Venetoclax Basket Trial for High Risk Hematologic Malignancies

This trial is evaluating the safety and tolerability of venetoclax with chemotherapy in pediatric and young adult patients with hematologic malignancies, including myelodysplastic syndrome (MDS), acute myeloid leukemia derived from myelodysplastic syndrome (MDS/AML), and acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LBL). The names of the study drugs involved in this study are below. Please note this is a list for the study as a whole, participants will receive drugs according to disease cohort. * Venetoclax * Azacitidine * Cytarabine * Methotrexate * Hydrocortisone * Leucovorin * Dexamethasone * Vincristine * Doxorubicin * Dexrazoxane * Calaspargase pegol * Hydrocortisone

This is an investigator-initiated open-label multi-institutional phase I study of venetoclax combination therapy in both myeloid and lymphoid hematologic malignancies. This study is designed as a basket trial with three separate cohorts. All cohorts include a dose finding portion (Part I) followed by a dose expansion at the Recommended Phase II dose (RP2D, Part II). This research study is looking to learn more about how Venetoclax works and aims to determine the safest, highest possible dose that can be combined with standard of care chemotherapies. Because of this, not everyone who participates in this research study may receive the same dose of the study drug. The dose participants receive will depend on the number of participants who have been enrolled in the study previously and how well the doses have been tolerated. Study procedures include screening for eligibility as well as study treatment visits including evaluations and follow up visits. * Cohort A: Patients with myelodysplastic syndrome (MDS), acute myelogenous leukemia arising from MDS (MDS/AML) or treatment-related myeloid neoplasms (tMDS/AML). It is expected that up to 18 people will participate in Part 1 (Dose Determination) and an additional 14-20 people will participate in Part 2 (Dose Expansion) of this cohort. * Cohort B: Patients with myelodysplastic syndrome (MDS), acute myelogenous leukemia arising from MDS (MDS/AML) or treatment-related myeloid neoplasms (tMDS/AML) with an underlying genetic condition that increases their risk of experiencing toxic side effects of chemotherapy. It is expected that up to 18 people will participate in Part 1 (Dose Determination) and an additional 6 people will participate in Part 2 (Dose Expansion) of this cohort. * Cohort C: Patients with relapsed/refractory acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL). It is expected that up to 18 people will participate in Part 1 (Dose Determination) and an additional 12 people will participate in Part 2 (Dose Expansion) of this cohort. This research study is a Phase I clinical trial, which tests the safety of an investigational drug and also tries to define the appropriate dose of the investigational drug to use for further studies. "Investigational" means that the drug is being studied. The U.S. Food and Drug Administration (FDA) has not approved Venetoclax for use in children. However, Venetoclax is FDA-approved as a treatment for certain types of leukemia in adults. It is actively being studied in children and adults with other types of cancer. Information from these research studies has suggested that venetoclax may also be effective in treating participants with MDS or leukemia, including MDS or leukemia that did not respond to standard treatment or that has come back after standard treatment. The survival of cancer cells is controlled by proteins within the cancer cell. One of these proteins is called BCL-2. The study drug, venetoclax, blocks this protein and is thought to reduce cell survival in some cancer cells.