T Cells
Vaccine
Cyclosphosphamide
Cytoxan
Neosar
Dendritic Cells
Tumor Infiltrating Lymphocytes
TIL Cells
MART Peptide
Fludarabine
Fludarabine Phosphate
Fludara
Proleukin
IL-2
Interleukin-2
Leptomeningeal disease

Additional relevant MeSH terms:
Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Vaccines
Cyclophosphamide
Fludarabine phosphate
Fludarabine
Aldesleukin
Interleukin-2
Vidarabine
Mesna
Immunologic Factors
Physiological Effects of Drugs
Immunosuppressive Agents
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antimetabolites
Antiviral Agents
Anti-Infective Agents
Analgesics, Non-Narcotic

ClinicalTrials.gov processed this record on July 21, 2016