AFAMITRESGENE AUTOLEUCEL for Myxoid/Round cell liposarcoma | Synovial sarcoma

Inclusion criteria

• {"criterion_text":"- Subject (or legally authorized representative) voluntarily agrees to participate by giving written Informed Consent (and Assent as applicable) in accordance with ICH GCP guidelines and applicable local regulations\n- Left ventricular ejection fraction (LVEF) ≥50%\n- Fit for leukapheresis and adequate venous access can be established for the cell collection\n- Female subjects of childbearing potential (FCBP) must have a negative urine or serum pregnancy test AND must agree to use an 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 a FCBP starting at the first dose of chemotherapy and continuing for 4 months thereafter (or longer if indicated in the country specific monograph/label for cyclophosphamide)\n- Must have adequate organ function as indicated by the laboratory values in the table (refer to protocol).\n- Subject (or legally authorized representative) agrees to abide by all protocol required procedures including study related assessments, and management by the treating institution for the duration of the study including long term follow-up\n- Age ≥16 and ≤75 years at the time the Pre-screening Informed Consent/Assent is signed\n- Diagnosis of advanced (metastatic or inoperable) synovial sarcoma or myxoid liposarcoma / myxoid round cell liposarcoma (Cohort 1 only) confirmed by cytogenetics. Inoperable refers to a tumor lesion in which clear surgical excision margins cannot be obtained without leading to significant functional compromise. a. For Synovial Sarcoma (Cohort 1, Cohort 2 and Cohort 3): confirmation by the presence of a translocation between SYT on the X chromosome and SSX1, SSX2 or, SSX4 on chromosome 18 (may be presented in the pathology report as t (X; 18)). b. For MRCLS (Cohort 1 only): confirmation by the presence of the reciprocal chromosomal translocation t(12;16)(q13;p11) or t(12; 22) (q13;q12)\n- Must have previously received either an anthracycline or ifosfamide containing regimen. 1st line metastatic treatment with ADP-A2M4 is permissible if ifosamide +/- doxorubicin has been administered in either the pre-operative (neoadjuvant) or post-operative (adjuvant) primary tumour setting. (Subjects who are intolerant of both anthracycline and ifosfamide must have previously received at least one other type of systemic therapy)\n- Measurable disease according to RECIST v1.1 prior to lymphodepletion.\n- Positive for HLA-A*02:01, HLA-A*02:02, 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 as these alleles in the peptide binding domains (p group) will also be included. Other HLA-A*02 alleles may be eligible after adjudication with the sponsor\n- Tumor (either an archival specimen or a fresh biopsy) shows MAGE-A4 expression of ≥2+ staining in ≥30% of the cells by immunohistochemistry. All samples must have been pathologically reviewed by an Adaptimmune designated central laboratory confirming expression\n- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1"}

Exclusion criteria

• {"criterion_text":"- Positive for HLA-A*02:05 in either allele via Adaptimmune designated central laboratory testing: • HLA-A*02:05 in either allele; 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; b) Other alleles may be exclusionary after adjudication with the sponsor\n- Pregnant or breastfeeding.\n- In the opinion of the Investigator, the subject is unlikely to fully comply with protocol requirements.\n- Received or plans to receive therapy/treatment prior to leukaphereseis or lymphodepleting chemotherapy (refer to table in the protocol)\n- Toxicity from previous anti-cancer therapy must have recovered to ≤ Grade 1 prior to enrollment (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\n- History of allergic reactions attributed to compounds of similar chemical or biologic composition to fludarabine, cyclophosphamide or other agents used in the study\n- 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\n- Symptomatic CNS metastases including leptomeningeal disease. Subjects with a prior history of symptomatic CNS metastasis including leptomeningeal disease must have received treatment (i.e., stereotactic radiosurgery (SRS), whole brain radiation (WBRT) and/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. Antiseizure 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\n- 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\n- Uncontrolled intercurrent illness including, but not limited to: • Ongoing or active infection; • Clinically significant cardiac disease defined by congestive heart failure New York Heart Association (NYHA) Class 3 or Class 4; • Uncontrolled clinically significant arrhythmia; • Acute Coronary Syndrome (ACS) (angina or MI) in last 6 months; • Interstitial lung disease (subjects with existing pneumonitis as a result of radiation are not excluded); • Subjects must not be oxygen dependent; • Congenital or family history of long QT syndrome; • Current uncontrolled hypertension despite optimal medical therapy; • History of stroke or central nervous system bleeding; transient ischemic attack (TIA) or reversible ischemic neurologic deficit (RIND) in last 6 months; • Incipient compression/occlusion of a vital structure (e.g. bronchus; superior vena cava; renal outflow tract) which cannot undergo prophylactic stenting; • COVID-19 infection or a positive COVID-19 RT- PCR test within 28 days of leukapheresis or lymphodepleting chemotherapy. If a subject has a positive COVID-19 test, then 2 subsequent negative tests are required, taken at least 7 days apart\n- Active infection with HIV, HBV, HCV or HTLV as defined below: • Positive serology for HIV; • Active hepatitis B infection as demonstrated by test for hepatitis B surface antigen. Subjects who are hepatitis B surface antigen negative but are hepatitis B core antibody positive must have undetectable hepatitis B DNA and receive prophylaxis against viral reactivation. Prophylaxis should be initiated prior to lymphodepleting therapy and continued for 6 months; • Active hepatitis C infection as demonstrated by hepatitis C RNA test. Subjects who are HCV antibody positive will be screened for HCV RNA by any RT PCR or bDNA assay. If HCV antibody is positive, eligibility will be determined based on a negative screening RNA value; • Positive serology for HTLV 1 or 2; • Re-screening for infectious disease markers is not required at baseline (prior to lymphodepletion) unless > 6 months has elapsed."}

Primary endpoints

• {"endpoint_text":"- Overall Response Rate (ORR) per RECIST v1.1 by independent review in Cohort 1.","definition_or_measurement_approach":"Measured as Overall Response Rate according to RECIST v1.1 assessed by independent review."}

Secondary endpoints

• {"endpoint_text":"- For Cohort 1 and across Cohorts (overall) separately for both all subjects and synovial sarcoma (SS) only, and in addition Cohort 2 and 3 combined (for SS only):: • Adverse events (AEs) including serious adverse events (SAEs) • Incidence, severity and duration of the AEs of special interest • Replication Competent Lentivirus (RCL) • T cell Clonality and Insertional oncogenesis (IO)","definition_or_measurement_approach":"Safety endpoints including incidence, severity and duration of AEs/SAEs and AEs of special interest; monitoring for replication competent lentivirus (RCL); assessment of T cell clonality and insertional oncogenesis per protocol-defined assays."}
• {"endpoint_text":"- Across Cohorts separately for both all subjects and synovial sarcoma (SS) only,and in addition Cohort 2 and 3 combined (for SS only): •Overall Response Rate (ORR) per RECIST v1.1 by independent review. For Cohort 1 and across Cohorts (overall) separately for both all subjects and synovial sarcoma (SS) only,and in addition Cohort 2 and 3 combined (for SS only). Please refer protocol for full information","definition_or_measurement_approach":"ORR assessed per RECIST v1.1 by independent review across cohorts and subgroups."}
• {"endpoint_text":"- For Cohort 1 and across cohorts (overall) separately for all subjects and SS only, and in addition Cohort 2 and 3 combined (SS only): • Retention of additional tumor tissue during Pre-screening to enable development and validation of the MAGE-A4 antigen expression companion diagnostic assay","definition_or_measurement_approach":"Retention and collection of additional tumor tissue during pre-screening for development/validation of companion diagnostic; measured as successful collection and storage per protocol procedures."}
• {"endpoint_text":"- For Cohort 1 and across Cohorts (overall) separately for all subjects and SS only, and in addition Cohorts 2 and 3 combined (SS only): •Peak persistence and other relevant PK parameters of ADP-A2M4 cells","definition_or_measurement_approach":"Cellular pharmacokinetic parameters including peak persistence and other PK metrics of ADP-A2M4 cells measured in blood per protocol-specified assays."}

Spain

Earliest CTIS Part Ii Submission Date

15-05-2024

Latest Decision Or Authorization Date

04-02-2026

Processing Time Days

630

Number Of Sites

3

Number Of Participants

16

France

Earliest CTIS Part Ii Submission Date

15-05-2024

Latest Decision Or Authorization Date

26-01-2026

Processing Time Days

621

Number Of Sites

4

Number Of Participants

32

Primary sponsor

Full Name

Adaptimmune LLC

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

Icon Clinical Research Limited

Responsibilities

Supplies study-required kits to investigative sites for blood collection for HLA testing, tumor biopsy collection for antigen testing and HLA Buccal swabs for EU sites

Name

Medidata Solutions Inc.

Responsibilities

Clinical data/technology support (platform/data management)

Third parties

• {"country":"Germany","full_name":"IMGM Laboratories GmbH","duties_or_roles":"Analysis of HLA high-resolution molecular typing on blood sample","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Ireland","full_name":"Icon Clinical Research Limited","duties_or_roles":"Supplies study-required kits to investigative sites for blood collection for HLA testing, tumor biopsy collection for antigen testing and HLA Buccal swabs for EU sites","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"American National Red Cross","duties_or_roles":"Support duties (sponsor duty code 4)","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Belgium","full_name":"CellCarta","duties_or_roles":"Histopathology","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United Kingdom","full_name":"Primevigilance Limited","duties_or_roles":"SUSAR Reporting","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Bioagilytix Labs LLC","duties_or_roles":"Central Laboratory - sample processing and analysis for safety monitoring and correlative sciences (PBMCs for RCL monitoring, persistence, pharmacogenetic analyses; serum for cytokine)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Medidata Solutions Inc.","duties_or_roles":"Clinical technology/data management support (sponsor duty code 7)","organisation_type":"Non-Pharmaceutical company"}