Clinical Trials /

CD8+ T Cell Therapy and Pembrolizumab in Treating Patients With Metastatic Gastrointestinal Tumors

NCT02757391

Description:

This phase I pilot trial studies the side effects of cluster of differentiation 8 (CD8)+ T cells in treating patients with gastrointestinal tumors that have spread to other places in the body. Tumor cells and blood are used to help create an adoptive T cell therapy, such as CD8+ T cell therapy, that is individually designed for a patient and may help doctors learn more about genetic changes in the tumor. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving CD8+ T cell therapy and pembrolizumab may work better in treating patients with gastrointestinal tumors.

Related Conditions:
  • Cholangiocarcinoma
  • Colorectal Adenocarcinoma
  • Esophageal Carcinoma
  • Gastric Carcinoma
  • Pancreatic Adenocarcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: CD8+ T Cell Therapy and Pembrolizumab in Treating Patients With Metastatic Gastrointestinal Tumors
  • Official Title: Pilot Study of Feasibility and Safety of Personalized Autologous CD8+ T Cell Therapy Plus Anti-PD1 Antibody in Advanced Solid Malignancies

Clinical Trial IDs

  • ORG STUDY ID: 2015-0152
  • SECONDARY ID: NCI-2016-01058
  • SECONDARY ID: 2015-0152
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT02757391

Conditions

  • Colorectal Adenocarcinoma
  • Metastatic Cholangiocarcinoma
  • Metastatic Colorectal Carcinoma
  • Metastatic Digestive System Carcinoma
  • Metastatic Esophageal Carcinoma
  • Metastatic Gastric Carcinoma
  • Metastatic Pancreatic Adenocarcinoma
  • Stage IV Colorectal Cancer AJCC v7
  • Stage IV Esophageal Cancer AJCC v7
  • Stage IV Gastric Cancer AJCC v7
  • Stage IV Pancreatic Cancer AJCC v6 and v7
  • Stage IVA Colorectal Cancer AJCC v7
  • Stage IVB Colorectal Cancer AJCC v7

Interventions

DrugSynonymsArms
Adoptive ImmunotherapyACT, ACT Therapy, Adoptive Cell Immunotherapy, Adoptive Cell Transfer, Adoptive Cell Transfer Immunotherapy, Adoptive Cell Transfer Therapy, adoptive cellular immunotherapy, adoptive cellular therapy, cellular adoptive immunotherapyTreatment (CD8 +T cell therapy, pembrolizumab)
Aldesleukin125-L-Serine-2-133-interleukin 2, Proleukin, r-serHuIL-2, Recombinant Human IL-2, Recombinant Human Interleukin-2Treatment (CD8 +T cell therapy, pembrolizumab)
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, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719Treatment (CD8 +T cell therapy, pembrolizumab)
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (CD8 +T cell therapy, pembrolizumab)

Purpose

This phase I pilot trial studies the side effects of cluster of differentiation 8 (CD8)+ T cells in treating patients with gastrointestinal tumors that have spread to other places in the body. Tumor cells and blood are used to help create an adoptive T cell therapy, such as CD8+ T cell therapy, that is individually designed for a patient and may help doctors learn more about genetic changes in the tumor. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving CD8+ T cell therapy and pembrolizumab may work better in treating patients with gastrointestinal tumors.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Assess the safety of using a personalized adoptive T cell therapy in patients with
      advanced gastrointestinal malignancies.

      SECONDARY OBJECTIVES:

      I. Assess the persistence of an immune response after T cell infusion. II. Determine the
      clinical benefit of adoptive T cell therapy in advanced gastrointestinal cancers.

      OUTLINE:

      Beginning 2 days prior to CD8+ T cell infusion, patients receive cyclophosphamide
      intravenously (IV) over 30 minutes. Patients undergo CD8+ T cell infusion IV over 2 hours on
      day 0 and receive aldesleukin subcutaneously (SC) twice daily (BID) on days 1-14. Beginning
      on day 1 about 24 hours after CD8+ T cell infusion, patients receive pembrolizumab IV over
      30-60 minutes on weeks 3, 6, 12, and 15.

      After completion of study treatment, patients are followed up for 24 weeks.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (CD8 +T cell therapy, pembrolizumab)ExperimentalBeginning 2 days prior to CD8+ T cell infusion, patients receive cyclophosphamide IV over 30 minutes. Patients undergo CD8+ T cell infusion IV over 2 hours on day 0 and receive aldesleukin SC BID on days 1-14. Beginning on day 1 about 24 hours after CD8+ T cell infusion, patients receive pembrolizumab IV over 30-60 minutes on weeks 3, 6, 12, and 15.
  • Adoptive Immunotherapy
  • Aldesleukin
  • Cyclophosphamide
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Histopathologic documentation of pancreatic adenocarcinoma, colorectal adenocarcinoma,
             cholangiocarcinoma, esophageal cancer and gastric cancer with radiographic evidence of
             metastatic disease

          -  Eastern Cooperative Oncology Group (ECOG)/Zubrod performance status of 0 or 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 at least 8 weeks after pembrolizumab is stopped; 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; acceptable forms of birth control include condom, diaphragm,
             hormonal, intrauterine device (IUD), or sponge plus spermicide; abstinence is also an
             acceptable form of birth control

          -  Men 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

          -  Adequate vein access: consider peripherally inserted central catheter (PICC) or other
             central line

          -  Patients must have adequate tissue (fresh or frozen) available or planned removal of
             adequate tissue for analysis; at least 250 mg of tumor are needed for peptide elution;
             there is no specific time limit on how long the tissue can remain frozen prior to use

          -  Patients can have any lines (including zero) of prior therapy to sign consent prior to
             tissue harvest

          -  Toxicity related to prior therapy must either have returned to =< grade 1, baseline,
             or been deemed irreversible

          -  ELIGIBILITY FOR TREATMENT: ECOG/Zubrod performance status of 0 to 2

          -  Bi-dimensionally measurable disease by radiographic imaging (computed tomography [CT]
             scan) that represents at least one measurable lesion per Response Evaluation Criteria
             in Solid Tumors (RECIST) version (v)1.1

          -  At least 4 weeks must have elapsed since the last chemotherapy, radiotherapy or major
             surgery

          -  Toxicity related to prior therapy must either have returned to less than or equal to
             grade 1, baseline, or been deemed irreversible

          -  Subjects must have received at least one line of chemotherapy prior to receiving
             adoptive T cell therapy and should have exhausted standard of care systemic therapy
             options; the decision to implement the T cell therapy will be at the discretion of the
             treating physician; the timing and total exposure to chemotherapy will depend on the
             tumor type in question (more systemic options for breast cancer; fewer for gastric
             cancer, for example); due to the heterogeneity of tumors being treated in this
             protocol, the discretion of the treating physician in terms of timing of immunotherapy
             will be critical

        Exclusion Criteria:

          -  EXCLUSION FOR ENROLLMENT: Any other malignancy from which the patient has been
             disease-free for less than 5 years, with the exception of adequately treated and cured
             basal or squamous cell skin cancer, superficial bladder cancer, and carcinoma in situ
             of the cervix

          -  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

          -  Significant cardiovascular abnormalities as defined by any one of the following:

               -  Congestive heart failure New York Heart Association (NYHA) classes II-IV;
                  patients with asymptomatic class I congestive heart failure (CHF) may participate
                  in conjunction with a cardiology consultation

               -  Clinically significant hypotension

               -  Symptoms of coronary artery disease

               -  Presence of arrhythmias in electrocardiography (EKG) requiring drug therapy

          -  Active and untreated central nervous system (CNS) metastases (including metastasis
             identified during screening MRI or contrast CT); patients with asymptomatic, treated
             metastases may be eligible if their lesion(s) have demonstrated stability over 2
             months

          -  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

          -  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

          -  White blood cell (WBC) less than or equal to 2000/uL

          -  Hematocrit (Hct) less than or equal to 24% or hemoglobin (Hgb) less than or equal to 8
             g/dL

          -  Absolute neutrophil count (ANC) less than or equal to 1000

          -  Platelets less than or equal to 75,000

          -  Creatinine greater than or equal to 1.5 x upper limit of normal (ULN) OR creatinine
             clearance > 50 ml/min/1.73 m^2 for patients with creatinine levels above institutional
             normal limits

          -  Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) greater than or equal
             to 2.5 x ULN

          -  Bilirubin greater than or equal to 2.0 x ULN

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

          -  EXCLUSION CRITERIA FOR TREATMENT: WBC less than or equal to 2000/uL

          -  EXCLUSION CRITERIA FOR TREATMENT: Hct less than or equal to 24%

          -  EXCLUSION CRITERIA FOR TREATMENT: Hgb less than or equal to 8 g/dL

          -  EXCLUSION CRITERIA FOR TREATMENT: ANC less than or equal to 1000

          -  EXCLUSION CRITERIA FOR TREATMENT: Platelets less than or equal to 75,000

          -  EXCLUSION CRITERIA FOR TREATMENT: Creatinine greater than or equal to 1.5 x ULN OR
             creatinine clearance > 50 ml/min/1.73m^2 for patients with creatinine levels above
             institutional normal limits

          -  EXCLUSION CRITERIA FOR TREATMENT: AST/ALT greater than or equal to 2.5 x ULN

          -  EXCLUSION CRITERIA FOR TREATMENT: Bilirubin greater than or equal to 2.0 x ULN

          -  Steroids are not permitted 3 days prior to T cell infusion and concurrently during
             therapy

          -  Uncontrolled concurrent illness including, but not limited to ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations that would limit compliance with
             study requirements

          -  Any non-oncology vaccine therapy used for the prevention of infectious disease within
             1 month before or after any anti-programmed cell death protein 1 (PD1) monoclonal
             antibody (anti-PD-1) dose

          -  After the T cell infusion, patients may not be on any other treatments for their
             cancer aside from those included in the treatment section of the protocol

          -  Coagulation 1.5 x ULN unless participant is receiving anticoagulant therapy as long as
             prothrombin time (PT) or a partial thromboplastin time (PTT) is within therapeutic
             range of intended use of anticoagulants
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of toxicity defined as grade 3 or 4 non-hematologic or grade 4 hematologic toxicity per Common Terminology Criteria for Adverse Events version 4.0
Time Frame:Up to 24 weeks
Safety Issue:
Description:Will monitor toxicity of the personalized vaccines in using cohorts of size of 5, starting from the 1st patient using the Bayesian approach of Thall, Simon, Estey.

Secondary Outcome Measures

Measure:Persistence of an immune response defined by level of tetramer positive T cell population over time after T cell infusion
Time Frame:Up to 24 weeks
Safety Issue:
Description:
Measure:Persistence of an immune response defined by T cell interferon gamma release in response to selected personalized peptide antigens
Time Frame:Up to 24 weeks
Safety Issue:
Description:
Measure:Persistence of an immune response defined by levels of intracellular cytokine staining of T cells in response to stimulation with personalized peptide antigens
Time Frame:Up to 24 weeks
Safety Issue:
Description:
Measure:Persistence of an immune response defined by detection of antigen spreading
Time Frame:Up to 24 weeks
Safety Issue:
Description:
Measure:Proportion of patients who have received T cell infusion that is alive and progression free (complete response [CR] + partial response [PR] + stable disease) defined based on response criteria according to Response Evaluation Criteria in Solid Tumors 1.1
Time Frame:At 12 weeks post infusion
Safety Issue:
Description:
Measure:Time to progression
Time Frame:Up to 24 weeks
Safety Issue:
Description:
Measure:Response rate (CR + PR)
Time Frame:Up to 24 weeks
Safety Issue:
Description:The response rate will be evaluated using a Simon optimal two-stage design.
Measure:Overall survival
Time Frame:Up to 24 weeks
Safety Issue:
Description:

Details

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

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