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A Prospective Randomized and Phase 2 Trial for Metastatic Melanoma Using Adoptive Cell Therapy With Tumor Infiltrating Lymphocytes Plus IL-2 Either Alone or Following the Administration of Pembrolizumab

NCT02621021

Description:

Background: Cell therapy is an experimental cancer therapy. It takes young tumor infiltrating lymphocytes (Young TIL) cells from a person s tumors and grows them in a lab. Then they are returned to the person. Researchers think adding the drug pembrolizumab might make the therapy more effective. Objective: To test if adding pembrolizumab to cell therapy is safe and effective to shrink melanoma tumors. Eligibility: People ages 18 70 years with metastatic melanoma Design: Participants will be screened with: Physical exam CT, MRI, or PET scans X-rays Heart and lung function tests Blood and urine tests Before treatment, participants will have: A piece of tumor taken from a biopsy or during surgery in order to grow TIL cells Leukapheresis: Blood flows through a needle in one arm and into a machine that removes white blood cells. The rest of the blood returns through a needle in the other arm. An IV catheter placed in the chest for getting TIL cells, aldesleukin, and pembrolizumab (if assigned) Participants will stay in the hospital for treatment. This includes: Daily chemotherapy for 1 week For some participants, pembrolizumab infusion 1 day after chemotherapy TIL cell infusion 2 4 days after chemotherapy, then aldesleukin infusion every 8 hours for up to 12 doses Possible filgrastim injection Recovery for 1 2 weeks After treatment, participants will: Take an antibiotic and antiviral for at least 6 months If assigned, have pembrolizumab treatment every 3 weeks for 3 more doses. They may have another round. Have 2-day follow-up visits every 1 3 months for 1 year and then every 6 months

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Prospective Randomized and Phase 2 Trial for Metastatic Melanoma Using Adoptive Cell Therapy With Tumor Infiltrating Lymphocytes Plus IL-2 Either Alone or Following the Administration of Pembrolizumab
  • Official Title: A Prospective Randomized and Phase 2 Trial for Metastatic Melanoma Using Adoptive Cell Therapy With Tumor Infiltrating Lymphocytes Plus IL-2 Either Alone or Following the Administration of Pembrolizumab

Clinical Trial IDs

  • ORG STUDY ID: 160027
  • SECONDARY ID: 16-C-0027
  • NCT ID: NCT02621021

Conditions

  • Melanoma

Interventions

DrugSynonymsArms
Cyclophosphamide2/ACT TIL+Pembro
Fludarabine2/ACT TIL+Pembro
Aldeslaukin2/ACT TIL+Pembro
Pembrolizumab2/ACT TIL+Pembro
young TIL2/ACT TIL+Pembro

Purpose

Background: Cell therapy is an experimental cancer therapy. It takes young tumor infiltrating lymphocytes (Young TIL) cells from a person s tumors and grows them in a lab. Then they are returned to the person. Researchers think adding the drug pembrolizumab might make the therapy more effective. Objective: To test if adding pembrolizumab to cell therapy is safe and effective to shrink melanoma tumors. Eligibility: People ages 18 70 years with metastatic melanoma Design: Participants will be screened with: Physical exam CT, MRI, or PET scans X-rays Heart and lung function tests Blood and urine tests Before treatment, participants will have: A piece of tumor taken from a biopsy or during surgery in order to grow TIL cells Leukapheresis: Blood flows through a needle in one arm and into a machine that removes white blood cells. The rest of the blood returns through a needle in the other arm. An IV catheter placed in the chest for getting TIL cells, aldesleukin, and pembrolizumab (if assigned) Participants will stay in the hospital for treatment. This includes: Daily chemotherapy for 1 week For some participants, pembrolizumab infusion 1 day after chemotherapy TIL cell infusion 2 4 days after chemotherapy, then aldesleukin infusion every 8 hours for up to 12 doses Possible filgrastim injection Recovery for 1 2 weeks After treatment, participants will: Take an antibiotic and antiviral for at least 6 months If assigned, have pembrolizumab treatment every 3 weeks for 3 more doses. They may have another round. Have 2-day follow-up visits every 1 3 months for 1 year and then every 6 months

Detailed Description

      Background:

      - Adoptive cell therapy (ACT) using autologous tumor infiltrating lymphocytes (TIL) can
      mediate the regression of bulky metastatic melanoma when administered along with highdose
      aldesleukin (IL-2) following a non-myeloablative lymphodepleting

      preparative regimen consisting of cyclophosphamide and fludarabine.

      - Pembrolizumab, a monoclonal antibody that binds to PD-1 and blocks the PD-1/PD-L1 axis,
      facilitates the activity of anti-tumor lymphocytes in the tumor micro environment.
      Pembrolizumab administration can result in objective tumor responses in patients with

      metastatic melanoma and is approved for use by the FDA for the treatment of these patients.

        -  Administered TIL express low levels of PD-1, though PD-1 can be re-expressed on TIL in
           vivo following TIL administration

        -  In pre-clinical models, the administration of an anti-PD1 antibody enhances the
           anti-tumor activity of transferred T-cells.

      Objectives:

      Primary Objectives:

        -  Determine in a prospective randomized trial whether the addition of pembrolizumab to the
           standard non-myeloablative conditioning regimen, TIL, and high-dose IL-2 can improve
           complete response rates in patients with metastatic melanoma who have received prior
           anti PD-1/PD-L1 therapy (Cohort 1)

        -  Determine the complete response rate to the standard non-myeloablative conditioning
           regimen, TIL, and high-dose IL-2 in combination with pembrolizumab in patients with
           metastatic melanoma who have not received prior anti-PD-1/PD-L1 therapy (Cohort 2)

      Eligibility:

        -  Age greater than or equal to 16 and less than or equal to 70 years

        -  Evaluable metastatic melanoma

        -  Metastatic melanoma lesion suitable for surgical resection for the preparation of TIL

        -  No allergies or hypersensitivity to high-dose aldesleukin administration

        -  No concurrent major medical illnesses or any form of immunodeficiency

      Design:

        -  Patients with metastatic melanoma will have lesions resected for TIL

        -  Patients will be assigned one of 2 cohorts: (1)

             -  patients who are refractory to prior anti PD-1/PD-L1

             -  patients who have not received prior anti PD-1/PD-L1

        -  After TIL growth is established:

             -  Patients assigned to Cohort 1 will be randomized to either receive or not receive
                pembrolizumab in combination with the standard non-myeloablative conditioning
                regimen, TIL and high dose IL-2

             -  All patients assigned to Cohort 2 will receive the standard nonmyeloablative
                conditioning regimen, TIL, and high-dose IL-2ACT in combination with pembrolizumab.

        -  For those patients receiving pembrolizumab- Pembrolizumab will be administered
           immediately prior to TIL administration and continue for an additional three cycles
           following the cell infusion.

        -  Up to 170 patients may be enrolled over 3-4 years.
    

Trial Arms

NameTypeDescriptionInterventions
1/ACT TILExperimentalNon-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine +young TIL + highdose aldesleukin (IL-2)
  • Cyclophosphamide
  • Fludarabine
  • Aldeslaukin
  • young TIL
2/ACT TIL+PembroExperimentalNon-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine +young TIL + highdose aldesleukin (IL-2) + pembrolizumab
  • Cyclophosphamide
  • Fludarabine
  • Aldeslaukin
  • Pembrolizumab
  • young TIL
3/RetreatmentExperimentalStandard dose pembrolizumab
  • Pembrolizumab

Eligibility 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 must have received at least one prior therapy for metastatic melanoma.

          4. 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.

          5. Greater than or equal to 16 years of age and less than or equal to 70 years of age.

          6. All participants and/or their parents or legally authorized representatives must sign
             a written informed consent. Assent will be obtained for all participants under the age
             of 18 years.

          7. All participants greater than or equal to 18 years of age or older must be willing to
             sign a durable power of attorney

          8. Clinical performance status of ECOG 0 or 1.

          9. 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.

         10. 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.

         11. Women of child-bearing potential must have a negative pregnancy test because of the
             potentially dangerous effects of the treatment on the fetus.

         12. Hematology

               -  Absolute neutrophil count greater than 1000/mm3 without the support of filgrastim

               -  WBC greater than or equal to 3000/mm3

               -  Platelet count greater than or equal to 100,000/mm3

               -  Hemoglobin > 8.0 g/dl

         13. 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 musthave a total bilirubin less than 3.0 mg/dl.

         14. 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).
             (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)

         15. Patients must demonstrate progressive disease at the time of treatment. (Note:
             Patients who have received tyrosine kinase inhibitors (e.g. vemurafinib) may be
             treated if they present with stable disease at the time of treatment).

         16. Subjects must be co-enrolled in protocol 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. History of major organ autoimmune disease

          6. Concurrent systemic steroid therapy.

          7. History of severe immediate hypersensitivity reaction to any of the agents used in
             this study.

          8. Grade 3 or 4 Major organ Immune-related Adverse Events (IRAEs) following treatment
             with anti PD-1/PD-L1.

          9. History of coronary revascularization or ischemic symptoms.

         10. 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 have a history of ischemic heart disease, chest pain.

         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

         12. Patients who are receiving any other investigational agents.
      
Maximum Eligible Age:70 Years
Minimum Eligible Age:16 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Response Rate
Time Frame:6 and 12 weeks after cell infusion, then every 3 months x3, then every 6 months x5 years, then PI discretion
Safety Issue:
Description:Percentage of patients who have a clinical response to treatment (objective tumor regression)

Secondary Outcome Measures

Measure:Frequency and severity of treatment-related adverse events
Time Frame:30 days after end of treatment
Safety Issue:
Description:Aggregate of all adverse events as well as their frequency and severity
Measure:Overall survival
Time Frame:Time of death
Safety Issue:
Description:Time from start of treatment to death from any cause

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • Melanoma
  • Skin Cancer
  • Immunotherapy
  • Cell Therapy

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