Clinical Trials /

AFPᶜ³³²T in Advanced HCC

NCT03132792

Description:

This first time in human study is intended for men and women at least 18 years of age who have advanced liver cancer which has grown or returned after being treated. Those who did not tolerate or refused other therapies may also participate. The purpose of this study is to test the safety of genetically changed T cells that target alpha-fetoprotein (AFP) and find out what effects, if any, they have in subjects with liver cancer. This study is for subjects who have a blood test positive for appropriate HLA-A*02 and have adequate AFP protein in blood or tumor, and whose noncancerous liver tissue has very little AFP protein. The study will take the subject's T cells, which are a natural type of immune cell in the blood, and send them to a laboratory to be modified. The changed T cells used in this study will be the subject's own T cells that have been genetically changed with the aim of attacking and destroying cancer cells. The manufacturing of T cells takes about 1 month to complete. The T cells will be given back to the subject through an intravenous infusion after 3 days of chemotherapy. The study will evaluate three different cell dose levels in order to find out the target cell dose. Once the target cell dose is determined, additional subjects will be enrolled to further test the safety and effects at this cell dose. Subjects will be hospitalized for at least 1 week after receiving their T cells back and then seen frequently by the Study Physician for the next 6 months. After that, subjects will be seen every three months. If subjects have disease progression or withdraw from the study, they will then be entered into a long-term follow up for safety monitoring. In long-term follow up, subjects will be seen every 6 months by their Study Physician for the first 5 years after the T cell infusion and annually for the next 10 years.

Related Conditions:
  • Hepatocellular Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: AFPᶜ³³²T in Advanced HCC
  • Official Title: A Phase I Open Label Clinical Trial Evaluating the Safety and Anti-Tumor Activity of Autologous T Cells Expressing Enhanced TCRs Specific for Alpha Fetoprotein (AFPᶜ³³²T) in HLA-A2 Positive Subjects With Advanced Hepatocellular Carcinoma (HCC)

Clinical Trial IDs

  • ORG STUDY ID: ADP-0033-001
  • NCT ID: NCT03132792

Conditions

  • Hepatocellular Cancer

Purpose

This study will investigate the safety and tolerability of AFPᶜ³³²T cell therapy in subjects who have the appropriate HLA-A2 tissue marker, whose liver tumor has the AFP protein and whose noncancerous liver tissue has very little AFP protein. This study will take a subject's T cells and give them a T cell receptor protein that recognizes and attacks the tumors.

Detailed Description

      This is a first time in human, dose escalation study of genetically engineered AFPᶜ³³²T
      cells in HLA-A *02:01 positive subjects with advanced hepatocellular cancer (HCC).

      Subjects who are eligible based on HLA type and have AFP positive, histologically confirmed
      measurable HCC that is not amenable to transplant, resection or locoregional therapy will be
      screened for general health, performance status and disease stage. Subjects must also have a
      relative absence of AFP expression in their noncancerous liver tissue.

      Following screening, subjects meeting all eligibility criteria will undergo leukapheresis to
      obtain cells for the manufacture of autologous AFP TCR bearing T cells. All eligibility
      criteria will be reconfirmed and baseline tumor measurements will be obtained prior to
      lymphodepleting therapy.

      Once manufacturing of AFPᶜ³³²T cells is complete, subjects will undergo lymphodepleting
      chemotherapy with cyclophosphamide alone (Group 1a) or cyclophosphamide plus fludarabine
      (Group 1B, 2 and 3), followed by infusion of transduced cells on Day 1. AFPᶜ³³²T cell dose
      escalation starts at 1 x 10⁸ cells with target cell dose of 5 x 10⁹ cells.
    

Trial Arms

NameTypeDescriptionInterventions
Autologous genetically modified AFPᶜ³³²T cellsExperimental

    Eligibility Criteria

            Inclusion Criteria:
    
              1. Subject is ≥ 18 years and ≤ 75 years of age and has voluntarily agreed to participate
                 by giving written informed consent
    
              2. Histologically confirmed HCC, not amenable to transplant, resection or locoregional
                 therapy
    
              3. Measurable disease according to RECIST 1.1 criteria.
    
              4. Progressive disease following or intolerant of or refuses sorafenib treatment
    
              5. HLA-A*02:01 positive during the escalation portion of the study. (Eligibility may be
                 broadened to include HLA-A*02:05, *02:06, or *02:07 for the expansion portion of the
                 study based on the accumulated safety experience, and approval of the safety review
                 committee (SRC).
    
              6. Subjects must have a tumor biopsy available for AFP expression evaluation prior to
                 enrollment. Either an archival specimen (taken within the past 6 months from
                 screening) or a new biopsy will be required. Both tumor and noncancerous cells must
                 be present for histological evaluation. Subjects will be eligible for enrollment if
                 their tumors have AFP expression of ≥2+ in ≥40% tumor cells by immunohistochemistry
                 and if their non-cancerous liver tissue has ≤5% cells stained for AFP by
                 immunohistochemistry. Based on the data from dose escalation cohort and with the
                 SRC's approval, subjects in the expansion portion of the study may be enrolled
                 without requiring noncancerous biopsy tissue. Subjects with serum AFP levels within
                 the normal range are unlikely to have AFP expressing tumors and generally should not
                 undergo new tumor biopsy for the purpose of participating in this study.
    
              7. Life expectancy of > 4 months
    
              8. Child-Pugh score ≤ 6
    
              9. ECOG 0-1
    
             10. Female subjects of childbearing potential (FCBP) must have a negative serum pregnancy
                 test. NOTE: FCBP is defined as premenopausal and not surgically sterilized. FCBP must
                 agree to use maximally effective birth control or to abstain from heterosexual
                 activity throughout the study, starting at the first dose of chemotherapy for at
                 least 12 months thereafter or 4 months after there is no evidence of persistence or
                 gene modified cells are in the subject's blood, whichever is longer. Effective
                 contraceptive methods include intra-uterine device, oral and injectable hormonal
                 contraception, or 2 adequate barrier methods (e.g. diaphragm with spermicide,
                 cervical cap with spermicide, or female condom with spermicide). Spermicides alone
                 are not an adequate method of contraception. Or Male subjects must be surgically
                 sterile or agree to use a double barrier contraception method or abstain from
                 heterosexual activity with a female of childbearing potential starting at the first
                 dose of chemotherapy and for 4 months thereafter.
    
             11. Subject must have adequate organ function as indicated by the following laboratory
                 values below:
    
                   -  White Blood Cells (WBS) ≥ 3.0 x10⁹/L
    
                   -  Absolute Neutrophil count (ANC) ≥ 1.5 x10⁹/L (without GCSF support)
    
                   -  Platelets ≥ 80 x10⁹/L (without transfusion support within 7 days from start of
                      leukapheresis)
    
                   -  Hemoglobin > 8 g/dL (without transfusion support within 7 days prior to
                      leukapheresis)
    
                   -  INR <1.7
    
                   -  Partial Thromboplastin Time (PTT) ≤ 1.5x upper limit of normal (ULN)
    
                   -  Calculated or measured creatinine clearance ≥ 50 mL/min
    
                   -  Serum total bilirubin <2.5 mg/dL (42 μmol/L)
    
                   -  Serum Albumin ≥3.0 g/dL
    
                   -  Alanine aminotransferase (ALT)/Serum Glutamic Pyruvic Transaminase (SGPT) ≤ 3x
                      ULN
    
                   -  Left ventricular ejection fraction (LVEF) by ECHO or MUGA ≥ 50%
    
            Exclusion Criteria:
    
              1. Positive for any of the following alleles: HLA-A*02:02, HLA-C*0404 or HLA-B*5103
    
              2. Prior liver transplant
    
              3. Received the following prior to leukapheresis:
    
                   1. Cytotoxic chemotherapy, immune therapy and biological therapy within 3 weeks
    
                   2. Corticosteroids or any other immunosuppressive therapy within 2 weeks. NOTE: Use
                      of inhaled steroids is not exclusionary.
    
                   3. Sorafenib within 1 week
    
                   4. Investigational treatment or clinical trial within 4 weeks.
    
                   5. Duration of treatment free intervals for any other anti-cancer therapies must be
                      discussed with Adaptimmune study physician.
    
              4. Received the following prior to lymphodepleting chemotherapy:
    
                   1. Cytotoxic chemotherapy or loco-regional therapy within 3 weeks, liver directed
                      radiation therapy within three months.
    
                   2. Corticosteroids or any other immunosuppressive therapy within 2 weeks. NOTE: Use
                      of inhaled steroids is not exclusionary
    
                   3. Bone/soft tissue directed palliative radiotherapy within 4 weeks.
    
                   4. Investigational treatment or clinical trial within 4 weeks.
    
                   5. Sorafenib within 1 week.
    
                   6. Prior cancer-directed immunotherapy within 3 weeks, including monoclonal
                      antibodies against PD-1 receptor or ligand.
    
                   7. Use of an experimental vaccine within 2 months in the absence of tumor response.
                      The subject should be excluded if their disease is responding to an experimental
                      vaccine given within 6 months
    
                   8. Any previous gene therapy using an integrated vector
    
                   9. Duration of treatment free intervals for any other anti-cancer therapies must be
                      discussed with Adaptimmune study physician.
    
              5. Toxicity persisting from previous anti-cancer therapy of ≥ Grade 2
    
              6. Major surgery within 4 weeks prior to lymphodepletion; subjects should have been
                 fully recovered from any surgical related toxicities.
    
              7. Bleeding ≥ grade 2 in the past 3 months
    
              8. Therapeutic anticoagulation (prophylactic heparin allowed)
    
              9. Clinically detectable ascites or ascites requiring medication
    
             10. Clinically detectable hepatic encephalopathy or hepatic encephalopathy requiring
                 medication
    
             11. Active viral hepatitis Subjects positive for hepatitis B surface antigen not on
                 antiviral treatment/prophylaxis or subjects with detectable hepatitis B DNA
    
                   1. Subjects with resolved (surface antigen negative, core antibody positive) or
                      chronic stable (surface antigen positive) hepatitis B on antiviral
                      treatment/prophylaxis with undetectable DNA are allowed
    
                   2. Subjects with hepatitis C allowed provided they meet all other eligibility
                      criteria
    
             12. Positive serology for HIV
    
             13. Positive serology for HTLV 1 or 2
    
             14. History of chronic or recurrent (within the last year) severe autoimmune or immune
                 mediated disease requiring steroids or other immunosuppressive treatments. Subjects
                 with history of idiopathic autoimmune hepatitis are excluded. Subjects who
                 experienced hepatitis during treatment with check point inhibiting antibodies are not
                 excluded.
    
             15. Subject has known history of brain metastases.
    
             16. Other active malignancy besides HCC within 2 years.
    
                   1. Subjects must be in complete remission from prior malignancy in order to be
                      eligible to enter the study.
    
                   2. Adequately treated malignancies not likely to require therapy (e.g. completely
                      resected non-melanomatous skin carcinoma or successfully treated in situ
                      carcinoma) are eligible to enter the study.
    
             17. Electrocardiogram (ECG) showing clinically significant abnormality at Screening or
                 showing a QTc interval ≥450 msec in males and ≥470 msec in females (≥480 msec for
                 subjects with Bundle Branch Block (BBB) over consecutive ECGs).
    
             18. Bacterial or opportunistic infection within 3 months of treatment (URI and
                 uncomplicated UTI allowed)
    
             19. Uncontrolled intercurrent illness considered by the Investigator to add appreciable
                 risk to study participation, including but not limited to:
    
                   1. Clinically significant cardiac disease defined by CHF New York Heart Association
                      (NYHA) > Class 1; uncontrolled clinically significant arrhythmia in last 6
                      months; Acute Coronary Syndrome (ACS) (angina or MI) in last 6 months.
    
                   2. Oxygen dependent lung disease.
    
                   3. Clinically significant psychiatric illness/social situations that would limit
                      compliance with study requirements.
    
             20. Pregnant or breastfeeding
    
             21. Alcohol or illicit drug dependency
          
    Maximum Eligible Age:75 Years
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Number of subjects with dose-limiting toxicity (DLT) and adverse events (AE), including serious adverse events (SAE).
    Time Frame:2 years
    Safety Issue:
    Description:Determine if treatment with autologous genetically modified T cells, (AFPᶜ³³²T) is safe and tolerable through assessment of DLTs, AEs, including SAEs; laboratory assessments including chemistry, hematology, coagulation and cardiac assessments, including ECG and ECHO/MUGA, persistence of AFPᶜ³³²T, and circulating cytokines

    Secondary Outcome Measures

    Measure:Proportion of subjects with a confirmed Complete Response (CR) or Partial Response (PR)
    Time Frame:2 years
    Safety Issue:
    Description:Evaluation of the efficacy of the treatment by assessment of the Overall Response Rate according to RECIST v1.1
    Measure:Interval between the date of first T cell infusion dose and first documented evidence of CR or PR
    Time Frame:2 years
    Safety Issue:
    Description:Evaluation of the efficacy of the treatment by assessment of time to first response
    Measure:Interval between the date of first documented evidence of CR or PR until first documented disease progression or death due to any cause
    Time Frame:2 years
    Safety Issue:
    Description:Evaluation of the efficacy of the treatment by assessment of duration of response
    Measure:Interval between the date of first documented evidence of SD until first documented disease progression or death due to any cause
    Time Frame:2 years
    Safety Issue:
    Description:Evaluation of the efficacy of the treatment by assessment of duration of stable disease
    Measure:Interval between the date of first T cell infusion and the earliest date of disease progression or death due to any cause
    Time Frame:2 years
    Safety Issue:
    Description:Evaluation of the efficacy of the treatment by assessment of progression-free survival
    Measure:Interval between the date of first T cell infusion and date of disease progression or death due to any cause
    Time Frame:2 years
    Safety Issue:
    Description:Evaluation of the efficacy of the treatment by assessment of overall survival

    Details

    Phase:Phase 1
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:Adaptimmune

    Trial Keywords

    • Alpha-fetoprotein
    • Cell Therapy
    • T Cell Therapy
    • SPEAR T Cell
    • Immuno-oncology
    • Metastatic
    • Previously treated
    • T Cell Receptor

    Last Updated

    May 10, 2017