SPEARHEAD-3 Pediatric Study

Study Overview
=================
Brief Summary
-----------------
This is a pediatric basket study to investigate the safety and efficacy of afamitresgene autoleucel in HLA-A*02 eligible and MAGE-A4 positive subjects aged 2-21 years of age with advanced cancers

Official Title
-----------------
A Phase 1/2 Open Label, Basket Study to Assess the Safety, Tolerability and Anti-Tumor Activity of Afamitresgene Autoleucel in Pediatric Subjects With MAGE-A4 Positive Tumors

Conditions
-----------------
Synovial Sarcoma, Malignant Peripheral Nerve Sheath Tumor (MPNST), Neuroblastoma, Osteosarcoma

Intervention / Treatment
-----------------
* Genetic: Afamitresgene autoleucel


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age 2-21 years Body weight ≥ 10 kg Subject has histologically confirmed diagnosis of any one of the following cancers: (A) Synovial Sarcoma, (B) MPNST, (C) Neuroblastoma, or (D) Osteosarcoma Must have previously received a systemic chemotherapy Measurable disease according to RECIST v1.1 (or INCR, 2017 Neuroblastoma only). HLA-A*02 positive Tumor shows MAGE-A4 expression confirmed by central laboratory. Performance Status: ECOG 0-1 or Lansky Score ≥ 80 Exclusion Criteria: HLA-A*02:05 in either allele; or any A*02 having same protein sequence as HLA-A*02:05 History of allergic reactions attributed to compounds of similar chemical or biologic composition to fludarabine, cyclophosphamide. History of autoimmune or immune mediated disease Known central nervous system (CNS) metastases. Other prior malignancy that is not considered by the Investigator to be in complete remission Clinically significant cardiovascular disease Active infection with human immunodeficiency virus, hepatitis B virus, hepatitis C virus, or human T cell leukemia virus Pregnant or breastfeeding

Ages Eligible for Study
-----------------
Minimum Age: 2 Years
Maximum Age: 21 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Afamitresgene autoleucel<br> | Genetic: Afamitresgene autoleucel<br>* Single infusion of afamitresgene autoleucel Dose: For subjects ≥10 kg to <40 kg: starting dose of 0.025 - 0.200 x 10'9 transduced cells/kg. For subjects ≥40 kg 1.0x109 to 10x109 transduced by a single intravenous infusion<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence, duration, and severity of Treatment Emergent Adverse Events as assessed by Investigator Evaluation. | Determination of incidence, severity and duration of adverse events Incidence of dose limiting toxicities DLTs 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) | 3.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy: Objective response rate (ORR) assessed by investigator per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (or by International Neuroblastoma Response Criteria [INRC] 2017 in NB subjects) | ORR is defined as incidence of complete responses or partial responses as assessed by RECIST v1.1 or INRC, 2017 | 3.5 years | 
| Time to response (TTR) | For patients who are observed to respond to afamitresgene autoleucel in the time from date of infusion to achieve a partial response or complete response (TTR) is assessed | 3.5 years | 
| Duration of Response (DoR) | For patients who are observed to respond to afamitresgene autoleucel the DoR is the date of initial response (including confirmation) from date of infusion up until disease progression | 3.5 years | 
| Best overall response (BOR) | BOR is assessed by the investigator per RECIST V1.1 or INCR, 2017 (for NB subjects) | 3.5 years | 
| Progression Free Survival (PFS) | PFS is assessed by the investigator from date of infusion of ADP-A2M4 up until the date of disease progression per RECIST v1.1 or INCR, 2017 (for NB subjects) or death. | 3.5 years | 
| Overall Survival (OS) | OS is assessed from date of infusion of ADP-A2M4 up until the date of patient death. | 15 years | 
| Pharmacokinetics (PK). Characterize the in vivo cellular pharmacokinetics (PK) profile of afamitresgene autoleucel by evaluation of PBMC samples for peak persistence. | Obtain PBMC samples for the evaluation of peak persistence of afamitresgene autoleucel. | 3.5 years | 
| Development and validation of an invitro diagnostic (IVD) assay for the screening of tumor antigen expression for regulatory approval. | Retention of additional tumor tissue during Pre-Screening to enable development and validation of the MAGE-A4 antigen expression companion diagnostic (CDx) assay. | 3.5 years | 
| Invitro diagnostic (IVD) assay for screening | Development and validation of the MAGE-A4 antigen expression companion diagnostic assay | 3.5 years |