Background: Acute lymphoblastic leukemia (ALL) relapse in children and adults is associated with poor prognosis. Venetoclax (VEN) is a potent, highly selective BCL-2 inhibitor, and navitoclax (NAV) inhibits various BCL family proteins, including BCL-2, BCL-W, and BCL-X_L. VEN and NAV have shown activity in a variety of ALL cell lines and xenografts, and their combination resulted in synergistic antitumor effect in most ALL xenografts (Khaw et al. Blood 2016;128:1382-95). This trial evaluates VEN in combination with NAV and chemotherapy in patients with relapsed ALL. Methods: This is an open-label, multicenter phase 1 dose-escalation trial (NCT03181126) in patients 4‒45 years old with relapsed or refractory ALL. Patients receive daily oral VEN, weight-adjusted to match the adult-equivalent exposure of 400 mg. Daily oral NAV administration starts on day 3. Based on the patients’ weight, up to 3 dose levels (25, 50, and 100 mg) will be explored. Chemotherapy consists of peg-asparaginase (1,250 IU/m² intravenous [IV] on days 9 and 22), vincristine (1.5 mg/m² IV on days 9, 15, 22, and 29), and dexamethasone (20 mg/m²/day orally on days 9–13 and 22–26). At the investigator’s discretion, chemotherapy may be delayed, not administered, or repeated for a second cycle. Dose escalation is guided by a Bayesian optimal interval design. For each weight group ( < 45 kg and ≥45 kg), the initial cohort at each dose level enrolls ≥3 dose-limiting toxicity (DLT)-evaluable patients, and additional cohorts ≥2. DLTs are assessed during the first 42 days. In the absence of progressive disease, patients may receive VEN + NAV for up to 9 months; thereafter, therapy may be continued for those with ongoing benefit. Primary endpoints are safety and DLTs of VEN + NAV and chemotherapy, and safety and pharmacokinetics of VEN + NAV. Secondary objectives include assessments of antitumor activity and number of patients who proceed to stem cell transplantation. BH3 profiling and comprehensive genomic analysis will be performed to explore biomarkers of disease response. Approximately 42 patients are planned to be enrolled. As of Jan 5, 2018, 3 patients were enrolled at dose level one. Clinical trial information: NCT03181126