Multi Tumor-Associated Antigen-Specific T Lymphocytes to Treat Patients With High Risk Solid Tumors

Phase I Research Study Utilizing Allogeneic Multi Tumor-Associated Antigen-Specific T Lymphocytes to Advance the Care of Patients With High-Risk Solid Tumors

This is an open-label phase I dose-escalation study to evaluate the safety of partially human leukocyte antigen (HLA)-matched multi tumor-associated antigen-specific T cell (TAA-T) therapy following lymphodepleting conditioning with or without local tumor ablation for pediatric and adult patients with high-risk solid tumors due to the presence of refractory, relapsed and/or minimal residual detectable disease following conventional therapy (e.g., chemotherapy, surgery, radiation, autologous stem cell transplant, or targeted therapy).

In this dose escalation trial, three dose levels will be tested for safety. TAA-T product will first be administered to patients as monotherapy at dose level 1 to determine safety.

All participants enrolled to DL2 or DL3 will be assigned to one of the following at Screening Eligibility:

• Treatment Regimen 1 (Tx-R1): Lymphodepleting chemotherapy + TAA-T therapy
• Treatment Regimen 2 (Tx-R2): Lymphodepleting chemotherapy + local tumor ablation with cryoablation or PEF (cryoablation/PEF) + TAA-T therapy

In this dose escalation trial, three dose levels will be tested for safety. The protocol-level accrual flow is described briefly as follows: TAA-T product will first be administered to adult patients (Arm A) as monotherapy at dose level 1 (Completed as of Protocol V5.0). Following demonstration of safety at DL1, adults will be enrolled at DL2. Following demonstration of safety at DL2 in adults, enrollment will proceed under the amended protocol to treatment regimens 1 and 2: Tx-R1 at DL3, and Tx-R2 at DL2 (upon approval of ATTACK Protocol V5.0).Tx-R1 and Tx-R2 may accrue in parallel to one another. Each regimen will independently escalate, expand, or de-escalate according to the 3+3 design until the MTD is identified or, if the MTD is not reached, the maximum administered dose, (MAD; DL3) is reached. A total of six patients will then be treated at each regimen's MTD (or MAD, as applicable).

Safety evaluations, including DLT assessment, maximum tolerated dose level (MTD) and recommended dose level (RDL) determination, will be performed separately for each regimen, however, if a protocol-defined stopping rule is met, enrollment and dosing in both regimens will be paused pending review.

The TAA-T product will be assessed for safety and anti-tumor activity.

Inclusion Criteria:

• Diagnosis of high-risk solid tumors known to express at least 2 targeted antigens by either histology or historical reference: Ewing sarcoma, Wilms tumor, neuroblastoma, rhabdomyosarcoma, soft tissue sarcoma, and osteosarcoma.
• HLA type and match through at least one allele with antigen-specific activity.
• Following conventional therapy: refractory disease, residual detectable disease, or relapsed disease.
• Age >= 1 year and <70 years
• Patient or parent/guardian capable of providing informed consent.
• No systemic corticosteroid exposure within 1 week of initiating protocol treatment.
• Karnofsky/Lansky score of ≥50%.
• For participant with history of total body irradiation (TBI), radiation to thorax, or treatment with cardiotoxic chemotherapy (anthracycline or equivalent): Left ventricular ejection fraction (LVEF) >50% OR left ventricular fractional shortening (FS) >27% (may be performed within the last 12 months, and after completion of such treatment/s)
• Hemoglobin >7.0 g/dL (level can be achieved with transfusion).
• Direct bilirubin ≤2.5 mg/dL or 3x ULN (whichever is higher).
• Aspartate transaminase (AST)/Alanine transaminase (ALT) ≤5 x the upper limit of normal for age.
• Serum creatinine <1.0 mg/dL or 2x the upper limit of normal for age (whichever is higher).
• Pulse oximetry of >90% on room air.
• Respiratory rate:
• <30 breaths per minute for patients aged <18 years
• <25 breaths per minute for patients aged ≥18 years
• Respiratory rate may be repeated if initial value is thought to be temporarily abnormal. If repeated, 2 values should be obtained ≥30 minutes apart prior to protocol treatment to be eligible.
• Twelve (12) weeks post last radiation dose to the mediastinum/chest with resolution of any respiratory symptoms.
• Negative pregnancy test in female patient of childbearing potential.
• Agree to use contraceptive measures during study protocol participation through 6 months post final TAAT infusion (for FOCBP).
• Prior to cycle #1 only (requisite for receiving lymphodepleting chemotherapy):
• Absolute neutrophil count (ANC) >1000 /ul.
• Platelet count >75,000 /ul.

Exclusion Criteria:

• Patients with uncontrolled infections. Uncontrolled infections are defined as bacterial, fungal, or viral infections with either clinical signs of worsening despite standard therapy. Progressing infection is defined as hemodynamic instability, worsening physical signs, or radiographic findings attributable to infection. Persisting fever without other signs or symptoms will not be interpreted as progressing infection.
• For bacterial infections, patients must be receiving definitive therapy and have no signs of progressing infection within 7 days prior to protocol treatment.
• For fungal infections, patients must be receiving definitive systemic anti-fungal therapy and have no signs of progressing infection within 7 days prior to initiating protocol treatment.
• Patients who received ATG, Campath or other immunosuppressive T cell monoclonal antibodies within 28 days prior to initiating protocol treatment.
• Exposure to chemotherapy or immunomodulatory medications within the last 2 weeks prior to initiating protocol treatment.
• Pregnant or lactating females.