Phase I Study of Cladribine (2-chlorodeoxyadenosie), Cytarabine and G-CSF Based Induction Therapy (CLAG) with ATRA (All-trans retinoic acid) and Midostaurin for Relapsed/Refractory AML,
Authors: Ramsingh Giridharan , Sprau Andrew , Westervelt Peter , McBride Ali , Stockerl-Goldstein Keith E. , Vij Ravi , Uy Geoffrey L. , Cashen Amanda , DiPersio John F. , Abboud Camille N. 
Published: October 2019

Abstract
Abstract 3609
Patients with relapsed or refractory AML have poor outcomes after conventional salvage chemotherapy with long-term remissions likely only with allogeneic stem cell transplantation. Hence, there is a need for better treatment options for these patients. Since it is known that multiple pathways are dysregulated in AML, combination therapy that targets multiple pathways may improve remission rates. The combination of salvage chemotherapy (CLAG), a multi-targeted tyrosine kinase inhibitor (midostaurin) and a differentiation inducing agent (ATRA) was investigated in patients with relapsed refractory AML in this study, to assess its tolerability and to identify the maximum tolerated dose (MTD) of midostaurin in the combination. Midostaurin is a multi-targeted kinase inhibitor that has been shown to inhibit FLT-3 (FMS like tyrosine kinase 3) mutations and wild type and other molecular targets thought to be important for the pathogenesis of AML including VEGFR-1, PDGFR, c-kit, H-ras, K-ras and MDR. FLT-3 mutations are seen in about 25–30% of patients with AML and is associated with poor long term survival. FLT-3 is highly expressed even in patients without FLT-3 mutations making FLT-3 a promising target in AML. In vitro studies have suggested that ATRA induces differentiation not only in AML-M3 but also in AML other than AML-M3. In AML cell lines ATRA has been shown to increase sensitivity to cytarabine. Addition of ATRA to induction therapy has shown to produce superior results in AML patients over 60 years of age. Here we conducted this single institutional phase I trial with the combination of midostaurin, ATRA and CLAG in patients with relapsed refractory AML. Patients ≥ 18 years of age with relapsed/refractory AML were included in the study. The treatment regimen consisted of CLAG (cladribine 5 mg/m2 IV days 2–6, cytarabine 2 g/m2 IV days 2–6, GCSF 300 mcg SC days 1–6), ATRA 15 mg/m2 PO days 7–20, midostaurin 25 mg (cohort 1) or 50 mg (cohort 2) PO BID days 7–20. Response was assessed by a bone marrow examination done at day 28–45. A total of 11 patients were enrolled in the study (4 in cohort 1 and 7 in cohort 2) of which 9 (3 in cohort 1 and 6 in cohort 2) were evaluable for the planned end points. The median age was 52 years (range 32–71) and male: female ratio was 45:55. FLT-3 mutation was positive in 6 patients, negative in 1 and unknown in the rest. 4 patients had complex karyotype cytogenetics. 7 patients were in enrolled at first relapse, 2 at second relapse and 2 after refractory disease following the first induction therapy. The ECOG performance score was 0 for all enrolled patients. No dose limiting toxicities was observed in either cohort. Grade 3/4 hematological toxicity was seen in 100% of patients as expected. Grade 3/4 non-hematological toxicity was seen in 2 patients: 1 patient died of pulmonary hemorrhage which was attributed to severe thrombocytopenia and another patient developed grade 4 hyperglycemia. No significant hepatotoxicity occurred in our two dosing cohorts with midostaurin and ATRA likely as echinocandins were used instead of azoles for antifungal therapy. Overall 3/9 (33.3%) evaluable patients achieved complete remission/ complete remission with incomplete count recovery. Five patients died, 4 of progressive disease and one from pulmonary hemorrhage. The levels of midostaurin and ATRA were measured at pretreatment, 1 hour, 4 hours, 8 hours, 12 hours, 7 days, 14 days and 20 days on treatment. The median levels of midostaurin were 2150 ng/ml (range 641–7210) in the 25 mg cohort and 1820 ng/ml (range 850–8930) in the 50 mg cohort. In summary CLAG+ midostaurin+ATRA regimen has an acceptable toxicity profile for relapsed refractory AML and the MTD of midostaurin defined in this trial is 50 mg. Additional phase 2 studies to assess the effectiveness of this regimen in relapsed refractory AML are warranted.

Disclosures:
Off Label Use: The purpose of the study is to investigate the use of midostaurin and ATRA in relapsed refractory AMl in compbination with chemotehrapy. Westervelt:Novartis: Speakers Bureau. Abboud:novartis: Consultancy, Research Funding, Speakers Bureau.