advanced esophageal or esophagogastric junction (EGJ) cancers MedDRA version: 21.0 Level: LLT Classification code 10015362 Term: Esophageal cancer System Organ Class: 100000004864
Conditions
Sponsors
Adaptimmune LLC
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Subject (or legally authorized representative) has voluntarily agreed to participate by giving written Informed Consent/Assent (as applicable) in accordance with International Council for Harmonization (ICH) GCP guidelines and applicable local regulations. 2. Subject (or legally authorized representative) has agreed to abide by all protocol-required procedures including study-related assessments and management by the treating institution for the duration of the study, including the LTFU. 3. Age = 18 years to = 75 years at the time the Pre-screening Informed Consent. 4. Histologically or cytogenetically confirmed diagnosis of advanced (metastatic or inoperable) esophageal or EGJ cancers. 5. Subject has received prior treatment for advanced or metastatic disease before treatment with ADP-A2M4CD8 as the next therapy. a. Esophageal or EGJ cancers Prior therapy requirements in the unresectable locally advanced or metastatic setting: - Subjects should have received a platinum and/or fluoropyrimidine-based regimen (such as FOLFOX). - Subjects may have been offered taxane-containing regimen, ramucirumab, and/or irinotecan-containing regimen, if available; unless discussed and agreed upon with the sponsor. - Subjects whose tumors are known to be HER2/neu positive should have received or refused trastuzumab, if available. b. Esophageal squamous cell carcinoma Prior therapy requirements in the metastatic or unresectable locally advanced: - Subjects should have received a platinum and/or fluoropyrimidine-based regimen (such as FOLFOX) and may include a taxane-containing regimen, and/or irinotecan-containing regimen. - Subjects whose tumors express PD-L1 or MSI-H/dMMR tumors, anti-PD-1/antiPD-L1 therapy should have been received or refused if available; unless discussed and agreed upon with the sponsor. 6. Measurable disease according to RECIST v1.1 criteria. 7. Positive for HLA-A*02:01, HLA-A*02:03, or HLA-A*02:06 allele via Adaptimmune-designated central laboratory testing. HLA-A*02 alleles having the same protein sequence in the peptide binding domains (P group) will also be included. Other HLAA*02 alleles may be eligible after adjudication with the Sponsor. The Sponsor will review the results of HLA typing for inclusion alleles and will adjudicate subject eligibility based on HLA results. 8. Tumor (either an archival specimen or a fresh biopsy) shows MAGE-A4 expression of = 2+ staining in = 30% of the cells by IHC. All samples must have been pathologically reviewed by an Adaptimmune-designated central laboratory confirming expression. 9. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. 10. Left ventricular ejection fraction (LVEF) = 50% or the institutional lower limit of normal range 11. Fit for leukapheresis and adequate venous access can be established for the cell collection. 12. Females of childbearing potential (FCBP) must have a negative urine or serum pregnancy test AND must agree to use a highly effective method of contraception starting at the first dose of chemotherapy and continuing for at least 12 months or 4 months after the gene modified cells are no longer detected in the blood, whichever is longer. OR Male subjects must be surgically sterile or agree to use a double barrier contraception method or abstain from heterosexual activity with an FCBP starting at the first dose of chemotherapy and continuing for 4 months thereafter (or longer if indicated in the country-specific monog
Exclusion criteria
Exclusion criteria: 1. Positive for HLA-A*02:05 in either allele via Adaptimmune-designated central laboratory testing. HLA-A*02 alleles having the same protein sequence as HLA-A*02:05 in the peptide binding domains (P groups) will also be excluded. Other alleles may be exclusionary after adjudication with the Sponsor. 2. Received or plans to receive the therapy/treatment listed in the protocol prior to leukapheresis or lymphodepleting chemotherapy. 3. Toxicity from previous anti-cancer therapy must have recovered to = Grade 1 prior to enrollment (except for non-clinically significant toxicities, e.g., alopecia and vitiligo). Subjects with Grade 2 toxicities that are deemed stable or irreversible (e.g., peripheral neuropathy) can be enrolled. 4. History of allergic reactions attributed to compounds of similar chemical or biologic composition to fludarabine, cyclophosphamide, or other agents used in the study. 5. History of autoimmune or immune-mediated disease. Subjects with hypothyroidism, diabetes, adrenal insufficiency, or pituitary insufficiency that are stable on replacement therapy are eligible. Subjects with disorders such as asthma, psoriasis, or atopic dermatitis that are well controlled without requiring systemic immunosuppression are also eligible. 6. Leptomeningeal disease, carcinomatous meningitis, or symptomatic CNS metastases. Subjects with a prior history of symptomatic CNS metastases must have received treatment (i.e., stereotactic radiosurgery and whole brain radiation or surgery) and be neurologically stable for at least 1 month, not requiring anti-seizure medications and off of steroids for at least 14 days prior to leukapheresis and lymphodepletion. Anti-seizure prophylaxis is permitted. Subjects who have asymptomatic CNS metastases without associated edema, shift, requirement for steroids, or anti-seizure medications for the treatment of seizures are eligible. 7. Any other prior malignancy that is not in complete remission. Resectable squamous or basal cell carcinoma of the skin is acceptable. Prior malignancies that have been surgically resected and show no evidence of disease are acceptable. 8. Uncontrolled intercurrent illness including, but not limited to: - Ongoing or active infection - COVID-19 infection or a positive COVID-19 RT-PCR test within 28 days of leukapheresis or lymphodepleting chemotherapy. If subject has had a positive COVID-19 test, then 2 subsequent negative tests are required, taken at least 7 days apart - Clinically significant cardiac disease defined by congestive heart failure New York Heart Association Class 3 or Class 4 - Uncontrolled clinically significant arrhythmia - Acute Coronary Syndrome (angina or myocardial infarction) in last 6 months - Congenital or family history of long QT syndrome or a history of torsade de pointes - Current uncontrolled hypertension despite optimal medical therapy - History of stroke or CNS bleeding; transient ischemic attack or reversible ischemic neurologic deficit in the last 6 months 9. Active infection with HIV, HBV, HCV, or HTLV as defined in the protocol. 10. Pregnant or breastfeeding. 11. In the opinion of the Investigator, the subject is unlikely to fully comply with protocol requirements.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the efficacy of autologous genetically modified SPEAR T-cells (ADP-A2M4CD8) in HLA-A*02 positive subjects with MAGE-A4 expressing advanced esophageal or EGJ cancers;Secondary Objective: To evaluate the safety and tolerability of autologous genetically modified T-cells (ADPA2M4CD8) in HLA-A*02 positive subjects with MAGE-A4 expressing advanced esophageal or EGJ cancers To evaluate the efficacy of autologous genetically modified T-cells (ADP-A2M4CD8) in HLA-A*02 positive subjects with MAGE-A4 expressing advanced esophageal or EGJ cancers Development and validation of an in vitro diagnostic (IVD) assay for the screening of tumor antigen expression for regulatory approval Characterize the surrogates of treatment effect;Primary end point(s): ORR per RECIST v1.1 by independent review;Timepoint(s) of evaluation of this end point: The clinical cut-off for the primary analysis will occur once the last subject dosed has up to 6 months follow-up post-T-cell infusion or has ended the Interventional phase of the study. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - Adverse events (AEs) including serious adverse events - Incidence, severity, and duration of the AEs of special interest - Replication competent lentivirus (RCL) - T-cell clonality and insertional oncogenesis (IO) - Time to response (TTR) per RECIST v1.1 by independent review - Duration of response (DoR) per RECIST v1.1 by independent review - Best overall response (BOR) per RECIST v1.1 by independent review - Progression-free survival (PFS) per RECIST v1.1 by independent review - Overall survival (OS) - Retention of additional tumor tissue during Pre-screening to enable development and validation of the MAGE-A4 antigen expression companion diagnostic assay - Peak expansion (i.e., maximum persistence) and time to peak expansion by responder status and overall;Timepoint(s) of evaluation of this end point: The clinical cut-off for the primary analysis will occur once the last subject dosed has up to 6 months follow-up post-T-cell infusion or has ended the Interventional phase of the study. At this time, all safety and secondary efficacy endpoints will also be summarized to provide supportive evidence to the primary assessment. | — |
Countries
Canada, France, Spain, United Kingdom, United States
Contacts
Public ContactRegulatory Affairs
Adaptimmune LLC
Outcome results
None listed