Interim Results of a Phase 1b/2 Study of Entospletinib (GS-9973) Monotherapy and in Combination with Chemotherapy in Patients with Acute Myeloid Leukemia

Abstract

Background:Spleen tyrosine kinase (SYK) is a nonreceptor cytoplasmic tyrosine kinase primarily expressed in cells of hematopoietic lineage. Constitutive activation of SYK in acute myeloid leukemia (AML) has been reported and targeted inhibition of SYK induced differentiation in vitro and demonstrated anti-leukemia activity in AML mouse models. SYK has also been shown to directly phosphorylate the FLT3 receptor, modulating its activation and possibly promoting its role in leukemogenesis. Entospletinib is an orally bioavailable, selective inhibitor of SYK shown to be clinically active in B-cell malignancies. Here we evaluate the combination of entospletinib in patients with untreated AML using a 14-day window phase to assess single-agent activity, then adding standard intensive chemotherapy. Methods: In this phase 1b/2 study (NCT02343939), patients age 18 to 70 years with previously untreated AML, preserved organ function, and ECOG ≤ 2 were eligible to receive dose escalated entospletinib for 14 days as monotherapy (days -14 to 0) followed by combination with daunorubicin 60 mg/m2/d, cycle 1 day 1 to 3, and cytarabine 100 mg/m2/d, cycle 1 day 1 to 7. All patients received entospletinib monotherapy for up to 14 days prior to starting induction. Chemotherapy could be initiated after 5 days of monotherapy (and entospletinib continued for 4+ weeks) in patients with leukemia-related complications necessitating chemotherapy. Patients enrolled to dose level (DL) 0 and DL 1 received entospletinib 200 mg po BID and 400 mg po BID, respectively. Patients with residual disease two weeks after chemotherapy received a second induction cycle identical to the first. Entospletinib was continued without interruption until remission was assessed at count recovery. Results:Twelve patients enrolled with a median age of 54 (range, 18-69) years. Patients were in the following European LeukemiaNet genetic risk groups: favorable (n=1), intermediate I (n=3), intermediate II (n=2), and adverse (n=4), respectively. Three patients were not evaluable for dose limiting toxicity (DLT) assessment and were replaced (due to detection of CNS disease requiring non-study therapy (n=1), and withdrawal of consent unrelated to drug toxicity (n=2)). Single-agent entospletinib during the window period was well tolerated; toxicities after combination with intensive chemotherapy were common and typical. Among 3 patients treated at 200mg BID, no DLT was observed. Of 3 patients treated at 400mg BID, a patient with documented fungal pneumonia developed grade 3 pneumonitis that was possibly related to entospletinib. Although this did not meet DLT criteria, DL 1 was expanded with 3 additional patients, none of whom experienced DLT. Overall, the most common non hematologic adverse events (inclusive of intensive chemotherapy periods) were febrile neutropenia, nausea, and diarrhea. Based on this clinical experience and compiled pharmacokinetic data demonstrating lack of benefit to further dose escalation, 400 mg BID was selected as the recommended phase 2 dose. Responses were seen at both levels. Among the 3 patients treated at 200 mg BID, two required a second induction but all achieved a complete remission (CR) (3/3; 100%). Of the 6 patients treated at 400mg BID, none required a second induction and the CR rate was also 100%. Remarkably, an 18 year old male with 11q23-rearranged AML achieved morphologic and cytogenetic CR after only the 14 day entospletinib monotherapy window (prior to chemotherapy). Another patient with 11q23-rearranged AML had significant platelet response during the window period (this patient refused disease evaluation by marrow aspiration prior to chemotherapy). Conclusions: Entospletinib appears to have significant clinical activity in AML, and its combination at doses up to 400mg BID with intensive chemotherapy is well tolerated. An extended phase 2 program is now underway. Patients with 11q23-rearranged AML may be uniquely sensitive to SYK inhibition by entospletinib. Detailed molecular analysis of these patients is ongoing and will be presented. Disclosures Walker: Gilead Sciences: Research Funding. Bhatnagar:Karyopharm: Research Funding. Marcondes:Gilead Sciences: Employment, Equity Ownership. DiPaolo:Gilead Sciences: Employment, Equity Ownership. Abella-Dominicis:Gilead Sciences: Employment, Equity Ownership.

Combinatorial efficacy of entospletinib and chemotherapy in patient-derived xenograft models of infant acute lymphoblastic leukemia

“…Total SYK expression was relatively consistent across all models. The observed constitutive basal pSYK levels, coupled with a previously suggested role of upregulated SYK as a driver in AML models with high HOXA9 and MEIS1 expression (25), and early reports of clinical responses in adults with relapsed KMT2A-R leukemias treated with entospletinib (42,43) led us to investigate the role of SYK signaling and therapeutic potential of ENTO specifically in infant KMT2A-R ALL PDX models.…”

Targeting DUBs to degrade oncogenic proteins

“…Early responses have been reported, especially in patients with FLT3-mutated AML and high HOXA9/MEIS1 expression, such as MLL (mixed-lineage leukaemia)-rearranged and NPM1c (cytoplasmic nucleophosmin 1) mutant leukaemia. 8,9 Prior studies report that combination therapy targeting SYK and FLT3 with inhibitors selective for each kinase are synergistic in vitro and improve response in vivo compared with each inhibitor alone in FLT3-mutated AML. 7,10 An alternative strategy, however, would be to deploy a small molecule kinase inhibitor that simultaneously targets both, such as the compound TAK-659.…”

Syk inhibitors in clinical development for hematological malignancies

“…Recently, the interim results of the entospletinib monotherapy and in combination with chemotherapy in patients with AML were presented. In this ongoing phase 1b/2 study (NCT02343939), entospletinib was well tolerated [ 51 ]. At the time of this report, the study enrolled 12 patients with a median age of 54 (range, 18–69) years.…”

“…Surprisingly, 9/9 patients (100%) treated at both levels achieved CR. One patient with 11q23-rearranged AML achieved morphologic and cytogenetic CR after 14 days on entospletinib monotherapy, indicating unique sensitivity to the drug in this patient with poor prognosis [ 51 ].…”