AFPᶜ³³²T in Advanced HCC

Adaptimmune39 enrolled

Overview

This first time in human study is intended for men and women between 18 and 75 years of age who have advanced liver cancer which has grown or returned after being treated or another AFP expressing tumor. 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 or other AFP expressing tumor types. This study is for subjects who have a blood test positive for appropriate HLA-A\*02 P Group and have adequate AFP protein in blood or tumor, and whose noncancerous liver tissue has very little AFP protein (Liver only). 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.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Eligibility

Sex: ALLMin age: 18 YearsMax age: 75 Years

Medical Language ↔ Plain English

Key Inclusion Criteria: 1. Subject is ≥ 18 years and ≤ 75 years of age and has voluntarily agreed to participate by giving written informed consent in accordance with ICH GCP Guidelines and applicable local regulations. 2. Histologically confirmed HCC, not amenable to transplant, resection. Subjects may undergo loco-regional therapy after enrollment but not at time of lymphodepletion. Or Histologically confirmed diagnosis of another AFP expressing tumor (e.g. cholangiocarcinoma). 3. Measurable disease according to RECIST 1.1 criteria prior to lymphodepletion. 4. Progressive disease following or intolerant of or refuses standard of care systemic therapy prior to lymphodepletion. 5. Positive for any A\*02:01 P group allele. 6. a) Group 1, 2, 3, (HCC) Subjects will be eligible for enrollment if they meet either one of these AFP expression criteria: * AFP expression of ≥1+ in ≥20% of tumor cells by immunohistochemistry and their non-cancerous liver tissue has ≤5% cells stained for AFP at any intensity by immunohistochemistry. * Serum AFP levels of ≥100ng/mL and their non-cancerous liver tissue has ≤5% cells stained for AFP at any intensity by immunohistochemistry. 6\. b) Group 4 (other AFP expressing tumor types) Subjects will be eligible for enrollment if they meet either one of these AFP expression criteria: o Serum AFP levels of ≥100ng/mL and their non-cancerous liver tissue (if applicable) has ≤5% cells stained for AFP at any intensity by immunohistochemistry. 7\. Life expectancy of \> 4 months 8. Child-Pugh score ≤ 6 9. Eastern Cooperative Oncology Group (ECOG) 0-1 10. Subject must have adequate organ function as defined in the protocol. Key Exclusion Criteria: 1. Positive for any of the HLA-A\*02 allele other than HLA-A\*02:01 P Group, HLA-A\*02:03 P group or null alleles or positive for the following alleles: HLA-C\*04:04 or HLA-B\*51:03. 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 or topical steroids is not exclusionary 3. Sorafenib/Regorafenib/Lenvatinib within 1 week 4. Cabozantinib within 2 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 or topical 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/Regorafenib/Lenvatinib within 1 week. 6. Cabozantinib within 2 weeks 7. Prior cancer-directed immunotherapy within 4 weeks, including monoclonal antibodies against PD-1 receptor or ligand. 8. 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 9. Any previous gene therapy using an integrated vector 10. 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 (except for non-clinically significant toxicities, e.g., alopecia, vitiligo). Subjects with Grade 2 toxicities that are deemed stable or irreversible (e.g. peripheral neuropathy) can be enrolled on a case-by-case basis with prior consultation and agreement with the Sponsor Study Physician. 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 prior to lymphodepletion 8. Therapeutic anticoagulation from lymphodepletion until platelet count recovery (prophylactic heparin allowed) 9. Clinically or radiographically detectable ascites (beyond trace/rim of 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 DNA levels of ≤100 IU/mL are allowed with HBV DNA monitoring after treatment 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 brain metastases. 16. Other active malignancy besides HCC or other eligible AFP expressing tumor types within 3 years. 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 (upper respiratory infection and uncomplicated urinary tract infection 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 myocardial infarction) in last 6 months. 2. Oxygen dependent lung disease. 3. Clinically significant psychiatric illness/social situations that would limit compliance with study requirements. 4. History of stroke or central nervous system bleeding; transient ischemic attack (TIA) or reversible ischemic neurologic deficit (RIND) in last 6 months. 20. Pregnant or breastfeeding 21. Alcohol or illicit drug dependency 22. Known contraindication to cyclophosphamide, fludarabine, mesna, G-CSF or other agents associated with study treatment.

Locations (21)

Mayo Clinic Arizona

Phoenix, Arizona, United States

USC/Norris Comprehensive Cancer Center

Los Angeles, California, United States

UCLA

Los Angeles, California, United States

University of Miami

Miami, Florida, United States

Winship Cancer Institute - Emory University

Atlanta, Georgia, United States

University of Maryland, Greenebaum Cancer Center

Baltimore, Maryland, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

Mayo Clinic Clinical Trial Referral Office

Rochester, Minnesota, United States

Washington University - School of Medicine

St Louis, Missouri, United States

MD Anderson Cancer Center

Houston, Texas, United States

...and 11 more locations

Outcomes

Primary Outcomes

Incidence of Dose-limiting Toxicities (DLTs)

Number of participants experiencing at least one dose-limiting toxicity (DLT) following administration of autologous genetically modified AFPᶜ³³²T cells, assessed during the protocol-defined DLT evaluation period.

Time frame: The DLT observation period was from the time of chemotherapy until 30 days following the infusion of AFPc332T cells for each participant in all groups.

Number of Participants With Treatment-Emergent Adverse Events (TEAEs)

Number of participants experiencing at least one treatment-emergent adverse event (TEAE) following administration of lymphodepleting chemotherapy and autologous genetically modified AFPᶜ³³²T cells.

Time frame: From first lymphodepleting chemotherapy through end of safety follow-up. Assessed at Days 9, 11, Weeks 2, 3, 4, 8, 12, 16, 24, then every 3 months until progression or withdrawal, up to approximately 4 years (data cut-off: 08 November 2022).

Number of Participants With Serious Adverse Events (SAEs)

Number of participants experiencing at least one serious adverse event (SAE) following administration of lymphodepleting chemotherapy and autologous genetically modified AFPᶜ³³²T cells

Secondary Outcomes

Overall Response Rate (ORR)

Overall Response Rate (ORR) defined as the proportion of participants with a confirmed Complete Response (CR) or Partial Response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST v1.1). CR = disappearance of all target lesions; PR = at least 30% decrease in the sum of diameters of target lesions. Response confirmation required a repeat assessment no less than 4 weeks after the criteria for response were first met.

Time frame: From first T-cell infusion; tumour assessments at Baseline, Weeks 4, 8, 16, 24, then every 3 months until disease progression or withdrawal, up to approximately 2 years (data cut-off: 08 November 2022).

Interval Between Date of First Documented Evidence of CR or PR Until First Documented Disease Progression or Death Due to Any Cause

Duration of response (DoR) was measured from the date of first documented confirmed Complete Response (CR) or Partial Response (PR) per RECIST v1.1 until the date of first documented disease progression or death due to any cause. Only participants achieving a confirmed CR or PR were included in this analysis.

Time frame: From date of first confirmed CR or PR until disease progression or death due to any cause, assessed at Weeks 4, 8, 16, 24 and every 3 months thereafter, up to approximately 2 years (data cut-off: 08 November 2022).

Interval Between the Date of First Documented Evidence of SD Until First Documented Disease Progression or Death Due to Any Cause

Duration of stable disease (DoSD) was measured from the date of first documented Stable Disease (SD) per RECIST v1.1 until the date of first documented disease progression or death due to any cause. Only participants achieving SD were included in this analysis.

Time frame: From date of first documented SD until disease progression or death due to any cause, assessed at Weeks 4, 8, 16, 24 and every 3 months thereafter, up to approximately 2 years (data cut-off: 08 November 2022).

Interval Between the Date of First T Cell Infusion and the Earliest Date of Disease Progression or Death Due to Any Cause

Progression-free survival (PFS) was measured from the date of first T-cell infusion until the date of first documented disease progression per RECIST v1.1 or death due to any cause, whichever occurred first. Participants without a PFS event were censored at the date of last tumour assessment.

Time frame: From date of first T-cell infusion until disease progression or death due to any cause, assessed at Weeks 4, 8, 16, 24 and every 3 months thereafter, up to approximately 2 years (data cut-off: 08 November 2022).

Interval Between the Date of First T-Cell Infusion and Date of Death Due to Any Cause

Overall survival (OS) was measured from the date of first T-cell infusion until the date of death due to any cause. Participants who had not died at the data cut-off were censored at the date last known to be alive.

Time frame: From date of first T-cell infusion until death due to any cause, assessed every 3 months until disease progression and every 6 months thereafter during long-term follow-up, up to approximately 4 years (data cut-off: 08 November 2022).