ZUMA-4: A Phase 1/2 Multicenter Study of KTE-X19 in Pediatric and Adolescent Patients With Relapsed/Refractory B Cell Acute Lymphoblastic Leukemia or Non-Hodgkin Lymphoma

Background: Although approximately 80% – 85% of patients with acute lymphoblastic leukemia (ALL), the most common childhood malignancy, achieve durable complete remissions (CRs) after initial treatment, the remaining 15% – 20% of patients with relapsed or refractory (R/R) ALL have unfavorable outcomes (Leukemia 2018;32:2316-25; N Engl J Med 2015;373:1541-52) and could benefit from effective new therapies. KTE-X19 is an autologous, anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for the treatment of R/R mantle cell lymphoma and under investigation for additional R/R hematologic malignancies including chronic lymphocytic leukemia, adult ALL, and pediatric B cell ALL and non-Hodgkin lymphoma (NHL). KTE-X19 treatment has shown high rates of CRs, with a manageable safety profile for adult patients with R/R B cell ALL in the Phase 1 portion of ZUMA-3, including those with poor risk factors (J Clin Oncol 2019;37[suppl, abstr]:7006). ZUMA-4 is an ongoing Phase 1/2 study evaluating KTE-X19 in pediatric and adolescent patients with R/R B cell ALL or NHL (NCT02625480). End-of-Phase 1 interim analysis of ZUMA-4 showed the feasibility of KTE-X19 therapy with optimized dosing and adverse event (AE) management strategies for the treatment of pediatric patients with R/R ALL (Pediatr Blood Cancer 2019;66[suppl]:S24). The protocol for Phase 2 of ZUMA-4 has been amended to include broader B cell ALL enrollment criteria with a focus on patients with early relapse associated with poorer outcomes, and an NHL cohort was added.

Methods: Key B cell ALL enrollment criteria include age ≤ 21 years, weight ≥ 10 kg, and B cell ALL that is primary refractory, relapsed within 18 months of first diagnosis, R/R after ≥ 2 lines of systemic therapy, or R/R after allogeneic stem cell transplantation at least 100 days prior to enrollment. Criteria for disease burden have been amended to also include patients with minimal residual disease-positive disease at enrollment. Patients with Philadelphia chromosome-positive ALL are eligible if intolerant to tyrosine kinase inhibitor therapy or if R/R after ≥ 2 tyrosine kinase inhibitor therapies. Patients with chronic myelogenous leukemia lymphoid blast crisis or clinically significant infections are not eligible.

For B cell NHL, key enrollment criteria include age < 18 years, weight ≥ 10 kg, histologically confirmed diffuse large B cell lymphoma not otherwise specified (DLBCL NOS), primary mediastinal large B cell lymphoma, Burkitt lymphoma (BL), Burkitt-like lymphoma or unclassified B cell lymphomas intermediate between DLBCL and BL, with ≥ 1 measurable lesion. For NHL, disease must be primary refractory, R/R after ≥ 2 lines of systemic therapy, or R/R after autologous or allogeneic stem cell transplantation ≥ 100 days prior to enrollment. Patients with acute graft-versus-host disease or chronic graft-versus-host disease requiring treatment within 4 weeks of enrollment are not eligible.

Patients with central nervous system-1 disease (no detectable lymphoblasts in cerebrospinal fluid), with central nervous system-2 disease (detectable disease, but white blood cell count < 5/μL in cerebrospinal fluid) without clinically evident neurologic changes, or who had prior blinatumomab treatment can be included in the ALL and NHL cohorts. Patients with prior CD19-directed therapy, except for blinatumomab, are excluded.

Patients receive conditioning chemotherapy with fludarabine 25 mg/m² on Days −4, −3, and −2 and cyclophosphamide 900 mg/m² on Day −2 followed by a single infusion of KTE-X19 at a target dose of 1 × 10⁶ anti-CD19 CAR T cells/kg on Day 0. The study has completed the Phase 1 portion and is currently enrolling in Phase 2, with a target accrual of approximately 50 additional patients with ALL and 16 with NHL. For ALL, the primary Phase 2 objective is to evaluate KTE-X19 efficacy as assessed by overall CR rate (CR + CR with incomplete hematologic recovery). For NHL, the primary Phase 2 objective is KTE-X19 efficacy assessment by objective response rate (complete response + partial response). Secondary Phase 2 objectives for ALL and NHL cohorts include safety and tolerability, additional efficacy endpoints, and changes in patient-reported outcome scores. ZUMA-4 is currently recruiting at 23 sites in the United States, Canada, France, and the Netherlands.