Final Results of Phase 2, Open-Label Study of E7070, Idarubicin and Cytarabine in Patients (Pts) with Relapsed or Refractory (R/R) Acute Myeloid Leukemia (AML) and High-Risk Myelodysplastic Syndrome (MDS)

Background: E7070 (Indisulam) is a sulfonamide anticancer agent that impacts cellular energy metabolism potentially through inhibition of carbonic anhydrase and malate dehydrogenase. E7070 shows anticancer properties through down-regulation of the expression of various cell cycle checkpoint molecules including cyclins A, B1, and H as well as CDK2, thereby blocking the phosphorylation of Rb protein and inducing p53 and p21. More recent studies definitively attribute its anticancer activity to aberrant splicing through E7070-induced proteasomal degradation of the splicing factor RBM39 (also designated as CAPERα). Pre-clinical and clinical studies have established synergy of E7070 with nucleoside analogs as well as topoisomerase inhibitors.

Methods: We designed a phase 2, open-label study of E7070 in combination with idarubicin (I) and cytarabine (A) in pts with R/R AML and high-risk MDS. In stage 1, pts were treated with E7070 at 400 mg/m2 intravenously (IV) on days 1 and 8 in a 28-day cycle and up to 6 cycles in case of response. If no response, pts proceeded to stage 2 to receive E7070 at the same dose on days 1 and 8 followed by idarubicin 8 mg/m2 IV daily x3 and cytarabine 1.0 g/m2 IV over 24 hours daily on days 9-12 (age <60 years) or days 9-11 (age>60 years) in a 28-day cycle (E7070+IA). Pts with response received up to 2 additional cycles. Because of lack of single agent activity of E7070, the protocol was modified after the first 21 patients to directly administer E7070 in combination with I+A as described. Primary endpoints were overall response rates (ORR), and safety and tolerability of the combination. Secondary endpoints included duration of response (DOR), and overall survival (OS).

Results: Forty pts with a median age of 63 years (range, 25-75) were enrolled; 17 (43%) with diploid cytogenetics and 13 (33%) with -5/-7 abnormalities. The median number of prior therapies was 2 (range, 1-6). Twenty-eight (70%) and 23 (58%) pts received prior intermediate to high dose cytarabine-based regimens and hypomethylating agents, respectively, while 9 (23%) pts had prior SCT. Of the 38 evaluable pts, 31 received E7070 along with I+A. Of them, 11 (35%) achieved complete remission (CR) or CR with incomplete counts recovery (CRi), including 1 pt who had prior SCT. None of the 11 responders had poor cytogenetics (p=0.006), or TP53 mutation (p=0.15) when compared to non-responders. The median DOR was 5.3 months (range, 0.4-13) and 7 responders later proceeded to SCT. The median OS for responders (n=11) was 17.4 months vs. 4.3 months for non-responders (p=0.004). The estimated 1-year OS was 51% for responders compared to 8 % for those who failed this therapy (p<0.001). The most common grade ≥3 non-hematological toxicities were electrolyte abnormalities (50%) and febrile neutropenia (28%).

Conclusions: The combination of E7070 with idarubicin and cytarabine was well-tolerated and yielded a promising ORR of 35% in heavily pre-treated pts with AML/MDS. 7 responders were subsequently bridged to SCT. E7070 had no single agent anti-leukemia activity. With emerging data identifying expression of DCAF15- which is a substrate receptor for RBM39 in the CUL4-RING E3 ubiquitin ligase complex- as a potential biomarker for activity, the combination of E7070 with idarubicin and cytarabine should be studied in a biomarker driven study in patients with AML or high risk MDS who are at early salvage.