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Protocol Details

A Phase 2 Single Arm Open-Label Clinical Trial of ADP-A2M4 SPEAR(TM) T Cells in Subjects with Advanced Synovial Sarcoma or Myxoid/Round Cell Liposarcoma

This study is currently recruiting participants.

Summary | Eligibility | Citations | Contacts

Summary

Number

21-C-0022

Sponsoring Institute

National Cancer Institute (NCI)

Recruitment Detail

Type: Participants currently recruited/enrolled
Gender: Male & Female
Min Age: 10 Years
Max Age: 75 Years

Referral Letter Required

No

Population Exclusion(s)

Pregnant Women

Keywords

Cell Therapy;
T Cell Therapy;
SPEAR T Cell

Recruitment Keyword(s)

None

Condition(s)

Sarcoma;
Liposarcoma;
Sarcoma Liposarcoma Sarcoma, Synovial;
Liposarcoma, Myxoid;
Neoplasms, Connective and Soft Tissue

Investigational Drug(s)

ADP-A2M4
Cyclophosphamide

Investigational Device(s)

None

Intervention(s)

Genetic: ADP-A2M4

Supporting Site

National Cancer Institute

Background:

T cells are immune cells. In gene therapy, T cells are taken from a person s blood, changed in a laboratory, then put back into the person s bloodstream to attack cancer cells. Researchers want to learn if these T cells are safe and work to kill certain cancer cells.

Objective:

To learn if a drug made up of changed T cells is safe and effective in killing Synovial Sarcoma or MRCLS cancer cells.

Eligibility:

People ages 10-75 with advanced Synovial Sarcoma or MRCLS that has grown or not responded to treatment.

Design:

Participants will be screened with:

Medical record review

Blood samples

Urine samples

Physical exam

Tumor biopsy (if needed)

Heart tests

Body scans. They will lie on a table that slides into a scanner. They may receive a contrast dye in a vein.

Participants will have leukapheresis. Needles will be put in their veins or they will get a central venous catheter. Their blood will be filtered through a machine that collects certain cells. The rest of the blood will be returned to them.

Participants will receive chemotherapy for 4 days. They will be admitted to the hospital. They will have an infusion of the study drug. Their doctor will decide how long they will remain in the hospital.

Participants will have frequent study visits. At these visits, they will repeat some screening tests. Medical photographs may be taken.

Participants may have biopsies taken from their tumor, skin, stomach or intestines, or bone marrow.

After completion of the initial study follow-up period, participants will start long-term follow-up. It will last for up to 15 years.

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Eligibility

INCLUSION CRITERIA:

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. Cohort 1: Age >=16 and <=75 years at the time the Pre-screening Informed Consent/Assent is signed

Cohort 2 and Cohort 3: Age >=10 and <=75 years at the time of Pre-Screening Informed Consent/Assent is signed and actual body weight >=40

kilograms.

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 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 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 Adaptimmune designated central laboratory confirming expression.

9. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1, For subjects aged >=10 to <16 years old: Lansky Score >= 60%

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 below:

System: Hematological

-System, Hematological: Absolute Neutrophil count (ANC); Laboratory Value: >=1.5 x10^9/L (without G-CSF support)(1) within 7 days prior to lymphodepletion and leukapheresis

-System, Hematological: Platelets; Laboratory Value: >= 100 x10^9/L (without transfusion support within 7 days prior to leukapheresis and lymphodepletion)

-System, Hematological: Hemoglobin; Laboratory Value: >= 80 g/L (without transfusion support within 7 days prior to leukapheresis and lymphodepletion)

System: Coagulation

-System, Hematological: Prothrombin Time or INR; Laboratory Value: <= 1.5x upper limit of normal (ULN) unless receiving therapeutic anticoagulation. Subjects receiving warfarin anticoagulation at baseline should be converted to either a low molecular weight heparin injection or a novel oral anticoagulant (NOAC). Reintroduction of warfarin after lymphodepleting chemotherapy/ADP-A2M4 dosing to attain the therapeutic INR range which was initially clinically indicated should only start when the platelet count is < Grade 2 CTCAE.

-System, Hematological: Partial Thromboplastin Time (PTT); Laboratory Value: <= 1.5x upper limit of normal (ULN) unless receiving therapeutic anticoagulation.

System: Renal

-System, Renal: Glomerular filtration rate; Laboratory Value: >= 60 mL/min

---(calculated CrCl using only the Cockcroft-Gault equation, or measured using either a 24-hr urine creatinine collection, or a radionuclide EDTA test for patients >=16 years old. (2)

---For patients < 16 years old, the Schwartz formula should be used, or an EDTA test

System: Hepatic

-System, Hepatic: Serum total bilirubin; Laboratory Value: <= 1.5 x ULN (unless subject has documented Gilbert s Syndrome with direct bilirubin <35% of total bilirubin)

-System, Hepatic: Alanine aminotransferase (ALT)/Serum Glutamic Pyruvic Transaminase (SGPT); Laboratory Value: <= 2.5x ULN

(1) >=1 x10^9/L (without G-CSF support) in 10 - <16 year olds

(2) 24-hour urine creatine clearance or radionuclide EDTA tests should be used to measure the GFR in all subjects: >= 65 years old; clinically obese (>= 30KG/m^2) or underweight (<=18.5KG/m^2); borderline low calculated CrCl (Cockcroft-Gault) at approximately 60mls/min.

Renal function will be reassessed at baseline using the same methodology.

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 following therapy/treatment prior to leukapheresis or lymphodepleting chemotherapy:

-Treatment/Therapy: Cytotoxic chemotherapy; Required Wash-out Prior to Leukapheresis: 3 weeks; Required Wash-out Prior to Lymphodepletion: 3 weeks

-Treatment/Therapy: Tyrosine kinase inhibitor (TKI) (e.g. pazopanib); Required Wash-out Prior to Leukapheresis: 1 week; Required Wash-out Prior to Lymphodepletion: 1 week

-Treatment/Therapy: Immune therapy (including monoclonal antibody therapy, checkpoint inhibitors,); Required Wash-out Prior to Leukapheresis: 4 weeks; Required Wash-out Prior to Lymphodepletion: 4 weeks

-Treatment/Therapy: Anti-cancer Vaccine; Required Wash-out 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 Wash-out Prior to Lymphodepletion: 8 week in the absence of tumor response.The subject should be excluded if their disease is responding to an experimental vaccine given within 6 months

-Treatment/Therapy: Gene therapy using an integrating vector; Required Wash-out Prior to Leukapheresis: Subjects who have received a gene therapy using any DNA-integrating vector other than a lentivirus (retrovirus, AAV, etc.) are excluded from this study. Subjects who have received a gene therapy using a lentiviral vector may be eligible for the study. Persistence result and patient history will be reviewed by Adaptimmune, discussed with the Investigator and documented prior to determining enrollment eligibility. Required Wash-out Prior to Lymphodepletion: Not permitted after leukapheresis and prior to lymphodepletion.

-Treatment/Therapy: Corticosteroids or any other immunosuppressive therapy. NOTE: Use of topical steroids is not an exclusion.; Required Wash-out Prior to Leukapheresis: 2 weeks; Required Wash-out Prior to Lymphodepletion: 2 weeks

-Treatment/Therapy: Investigational treatment or interventional clinical trial; Required Wash-out Prior to Leukapheresis: 4 weeks; Required Wash-out Prior to Lymphodepletion: 4 weeks

-Treatment/Therapy: Allogeneic hematopoietic stem cell transplant; Required Wash-out Prior to Leukapheresis: Not permitted within any amount of time; Required Wash-out Prior to Lymphodepletion: Not permitted within any amount of time

-Treatment/Therapy: Radiotherapy to the target lesions; Required Wash-out Prior to Leukapheresis: N/A; Required Wash-out Prior to Lymphodepletion: 3 months. A lesion with unequivocal progression may be considered a target lesion regardless of time from last radiotherapy dose. (Note: there is no washout period for palliative radiation to non-target organs).

-Treatment/Therapy: Major surgery; Required Wash-out Prior to Leukapheresis: N/A; Required Wash-out Prior to Lymphodepletion: 4 weeks. A subject must be fully 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 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. 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;

-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.


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Citations:

Not Provided

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Contacts:

Principal Investigator

Referral Contact

For more information:

John W. Glod, M.D.
National Cancer Institute (NCI)
NIHBC 10 - CRC BG RM 1-3750
10 CENTER DR
BETHESDA MD 20892
(240) 760-6194
john.glod@nih.gov

Jo H. Hurtt, R.N.
National Cancer Institute (NCI)
National Institutes of Health
Building 10
Room 3-2341
10 Center Drive
Bethesda, Maryland 20892
(240) 858-7012
jo.hurtt@nih.gov

NCI Referral Office
National Institute of Health Clinical Center (CC), 9000 Rockville Pike, Bethesda, Maryland 20892, United States: NCI Clinical Trials Referral Office
1-888-NCI-1937

Clinical Trials Number:

NCT04044768

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