ADP-A2M4 in Advanced Synovial Sarcoma or Myxoid/Round Cell Liposarcoma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Uswm Ct Llc

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

11 Dec 2019 → ongoing

Decision date (initial)

2024-06-10

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

USWM Ct LLC

External identifiers

EU CT number

2024-512847-21-00

EudraCT number

2019-000589-39

ClinicalTrials.gov

NCT04044768

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Diagnosis, Safety, Pharmacokinetic

To evaluate the efficacy of autologous genetically modified T cells (ADP- A2M4) in HLA-A*02 positive subjects with MAGE-A4 expressing advanced synovial sarcoma or MRCLS

Secondary objectives 4

1. To evaluate the safety and tolerability of autologous genetically modified T cells (ADP-A2M4) in HLA-A*02 positive subjects with MAGE- A4 expressing advanced synovial sarcoma or MRCLS
2. To evaluate the efficacy of autologous genetically modified T cells (ADP-A2M4) in HLA-A*02 positive subjects with MAGE-A4 expressing advanced synovial sarcoma or MRCLS
3. Development and validation of an in vitro diagnostic (IVD) assay for the screening of tumor antigen expression for regulatory approval
4. Characterize the in vivo cellular pharmacokinetics (PK) profile of ADP- A2M4 cells

Conditions and MedDRA coding

Advanced Synovial Sarcoma

Study design 1 period

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-002867-PIP01-20

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. 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
2. 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
3. Age ≥16 and ≤75 years at the time the Pre-screening Informed Consent/Assent is signed
4. 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)
5. 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)
6. Measurable disease according to RECIST v1.1 prior to lymphodepletion.
7. Positive for HLA-A*02:01, HLA-A*02:02, HLA-A*02:03 or HLA-A*02:06 allele via the sponsor’s 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
8. 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 the sponsor’s designated central laboratory confirming expression.
9. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
10. Left ventricular ejection fraction (LVEF) ≥50%
11. Fit for leukapheresis and adequate venous access can be established for the cell collection
12. 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)
13. Must have adequate organ function as indicated by the laboratory values in the table (refer to protocol).

Exclusion criteria 11

1. Positive for HLA-A*02:05 in either allele via the sponsor’s 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 therapy/treatment prior to leukaphereseis or lymphodepleting chemotherapy (refer to table in the protocol)
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, 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. 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
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; • 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
9. 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.
10. Pregnant or breastfeeding.
11. In the opinion of the Investigator, the subject is unlikely to fully comply with protocol requirements.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Overall Response Rate (ORR) per RECIST v1.1 by independent review in Cohort 1.

Secondary endpoints 4

1. 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)
2. 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
3. For Cohort 1 and across cohorts (overall) separately for all subjects and SS only, and in addition Cohorts 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
4. 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

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Uswm Ct Llc

Sponsor organisation

USWM Ct LLC

Address

4441 Springdale Road

City

Louisville

Postcode

40241-1086

Country

United States

Scientific contact point

Organisation

USWM Ct LLC

Contact name

Regulatory Affairs

Public contact point

Organisation

USWM Ct LLC

Contact name

Regulatory Affairs

Third parties 7

Locations

2 EU/EEA countries · 8 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Corrective measures 1 · Art. 77 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 35 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications