A Phase 1b, Open-Label, Dose Escalation and Expansion Study Evaluating the Safety and Efficacy of Entospletinib (GS-9973) with Vincristine and Dexamethasone in Adult Subjects with Relapsed or Refractory Acute Lymphoid Leukemia (ALL)

Background: Despite progress in understanding the biology and improvements in the treatment of ALL resulting in the majority of adults entering a complete remission (CR), ultimately most patients relapse. Allogeneic hematopoietic stem cell transplantation (HSCT) after initial cytoreduction in a second or subsequent CR offers a chance of cure in a small, highly selected group of subjects. Therefore, re-induction of a CR is the first step in the treatment of relapsed disease. Current treatments for relapsed ALL are generally unsuccessful and most die of their disease, underscoring the need for novel therapeutic approaches.

Spleen tyrosine kinase (SYK) is a mediator of B-cell receptor signaling in normal and transformed B-cells. Increased activity of SYK in ALL cells may play a role in leukemia cell survival and proliferation. Deregulated SYK activity allows growth factor-independent proliferation and transformation of bone marrow-derived pre-B cells in mice. B-ALL results from the abnormal accumulation of transformed progenitor or precursor B lymphocytes (Wossning T, et al. JEM 2006), and inhibition of SYK has been shown to attenuate the growth of B-ALL in vitro and in vivo in mouse models. SYK activation occurs in human B-ALL and is sensitive to small molecule SYK inhibitors; in vitro treatment of primary patient-derived B-ALL cells with a SYK-inhibitor inhibits the proliferation of B-ALL cells (Perova T, et al. Sci Transl Med 2014).

Entospletinib is an orally bioavailable, selective inhibitor of SYK which has shown tolerable safety and clinical activity in mature B-cell malignancies (Sharman J, et al. Blood. 2015). In pre-clinical models, the anti-leukemia effect of entospletinib was synergistic with vincristine (M. Axelrod, et al. ASH abstract 2015). We are conducting a Phase 1b trial (NCT02404220) evaluating entospletinib in combination with standard chemotherapy (vincristine and dexamethasone) for the treatment of relapsed or refractory adult Pre B-ALL (figure 1).

Methods: This dose escalation trial will follow a 3+3 design. A subsequent dose expansion will enroll 15 additional subjects at the recommended dose level from the dose escalation.

Key inclusion criteria for the trial include: previously treated B-ALL (Ph+ or Ph-), ≥18 years of age, ECOG PS≤2 with adequate organ function and resolution of all toxic effects of any prior therapy to ≤Grade 1.

Key exclusion criteria include: diagnosis of mature B-ALL (Burkitts leukemia), active or symptomatic CNS disease, history of myelodysplastic syndrome or solid organ transplantation, allogeneic bone marrow progenitor cell transplant within 100 days or on active immunosuppression for GVHD, ongoing/active pneumonitis, and current therapy with proton pump inhibitors.

Results: As of 7/21/2015, 3 patients have been enrolled into dose level 1, and 1 patient (64 y.o. female in 1^st relapse) has completed the protocol-specified 2 induction cycles of treatment without dose-limiting toxicity. At the end of the 2nd induction cycle, that patient became transfusion independent and bone marrow evaluation showed morphologic CR (MRD positive) with recovery of normal hematopoiesis.

Conclusions: The safety of entospletinib administered in combination with vincristine and dexamethasone is being investigated for the treatment of relapsed/refractory adult ALL.

Figure 1.

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Treatment outline for Phase 1b dose escalation

Figure 1.

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Treatment outline for Phase 1b dose escalation

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