Phase I clinical trial of selinexor in combination with daunorubicin and cytarabine in previously untreated poor-risk acute myeloid leukemia
Mené sur 21 patients atteints d'une leucémie myéloïde aiguë à faible risque de récidive, cet essai de phase I évalue la dose maximale tolérée du sélinexor en combinaison avec la daunorubicine et la cytarabine en traitement de première ligne (durée médiane de suivi : 28,9 mois)
Purpose: Induction chemotherapy results in complete remission (CR) rates of 20% to 50% among poor-risk AML patients. 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. Experimental Design: This was a single-arm phase 1 clinical trial of selinexor combined with cytarabine and daunorubicin (7+3). Dose escalation was selinexor alone (3+3) with an expansion at the maximum tolerated dose (MTD). Cohorts 1 and 2 received 60 mg 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 2 dose of selinexor were the primary endpoints. Results: Twenty-one poor-risk AML patients 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, 2/week) 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. Conclusions: Selinexor plus 7+3 is a safe regimen for newly diagnosed poor-risk AML patients and warrants further investigation in a larger clinical trial.