A Phase II Study of the Combination of Ponatinib With Mini-hyper CVD Chemotherapy and Venetoclax in Patients With Relapsed or Refractory T-cell Acute Lymphoblastic Leukemia

1. Participant is pregnant or breastfeeding

2. Participants under 40kg

3. Participants with uncontrolled active infection

4. Hepatitis B or C infection, or known seropositivity for human immunodeficiency virus (HIV)

5. Major surgery or radiation therapy within 4 weeks prior to the first study dose

6. Systemic chemotherapy/radiotherapy/investigational therapy within 14 days (with the exception of hydroxyurea, dexamethasone, or one dose of cytarabine) prior to starting therapy

7. No clinical, radiological or laboratory evidence of pancreatitis, including:

1. Serum lipase must be \<2 times the ULN, and

2. Serum amylase must be \<2 times the ULN

8. Symptomatic or untreated leptomeningeal disease or spinal cord compression. Participants with prior h/o CNS disease are eligible as long as no active CNS disease as documented by recent CSF analysis and/or imaging studies.

9. Participants with active heart disease \[New York Heart Association (NYHA) class 3-4 as assessed by history and physical examination, unstable angina/stroke/myocardial infarction within the last 6 months\]

10. Clinically significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to:

* Myocardial infarction (MI), stroke, revascularization, unstable angina or transient ischemic attack within 6 months

* Left ventricular ejection fraction (LVEF) less than 50%

* Diagnosed or suspected congenital long QT syndrome

* Clinically significant atrial or ventricular arrhythmias (such as uncontrolled, clinically significant atrial fibrillation, ventricular tachycardia, ventricular fibrillation, or Torsades de pointes) as determined by the treating physician

* Prolonged QTc interval on pre-entry electrocardiogram (\> 480 msec) unless corrected after electrolyte replacement or Currently taking drugs that are known to have a risk of causing prolonged QTc or torsades de pointes (TdP) (unless these can be changed to acceptable alternatives or discontinued)

* History of venous thromboembolism including deep venous thrombosis or pulmonary embolism within the past 3 months, excluding line-associated DVT of the upper extremity

* Uncontrolled hypertension (diastolic blood pressure \>100mmHg; systolic \>150mmHg).

10\. Uncontrolled hypertriglyceridemia (triglycerides \> 450mg/dL) 11. History of another primary invasive malignancy that has not been definitively treated or in remission for at least 2 years. Participants with non-melanoma skin cancers or with carcinomas in situ are eligible regardless of the time from diagnosis (including concomitant diagnoses) 12. Taking any medications or herbal supplements that are known to be strong inhibitors (such as fluconazole, ketoconazole, voriconazole, and clarithromycin) or inducers (such as rifampin, rifabutin, phenytoin, carbamazepine, and St. John's Wort) of cytochrome P450 (CYP)3A4 within at least 7 days before the first dose of ponatinib or within 3 days of starting venetoclax.

13\. Consumed grapefruit, grapefruit products, Seville oranges, or star fruit within 3 days prior to starting venetoclax 14. Malabsorption syndrome or other conditions that preclude enteral route of administration 15. Other severe 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 participants inappropriate for enrollment into this study

What this study is about