Calaspargase Pegol-mknl and Decitabine Combined with Venetoclax for the Treatment of Pediatric, Adolescent, and Young Adult Patients with Relapsed or Refractory T-cell Acute Lymphoblastic Leukemia or T-cell Lymphoblastic Lymphoma

Inclusion Criteria

• Pediatric, adolescent, or young adult patients who have relapse or refractory T-cell lymphoblastic leukemia (T-ALL) or T-Cell lymphoblastic lymphoma (T-LLy) according to 2017 World Health Organization (WHO) classification and National Comprehensive Cancer Network (NCCN) version (v)1 2021
• Patients have adequate performance status (Eastern Cooperative Oncology Group [ECOG] ≤ 2) for patients ≥ 16 years old, Lansky score > 50 for patients < 16 years old
• Patients must be ≥ 1 month (mo) to 21 years of age at time of signing/or having proxy sign the informed consent
• Patients with asymptomatic central nervous system (CNS) disease are eligible
• The following conditions are allowed on study: conditions requiring systemic glucocorticoid use, such as autoimmune disease, acute or chronic controlled graft versus host disease (GVHD) or severe asthma. Patients are also allowed up to 5 days of glucocorticoids as cytoreduction in combination with up to 3 doses of cyclophosphamide (200 mg/m^2/day) are allowed as standard pre-phase treatment up to 1 day before start of study treatment or cytarabine up to 2gm/m^2. This can also be discussed with principal investigator (PI)
• Total serum bilirubin ≤ 1.5 x upper limit of normal (ULN) (obtained within 14 days of enrollment) * Patients with known Gilbert's syndrome may have a total bilirubin up to ≤ 3 x ULN
• Adequate renal function per age unless related to the disease (obtained within 14 days of enrollment)
• Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 3 x ULN; ≤ 5 x ULN unless in case of suspected leukemic liver involvement (obtained within 14 days of enrollment)
• Amylase, lipase and triglycerides must be within normal limit (WNL) prior to administration of calaspargase pegol-mknl. If the lab values are outside the normal range, the treating physicians can discuss dosing/enrolling per PI discretion (obtained within 14 days of enrollment)
• 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. Effective methods of birth control include: * Birth control pills, skin patches, birth control injections, implants (placed under the skin by a health care provider) * Intrauterine devices (IUDs) and intra-uterine hormone-releasing systems (IUS) * Condom * Abstinence * Bilateral tubal occlusion/ligation or bilateral tubal occlusion/ligation by hysteroscopy with a hysterosalpingogram to confirm the procedure's success
• Males need to inform the doctor right away if the partner becomes pregnant or suspects pregnancy. While in this study and for 90 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 90 days after the last treatment
• Patients must have had at least 30 days between prior hematopoietic stem cell transplant and first dose of study drug
• Patients able and willing to swallow tablets or use oral dispersible tablets. No liquid formulation is available

Exclusion Criteria

• Past or current history of a secondary or other primary tumor or a chronic myeloid leukemia (CML) blast crisis with exception of: * Curatively treated non-melanomatous skin cancer * Other primary solid tumor treated with curative intent and no known active disease present and no treatment administered during the last 2 years
• Presence of clinically significant uncontrolled CNS pathology such as epilepsy, paresis, aphasia, stroke, severe brain injuries, organic brain syndrome, or psychosis. Presence of the following are allowed: headaches, vomiting, nerve palsy
• Significant traumatic injury or major surgery (major surgery means opening of a body cavity, e.g., thoracotomy, laparotomy, laparoscopic organ resection, and major orthopedic procedures, e.g. joint replacement, open reduction and internal fixation) within 14 days of scheduled dosing day 1
• Male or female subjects of childbearing potential, unwilling to use an approved, effective means of contraception in accordance with institution's standards
• Patients with uncontrolled infections (viral, bacterial, or fungal) per PI’s discretion. Infections controlled on concurrent anti-microbial agents are acceptable, and anti-microbial prophylaxis per institutional guidelines are acceptable
• Medical history of cardiovascular disease such as: * Clinically significant cardiac disease including congestive heart failure (New York Heart Association [NYHA] class III or IV), arrhythmia or conduction abnormality requiring medication, or cardiomyopathy
• Female patient who is pregnant or breastfeeding. Female patient who is considering becoming pregnant during the study, or within approximately 30 days after the last dose of venetoclax. For chemotherapy, also see the relevant chemotherapy product label for pregnancy precautions. Male patient who is considering fathering a child within approximately 30 days or donating sperm during the study, within approximately 90 days after the last dose to venetoclax. For chemotherapy, also see the relevant chemotherapy product label for not fathering a child and donating sperm
• Patients may be excluded if they are currently enrolled in another ongoing clinical trial with investigational products
• Liver cirrhosis or other active severe liver disease or with suspected active alcohol abuse
• Patients who are unable or unwilling to comply with all study requirements for clinical visits, examinations, tests, and procedures
• If patient has not recovered from grade 2 clinically significant adverse effect(s)/toxicity(s) of the previous therapy- (exception no grade 3 or higher peripheral neuropathy) from previous chemotherapy, surgery, radiation before the start of study drugs
• Pancreatitis: Patients will be excluded in the presence of grade 3 or 4 pancreatitis or if history of anaphylaxis or grade 3 pancreatitis from asparaginase
• Other severe, uncontrolled acute or chronic medical or psychiatric condition or laboratory abnormality that in the opinion of the Investigator may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and/or would make the patient inappropriate for enrollment into this study
• History of serious hypersensitivity reactions including analphylaxis to pegylated L-asparaginase therapy
• Known history of coagulopathy (e.g., hemophilia and know protein S deficiency)
• Active thromboembolic event(s) (i.e., symptomatic despite initiation of anti-coagulation therapy), or history of CNS thromboses
• Patients should not have received the following within 7days prior to the first dose of study drug: Strong and moderate CYP3A inducers
• Malabsorption syndrome or any other condition that precludes enteral administration
• Has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or star fruit within 3 days prior to the first dose of venetoclax