A Phase 1/2, Open-Label, Dose-Escalation Study of Midostaurin in Pediatric Patients (Pts) with Relapsed or Refractory (R/R) Acute Leukemia: Final Results of Study ITCC-024 (CPKC412A2114)
Authors: Zwaan C. Michel , Söderhäll Stefan , Brethon Benoit , Luciani Matteo , Rizzari Carmelo , Sternberg David , Besse Emmanuelle , Dutreix Catherine , Fagioli Franca , Ho Phoenix , Dufour Carlo , Pieters Rob 
Published: October 2019

Abstract
Introduction Outcomes for acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) have improved, but the prognosis for pts with R/R disease remains poor. Childhood AML and MLL-rearranged ALL (MLL r-ALL) often overexpress or have activating mutations in the FLT3 tyrosine kinase (TK). Midostaurin (PKC412) is an orally available TK inhibitor that targets FLT3, KIT, and other kinases. Data in adults for single-agent midostaurin, including from studies CPKC412A2104 and CPKC412A2106, showed that 100 mg bid (≈ 60 mg/m2 bid) was adequately tolerated, elicited leukemic blast reduction, and inhibited FLT3 autophosphorylation. Here, we present the safety and preliminary clinical activity of midostaurin in children with R/R acute leukemia.
Methods In this multicenter dose-escalation study, children (3 mo to < 18 y) with FLT3 -mutated AML or MLL r-ALL refractory to standard induction therapy or in second or subsequent relapse received oral midostaurin solution (NCT00866281). The primary objective was to estimate the maximum tolerated dose (MTD) or recommended dose for expansion (RDE) for 2 age groups: younger (3 mo to 2 y) and older (> 2 y to < 18 y). The secondary objective was to evaluate response, time to relapse, overall survival (OS), pharmacokinetics (PK), pharmacodynamics, safety, and tolerability. In the dose-escalation phase (starting dose, 30 mg/m2 bid), each cohort received increasing doses until a maximum dose of 60 mg/m2 bid was reached. Dose escalation was determined using a Bayesian logistic regression design, allowing separate dose escalation in each age group. Dose-limiting toxicity (DLT) was defined as a grade 3/4 nonhematologic adverse event (AE), abnormal drug-related laboratory value, or drug discontinuation within 14 days of study start.
Results This study enrolled 22 pts (7 at 30 mg/m2 bid [2 younger, 5 older]; 15 at 60 mg/m2 bid [9 younger, 6 older]) starting on Sep 21, 2009. The median age was 2 y (range, 0.5-17 y); 9 pts (9 older) had AML and 13 pts (11 younger, 2 older) had ALL. The dose-determining set included 17 pts.
No DLTs occurred at 30 mg/m2 bid; thus, in each age group, the dose was escalated directly to 60 mg/m2 bid. One DLT (increased alanine aminotransferase [ALT]) occurred in a younger pt receiving 60 mg/m2 bid; no older pts had a DLT. The most common AEs regardless of study drug relationship (any grade/grade 3/4) were vomiting (68%/5%), pyrexia (41%/14%), and thrombocytopenia (41%/36%). Grade 3/4 AEs (particularly thrombocytopenia, elevated ALT, and anemia) were more common with the higher dose. Consistent with the safety profile of midostaurin in adults, the most frequent drug-related any-grade AEs were vomiting (55%), nausea (32%), and diarrhea (18%). The MTD was not reached.
Median OS was 3.7 mo (95% CI, 2.7-8.3 mo) in pts with AML and 1.4 mo (95% CI, 1.0-2.9 mo) in pts with ALL. All 5 on-treatment deaths (ie, death while on study drug or within < 28 days of final dose) were due to underlying AML (n = 4) or ALL (n = 1); 16 additional pts (4 with AML, 12 with ALL) died ≥ 28 days after the final dose. One pt was alive at trial end.
Midostaurin demonstrated limited single-agent clinical activity in this study. Five pts (56% [95% CI, 21%-86%]) with AML achieved a clinical response. The best response was a morphological complete remission with incomplete count recovery on day 14. The pt remained in remission until stopping treatment on day 64, received a stem cell transplant (SCT) on day 76, and was alive at day 960 after completing the per-protocol survival follow-up. Three pts (23% [95% CI, 5%-54%]) with ALL achieved a clinical response; all were peripheral blood blast responses.
All pts discontinued treatment; reasons were disease progression (64%), start of new cancer therapy (including SCT [18%]), withdrawn consent (14%), or AEs (5%). Median duration of exposure was 15.5 days (range, 3-64 days).
Time-dependent PK and exposures of midostaurin and its 2 active metabolites (CGP52421 and CGP62221) at the selected doses were similar to adult data.
Conclusions Single-agent midostaurin was adequately tolerated at 60 mg/m2 bid, the highest dose evaluated. Only limited clinical activity was demonstrated; thus, future trials in children with FLT3 -mutated AML should be in combination with established chemotherapies. The RDE of midostaurin for such studies is 30 mg/m2 bid due to a higher frequency of grade 3/4 AEs in the 60 mg/m2 bid dose group and known toxicities of existing standard pediatric AML regimens.

Disclosures
Zwaan: Janssen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Söderhäll:Novartis: Other: Investigator in clinical trials within my duties or ordinary salary at the hospital; Merck: Other: Investigator in clinical trials within my duties or ordinary salary at the hospital. Sternberg:Novartis Oncology: Employment, Equity Ownership. Besse:Novartis: Employment. Dutreix:Novartis: Employment. Ho:Seattle Genetics (employment started after completion of involvement in presented study): Employment. Dufour:Pfizer: Consultancy.