T2009-012, A Phase I Dose Finding Study Of Panobinostat In Children With Refractory Hematologic Malignancies
Subjects with leukemia will take panobinostat by mouth 3 times a week on a Monday, Wednesday, Friday schedule every week, for 4 weeks. During the first course, on the first day of therapy he/she will receive intrathecal therapy (IT) with cytarabine. The subject will get another dose of IT cytarabine on day 29 of each course.
Subjects with HD or NHL, will take panobinostat 3 times a week on a Monday, Wednesday, Friday schedule, every other week for 4 weeks.
Most subjects will get 2 courses of therapy. If his/her cancer responds well to therapy the subject may continue to receive up to 6 additional courses of panobinostat for a total of 8 courses.
The Phase I component of the trial will be a standard 3+3 dose escalation design with different doses and schedules for panobinostat. On the adult trials, 60 mg per day three days a week every week was determined to be the MTD for leukemia patients. A much higher degree of thrombocytopenia was tolerated for leukemia patients than other patients, hence the higher dose and dose intensity. The average BSA of patients on the adult trial was 1.92 m2, higher than normal for adults. This calculates to an MTD of about 31.25 mg/ m2 for adults with leukemia. Thus, we will begin the dose escalation with a dose approximately 80% of the anticipated MTD, Dose level 1 = 24 mg/m2. For lymphoma, 40 mg per day three days a week every other week was determined to be the adult MTD, using a BSA again of 1.92 m2, approximately equal to 20 mg/m2. Thus, for lymphoma, 16 mg/m2/day will be the starting dose (approximately equal to 80% of the planned adult Phase II dose). 20 mg/m2/day is dose level 2.
Patients will be assigned to one of two stratum at time of enrollment:
* Stratum 1: Patients with relapsed ALL or AML
* Stratum 2: Patients with relapsed HD or NHL
Dose escalation will occur separately within each stratum. A modified 3-patient cohort dose-escalation design will be used in each stratum. If the MTD has been exceeded at the first dose level, then the dose in that stratum will back down to dose level [Double Quote]0[Double Quote]. If the MTD is exceeded at dose level [Double Quote]0[Double Quote] then the study will close. If no DLT is experienced upon completion of dose level 3, the study will be re-evaluated to determine if additional escalation within that stratum is warranted.
If during any course of therapy the patient experiences any adverse event which qualifies as a dose limiting toxicity (DLT), the patient should be removed from the study to pursue alternative therapy. All DLT[Right Quote]s require continued monitoring and follow-up reporting until they resolve to grade 1 or less, until the patient enters in to another treatment regimen or until the toxicity is determined to be unresolvable.
The primary endpoints for this study include:
* The determination of the safety and RP2D for children with leukemia and lymphoma.
Secondary endpoints for this study include:
* The pharmacokinetic profile of oral panobinostat in children.
* The pre-treatment measurement of HR23B by IHC in the tumors of children on study.
* The response rate, time to response, duration of response, and progression-free survival.
-- Patients must be >= 1 and <= 21 years of age at the time of enrollment.
-- Patients must have one of the following:
a. Patient must have relapsed/refractory acute myelogenous leukemia (AML) with >= 5% blast in the bone marrow or biopsy confirmed chloroma. Patient may have CNS 1, 2 or 3 disease. Isolated CNS relapse is not eligible. Patients with secondary AML are eligible.
b. Patient must have relapsed/refractory acute lymphoblastic leukemia (ALL) with >= 5% blasts in the bone marrow or biopsy confirmed extramedullary disease. Patient may have CNS 1, 2 or 3 disease. Isolated CNS relapse is not eligible.
c. Patient must have relapsed or refractory non-Hodgkin[Single Quote]s lymphoma (NHL) or Hodgkin[Single Quote]s disease. Patients must have CNS 1 disease.
-- Performance Level of > 50% for patients using Karnofsky and Lansky scales.
-- Patient must have a life expectancy of 8 weeks.
-- Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.
-- Patient must have adequate renal, hepatic and cardiac function
-- Female patients of childbearing potential must have a negative urine or serum pregnancy test confirmed prior to enrollment.
-- Female patients with infants must agree not to breastfeed their infants while on this study.
-- Male and female patients of child-bearing potential must agree to use an effective method of contraception approved by the investigator during the study.