Phase I Clinical Trial of Selinexor in Combination with Daunorubicin and Cytarabine in Previously Untreated Poor-Risk Acute Myeloid Leukemia

• Published in: Clinical cancer research 2020-01, Vol.26 (1), p.54-60
• Main Authors: Sweet, Kendra, Komrokji, Rami, Padron, Eric, Cubitt, Christopher L, Turner, Joel G, Zhou, Junmin, List, Alan F, Sallman, David A, Dawson, Jana L, Sullivan, Daniel M, Chavez, Julio, Shah, Bijal D, Lancet, Jeffrey E
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Cytarabine - administration & dosage; Daunorubicin - administration & dosage; Female; Humans; Hydrazines - administration & dosage; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - mortality; Leukemia, Myeloid, Acute - pathology; Male; Maximum Tolerated Dose; Middle Aged; Patient Safety; Survival Rate; Tissue Distribution; Treatment Outcome; Triazoles - administration & dosage
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-19-2169

Induction chemotherapy results in complete remission (CR) rates of 20% to 50% among patients with poor-risk AML. Selinexor is an oral selective inhibitor of nuclear export with promising single-agent activity. By inhibiting the primary export protein, XPO1, selinexor localizes and activates tumor suppressor proteins in the nucleus and inhibits DNA damage repair, rationalizing combination with DNA-damaging agents. This was a single-arm phase I clinical trial of selinexor combined with cytarabine and daunorubicin (7+3). Dose escalation was selinexor alone (3+3) with an expansion at the MTD. Cohorts 1 and 2 received 60 and 80 mg orally, respectively, twice weekly during induction. Consolidation cycles (≤ 2) with selinexor at induction dose plus 5+2 were allowed for patients who achieved CR. MTD and recommended phase II dose of selinexor were the primary endpoints. Twenty-one patients with poor-risk AML were enrolled. All 21 patients were included in the safety evaluations and survival analyses (4 in each of 2 cohorts; 13 in the expansion); 8 (53%) of the 19 patients evaluable for response achieved CR/CRi. MTD was not reached. Selinexor 80 mg (orally, twice weekly) was used in the expansion phase. The most common grade 3/4 nonhematologic treatment-emergent adverse events were febrile neutropenia (67%), diarrhea (29%), hyponatremia (29%), and sepsis (14%). At median follow-up (28.9 months), 38% of patients were alive. Median overall survival was 10.3 months. Selinexor plus 7+3 is a safe regimen for patients with newly diagnosed poor-risk AML and warrants further investigation in a larger clinical trial.