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

Official title

A Phase 1b Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of Xaluritamig in Adult, Adolescent and Pediatric Participants With Relapsed or Refractory Ewing Sarcoma

Overview

The main objectives of this trial are to determine the recommended dose for expansion of xaluritamig (dose confirmation part only) and to determine the safety and tolerability of xaluritamig in adult, adolescent and pediatric participants with relapsed or refractory EWS.

Interventions

• Drug Xaluritamig
  Participants will receive xaluritamig via short-term intravenous (IV) infusion.

Primary outcome measures

• Number of Participants Experiencing a Dose-limiting Toxicity (DLT) (Part 1 Only) [Time frame: Up to 42 days]
• Number of Participants with Treatment-emergent Adverse Events [Time frame: Up to approximately 2.5 years]

Secondary outcome measures (12)

• Maximum Serum Concentration (Cmax) of Xaluritamig [Time frame: Up to approximately 6 months]
• Time to Cmax (tmax) of Xaluritamig [Time frame: Up to approximately 6 months]
• Minimum Serum Concentration (Cmin) of Xaluritamig [Time frame: Up to approximately 6 months]
• Accumulation Following Multiple Doses of Xaluritamig [Time frame: Up to approximately 6 months]
• Serum Concentration Before Dosing (Ctrough) of Xaluritamig [Time frame: Up to approximately 6 months]
• Half-life (t½) of Xaluritamig [Time frame: Up to approximately 6 months]
• Area Under the Serum Concentration-time Curve (AUC) of Xaluritamig [Time frame: Up to approximately 6 months]
• Confirmed Objective Response per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 [Time frame: Up to approximately 6 months]
• Disease Control per RECIST v1.1 [Time frame: Up to approximately 6 months]
• Time to Response (TTR) per RECIST v1.1 [Time frame: Up to approximately 6 months]
• Duration of Confirmed Response (DOR) per RECIST v1.1 [Time frame: Up to approximately 6 months]
• Progression-free Survival (PFS) per RECIST v1.1 [Time frame: Up to approximately 6 months]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Basic science

Study locations

United States · 5 centers

• Cedars Sinai Medical Center — Los Angeles
• University of California Los Angeles — Los Angeles
• Dana Farber Cancer Institute — Boston
• Memorial Sloan Kettering Cancer Center — New York
• University of Texas MD Anderson Cancer Center — Houston

Australia · 3 centers

• Chris OBrien Lifehouse — Camperdown
• Peter MacCallum Cancer Centre — Melbourne
• Perth Childrens Hospital — Nedlands

Identifiers

NCT: NCT07297979 · 20200034

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗