This study is currently recruiting participants.
Some cancers that appear in children express a type of protein called MAGE-A4. These cancers include synovial sarcomas, malignant peripheral nerve sheath tumors, neuroblastomas, and osteosarcomas. Researchers want to test a treatment that targets MAGE-A4 proteins.
To test a study drug (afamitresgene autoleucel) in children and teens with cancers that express MAGE-A4.
People aged 2 to 21 years with cancers that express MAGE-A4.
Participants will be pre-screened. A swab will be rubbed on the inside of their cheek. This swab will be tested for markers to show whether their cancer expresses MAGE-A4. Further screening will include imaging scans and tests of their heart functions.
Afamitresgene autoleucel is made by collecting the participant s own T cells (a type of white blood cell). T cells play a role in the immune system. The collected T cells will be changed in a lab to make them better at targeting MAGE-A4 proteins. The goal is that the changed T cells will be better able to kill cancer cells.
Participants will undergo leukapheresis: Blood will be drawn via a tube in an arm. The blood will pass through a machine that separates out the T cells. The remaining blood will be returned to the body through a second tube.
Participants will have 4 consecutive days of chemotherapy.
The next day, the changed T cells will be returned to the participant s bloodstream. They will stay in the hospital at least 1 day after this procedure.
Participants will have about 25 follow-up visits in the first 6 months after the procedure. Long-term follow-up will continue up to 15 years.
INCLUSION CRITERIA:
A subject must meet the following criteria prior to Leukapheresis to be eligible to participate in the study:
1. Subject (or legally authorized representative) voluntarily agrees to participate by giving written Informed Consent (and assent as applicable) in accordance with the ICH Good Clinical Practice (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 LTFU.
3. SS: Age 2 to 17 years at the time informed consent/assent is signed. Dosing should be complete by 18 years of age (but if there are extenuating circumstances, this can be discussed with the Sponsor). NB, OS, MPNST: Age 2 to 21 years at the time informed consent/assent is signed for subjects in. Dosing should be complete by 22 years of age (but if there are extenuating circumstances, this can be discussed with the Sponsor).
4. Body weight >= 10 kg
5. Subject has histologically confirmed diagnosis of any one of the following cancers: (A) SS, (B) MPNST, (C) high risk NB, or (D) OS. Subjects with neuroblastoma must be considered high risk per Children s Oncology Group (COG) risk assessment at the time of enrollment.
6. Must have previously received a systemic chemotherapy with no options for cure at time of consent/assent. 1st-line metastatic treatment with afamitresgene autoleucel is permissible if tumor specific treatment detailed below has been administered in either the pre-operative (neoadjuvant) or post-operative (adjuvant) primary tumor setting. (Subjects who are intolerant these treatments must have previously received at least one other type of systemic therapy).
a. SS, MPNST: should have received prior treatment with ifosfamide or anthracycline containing regimen.
b. High Risk NB: should have received initial platinum based chemotherapy and should have received at least one cycle of induction therapy per local standard of care for relapsed/refractory disease.
c. OS: should have received prior treatment with methrotrexate, doxorubicin and cisplatin containing regimen.
7. 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 in the peptide binding domains (P group) will also be included.
8. Measurable disease prior to lymphodepletion according to RECIST v1.1 (or Revised INRC, 2017 for NB) (Not required prior to apheresis).
9. Tumor tissue shows MAGE-A4 expression as follows:
a. IHC analysis of tissue (either an archival specimen or a fresh biopsy) showing >=2+ staining in >=30% of the cells. Only subjects with a tumor sample satisfying these criteria will be eligible. All samples must have been stained using Adaptimmune s IHC CTA and pathologically reviewed by an Adaptimmune designated central laboratory confirming the expression.
10. Performance status: a. Subjects >=16: Eastern Cooperative Oncology Group (ECOG) 0 or 1
b. Subjects 2 to <16: Lansky score >= 80
11. Left ventricular ejection fraction (LVEF) >=50%
12. Fit for leukapheresis and adequate venous access can be established for the cell collection.
13. Pregnancy:
a. 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 if sexually active starting at the 1st 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
b. Sexually active 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 1st dose of chemotherapy and continuing for 6 months thereafter (or longer if indicated in the country specific monograph/label for cyclophosphamide).
14. Must have adequate organ function as indicated by the laboratory values in the table below:
System/Laboratory Value*
Hematological:
- Absolute neutrophil count (ANC)
-- >= 1000 cells/mm^3 (without granulocyte-colony stimulating factor [G-CSF] support) within 7 days prior to leukapheresis and lymphodepletion
-Platelets
-->= 100 x 10^9 cells/L (without transfusion or thrombopoetin agonist support within 7 days prior to leukapheresis and lymphodepletion)
-Hemoglobin
-- >=80 g/L (without transfusion support within 7 days prior to leukapheresis and lymphodepletion)
Coagulation
-Prothrombin time (PT) or international normalized ration (INR)
-- <= 1.5 x upper limit of normal (ULN), unless receiving therapeutic anticoagulation
-Partial thromboplastin time (PTT)
--<= 1.5 x ULN, unless receiving therapeutic anticoagulation
Renal:
-Glomerular filtration rate (GFR) or creatinine clearance (CrCl) (estimated or calculated)(a).
(Calculated CrCl using only the Cockcroft-Gault equation or measured using either a 24-hour urine creatinine collection or a radionuclide ethylenediaminetetraacetic acid [EDTA] test for patients >=16 years old.)(a)
For patients < 16 years old, the Schwartz formula should be used or an EDTA test.
-->= 60 mL/min or >= 60 mL/min/1.73 m^2 (Schwartz)
(a)Renal function (GFR or CrCl) will be obtained or estimated by a 24-hour creatinine collection or by the nuclear medicine EDTA GFR measurement or calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation or calculated using the Cockcroft-Gault equation.
Renal function will be reassessed at Baseline using the same methodology.
Hepatic:
-Serum total bilirubin
--<= 1.5 x ULN (unless subject has documented Gilbert s Syndrome with direct bilirubin <35% of total bilirubin)
-Alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT)
-- <= 2.5 x ULN
*Note: Laboratory values that are slightly out of the laboratory test parameters, if assessed as not clinically significant by the Study Investigator, may be acceptable after discussion and review by the Sponsor Study Physician. This applies to screening laboratory tests and baseline assessments.
15. Subject has anticipated life expectancy of greater than 3 months in the opinion of the investigator.
EXCLUSION CRITERIA:
A subject meeting any of the following criteria is not eligible for participation in the study:
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. Subject has received or plans to receive the following therapy/treatment prior to leukapheresis or Lymphodepleting Chemotherapy:
Note: The washout periods are provided as a guideline in the table below. Minor modifications in the washout periods if assessed as not clinically significant by the site Study Investigator (or designee) may be acceptable after discussing with the Sponsor Study Physician.
Treatment/Therapy:
-Cytotoxic chemotherapy
--Required Washout Prior to Leukapheresis: 3 weeks
--Required Washout Prior to Lymphodepletion: 3 weeks
-Tyrosine kinase inhibitor (TKI) (e.g., pazopanib)
--Required Washout Prior to Leukapheresis: 1 week
--Required Washout Prior to Lymphodepletion: 1 week
-Immune therapy (including monoclonal antibody therapy and checkpoint inhibitors)
--Required Washout Prior to Leukapheresis: 4 weeks
--Required Washout Prior to Lymphodepletion: 4 weeks
-Anti-cancer vaccine
--Required Washout Prior to Leukapheresis: 8 weeks in the absence of tumor response.The subject should be excluded if their disease is responding to an experimental vaccine given within 6 months.
--Required Washout Prior to Lymphodepletion: 8 weeks in the absence of tumor response. The subject should be excluded if their disease is responding to an experimental vaccine given within 6 months.
-Gene therapy using an integrating vector
--Required Washout Prior to Leukapheresis: Use of previous gene therapy using integrating vectors other than lentiviruses is prohibited. Use of previous gene therapy using a lentiviral vector is permitted only if transduced T-cells represent less than 1% of peripheral blood mononuclear cell (PBMC) (< 1500 copies of vectors per microgram of PBMC deoxyribonucleic acid [DNA]) at the time of Screening. Eligibility testing must be done by Adaptimmune s designated Contract Research Organization (CRO). Prior use of integrating vectors other than lentiviral vectors or of gene-editing methods in T-cells or hematopoietic stem cells is not permitted.
--Required Washout Prior to Lymphodepletion: Use of previous gene therapy using integrating vectors other than lentiviruses is prohibited.
-Corticosteroids or any other immunosuppressive therapy
Note: Use of topical steroids or physiological replacement steroids is not an exclusion.
--Required Washout Prior to Leukapheresis: 2 weeks
--Required Washout Prior to Lymphodepletion: 2 weeks
-Anti-MAGE-A4 therapy
Note: Fresh screening biopsy post anti-MAGE-A4 therapy must be obtained to confirm MAGE-A4 positivity within 2 weeks.
--Required Washout Prior to Leukapheresis: 2 weeks
--Required Washout Prior to Lymphodepletion: 2 weeks
-Investigational treatment or interventional clinical trial
--Required Washout Prior to Leukapheresis: 2 weeks or 5 half-lives, whichever is shorter
--Required Washout Prior to Lymphodepletion: 2 weeks or 5 half-lives, whichever is shorter
-Allogeneic hematopoietic stem cell transplant
--Required Washout Prior to Leukapheresis: Not permitted within any amount of time
--Required Washout Prior to Lymphodepletion: Not permitted within any amount of time
Radiotherapy to the target lesions
--Required Washout Prior to Leukapheresis: N/A
--Required Washout Prior to Lymphodepletion: 3 months prior to Lymphodepleting Chemotherapy. A lesion with unequivocal progression may be considered a target lesion.
Note: There is no washout period for palliative radiation to non-target organs.
-Major surgery
--Required Washout Prior to Leukapheresis: NA
--Required Washout Prior to Lymphodepletion: 4 weeks. Subjects must have recovered from any surgical related toxicities.
Note: Duration of any other anti-cancer therapies must be discussed with the Sponsor Study Physician.
3. Toxicity from previous anti-cancer therapy must have recovered to <= Grade 1 prior to enrollment (except for nonclinically 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. Known central nervous system (CNS) metastases
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 the following:
a. Active infection requiring systemic therapy
b. Clinically significant cardiac disease defined by congestive heart failure New York Heart Association (NYHA) Class 3 or Class 4
c. Uncontrolled clinically significant arrhythmia
d. Interstitial lung disease (subjects with existing pneumonitis as a result of radiation are not excluded; however, subjects must not be oxygen dependent)
e. Congenital or family history of long QT syndrome
f. Current uncontrolled hypertension despite optimal medical therapy
g. History of stroke or CNS bleeding; transient ischemic attack (TIA) or reversible ischemic neurologic deficit (RIND) in the last 6 months
h. Incipient compression/occlusion of a vital structure (e.g., bronchus, superior vena cava, and renal outflow tract), which cannot undergo prophylactic stenting
9. Incipient compression/occlusion of a vital structure (e.g., bronchus, superior vena cava, and renal outflow tract), which cannot undergo prophylactic stenting. Inadequate pulmonary function defined as pulse ox <92% on room air and diffusing capacity of the lung for carbon monoxide (DLCO) <60% if pulmonary function tests are clinically appropriate as determined by the investigator Ongoing or active infection (for COVID-19 infection.
10. Active infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), or human T-cell leukemia virus (HTLV) as defined below:
a. Positive serology for HIV
b. 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.
c. 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-polymerase chain reaction (PCR) or branched DNA (bDNA) assay. If HCV antibody is positive, eligibility will be determined based on a negative screening RNA value.
d. Positive serology for HTLV 1 or 2
Note: Re- Screening for infectious disease markers is not required at Baseline (prior to lymphodepletion) unless > 6 months has elapsed.
11. Pregnant or breastfeeding
12. In the opinion of the Investigator, the subject is unlikely to fully comply with protocol requirements.
13. Subject is not experiencing ongoing rapid disease progression at baseline/prior to the start of LD chemo that in the opinion of the investigator significantly increases the subjects risk associated with treatment.