Evaluation of Xaluritamig in Adults, Adolescents and Children With Relapsed or Refractory Ewing Sarcoma (EWS)

Inclusion criteria

• Part 1: evaluable disease as defined by RECIST v1.1, as determined by the site investigator.

Part 2: measurable disease as defined by RECIST v1.1, as determined by the site investigator.

• Histologically or cytologically confirmed EWS with molecular evidence of an EWSR1 translocation with an E26 transformation-specific (ETS) family gene, eg, FLI1, ETS-related gene [ERG]) via next generation sequencing (based on local testing).
• Relapsed or refractory EWS following at least 1 line of chemotherapy (including treatment with an anthracycline and at least 1 alkylating agent).
• Performance status:

• Karnofsky ≥ 70% for participants ≥ 16 years of age.
• Lansky ≥ 70% for participants < 16 years of age.
• Adequate organ function, defined as follows:

a. Hematological function: i. Absolute neutrophil count ≥ 1.0 x 109/L, provided that:

• the participant has not received short-acting growth factor support within 7 days before screening assessment, and
• the participant has not received long-acting growth factor support within 14 days before screening assessment.

ii. Platelet count ≥ 75 x 109/L, provided that:

• the participant has not received a platelet transfusion within 7 days before screening assessment, and
• the participant has not received a platelet stimulating agent within 14 days before screening assessment.

b. Renal function: i. Estimated glomerular filtration rate based on Modification of Diet in Renal Disease (MDRD) calculation ≥ 30 mL/min/1.73 m^2 for participants ≥ 18 years of age.

ii. estimated glomerular filtration rate based on Schwartz (2009) calculation ≥ 30 mL/min/1.73 m^2 for participants < 18 years of age.

c. Hepatic function: i. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x upper limit of normal (ULN) (or ≤ 5 x ULN for participants with liver metastases).

ii. Total bilirubin (TBL) ≤ 1.5 x ULN (unless related to Gilbert's or Meulengracht disease).

d. Pulmonary function: i. Baseline oxygen saturation > 92% in room air at rest and no oxygen supplementation.

e. Cardiac function: i. Left ventricular ejection fraction ≥ 50%. If left ventricular ejection fraction cannot be measured, then left ventricular fractional shortening ≥ 28%.

• Participants of childbearing potential must use protocol-specified contraception to prevent pregnancy during treatment and for an additional 6 months after the last dose of xaluritamig.

Exclusion criteria

• Untreated central nervous system (CNS) metastases or leptomeningeal disease. Participants with a history of treated CNS metastases are eligible if there is radiographic evidence of improvement upon the completion of CNS-directed therapy and no evidence of interim progression between the completion of CNS-directed therapy and the screening radiographic study.
• History of other malignancy within the past 2 years, except for malignancy treated with curative intent with low risk for recurrence (approximately < 10%) and with no known active disease present for >1 year before enrollment.
• Active autoimmune disease that has required systemic treatment (except physiologic adrenal hormone replacement therapy) within the past 2 years or any other diseases requiring immunosuppressive therapy while on study. Participants with Type 1 diabetes, vitiligo, psoriasis, hypo- or hyper-thyroid disease not requiring immunosuppressive treatment are permitted.
• Participants who received anti-cancer therapy administered within the following minimum washout periods prior to first dose of xaluritamig:

• Cytotoxic chemotherapy: 21 days.
• Small molecules including tyrosine kinase inhibitors: 7 days or 5 half-lives, whichever is shorter.
• Monoclonal antibodies, immune checkpoint inhibitors, bispecific antibodies and other biologic agents: 28 days or 5 half-lives, whichever is shorter.
• Cellular therapies including Chimeric Antigen Receptor T-cell therapy (CAR-T), adoptive T-cell therapy: 56 days.
• Radiotherapy: 14 days for focal therapy, 28 days for large field therapy or involving > 30% of the bone marrow.
• Stem cell transplant: 12 weeks for autologous, 6 months for allogeneic, with no active graft-versus-host disease.
• Any other therapy or investigational agent: 28 days or 5 half-lives, whichever is longer.
• Requirement for chronic systemic corticosteroid therapy (prednisone dose > 10 mg/day [> 0.25 mg/kg/day if < 40 kg] or equivalent) or any other immunosuppressive therapies (including anti-tumour necrosis factor α (TNFα) therapies) unless stopped (with adequate tapering) within 28 days before first dose of xaluritamig.
• Currently pregnant (confirmed with positive pregnancy test) or breastfeeding or planning to become pregnant, donate eggs, or breastfeed while on trial until an additional 6 months after the last dose of trial intervention.
• Unwilling to abstain from donating sperm during treatment and for an additional 6 months after the last dose of xaluritamig.