M16-106, A Phase 1 Dose Escalation, Open-Label Study of Venetoclax in Combination with Navitoclax and Chemotherapy in Subjects with Relapsed/Refractory Acute Lymphoblastic Leukemia or Relapsed/Refractory Lymphoblastic Lymphoma (LL)
Study ID: STU 062017-026
This is an open-label, Phase 1 dose escalation study in pediatric and adult subjects with relapsed/refractory acute lymphoblastic leukemia (aLL) or relapsed/refractory lymphoblastic lymphoma (LL). all subjects will receive venetoclax, adjusted by weight, to match the exposure of the adult equivalent target doses. navitoclax will be explored at up to three dose levels (25, 50, 100 mg) in patients weighing [GreaterThanorequalTo] 45 kg, and up to two dose levels (25, 50 mg) in patients weighing [Less Than] 45 kg. Subjects weighing [GreaterThanorequalTo] 45 kg will be the first subjects to enroll into the study. These subjects will be enrolled at a navitoclax dose of 25 mg (Dose Level 1). after escalation proceeds to 50 mg (Dose Level 2) in the [GreaterThanorequalTo] 45 kg weight group, subjects weighing [Less Than] 45 kg will begin enrollment at a navitoclax dose of 25 mg (Dose Level 2). Subjects who experience a 10% change in weight may increase or decrease to the next weight group for the appropriate venetoclax and navitoclax dosing. Subjects who have a 10% decrease in weight while receiving 170 mg of venetoclax or 25 mg of navitoclax will continue to receive the same dose. Subjects may begin the following chemotherapy schedule on Day 9 (or Day 8, when appropriate, after bone marrow assessment is performed). Chemotherapy regimen with tyrosine kinase inhibitor for subjects with aLL with Philadelphia chromosome or with an abelson murine leukemia (aBL) class targetable fusion is listed in the protocol. * Peg-asparaginase 1,250 iu/m2 (maximum 3,750 iu) iV (intravenous) or iM (intramuscular) equivalent, on Day 9 and Day 22. * For patients with allergy or intolerance to peg-asparaginase, erwinia asparaginase is acceptable. * other forms of asparaginase may be used in place of peg-asparaginase, per local standard of care * Vincristine 1.5 mg/m2 (maximum 2 mg) iV, weekly on Days 9, 15,* 22, 29; * Dexamethasone 20 mg/m2/day Po (by mouth) divided twice daily, on Days 9 x 13 and Days 22 x 26; * alternatively, a flat dose of 40 mg once a day is allowed * Lower doses of dexamethasone may be discussed with the abbVie Therapeutic area Medical Director (Ta MD) for subjects who may not be able to tolerate these doses * The Po equivalent may be given as iV dose * Please note, chemotherapy will re-commence on Day 15 rather than 7 days post Day 9. if the start of chemotherapy is delayed post Day 9, then subsequent chemotherapy doses should be given at 7 day intervals. This regimen may be repeated for a second cycle. Peg-asparaginase (or any other forms of asparaginase), vincristine, dexamethasone, and/or tyrosine kinase inhibitor (TKi) may be delayed, reduced or omitted from the regimen at the discretion of the investigator. Chemotherapy may continue after Cycle 2 at the discretion of the investigator after discussion with the abbVie Ta MD.
1. The subject, parent or guardian must voluntarily sign and date an informed consent approved (in addition to pediatric assent, if required) by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study specific procedures. 2. Subjects must have relapsed or refractory acute lymphoblastic leukemia (ALL) or relapsed or refractory lymphoblastic lymphoma (LL) (Refractory is defined as persistent disease after at least 2 courses of chemotherapy). * Subjects with ALL with Philadelphia chromosome or with an Abelson murine leukemia (ABL) class targetable fusion are eligible. * Subjects with LL must have radiographic evidence of disease. 3. Subjects must be >= 4 years of age. 4. Subjects must weigh >= 20 kg. 5. Subjects must be able to swallow pills. 6. Subjects must have adequate hepatic function: * ALT (alanine aminotransferase) and AST (aspartate aminotransferase) <= 3 x ULN (upper limit of normal) and bilirubin <= 1.5 x ULN, * Subjects with documented Gilbert's Syndrome may have total bilirubin up to 4 x ULN but must have a direct bilirubin of <= 1.5 x ULN. 7. Subjects must have INR (international normalized ratio) <= 1.5 x ULN and aPTT (activated partial thromboplastin time) <= 1.5 x ULN. 8. Subjects must have normal creatinine for age or have a calculated creatinine clearance >= 60 mL/min/1.73 m2. 9. Subjects must have adequate performance status: * Subjects <= 16 years of age: Lansky >= 50, * Subjects > 16 years of age: Karnofsky >= 50 or ECOG < 3. 10. Female subjects of childbearing potential (i.e., those who are not postmenopausal for at least 1 year or surgically sterile by bilateral oophorectomy, bilateral salpingectomy, or hysterectomy) and their male partner must practice at least 1 method of birth control during the study and through at least 30 days after the last dose of study drugs. 11. Female subjects of childbearing potential must have negative results for serum or urine pregnancy test performed during Screening. Females of non-childbearing potential at Screening do not require pregnancy testing. 12. Male subjects who are sexually active with women of child bearing potential must agree to use condoms during the study and through at least 30 days after the last doses of venetoclax and navitoclax and if on chemotherapy, the subjects are required to follow instructions from the chemotherapy product label. Male subjects must agree to not donate sperm from Study Day 1 through at least 90 days after the last dose of study drugs.
- Cancer Related
- Healthy Volunteers
- UT Southwestern Principal Investigator
- Theodore W Laetsch