Novel AKT Inhibitor GSK2110183 Shows Favorable Safety, Pharmacokinetics, and Clinical Activity in Multiple Myeloma. Preliminary Results From a Phase I First-Time-In-Human Study

Despite significant progress in treatment, multiple myeloma (MM) remains an incurable disease. There is a well recognized need for new agents with novel mechanisms of action, which would complement currently available drugs. The PI3K/AKT pathway is constitutively active in MM, providing proliferative and anti-apoptotic signals and possibly contributing to resistance to treatment. Therefore, AKT is a potential pharmacologic target in MM. GSK2110183 is a potent, orally available, ATP competitive inhibitor of all three isoforms of AKT.

We conducted a phase I study to define the maximum tolerated dose (MTD) and to evaluate the PK, PD and clinical activity in patients with advanced hematologic malignancies. This two-part study consisted of dose escalation (Part1) followed by expansion in selected malignancies (Part2) to evaluate safety and clinical activity at the MTD. GSK2110183 was administered continuously once daily until unacceptable toxicity or disease progression.

Preliminary data are available for 73 patients who have received >1 dose of GSK2110183. Patients had the following malignancies: Non-Hodgkin's Lymphoma (NHL, 14), Hodgkin lymphoma (HL, 8), chronic lymphocytic leukemia (CLL 7), MM (34), acute leukemia (10). In Part1 GSK2110183 was administered at daily doses of 25mg, 75mg, 100mg, 125mg and 150mg. Dose limiting toxicities (DLTs) were observed in 3 of 6 patients at 150mg, thereby defining the MTD as 125mg daily. DLTs at 150mg were: short term memory loss (n=1) and elevation of AST/ALT accompanied by AP and bilirubin elevations (n=2). One of the two patients with liver toxicities also had serum lipase and amylase elevations. DLTs were reversible upon drug discontinuation in two patients. The third patient had diffuse large B cell lymphoma with hepatic involvement, which led to persistent liver enzyme elevations. The most common observed drug-related adverse events for all patients (>10%) were: nausea (20%), diarrhea (16%), dyspepsia (15%), fatigue (15%), anorexia (12%) and gastrointestinal reflux disease (11%). Observed grade 3 drug related hematologic toxicities were: neutropenia (n=4), and thrombocytopenia (n=1). No grade 4 hematologic toxicities were observed. In general, therapy was well-tolerated, with subjects continuing on therapy for up to 21 months. Mean AUC(0–24) and C_max values increased with increasing doses; however, there was variability among subjects. Median T_max across doses was 2 hrs, and the mean t _1/2 was approximately 1.7 days. GSK2110183 accumulated 1.4 to 5.1-fold with repeat daily dosing. Median (range) duration of treatment for different types of malignancies was as follows: NHL 88.5 days (12–597), HL 266 days (38–478), CLL 64 days (1–546), MM 87 days (8–323) and acute leukemia 37days (22–85). Subjects with MM were the main focus of the expansion cohort to evaluate for preliminary signals of efficacy. A total of 32 heavily pretreated, relapsed/refractory MM patients were treated at the 125mg dose, achieving an overall response rate of 19% (3 PR, 3 MR). All but one responder had prior treatment with proteasome inhibitor (PI), immunomodulatory agents (IMID) and alkylating agents. Responders were as equally heavily pretreated as the non-responders, with a median of 5 prior lines of treatment (range 2–8). Most significant reductions in M protein occurred very early in the treatment course (4/6 within 21 days). The respective mean (range) duration on study treatment for those who achieved MR or PR was 216 days (105–315), for subjects achieving stable disease 117 days (84–147), and for subjects with progressive disease 52 days (15–105).

The AKT inhibitor GSK2110183 is well tolerated and demonstrates clinical activity as monotherapy in heavily pretreated MM patients. Further work is ongoing to identify the patients who are most likely to respond to AKT inhibition, as well as to define the most rational combination of the AKT inhibitor with other agents in order to maximize the clinical benefit for MM patients.

Spencer:GSK: Honoraria, Research Funding. Yoon:GSK: Honoraria. Harrison:GSK: Honoraria, Research Funding. Morris:GSK: Employment. Smith:GSK: Employment. Freedman:GSK: Employment. Brigandi:GSK: Employment. Oliff:GSK: Employment. Opalinska:GlaxoSmithKline: Employment. Chen:GSK: Research Funding.