Clinical Trials /

Autologous CD8+ SLC45A2-Specific T Lymphocytes With Cyclophosphamide, Aldesleukin, and Ipilimumab in Treating Patients 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 patients with uveal melanoma that has spread to other places in the body (metastatic). To make specialized CD8+ T cells, researchers separate out T cells collected from patients' blood and treat them so they are able to target melanoma cells. The blood cells are then given back to the patients. 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 patients with metastatic uveal melanoma.

Related Conditions:
  • Uveal Melanoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Uveal Melanoma T Cel Therapy
  • 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
  • SECONDARY ID: NCI-2018-01291
  • SECONDARY ID: 2016-0414
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03068624

Conditions

  • Metastatic Uveal Melanoma
  • Uveal Melanoma Metastatic in the Liver

Interventions

DrugSynonymsArms
Aldesleukin125-L-Serine-2-133-interleukin 2, Proleukin, r-serHuIL-2, Recombinant Human IL-2, recombinant human interleukin-2Treatment (cyclophosphamide, T-cells, aldesleukin, ipilimumab)
Autologous CD8+ SLC45A2-specific T LymphocytesAutologous SLC45A2-specific CTLs, Autologous SLC45A2-specific Cytotoxic T LymphocytesTreatment (cyclophosphamide, T-cells, aldesleukin, ipilimumab)
Cyclophosphamide(-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamide Monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719Treatment (cyclophosphamide, T-cells, aldesleukin, ipilimumab)
IpilimumabAnti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, MDX-010, MDX-CTLA4, YervoyTreatment (cyclophosphamide, T-cells, aldesleukin, ipilimumab)

Purpose

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 patients with uveal melanoma that has spread to other places in the body (metastatic). To make specialized CD8+ T cells, researchers separate out T cells collected from patients blood and treat them so they are able to target melanoma cells. The blood cells are then given back to the patients. 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 patients with metastatic uveal melanoma.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To determine the maximum tolerated dose (MTD) of adoptively transferred SLC45A2-specific
      cytotoxic T-lymphocytes (CTL) for the treatment of patients with metastatic uveal melanoma.

      SECONDARY OBJECTIVES:

      I. To establish the anti-tumor efficacy as measured by immune-related response criteria
      (irRC) and duration of response in metastatic uveal melanoma patients receiving autologous
      CD8+ T cells against SLC45A2.

      II. To assess the safety and tolerability of adoptively transferred SLC45A2-specific CTL in
      combination with immune checkpoint blockade in metastatic uveal melanoma patients.

      III. To quantify in vivo numeric and functional persistence of transferred CTL, and
      development of antigen spreading.

      IV. To assess overall survival and progression-free survival in metastatic uveal melanoma
      patients.

      OUTLINE: This is a dose escalation study of autologous CD8+ SLC45A2-specific T lymphocytes.

      PREPARATIVE REGIMEN: Patients receive cyclophosphamide intravenously (IV) over 30-60 minutes
      on day -2.

      T-CELL INFUSION: Patients receive autologous CD8+ SLC45A2-specific T lymphocytes via hepatic
      arterial infusion over 60 minutes on day 0. Within 6 hours of T-cell infusion, patients also
      receive aldesleukin twice daily (BID) subcutaneously (SC) for 14 days in the absence of
      disease progression or unacceptable toxicity.

      POST T-CELL INFUSION: Patients in dose expansion receive ipilimumab IV over 90 minutes on
      days 1, 22, 43, and 64 in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at days 84 and 168, and then
      every 3 months for up to 5 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (cyclophosphamide, T-cells, aldesleukin, ipilimumab)ExperimentalPREPARATIVE REGIMEN: Patients receive cyclophosphamide IV over 30-60 minutes on day -2. T-CELL INFUSION: Patients receive autologous CD8+ SLC45A2-specific T lymphocytes via hepatic arterial infusion over 60 minutes on day 0. Within 6 hours of T-cell infusion, patients also receive aldesleukin BID SC for 14 days in the absence of disease progression or unacceptable toxicity. POST T-CELL INFUSION: Patients in dose expansion receive ipilimumab IV over 90 minutes on days 1, 22, 43, and 64 in the absence of disease progression or unacceptable toxicity.
  • Aldesleukin
  • Autologous CD8+ SLC45A2-specific T Lymphocytes
  • Cyclophosphamide
  • Ipilimumab

Eligibility Criteria

        Inclusion Criteria:

          -  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.

          -  Hematocrit (HCT) >= 24% or hemoglobin (HB) >= 8g/dL.

          -  Platelets > 50,000.

          -  Expression of human leukocyte antigen (HLA)-A:0201 or HLA-A:2402.

          -  Eastern Cooperative Oncology Group (ECOG)/ Zubrod performance status of 0-1.

          -  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.

          -  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.

          -  Willing and able to give informed consent.

          -  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 principal
             investigator (PI).

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

          -  Bi-dimensionally measurable disease by palpation on clinical exam, or radiographic
             imaging per immune-related response criteria (irRC).

          -  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.

          -  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.

          -  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.

        Exclusion Criteria:

          -  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.

          -  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.

          -  Clinically significant pulmonary dysfunction, as determined by medical history and
             physical exam. Patients so identified will undergo pulmonary functions testing and
             those with forced expiratory volume in one second (FEV1) < 2.0 L or diffusion lung
             capacity [DLCO] corrected [corr] for hemoglobin [Hgb]) < 50% will be excluded.

          -  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 electrocardiogram (EKG) requiring drug therapy

          -  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.

          -  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.

          -  Positive screening tests for human immunodeficiency virus (HIV), hepatitis B virus
             (Hep B), and hepatitis C virus (Hep C). If positive results are not indicative of true
             active or chronic infection, the patient can be treated.

          -  White blood cell (WBC) =< 2000/uL (prior to cyclophosphamide and T cell infusions).

          -  Hct =< 24% or Hb =< 8 g/dL (prior to cyclophosphamide and T cell infusions).

          -  Absolute neutrophil count (ANC) =< 1000 (prior to cyclophosphamide and T cell
             infusions).

          -  Platelets =< 50,000 (prior to cyclophosphamide and T cell infusions).

          -  Creatinine >= 3.0 x upper limit of normal (ULN) (prior to cyclophosphamide and T cell
             infusions).

          -  Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 5 x ULN (since all
             patients will have liver metastasis) (prior to cyclophosphamide and T cell infusions).

          -  Bilirubin >=3 x ULN (prior to cyclophosphamide and T cell infusions).

          -  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.

          -  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.

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

          -  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.

          -  Participation in any other immunotherapy treatment, that in the opinion of the
             principal investigator would be unsafe to receive further checkpoint blockade
             immunotherapy.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD)
Time Frame:Up to 6 weeks
Safety Issue:
Description:As determined by dose limiting toxicity (DLT). MTD defined at the highest dose at which no more than 1 in 6 patients has experienced DLT.

Secondary Outcome Measures

Measure:Overall response rate
Time Frame:Up to 5 years
Safety Issue:
Description:As measured by immune-related response criteria. Overall response will be monitored simultaneously using the Bayesian approach of Thall, Simon, Estey and the extension by Thall and Sung. Logistic regression will be used to assess the impact of patient characteristics on the overall response rate.
Measure:Duration of clinical response (DOR)
Time Frame:From the start of study treatment up to 5 years
Safety Issue:
Description:DOR will be estimated using the method of Kaplan and Meier. Comparison of time-to-event endpoints by important subgroups of patients will be made using the log-rank test. Cox (proportional hazards) regression will be used to evaluate multivariable predictive models of time-to-event outcomes. Continuous variables (e.g., age, etc.) will be summarized using the mean (standard deviation) or median (range). Frequency tables will be used to summarize categorical variables.
Measure:Persistence of in vivo T cells and non-target antigen recognition
Time Frame:From the start of study treatment up to 5 years
Safety Issue:
Description:Continuous variables (e.g., age, etc.) will be summarized using the mean (standard deviation) or median (range). Frequency tables will be used to summarize categorical variables. The distribution of time-to-event endpoints will be estimated using the method of Kaplan and Meier. Comparison of time-to-event endpoints by important subgroups of patients will be made using the log-rank test. Cox proportional hazards) regression will be used to evaluate multivariable predictive models of time-to-event outcomes.
Measure:Overall survival (OS)
Time Frame:From the start of study treatment up to 5 years
Safety Issue:
Description:OS will be estimated using the method of Kaplan and Meier. Comparison of time-to-event endpoints by important subgroups of patients will be made using the log-rank test. Cox (proportional hazards) regression will be used to evaluate multivariable predictive models of time-to-event outcomes. Continuous variables (e.g., age, etc.) will be summarized using the mean (standard deviation) or median (range). Frequency tables will be used to summarize categorical variables.
Measure:Progression-free survival (PFS)
Time Frame:From the start of study treatment up to 5 years
Safety Issue:
Description:PFS will be estimated using the method of Kaplan and Meier. Comparison of time-to-event endpoints by important subgroups of patients will be made using the log-rank test. Cox (proportional hazards) regression will be used to evaluate multivariable predictive models of time-to-event outcomes. Continuous variables (e.g., age, etc.) will be summarized using the mean (standard deviation) or median (range). Frequency tables will be used to summarize categorical variables.
Measure:Time to response
Time Frame:From the start of study treatment up to 5 years
Safety Issue:
Description:Continuous variables (e.g., age, etc.) will be summarized using the mean (standard deviation) or median (range). Frequency tables will be used to summarize categorical variables. The distribution of time-to-event endpoints will be estimated using the method of Kaplan and Meier. Comparison of time-to-event endpoints by important subgroups of patients will be made using the log-rank test. Cox proportional hazards) regression will be used to evaluate multivariable predictive models of time-to-event outcomes.
Measure:Incidence of toxicity
Time Frame:Up to 5 years
Safety Issue:
Description:Toxicity will be monitored simultaneously using the Bayesian approach of Thall, Simon, Estey and the extension by Thall and Sung. An Efficacy/ Summary will be submitted to the Investigational New Drug (IND) Office Medical Monitor after every six evaluable patients complete 12 weeks of study treatment.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

December 27, 2019