AFPᶜ³³²T in Advanced HCC

Sponsor

Adaptimmune (Industry)

Overall Status

Recruiting

CT.gov ID

NCT03132792

Collaborator

(none)

Enrollment

Locations

Arm

108.8

Anticipated Duration (Months)

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Hepatocellular Cancer AFP Expressing Tumors	Genetic: Autologous genetically modified AFPᶜ³³²T cells	Phase 1

Study Design

Study Type:

Interventional

Anticipated Enrollment :

45 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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) or Other AFP Expressing Tumor Types

Actual Study Start Date :

May 8, 2017

Anticipated Primary Completion Date :

Sep 1, 2023

Anticipated Study Completion Date :

Jun 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Autologous genetically modified AFPᶜ³³²T cells	Genetic: Autologous genetically modified AFPᶜ³³²T cells Infusion of autologous genetically modified AFPᶜ³³²T cells

Arm

Intervention/Treatment

Experimental: Autologous genetically modified AFPᶜ³³²T cells

Genetic: Autologous genetically modified AFPᶜ³³²T cells

Infusion of autologous genetically modified AFPᶜ³³²T cells

Outcome Measures

Primary Outcome Measures

Number of subjects with dose-limiting toxicity (DLT) and adverse events (AEs) and determination of optimally tolerated dose range, including serious adverse events (SAE). [2 years]
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, cardiac assessments including ECG, and cardiac Troponin

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Key Inclusion Criteria:

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.
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).
Measurable disease according to RECIST 1.1 criteria prior to lymphodepletion.
Progressive disease following or intolerant of or refuses standard of care systemic therapy prior to lymphodepletion.
Positive for any A*02:01 P group allele.
1. 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.

1. 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.

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:

Positive for any of the HLA-A02 allele other than HLA-A02:01 P Group, HLA-A02:03 P group or null alleles or positive for the following alleles: HLA-C04:04 or HLA-B*51:03.
Prior liver transplant
Received the following prior to leukapheresis:
Cytotoxic chemotherapy, immune therapy and biological therapy within 3 weeks
Corticosteroids or any other immunosuppressive therapy within 2 weeks. NOTE: Use of inhaled or topical steroids is not exclusionary
Sorafenib/Regorafenib/Lenvatinib within 1 week
Cabozantinib within 2 weeks
Duration of treatment free intervals for any other anti-cancer therapies must be discussed with Adaptimmune Study Physician.
Received the following prior to lymphodepleting chemotherapy :
Cytotoxic chemotherapy or loco-regional therapy within 3 weeks, liver directed radiation therapy within three months.
Corticosteroids or any other immunosuppressive therapy within 2 weeks. NOTE: Use of inhaled or topical steroids is not exclusionary
Bone/soft tissue directed palliative radiotherapy within 4 weeks.
Investigational treatment or clinical trial within 4 weeks.
Sorafenib/Regorafenib/Lenvatinib within 1 week.
Cabozantinib within 2 weeks
Prior cancer-directed immunotherapy within 4 weeks, including monoclonal antibodies against PD-1 receptor or ligand.
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
Any previous gene therapy using an integrated vector
Duration of treatment free intervals for any other anti-cancer therapies must be discussed with Adaptimmune Study Physician.
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.
Major surgery within 4 weeks prior to lymphodepletion; subjects should have been fully recovered from any surgical related toxicities.
Bleeding ≥ Grade 2 in the past 3 months prior to lymphodepletion
Therapeutic anticoagulation from lymphodepletion until platelet count recovery (prophylactic heparin allowed)
Clinically or radiographically detectable ascites (beyond trace/rim of ascites) or ascites requiring medication
Clinically detectable hepatic encephalopathy or hepatic encephalopathy requiring medication
Active viral hepatitis Subjects positive for hepatitis B surface antigen not on antiviral treatment/prophylaxis or subjects with detectable hepatitis B DNA
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
Subjects with hepatitis C allowed provided they meet all other eligibility criteria
Positive serology for HIV
Positive serology for HTLV 1 or 2
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.
Subject has brain metastases.
Other active malignancy besides HCC or other eligible AFP expressing tumor types within 3 years.
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).
Bacterial or opportunistic infection within 3 months of treatment (upper respiratory infection and uncomplicated urinary tract infection allowed)
Uncontrolled intercurrent illness considered by the Investigator to add appreciable risk to study participation, including but not limited to:
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.
Oxygen dependent lung disease.
Clinically significant psychiatric illness/social situations that would limit compliance with study requirements.
History of stroke or central nervous system bleeding; transient ischemic attack (TIA) or reversible ischemic neurologic deficit (RIND) in last 6 months.
Pregnant or breastfeeding
Alcohol or illicit drug dependency
Known contraindication to cyclophosphamide, fludarabine, mesna, G-CSF or other agents associated with study treatment.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic Arizona	Phoenix	Arizona	United States	85054
2	USC/Norris Comprehensive Cancer Center	Los Angeles	California	United States	90033
3	UCLA	Los Angeles	California	United States	90095
4	University of California, San Francisco	San Francisco	California	United States	94143
5	University of Miami	Miami	Florida	United States	33136
6	Winship Cancer Institute - Emory University	Atlanta	Georgia	United States	30322
7	University of Maryland, Greenebaum Cancer Center	Baltimore	Maryland	United States	21201
8	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
9	Mayo Clinic Clinical Trial Referral Office	Rochester	Minnesota	United States	55905
10	Washington University - School of Medicine	Saint Louis	Missouri	United States	63110
11	MD Anderson Cancer Center	Houston	Texas	United States	77030
12	Fred Hutchinson Cancer Research Centre	Seattle	Washington	United States	98109
13	SCCA Immunotherapy Trials Intake	Seattle	Washington	United States	98109
14	Paoli Calmettes Institute	Marseille Cedex		France
15	Centre Eugène Marquis	Rennes		France
16	Institute Gustave Roussy	Villejuif		France
17	University Hospital of Barcelona	Barcelona		Spain	08036
18	University Hospital of Navarra	Pamplona		Spain	31008
19	Beatson West of Scotland Cancer Centre	Glasgow		United Kingdom
20	Guy's Hospital	London		United Kingdom	SE1 9RT
21	NIHR UCLH Clinical Research	London		United Kingdom	W1T7HA
22	The Christie NHS Foundation Trust	Manchester		United Kingdom	M20 4BX