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Summary

for people ages 18–75 (full criteria)
at San Francisco, California and other locations
study started
estimated completion:
Robin K Kelley

Description

Summary

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.

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)

Details

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.

Keywords

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

Eligibility

You can join if…

Open to people ages 18–75

  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%

You CAN'T join if...

  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:
  4. Cytotoxic chemotherapy, immune therapy and biological therapy within 3 weeks
  5. Corticosteroids or any other immunosuppressive therapy within 2 weeks. NOTE: Use of inhaled steroids is not exclusionary.
  6. Sorafenib within 1 week
  7. Investigational treatment or clinical trial within 4 weeks.
  8. Duration of treatment free intervals for any other anti-cancer therapies must be discussed with Adaptimmune study physician.
  9. Received the following prior to lymphodepleting chemotherapy:
  10. Cytotoxic chemotherapy or loco-regional therapy within 3 weeks, liver directed radiation therapy within three months.
  11. Corticosteroids or any other immunosuppressive therapy within 2 weeks. NOTE: Use of inhaled steroids is not exclusionary
  12. Bone/soft tissue directed palliative radiotherapy within 4 weeks.
  13. Investigational treatment or clinical trial within 4 weeks.
  14. Sorafenib within 1 week.
  15. Prior cancer-directed immunotherapy within 3 weeks, including monoclonal antibodies against PD-1 receptor or ligand.
  16. 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
  17. Any previous gene therapy using an integrated vector
  18. Duration of treatment free intervals for any other anti-cancer therapies must be discussed with Adaptimmune study physician.
  19. Toxicity persisting from previous anti-cancer therapy of ≥ Grade 2
  20. Major surgery within 4 weeks prior to lymphodepletion; subjects should have been fully recovered from any surgical related toxicities.
  21. Bleeding ≥ grade 2 in the past 3 months
  22. Therapeutic anticoagulation (prophylactic heparin allowed)
  23. Clinically detectable ascites or ascites requiring medication
  24. Clinically detectable hepatic encephalopathy or hepatic encephalopathy requiring medication
  25. Active viral hepatitis Subjects positive for hepatitis B surface antigen not on antiviral treatment/prophylaxis or subjects with detectable hepatitis B DNA
  26. 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
  27. Subjects with hepatitis C allowed provided they meet all other eligibility criteria
  28. Positive serology for HIV
  29. Positive serology for HTLV 1 or 2
  30. 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.
  31. Subject has known history of brain metastases.
  32. Other active malignancy besides HCC within 2 years.
  33. Subjects must be in complete remission from prior malignancy in order to be eligible to enter the study.
  34. 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.
  35. 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).
  36. Bacterial or opportunistic infection within 3 months of treatment (URI and uncomplicated UTI allowed)
  37. Uncontrolled intercurrent illness considered by the Investigator to add appreciable risk to study participation, including but not limited to:
  38. 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.
  39. Oxygen dependent lung disease.
  40. Clinically significant psychiatric illness/social situations that would limit compliance with study requirements.
  41. Pregnant or breastfeeding
  42. Alcohol or illicit drug dependency

Locations

  • UCLA accepting new patients
    Los Angeles, California, 90095, United States

Details

Status
accepting new patients
Start Date
Completion Date
(estimated)
Sponsor
Adaptimmune
ID
NCT03132792
Phase
Phase 1
Lead Scientist
Robin K Kelley
Study Type
Interventional
Last Updated
August 1, 2017
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