20140106 (former CFZ008), Phase 1b Study of Carfilzomib in Combination with Induction Chemotherapy in Children with Relapsed or Refractory Acute Lymphoblastic Leukemia
- Children’s Medical Center (Dallas, Plano, Southlake)
Theodore Laetsch, M.D.
This is a non-randomized, multi-center, Phase 1b dose-escalation study of carfilzomib in combination with induction chemotherapy, comprising either an
R3 backbone of dexamethasone, mitoxantrone, PeG-asparaginase, and vincristine (Dose escalation 1) or a VXLD backbone of vincristine,
dexamethasone, PeG-asparaginase, and daunorubicin (Dose escalation 2) in children with relapsed or refractory acute lymphoblastic leukemia.
During the Dose escalation 1 (R3) portion of the study only, the induction Cycle will be preceded by a 1-week carfilzomib single-agent Lead-in Window. Subjects in both dose escalation portions of the study will receive a 4-week cycle of induction chemotherapy and have the option to receive a 4-week cycle of consolidation chemotherapy, if stable disease (SD) or better response is achieved at the end of the induction Cycle.
a cohort size of 2 will be used in Dose escalation 1 (R3). The starting dose is 20 mg/m2; the maximum planned dose and the minimum planned dose are 45 mg/m2 and 20 mg/m2, respectively. one or more cohorts of 2 subjects may be enrolled to each dose level, depending on the toxicity observed. The Cohort Safety Review Committee (CSRC) will review the safety data and dose level recommended by the algorithm after every cohort has completed the 4-week induction Cycle. The CSRC will expand the dose level by 2 subjects, advance to the next dose level, or de-escalate to a lower dose level, based on the available data. no dose-level skipping will be allowed in dose-escalation decisions. There is no such constraint on de-escalation decisions. The algorithm will stop when the sample size reaches 18 or when the dose limiting toxicity (DLT) rate of the recommended maximum tolerated dose (MTD) has a 95% posterior credible interval within the prespecified range of 5% to 60%.
a cohort size of 3 will be used in Dose escalation 2 (VXLD). The starting dose level is 27 mg/m2; the planned dose levels are 27, 36, and 45 mg/m2. one or more cohorts of 3 subjects may be enrolled to each dose level, depending on the toxicity observed. The CSRC will review the safety data and dose level recommended by the algorithm after every cohort has completed the 4-week induction Cycle. The CSRC will expand the dose level by 3 subjects, advance to the next dose level, or de-escalate to a lower dose level, on the basis of the available data. no dose-level skipping will be allowed in dose-escalation decisions. There is no such constraint on de-escalation decisions. The algorithm will stop when the sample size reaches 18 or if both of following criteria are met:
* The probability of the Target Toxicity interval at the candidate MTD exceeds 40% anD
* a minimum of 2 cohorts (6 subjects) are accrued and treated at the candidate MTD a minimum of 2 subjects (1 cohort) will be enrolled at the starting dose level in Dose escalation 1 (R3). For the nCRM, the relationship between dose and the probability of DLT will be updated as additional subject safety information becomes available (e.g., after the last subject in the cohort completes the induction Cycle). after all subjects enrolled at the starting dose level are DLT evaluable, the Bayesian Logistic Regression (BLR) model will be updated, and the nCRM will recommend the next dose level from the updated probabilities for target toxicity interval and excessive/unacceptable toxicity interval. The next dose level (e.g., the Dose Level 2 or continuation of Dose Level 1) will be the dose with the highest posterior probability of having a toxicity rate in the target toxicity interval, which is defined as 20%x33%, and will be subject to the constraint that the probability of excessive/unacceptable toxicity, which is defined as [Greater Than] 33%x100%, is less than 40%. The MTD will be selected based on the above criteria and the clinical judgment of the CSRC. a minimum of 3 subjects (1 cohort) will be enrolled at the starting dose level in Dose escalation 2 (VXLD).
1. Age 21 years or younger at the time of initial ALL diagnosis and age > 1 year at the time of study treatment initiation.
2. Subjects must have a diagnosis of ALL with >= 5% blasts in the bone marrow (M2 or M3 disease), with or without extramedullary disease.
* To be eligible subjects must have had 1 or more prior therapeutic attempts, defined as:
o Early first relapse (< 36 months from original diagnosis) after achieving a CR (B-ALL) or first relapse any time following
o Relapse after achieving a CR following the first or subsequent relapse (i.e., >= 2 relapses)
o Failing to achieve a CR from original diagnosis after at least 1 induction attempt
3. Subjects must have fully recovered from the acute toxic effects of all previous chemotherapy, immunotherapy, or radiotherapy treatment before enrollment.
4. Subjects must have a serum creatinine level that is <= 1.5 x institutional upper limit of normal (ULN) according to age. If serum creatinine level is > 1.5 x ULN, the subject must have a calculated creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m2.
5. Adequate liver function, defined as both of the following:
* Total bilirubin <= 1.5 x institutional ULN, except in the presence of Gilbert syndrome. For those with hyperbilirubinemia due to
Gilbert syndrome, subjects are only eligible if they have a direct bilirubin <= 1.5 x institutional ULN.
* Alanine aminotransferase (ALT) <= 5 x institutional ULN
6. Performance status: Karnofsky or Lansky scores >= 50 for subjects > 16 years old or <= 16 years old, respectively.
7. Females of childbearing potential (FCBP) must have a negative serum pregnancy test within 48 hours prior to study treatment initiation.
8. Females of childbearing potential and male subjects who are sexually active with a female of childbearing potential (FCBP) must agree to use a highly effective method of contraception plus a male condom during the study and for 6 months following the last dose of study treatment. The methods of contraception are defined in the informed consent form (ICF). Where required by local laws, regulations and/or guidelines, additional country-specific requirements are outlined in a country-specific protocol supplement.
9. Subjects must provide written informed consent and pediatric assent in accordance with federal, local, and institutional laws and regulations.