Sorafenib

The AAML1031 study was an open-label multi-center randomized trial including patients aged 0 to 29.5 years with previously untreated primary AML. Exclusion criteria were: prior chemotherapy, acute promyelocytic leukemia [t(15;17)], juvenile myelomonocytic leukemia, bone marrow failure syndromes, or secondary AML. The National Cancer Institute’s central institutional review board (IRB) and IRB at each enrolling center approved the study; patients and families provided informed consent or assent as appropriate. The trial was conducted in accordance with the Declaration of Helsinki. The trial was registered at clinicaltrials.gov identifier: NCT01371981.
Patients were randomly assigned at enrollment to either standard AML treatment or standard treatment with bortezomib. Randomization was conducted in blocks of four. Bortezomib was administered at a dose of 1.3 mg/m² once on days 1, 4, and 8 of each chemotherapy course.
Patients with high allelic ratio FLT3 ITD were offered enrollment on a phase I sorafenib treatment arm if that arm was open. Patients with HAR FLT3 ITD who declined enrollment in the sorafenib arm, or who enrolled while the arm was suspended, continued to receive treatment according to their initial randomization. These patients were included in safety analyses but were excluded from all efficacy analyses.
Patients were classified as low- or high-risk after Induction I. Low-risk patients received four courses of chemotherapy and high-risk patients received three courses of chemotherapy followed by allogeneic SCT. High-risk patients without an appropriate donor received four courses of chemotherapy.
The primary end point was EFS from study entry. EFS was defined as the time from study entry until death, refractory disease, or relapse of any type, whichever occurred first. The secondary end points were OS, remission rates, relapse risk, post induction disease-free survival (DFS), and treatment-related mortality (TRM). OS was defined as time from study entry until death. Relapse risk was defined as the time from the end of Induction II for patients in complete remission (CR) to relapse, where deaths without a relapse were considered competing events. DFS was defined as the time from end of Induction II for patients in CR until relapse or death. Refractory disease was defined as the persistence of central nervous system (CNS) disease after Induction I, or the presence of morphologic bone marrow blasts ≥5% or any extramedullary disease at the end of Induction II. Patients with refractory disease were removed from protocol therapy. TRM was defined as the time from either study entry, or from end of Induction II for patients in CR, to deaths without a relapse, with relapses considered as competing events. Patients without an event were censored at their date of last known contact. However, for TRM analyses, patients were censored 30 days post end of therapy or 200 days post SCT.

RFS was defined as the time from randomisation to the first documented disease recurrence by independent radiological assessment or death by any cause, whichever happened first. The primary endpoint was to identify biomarkers predicting sorafenib efficacy in preventing HCC recurrence in terms of RFS. The secondary endpoint was to define prognostic biomarkers of RFS and/or validate those previously reported. In the BIOSTORM cohort, all events were recurrences (70 RFS events in 188 patients), and thus time to progression was equivalent to RFS. Biomarkers were considered predictive of sorafenib efficacy in preventing HCC recurrence when p of interaction was <0.05. Patients who had undergone less than one treatment cycle (4 weeks) were excluded from the predictive biomarker analysis (sorafenib: n=9 out of 83; placebo: n=6 out of 105). All statistical tests were two sided. Data were analysed with SPSS V.23.0 (SPSS) and the R statistical package. See also online supplementary materials and methods.