Trial Treating Relapsed Acute Lymphoblastic Leukemia With Venetoclax and Navitoclax

This is a non-randomized phase I/II clinical trial. In Block I, all patients receiving common therapy evaluating the activity of combination chemotherapy with venetoclax and navitoclax in children with relapsed or refractory acute lymphoblastic leukemia or lymphoma (rALL).

In Block 2, a phase 1 rolling six design and phase 2 extension will be used to assess the combination dose of venetoclax combinations with either blinatumomab for CD19-positive patients or navitoclax and high-dose cytarabine for CD19-negative patients. One to six participants can be concurrently enrolled onto a dose level, depending on the number of participants enrolled at the current dose level, the number of participants who have experienced a dose/combination limiting toxicity (DLT) at the current dose level, and the number of participants entered but with tolerability data pending. Dose de-escalation will occur if 2 patients at a dose level experience a targeted toxicity. If 6 patients complete a therapy block and experience 0-1 DLT, that dose will be considered the recommended phase 2 dose (RP2D). New enrollment on an arm (2a/2b) will be paused if further enrollment would result in more than 6 patients being treated on that arm before the RP2D is identified.

The primary outcome assessment will be a bone marrow with MRD testing on Day 29 of Block 1 therapy. Following that assessment, patients should continue with protocol therapy including either Block 2A (which includes high-dose cytarabine with venetoclax and navitoclax) for patients with CD19 negative leukemia, those with isolated extramedullary relapse, or whose treating physician determines that blinatumomab therapy is not in the patient's best interest; or Block 2B for patients with leukemia which is CD19 positive. Following recovery from Block 2 therapy, all patients except those with late first relapse of B-ALL (≥ 36 months from diagnosis) who are MRD-negative at \<0.01% after Block 1 therapy are off therapy. Further therapy for these patients is at the treating physician's discretion. Patients with late first relapse B-ALL relapse and who are MRD negative will proceed with intensification, interim continuation, and continuation therapy. Patients with Down's Syndrome with CD19 negative leukemia will be off therapy after Block 1 as they are ineligible for Block 2A. Patients in exploratory cohorts I and N who are late first relapse B-ALL and who are MRD-negative after Block 1 therapy may continue on protocol therapy after Block 2 or receive alternative therapy at their treating physician's discretion. Patients in exploratory cohort M and O are off therapy after Block 2.

Intervention:

Block 1 Therapy: