A Phase I Study of Hyper-CVAD In Combination With Venetoclax In Pediatric Patients With Relapsed or Refractory Acute Leukemias That Are of the Lymphoid Lineage Including Bi-Phenotypic or Undifferentiated Leukemias

1. Relapsed/refractory leukemias as defined as:

1. Pediatric, adolescent, or young adult patients with relapsed or refractory acute leukemias that are of the lymphoid lineage including bi-phenotypic or undifferentiated leukemias as per NCCN v2.2021 and W.H.O. classification in relapse or primary refractory.

2. Participants must have ≥5% blasts in the bone marrow as assessed by morphology. However, if an adequate bone marrow sample cannot be obtained, patients may be enrolled if there is unequivocal evidence of leukemia with ≥5% blasts in the peripheral blood.

2. Participants have adequate performance status (ECOG ≤2) for patients ≥16 years old, Lansky score \>50 for patients \<16 years old.

3. Participants must be ≥ 2 years old or less than or equal to 21 years of age at time of signing/or having proxy sign the informed consent to be enrolled on study.

4. Participants with asymptomatic CNS disease are eligible.

5. These conditions are allowed on study: conditions requiring chronic systemic glucocorticoid use, such as autoimmune disease, graft versus host disease (GVHD) (well controlled on a stable dose of steroid or alternative therapy) or severe asthma. Participants are also allowed up to 5 days of glucocorticoids as cytoreduction, the use of hydroxyurea and the usage of cytarabine up to 2gm/m2. This should also be discussed with PI.

1. For participants on chronic glucocorticoid therapy: Participants should be on stable systemic steroid doses less than or equal to 11.6mg/m2 (20 mg max) of prednisone daily

* During times of dexamethasone dosing (cycles 1,3,5 and 7): Hold chronic steroids on days dexamethasone is given then resume normally scheduled chronic steroid dosing the following day.

* Participants on chronic steroids \> 11.6mg/m2 (20 mg max) prednisone equivalent will be excluded from the study.

2. The use of topical steroids for cutaneous graft-versus-host disease (GVHD) is allowed.

3. Participants should be at least 2 weeks or 5 half-lives (whichever is longer) from prior therapy, other than hydroxyurea, glucocorticoids or low dose cytarabine (as mentioned above) to maintain blast count prior to initiation of study therapy.

6. Participants must have adequate organ function and laboratory results (obtained within 14 days of enrollment):

6.1. Total serum bilirubin ≤1.5 x upper limit of normal (ULN). Participants with known Gilbert's syndrome may have a total bilirubin up to ≤3 x ULN.

6.2. Adequate renal function (creatinine clearance \>30mL/min) unless related to the disease.

6.3. Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤3 x ULN; ≤5 x ULN unless in case of suspected leukemic liver involvement Females of childbearing potential must have a negative serum or urine beta-human chorionic gonadotropin (beta-hcg) pregnancy test result within 14 days prior to the first dose of study drugs and must agree to use one of the following effective contraception methods during the study and for 3 months following the last dose of study drug.

The effects of these investigational agents on the developing human fetus are unknown. For this reason and because chemotherapeutic and inhibiting agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. This includes all female patients, between the onset of menses (as early as 8 years of age) and 55 years unless the patient presents with an applicable exclusionary factor which may be one of the following:

* Postmenopausal (no menses in greater than or equal to 12 consecutive months).

* History of hysterectomy or bilateral salpingo-oophorectomy.

* Ovarian failure (Follicle Stimulating Hormone and Estradiol in menopausal range, who have received Whole Pelvic Radiation Therapy).

* History of bilateral tubal ligation or another surgical sterilization procedure.

* Approved methods of birth control are as follows: Hormonal contraception (i.e. birth control pills, injection, implant, transdermal patch, vaginal ring), Intrauterine device (IUD), Tubal Ligation or hysterectomy, Subject/Partner post vasectomy, Implantable or injectable contraceptives, and condoms plus spermicide. Not engaging in sexual activity for the total duration of the trial and the drug washout period is an acceptable practice; however periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.

7. Males need to inform the doctor right away if the partner becomes pregnant or suspects pregnancy. While in this study and for 30 days after the last treatment the patient should not donate sperm for the purposes of reproduction. He will need to use a condom while in this study and for 30 days after the last treatment.

8. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of all study drug administration. Participants must have had at least 30 days between prior hematopoietic stem cell transplant and first dose of study drug.

9. For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.

11. Ability to understand and the willingness to sign a written informed consent document.

12. Participants with CD19+ B-ALL need to have received CD19-directed therapy prior to being considered for enrollment on this study.

What this study is about