Immunotherapy Using Tumor Infiltrating Lymphocytes Comparing 2 Different Conditioning Regimens for Patients With Metastatic Melanoma

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier:
NCT01993719
First received: November 22, 2013
Last updated: July 23, 2015
Last verified: August 2014
  Purpose

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 200 patients with melanoma.
  • The standard chemotherapy alone preparative regimen requires in-patient treatment and is associated with side-effects. In this trial, we are lowering the dose of the chemotherapy regimen and comparing it to the standard dose regimen to see if this treatment can be given as an outpatient prior to the infusion of cell therapy.

Objectives:

- To compare the low dose chemotherapy with the standard dose of chemotherapy prior to white blood cell therapy and determine if it is a safe and effective treatment for metastatic melanoma

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 be randomized to receive either the low dose chemotherapy or standard dose chemotherapy. Participants randomized to the standard arm will have one week of chemotherapy to prepare their immune system to accept the white blood cells and those randomized to the low dose chemotherapy arm will have three days of 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 Intervention Phase
Metastatic Melanoma
Drug: Aldesleukin
Drug: Fludarabine
Drug: Cyclophosphamide
Biological: Young Tumor Infiltrating Lymphocytes (Young TIL)
Drug: Keytruda
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: 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

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Determine whether patients receiving TIL plus a lower dose chemotherapy preparative regimen followed by aldesleukin are able to attain a response rate equivalent to TIL plus our standard chemotherapy regimen followed by aldesleukin. [ Time Frame: 4-5 years ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • To evaluate the relative platelet and red cell transfusion requirements on the two arms [ Time Frame: 5 years ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 64
Study Start Date: November 2013
Estimated Study Completion Date: September 2019
Estimated Primary Completion Date: October 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm 1
Patients will receive lymphocyte depleting chemotherapy (standard regimen) of cyclophosphamide and fludarabine followed by cells and high dose aldesleukin
Drug: Aldesleukin
Arms 1 and 2 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 5 days (maximum 15 doses).
Drug: Fludarabine

Arm 1 (standard chemotherapy regimen) Fludarabine 25 mg/m(2)/day IVPB daily over 30 minutes for 5 days.

Arm 2 (low dose chemotherapy regimen) Fludarabine 30 mg/m(2)/day IVPB daily over 30 minutes for 3 days.

Drug: Cyclophosphamide

Arm 1 (standard chemotherapy regimen) Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 mlD5W with Mesna 15 mg/kg/day X 2 days over 1 hr.

Arm 2 (low dose chemotherapy regimen) Cyclophosphamide 300 mg/m(2)/day X 3 days IV

Biological: Young Tumor Infiltrating Lymphocytes (Young TIL)
Arms 1 and 2 Cells (young TIL) will be infused intravenously (i.v.) on the Patient Care Unti via non-filtered tubing, gently agitating the bag during infusion to prevent clumping.
Drug: Keytruda

Arms 1 and 2 and ONLY FOR RETREATMENT

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 in the RETREATMENT ARM will receive 4 doses of Pembrolizumab at the NIH Clinical Center as follows:

  • Day 0 (two to four days after the last dose of fludarabine) - Pembrolizumab 2mg/kg IV approximately 4 hours prior to cell infusion given over approximately 30 minutes
  • Day 21 (+/- 2 days) following cell infusion - Pembrolizumab 2mg/kg IV given over approximately 30 minutes
  • Day 42 (+/- 2 days) following cell infusion - Pembrolizumab 2mg/kg IV given over approximately 30 minutes
  • Day 63 (+/- 2 days) following cell infusion - Pembrolizumab 2mg/kg IV given over approximately 30 minutes
Experimental: Arm 2
Patients will receive lymphocyte depleting chemotherapy (low dose regimen) of cyclophosphamide and fludarabine followed by cells and high dose aldesleukin
Drug: Aldesleukin
Arms 1 and 2 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 5 days (maximum 15 doses).
Drug: Fludarabine

Arm 1 (standard chemotherapy regimen) Fludarabine 25 mg/m(2)/day IVPB daily over 30 minutes for 5 days.

Arm 2 (low dose chemotherapy regimen) Fludarabine 30 mg/m(2)/day IVPB daily over 30 minutes for 3 days.

Drug: Cyclophosphamide

Arm 1 (standard chemotherapy regimen) Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 mlD5W with Mesna 15 mg/kg/day X 2 days over 1 hr.

Arm 2 (low dose chemotherapy regimen) Cyclophosphamide 300 mg/m(2)/day X 3 days IV

Biological: Young Tumor Infiltrating Lymphocytes (Young TIL)
Arms 1 and 2 Cells (young TIL) will be infused intravenously (i.v.) on the Patient Care Unti via non-filtered tubing, gently agitating the bag during infusion to prevent clumping.
Drug: Keytruda

Arms 1 and 2 and ONLY FOR RETREATMENT

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 in the RETREATMENT ARM will receive 4 doses of Pembrolizumab at the NIH Clinical Center as follows:

  • Day 0 (two to four days after the last dose of fludarabine) - Pembrolizumab 2mg/kg IV approximately 4 hours prior to cell infusion given over approximately 30 minutes
  • Day 21 (+/- 2 days) following cell infusion - Pembrolizumab 2mg/kg IV given over approximately 30 minutes
  • Day 42 (+/- 2 days) following cell infusion - Pembrolizumab 2mg/kg IV given over approximately 30 minutes
  • Day 63 (+/- 2 days) following cell infusion - Pembrolizumab 2mg/kg IV given over approximately 30 minutes

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 whether autologous Young TIL infused with the administration of high-dose aldesleukin may result in clinical tumor regression in patients with metastatic melanoma receiving a non-myeloablative lymphoid depleting preparative

regimen, separately according to whether they receive prior anti-PD1 or not.

-To Evaluate the safety and efficacy of pembrolizumab in combination with TIL therapy.

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.
  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

-INCLUSION CRITERIA:

  1. Measurable metastatic melanoma with at least one lesion that is resectable for TIL generation.
  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. Able to understand and sign the Informed Consent Document
  6. Clinical performance status of ECOG 0 or 1.
  7. Life expectancy of greater than three months.
  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. 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. Note: Patients who have previously received ipilimumab and have documented GI toxicity must have a 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 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, 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.
  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. Documented LVEF of less than or equal to 45%, testing is required in patients with:

    • Age greater than or equal to 60 years old
    • Clinically significant atrial and or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, second or third degree heart block.
  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: NCT01993719

Contacts
Contact: Linda Williams, R.N. (866) 820-4505 ncisbirc@mail.nih.gov
Contact: Steven A Rosenberg, M.D. (301) 496-4164 sar@mail.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    ncisbirc@mail.nih.gov   
Sponsors and Collaborators
Investigators
Principal Investigator: Steven A Rosenberg, 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: NCT01993719     History of Changes
Other Study ID Numbers: 140022, 14-C-0022
Study First Received: November 22, 2013
Last Updated: July 23, 2015
Health Authority: United States: Federal Government

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

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

ClinicalTrials.gov processed this record on August 03, 2015