A Phase 1 Study Of FLAG Chemotherapy In Combination With Lisaftoclax And Pelcitoclax In Patients With Relapsed/Refractory T-Cell Acute Lymphoblastic Leukemia

A Phase 1 Study Of FLAG Chemotherapy In Combination With Lisaftoclax And Pelcitoclax In Patients With Relapsed/Refractory T-Cell Acute Lymphoblastic Leukemia

To find safe and effective doses of lisaftoclax and pelcitoclax in combination with FLAG chemotherapy in patients with relapsed/refractory T-ALL.

Primary Objectives

• To establish the minimum safe and biologically-effective doses of lisaftoclax and pelcitoclax in combination with FLAG chemotherapy

Secondary Objectives

• To determine the CR/CRi rate of the combination regimen
• To assess other efficacy endpoints (CR rate, measurable residual disease negativity by flow cytometry and clonoSEQ, relapse-free survival, overall survival, event-free survival)
• To determine the safety of the combination regimen

Inclusion Criteria

• Diagnosis: Age ≥18 years with relapsed or refractory T-cell ALL.

• Performance status ≤2 (ECOG Scale).

• Adequate liver, cardiac, renal and pancreatic function as defined by the following criteria:

  1. Total serum bilirubin <2x upper limit of normal (ULN), unless due to Gilbert's syndrome, hemolysis or the underlying leukemia approved by the PI
  2. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) <3 x ULN, unless due to the underlying leukemia approved by the PI
  3. Creatinine clearance ≥30 mL/min
  4. Ejection fraction ≥40%

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

• Willingness to use adequate contraception prior to study entry, for the duration of study participation, and for 6 months after completion of study participation. For women of childbearing potential, adequate methods of contraception include: complete abstinence, 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.

Exclusion Criteria

• Participant s who previously received lisaftoclax or any Bcl-xL inhibitor

• Active and uncontrolled infection

• Active secondary malignancy. Participant s with a prior or concurrent malignancy whose natural history or treatment is not anticipated to interfere with the safety or efficacy assessment of the investigational regimen may be included only after discussion with the PI.

• Clinically significant, uncontrolled, active cardiovascular disease, including active grade III-V cardiac failure as defined by the New York Heart Association Criteria

• Prior investigational therapy within 14 days of enrollment, unless the participant has rapidly progressive disease judged to be life-threatening by the investigator. Cytoreduction with corticosteroids and/or hydroxyurea, is permitted.

• Recent exposure to strong inducer of CYP3A or p-glycoprotein within 14 days of study enrollment, or 5 half-lives, whichever is longer. Agents include but are not limited to: carbamazepine, phenytoin, rifampin, and St. John's wart

• Pregnant or lactating women

• Inability to swallow

• Unable or unwilling to sign the consent form

• Known hepatitis B surface antigen seropositive or known or suspected active hepatitis C infection

  o Note: Participants who have isolated positive hepatitis B core antibody (ie, in the setting of negative hepatitis B surface antigen and negative hepatitis B surface antibody) must have an undetectable hepatitis B viral load. Participants who have positive hepatitis C antibody may be included if they have an undetectable hepatitis C viral load.

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to fludarabine, cytarabine, filgrastim, pegfilgrastim, lisaftoclax, and pelcitoclax or other agents used in study.

• Participants with psychiatric illness/social situations that would limit compliance with study requirements.