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Immunotherapy Using Tumor Infiltrating Lymphocytes for Patients With Metastatic Melanoma

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ClinicalTrials.gov Identifier: NCT01993719
Recruitment Status : Recruiting
First Posted : November 25, 2013
Last Update Posted : May 24, 2018
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:

Background:

  • The NCI Surgery Branch has developed an experimental therapy that involves taking white blood cells from patients' tumors, growing them in the laboratory in large numbers, and then giving the cells back to the patient. These cells are called Tumor Infiltrating Lymphocytes, or TIL and we have given this type of treatment to over 400 patients with melanoma.
  • In this trial, we are determining if there is a difference in the response between patients who have received prior anti-PD1 treatment to those who have not received this prior ant-PD1 treatment.

Objectives:

- To determine if there is a difference in the rate of response between patients who have received prior anti-PD1 and those who have not.

Eligibility:

- Individuals at least 18 years and less than or equal to 70 years of age who have metastatic melanoma.

Design:

  • Work up stage: Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected.
  • Surgery: Surgery or biopsy will be performed to obtain tumor from which to grow white blood cells. White blood cells will be grown from the tumor in the laboratory.
  • Leukapheresis: Participants will have leukapheresis to collect additional white blood cells. (Leukapheresis is a common procedure which removes only the white blood cells from the patient.)
  • Treatment: Participants will receive standard dose chemotherapy to prepare their immune system to accept the white blood cells. Participants will receive an infusion of their own white blood cells grown from tumor. They will also receive aldesleukin for up to five days to boost the immune system s response to the white blood cells. They will stay in the hospital for about 4 weeks for the treatment.
  • Follow up: Patients will return to the clinic for a physical exam, review of side effects, lab tests, and scans about every 1-3 months for the first year, and then every 6 months to 1 year as long as their tumors are shrinking. Follow up visits take up to 2 days.

Condition or disease Intervention/treatment Phase
Metastatic Melanoma Drug: Aldesleukin Drug: Fludarabine Drug: Cyclophosphamide Biological: Young Tumor Infiltrating Lymphocytes (Young TIL) Drug: Pembrolizumab (Keytruda) Phase 2

Detailed Description:

Background:

  • Adoptive cell therapy (ACT) using autologous tumor infiltrating lymphocytes can mediate the regression of bulky metastatic melanoma when administered along with high-dose aldesleukin (IL-2) following a non-myeloablative lymphodepleting chemotherapy preparative regimen consisting of cyclophosphamide and fludarabine.
  • In a series of consecutive trials using this chemotherapy preparative regimen alone or with 2 Gy or 12 Gy total body irradiation (TBI) objective response rates using RECIST criteria were 49%, 52%, and 72%, respectively. Of the 20 complete regressions seen in this trial, 19 are on-going at 70 to 114 months.
  • The chemotherapy alone preparative regimen required in-patient treatment and was associated with significant neutropenia and thrombocytopenia requiring multiple transfusions and treatment for febrile neutropenia.

Objectives:

  • With amendment D, to determine if there is a difference in the rate of response between patients who have received prior anti-PD1 and those who have not; both groups will receive non-myeloablative lymphoid depleting preparative regimen followed by autologous young TIL and administration of high dose aldesleukin.
  • To determine the toxicity of the treatment.

Eligibility:

  • Age greater than or equal to 18 and less than or equal to 70 years
  • Evaluable metastatic melanoma
  • Metastatic melanoma lesion suitable for surgical resection for the preparation of TIL
  • No contraindications to high-dose aldesleukin administration
  • No concurrent major medical illnesses or any form of immunodeficiency

Design:

  • Patients with metastatic melanoma will have lesions resected and after TIL growth is established, patients will receive ACT with TIL plus aldesleukin following high dose chemotherapy preparative regimen.
  • Up to 64 patients may be enrolled over 4-5 years.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 64 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study for Metastatic Melanoma Using High Dose Chemotherapy Preparative Regimen Followed by Cell Transfer Therapy Using Tumor Infiltrating Lymphocytes Plus IL-2 With the Administration of Pembrolizumab in the Retreatment Arm
Study Start Date : November 22, 2013
Estimated Primary Completion Date : October 27, 2028
Estimated Study Completion Date : September 28, 2029

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Melanoma
U.S. FDA Resources

Arm Intervention/treatment
Experimental: 1/High-Dose Chemotherapy
Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine +young TIL + highdose aldesleukin
Drug: Aldesleukin
Administered at a dose of 720,000 IU/kg (based on total body weight) as an intravenous bolus over a 15 minute period approximately every eight hours (+/- 1hr)beginning within 24 hours of cell infusion and continuing for up to 4 days (maximum 12 doses).
Drug: Fludarabine

Days -7 to -3 (high- dose and retreatment arms): Fludarabine 25 mg/m2/day IVPB daily over 15-30 minutes for 5 days.

Days -5 to -3 (low- dose arm-CLOSED): Fludarabine 30 mg/m2 IV over 30 minutes after cyclophosphamide infusion.

Drug: Cyclophosphamide

Days -7 and -6 (highdose and retreatment arms): Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 mL D5W with Mesna 15 mg/kg/day X 2 days over 1 hr.

Cyclophosphamide 30 mg/kg/day X 2 days will be considered for patients who have a history of prolonged hematologic recovery from prior chemotherapy treatments.

Days -5 to -3 (lowdose arm-CLOSED): Cyclophosphamide 300 mg/m2 IV over 60 minutes.

Biological: Young Tumor Infiltrating Lymphocytes (Young TIL)
Day 0: Cells will be infused intravenously (IV) on the Patient Care Unit over 20-30 minutes.
Experimental: 2/Low-Dose Chemotherapy (CLOSED)
Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine +young TIL + highdose aldesleukin (CLOSED)
Drug: Aldesleukin
Administered at a dose of 720,000 IU/kg (based on total body weight) as an intravenous bolus over a 15 minute period approximately every eight hours (+/- 1hr)beginning within 24 hours of cell infusion and continuing for up to 4 days (maximum 12 doses).
Drug: Fludarabine

Days -7 to -3 (high- dose and retreatment arms): Fludarabine 25 mg/m2/day IVPB daily over 15-30 minutes for 5 days.

Days -5 to -3 (low- dose arm-CLOSED): Fludarabine 30 mg/m2 IV over 30 minutes after cyclophosphamide infusion.

Drug: Cyclophosphamide

Days -7 and -6 (highdose and retreatment arms): Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 mL D5W with Mesna 15 mg/kg/day X 2 days over 1 hr.

Cyclophosphamide 30 mg/kg/day X 2 days will be considered for patients who have a history of prolonged hematologic recovery from prior chemotherapy treatments.

Days -5 to -3 (lowdose arm-CLOSED): Cyclophosphamide 300 mg/m2 IV over 60 minutes.

Biological: Young Tumor Infiltrating Lymphocytes (Young TIL)
Day 0: Cells will be infused intravenously (IV) on the Patient Care Unit over 20-30 minutes.
Experimental: 3/Retreatment
Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine +young TIL + highdose aldesleukin + pembrolizumab
Drug: Aldesleukin
Administered at a dose of 720,000 IU/kg (based on total body weight) as an intravenous bolus over a 15 minute period approximately every eight hours (+/- 1hr)beginning within 24 hours of cell infusion and continuing for up to 4 days (maximum 12 doses).
Drug: Fludarabine

Days -7 to -3 (high- dose and retreatment arms): Fludarabine 25 mg/m2/day IVPB daily over 15-30 minutes for 5 days.

Days -5 to -3 (low- dose arm-CLOSED): Fludarabine 30 mg/m2 IV over 30 minutes after cyclophosphamide infusion.

Drug: Cyclophosphamide

Days -7 and -6 (highdose and retreatment arms): Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 mL D5W with Mesna 15 mg/kg/day X 2 days over 1 hr.

Cyclophosphamide 30 mg/kg/day X 2 days will be considered for patients who have a history of prolonged hematologic recovery from prior chemotherapy treatments.

Days -5 to -3 (lowdose arm-CLOSED): Cyclophosphamide 300 mg/m2 IV over 60 minutes.

Biological: Young Tumor Infiltrating Lymphocytes (Young TIL)
Day 0: Cells will be infused intravenously (IV) on the Patient Care Unit over 20-30 minutes.
Drug: Pembrolizumab (Keytruda)
ONLY FOR RETREATMENT RETREATMENT ARM ONLY: Patients who do not respond or who experience a partial or complete response and subsequently progress and have received prior therapy with either pembrolizumab or nivolumab may receive a second treatment. Patients will receive pembrolizumab 2 mg/kg IV at the NIH Clinical Center over 30 minutes on Days -2, 21 (+/- 2 days), 42 (+/- 2 days), and 63 (+/- 2 days).



Primary Outcome Measures :
  1. Frequency and severity of treatment-related adverse events [ Time Frame: 30 days after end of treatment ]
    Aggregate of all adverse events, as well as their frequency and severity

  2. Response rate [ Time Frame: 6 and 12 weeks after cell infusion, then every 3 months x3, then every 6 months x5 years, then per PI discretion ]
    Percentage of patients who have a clinical response to treatment (objective tumor regression)


Secondary Outcome Measures :
  1. Progression-free and overall survival [ Time Frame: Time to progression and time to death ]
    Time to disease progression following the start of treatment, and time to death following the start of treatment

  2. Safety and efficacy of pembrolizumab + TIL therapy [ Time Frame: 6 and 12 weeks after cellinfusion, then every 3 months x3, then every 6 months x5 years, then per PI discretion ]
    Response rate and evaluation of treatment-related adverse events for patients who received pembrolizumab



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

-INCLUSION CRITERIA:

  1. Measurable metastatic melanoma with at least one lesion that is resectable for TIL generation and at least one other lesion that can be measured by RECIST criteria.
  2. Confirmation of diagnosis of metastatic melanoma by the Laboratory of Pathology of NCI.
  3. Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and asymptomatic are eligible. Lesions that have been treated with stereotactic radiosurgery must be clinically stable for 1 month after treatment for the patient to be eligible. Patients with surgically resected brain metastases are eligible.
  4. Greater than or equal to 18 years of age and less than or equal to 70 years of age.
  5. Ability of subject to understand and the willingness to sign the Informed Consent Document
  6. Willing to sign a durable power of attorney.
  7. Clinical performance status of ECOG 0, 1 or 2.
  8. Patients of both genders must be willing to practice birth control from the time of enrollment on this study and for up to four months after treatment.
  9. 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 are less responsive to the experimental treatment and more susceptible to its toxicities.)
    • Seronegative for hepatitis B antigen, and seronegative for hepatitis C antibody. If hepatitis C antibody test is positive, then patient must be tested for the presence of antigen by RT-PCR and be HCV RNA negative.
  10. Women of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the treatment on the fetus.
  11. Hematology:

    • Absolute neutrophil count greater than 1000/mm(3) without the support of filgrastim
    • WBC greater than or equal to 3000/mm(3)
    • Platelet count greater than or equal to 100,000/mm(3)
    • Hemoglobin > 8.0 g/dl
  12. Chemistry:

    • Serum ALT/AST less than or equal to 2.5 times the upper limit of normal
    • Serum Creatinine less than or equal to 1.6 mg/dl
    • 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 toxicities such as alopecia or vitiligo). Patients must have progressive disease after prior treatment.

    Note: Patients may have undergone minor surgical procedures within the past 3 weeks, as long as all toxicities have recovered to grade 1 or less.

  14. Subjects must be co-enrolled in 03-C-0277

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. 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. Active systemic infections, (e.g.: requiring anti-infective treatment), coagulation disorders or any other active major medical illnesses.
  5. Concurrent systemic steroid therapy.
  6. History of severe immediate hypersensitivity reaction to any of the agents used in this study.
  7. History of coronary revascularization or ischemic symptoms.
  8. Any patient known to have an LVEF less than or equal to 45%
  9. Documented LVEF of less than or equal to 45%, note: testing is required in patients with:

    • Age greater than or equal to 65 years old
    • Clinically significant atrial and or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, second or third degree heart block or history of ischemic heart disease or chest pain.
  10. Patients who are receiving other investigational agents
  11. Documented FEV1 less than or equal to 60% predicted tested in patients with:

    • A prolonged history of cigarette smoking (20 pk/year of smoking within the past 2 years).
    • Symptoms of respiratory dysfunction

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01993719


Contacts
Contact: Abigail R Johnson, R.N. (866) 820-4505 IRC@nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact NCI/Surgery Branch Recruitment Center    866-820-4505    irc@nih.gov   
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Steven A Rosenberg, M.D. National Cancer Institute (NCI)

Additional Information:
Publications:
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01993719     History of Changes
Other Study ID Numbers: 140022
14-C-0022
First Posted: November 25, 2013    Key Record Dates
Last Update Posted: May 24, 2018
Last Verified: April 18, 2018

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
Metastatic
Melanoma
Adoptive Cell Therapy

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
Cyclophosphamide
Fludarabine phosphate
Pembrolizumab
Fludarabine
Aldesleukin
Vidarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antimetabolites
Antiviral Agents
Anti-Infective Agents
Anti-HIV Agents
Anti-Retroviral Agents