Clinical Trials /

Autologous CD8+ SLC45A2-Specific T Lymphocytes With Cyclophosphamide, Aldesleukin, and Ipilimumab in Treating Participants With Metastatic Uveal Melanoma

NCT03068624

Description:

This phase Ib trial studies the side effects and best dose of autologous CD8 positive (+) SLC45A2-specific T lymphocytes when given together with cyclophosphamide, aldesleukin, and ipilimumab, and to see how well they work in treating participants with uveal melanoma that has spread to other places in the body. To make specialized CD8+ T cells, researchers separate out T cells collected from participant blood and treat them so they are able to target melanoma cells. The blood cells are then given back to the participant. This is known as "adoptive T cell transfer" or "adoptive T cell therapy." Drugs used in chemotherapy, such as cyclophosphamide, may work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Biological therapies, such as aldesleukin, use substances made from living organisms that may stimulate the immune system in different ways and stop tumor cells from growing. Immunotherapy with monoclonal antibodies, such as ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving autologous CD8+ SLC45A2-specific T lymphocytes together with cyclophosphamide, aldesleukin, and ipilimumab may work better in treating participants with metastatic uveal melanoma.

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study of Cellular Adoptive Immunotherapy Using Autologous CD8+ Antigen-Specific T Cells and Anti-CTLA4 for Patients With Metastatic Uveal Melanoma
  • Official Title: Phase Ib Study of Cellular Adoptive Immunotherapy Using Autologous CD8+ Antigen-Specific T Cells and Anti-CTLA4 for Patients With Metastatic Uveal Melanoma

Clinical Trial IDs

  • ORG STUDY ID: 2016-0414
  • NCT ID: NCT03068624

Conditions

  • Melanoma and Other Malignant Neoplasms of Skin

Interventions

DrugSynonymsArms
CyclophosphamideCytoxan, NeosarCD 8+ T Cells + Cyclophosphamide + IL-2 + Ipilimumab
Interleukin-2IL-2, Aldesleukin, ProleukinCD 8+ T Cells + Cyclophosphamide + IL-2 + Ipilimumab
IpilimumabYervoy, BMS-734016, MDX010CD 8+ T Cells + Cyclophosphamide + IL-2 + Ipilimumab

Purpose

This clinical research study is divided into 2 parts: leukapheresis and treatment. In the leukapheresis part, white blood cells called T cells will be collected from participant to be made into specialized CD8+T cells. To make specialized CD8+T cells, researchers separate out T cells from blood and treat them so they are able to target melanoma cells. The blood cells are then given back to the participant in the treatment part of the study. This is known as "adoptive T cell transfer" or "adoptive T cell therapy".

This consent form is for the treatment part of the study.

The goal of this clinical research study is to learn about the safety of giving CD8+T cells with ipilimumab, cyclophosphamide, and IL-2 (aldesleukin) to participants with uveal melanoma that is metastatic (has spread). Researchers also want to learn if this combination can help to control the disease.

Detailed Description

Study Groups:

If participant is found to be eligible to take part in this study, participant will be assigned to a dose level of CD 8+ T cells based on when participant joins this study. Up to 3 dose levels of CD 8+T cells will be tested. At least 3 participants will be enrolled at each dose level. After the first group receives a dose level of the CD 8+ T cells, another group will be enrolled at a higher or lower dose level based on any side effects that are seen. It is then possible that a third group will be enrolled at a higher or lower dose level than the second group.

All participants will receive the same dose levels of all other drugs on this study.

Study Drug Administration:

Participant will receive cyclophosphamide by vein over about 30-60 minutes on Day -2 (2 days before participant receives the CD8+ T cells). If the doctor thinks it is needed, participant will be given standard drugs to help decrease the risk of side effects. Participant may ask the study staff for information about how these drugs are given and their risks.

On Day -1 participant will be admitted to the hospital and have a hepatic arterial catheter placed. This catheter is a sterile flexible tube that will be placed into a blood vessel in participant's liver while participant is under local anesthesia. Participant's doctor will explain this procedure to participant in more detail, and participant will be required to sign a separate consent form. Participant will stay in the hospital overnight after the placement.

On Day 0, participant will receive the CD8+ T cells through the catheter over 60 minutes. Participant will stay in the hospital overnight after the dose.

Starting within 6 hours after the CD8+T cell infusion and then 2 times each day after that for 14 days, participant will receive aldesleukin as an injection into the skin around participant's abdomen. Participant will be taught how to give participant these injections.

On Days 1, 22, 43, and 64, participant will receive ipilimumab by vein over about 90 minutes.

Study Visits:

On Day -2:

- Participant will have a physical exam.

- Blood (about 1 tablespoon) will be drawn for routine tests. This routine blood draw will include a pregnancy test if participant can become pregnant. To continue participation in this study, participant cannot be pregnant.

On Days 0, 7, 14, 22, 28, 35, 43, 49, 56, 64, 70, 77, 84, 112, and 140:

- Participant will have a physical exam.

- Blood (about 5½ tablespoons) will be drawn for routine tests, immune system tests, and tests on how long the T-cells survive in participant's body.

- Sometime between Days 35 and 42 and again between Days 77 and 84, participant will have a CT scan to check the status of the disease.

On Day 3, blood (about 5½ tablespoons) will be drawn for routine tests, immune system tests, and tests on how long the T-cells survive in participant's body.

If the doctor thinks it is needed to check the status of the disease, blood (about 1½ tablespoons) will be drawn every 3-6 months for up to 3 years.

The study tests may be repeated or participant may have additional tests performed anytime the doctor thinks it is needed.

Some of the study tests may be done at participant's local clinic if participant cannot return to MD Anderson. The study staff will discuss this with participant.

Length of Treatment:

The treatment portion of the study will last until Day 64. Participant will no longer be able to take the study drugs if the disease gets worse, if intolerable side effects occur, or if participant is unable to follow study directions.

Participation on the study will be over after the follow-up.

End-of-Study Visit:

At Day 168:

- Participant will have a physical exam.

- Blood (about 5½ tablespoons) will be drawn for routine tests, immune system tests, and tests on how long the T-cells survive in participant's body.

Follow-Up:

Every 3 months after Day 84, unless the disease gets worse or participant starts another cancer therapy, participant will have a CT scan or x-rays to check the status of the disease. Every 3 months for up to 5 years, the study staff will call participant or ask participant's doctor how participant is doing. If participant is called, the calls should last about 10-15 minutes.

If the doctor thinks it is needed, participant will return to the clinic every 4-6 weeks or more often if the doctor thinks is needed. Blood (about 5½ tablespoons) will be drawn for routine tests, immune system tests, and tests on how long the T-cells survive in participant's body.

This is an investigational study. Specialized CD8+T cells are not FDA approved or commercially available. They are currently being used for research purposes only. Cyclophosphamide, ipilimumab, and aldesleukin are FDA approved and commercially available for the treatment of uveal melanoma.

Up to 30 participants will be enrolled in this study. All will take part at MD Anderson.

Trial Arms

NameTypeDescriptionInterventions
CD 8+ T cellsExperimentalDose Escalation Run-In Cohort: The first cohort of patients receive a single infusion of 3.3 x 109 cells/m2 on Day 0 and observed for any signs of toxicity. If no dose-limiting toxicity (DLT) is seen in any of the three patients, then escalation to the next dose level is permitted. Treatment continues in cohorts of three until maximum tolerated dose achieved.
    CD 8+ T Cells + Cyclophosphamide + IL-2 + IpilimumabExperimentalExpansion Cohort: Cyclophosphamide administered at 300 mg/m2 by vein 48 to 72 hours prior (Day -3 to Day -2) to T cell infusion as an outpatient procedure. Maximum tolerated dose of CD 8+ T Cells from Dose Escalation Run-In given on Day 0. Low-dose IL-2 initiated within 6 hours of T cell infusion. IL-2 administered at 250,000 U/m2 subcutaneously twice daily for 14 days. Ipilimumab administration initiated approximately 24 hours after the T cell infusion at a dose of 3mg/kg over approximately 90 minutes by vein and every 3 weeks thereafter for a total of 4 doses.
      • Cyclophosphamide
      • Interleukin-2
      • Ipilimumab

    Eligibility Criteria

    Inclusion Criteria:

    1. Eligibility for Pheresis: (Turnstile 1) Histopathologic documentation of melanoma concurrent with the diagnosis of metastatic disease. A diagnosis of uveal melanoma can be made clinically without primary tissue evaluation, based on history and records. A prior history of brachytherapy to the eye is sufficient clinical support for a diagnosis of uveal melanoma.

    2. Male or female subjects >/= 18 years of age.

    3. Expression of HLA-A:0201.

    4. ECOG/ Zubrod performance status of 0-1.

    5. Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study in such a manner that the risk of pregnancy is minimized. Suggested precautions should be used to minimize the risk or pregnancy for at least 1 month before start of therapy, and while women are on study for up to 3 months after completion of the study. WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal.

    6. Male patients must be willing and able to use an acceptable method of birth control, during and for at least 3 months after completion of the study, if their sexual partners are WOCBP.

    7. Willing and able to give informed consent.

    8. Toxicity related to prior therapy must either have returned to </= grade 1, baseline, or been deemed irreversible. Certain non-serious exceptions include alopecia, hypothyroidism, neuropathy, nausea, adrenocortical deficiency requiring physiologic replacement dose of steroids, and other conditions noted and approved by the PI.

    9. Eligibility for T cell infusion (Includes Cyclophosphamide, T cell, anti-CTLA4 infusions and s.c. IL-2) (Turnstile 2) (Note: evaluate at least 1 week before T cell infusion). ECOG/Zubrod performance status of 0-1.

    10. Bi-dimensionally measurable disease by palpation on clinical exam, or radiographic imaging per irRC.

    11. At least 4 weeks must have elapsed since the last chemotherapy, targeted therapy, immunotherapy, radiotherapy, liver-directed therapy, or major surgery. At least 6 weeks for nitrosoureas, mitomycin C and liposomal doxorubicin. If started before T-cell administration, ipilimumab infusions must be least 21 days apart.

    12. Toxicity related to prior therapy must either have returned to </=grade 1, baseline, or been deemed irreversible. Certain non-serious exceptions include alopecia, hypothyroidism, neuropathy, nausea, adrenocortical deficiency requiring physiologic replacement dose of steroids, and other conditions noted and approved by the PI.

    13. Persons of reproductive potential must agree to use and utilize an adequate method of contraception throughout treatment and for at least 3 months after completion of study.

    14. Willing and able to give informed consent.

    15. Patients must have liver metastases.

    Exclusion Criteria:

    1. Exclusion Criteria for Leukapheresis: Any other malignancy from which the patient has been disease-free for less than 2 years, with the exception of adequately treated and cured basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast, or melanoma in-situ.

    2. Pregnant women, nursing mothers, men or women of reproductive ability who are unwilling to use effective contraception. Women of childbearing potential with a positive pregnancy test within 3 days prior to pheresis.

    3. Clinically significant pulmonary dysfunction, as determined by medical history and physical exam. Patients so identified will undergo pulmonary functions testing and those with FEV1 < 2.0 L or DLCO (corr for Hgb) < 50% will be excluded.

    4. Significant cardiovascular abnormalities as defined by any one of the following: • Congestive heart failure, • Clinically significant hypotension, • Symptoms of coronary artery disease (angina, dyspnea), • Presence of cardiac arrhythmias on EKG requiring drug therapy,

    5. Autoimmune disease: Patients with a history of Inflammatory Bowel Disease are excluded from this study, as are patients with a history of autoimmune disease (e.g. Systemic Lupus Erythematosus, vasculitis, infiltrating lung disease) whose possible progression during treatment would be considered by the Investigator to be unacceptable. Acceptable exclusions include: Hashimoto's thyroiditis, Type 1 diabetes mellitus, and other localized or inactive conditions with approval of the PI.

    6. Any underlying medical or psychiatric condition, which in the opinion of the Investigator, will make the administration of study drug hazardous or obscure the interpretation of adverse events, such as a condition associated with frequent diarrhea.

    7. Positive screening tests for HIV, Hep B, and Hep C. If positive results are not indicative of true active or chronic infection, the patient can be treated.

    8. Exclusion Criteria for Treatment: a CBC and Chemistry profile prior to cyclophosphamide and T cell infusions: • WBC </= 2000/uL • Hct </= 24% or Hb </=8 g/dL • ANC </= 1000 • Platelets </= 50,000 • Creatinine >/= 3.0 x ULN • AST/ALT </= 5 x ULN (since all patients will have liver metastasis) • Bilirubin >/=3 x ULN

    9. Pregnant women, nursing mothers, men or women of reproductive ability who are unwilling to use effective contraception. Women of childbearing potential with a positive pregnancy test within 3 days prior to entry.

    10. Steroids (at prednisone equivalent doses > 10 mg) are not permitted 3 days prior to T cell infusion and concurrently during therapy. Exceptions include use of systemic prednisone equivalent doses </= 10 mg/ day, topical steroids or physiologic replacement dose of steroids for adrenocortical deficiency.

    11. Any non-oncology vaccine therapy used for the prevention of infectious disease within 1 month before or after any ipilimumab dose.

    12. Patients may not be on any other treatments for their cancer aside from those included in the protocol. Patients may not undergo another form of treatment concurrently with this study. Oncology supportive treatments such as growth factors, bone modifying agents, pain or nausea management are allowed.

    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Maximum Tolerated Dose (MTD) of Autologous CD8+ Antigen-Specific T Cells in Metastatic Uveal Melanoma Participants
    Time Frame:6 weeks
    Safety Issue:
    Description:MTD defined at the highest dose at which no more than 1 in 6 patients has experienced dose limiting toxicity (DLT). DLT defined as occurring in the first 6 weeks of study treatment: Any ≥ Grade 2 eye pain or reduction of visual acuity that does not respond to topical therapy and does not improve to ≤ Grade 1 severity within 2 weeks of starting therapy, OR, requires systemic treatment; Any ≥ Grade 3 bronchospasm or other hypersensitivity reaction; Any adverse event, laboratory abnormality or inter current illness which, in the judgment of the Investigator, presents a substantial clinical risk to the patient with continued dosing Any other ≥ Grade 3 non-skin related adverse event that does not return to baseline levels within 7 days.

    Secondary Outcome Measures

    Measure:Response of Autologous CD8+ T Cells Against SLC45A2 in Metastatic Uveal Melanoma Participants
    Time Frame:Assessed after 1 cycle, 12 weeks
    Safety Issue:
    Description:Response measured by immune-related response criteria (irRC) of evaluable participants.

    Details

    Phase:Phase 1
    Primary Purpose:Interventional
    Overall Status:Not yet recruiting
    Lead Sponsor:M.D. Anderson Cancer Center

    Trial Keywords

    • Melanoma and Other Malignant Neoplasms of Skin
    • Metastatic uveal melanoma
    • Autologous CD8+ T cells
    • Cyclophosphamide
    • Cytoxan
    • Neosar
    • Interleukin-2
    • IL-2
    • Aldesleukin
    • Proleukin
    • Ipilimumab
    • Yervoy
    • BMS-734016
    • MDX010

    Last Updated

    February 24, 2017