mk-2206 and Hematologic-Diseases

We conducted a phase II study of the AKT inhibitor, MK2206 in patients with relapsed or refractory lymphoma of any histology excluding Burkitt lymphoma or lymphoblastic lymphoma. MK-2206 was administered orally at 200 mg once weekly in 28-d cycles up to 12 cycles in the absence of progression or significant toxicity. The dose was adjusted based on tolerance. A total of 59 patients were enrolled. The final doses patients received were 300 mg (n = 33), 250 mg (n = 2), 200 mg (n = 16) and 135 mg (n = 8). Based on intent-to-treat analysis, objective response was observed in 8 (14%) patients (2 complete response and 6 partial response), with median response duration of 5·8 months. The overall response rate was 20% in 25 patients with classical Hodgkin lymphoma. Rash was the most common toxicity (any grade 53%, Grade 3 in 15%) and was observed in a dose-dependent manner. The correlative cytokine analysis showed paradoxical increase in several cytokines, which may be explained by negative feedback mechanism induced by the on-target effect of AKT inhibitor. Our data demonstrate that MK2206 has a favourable safety profile with a modest activity in patients with relapsed Hodgkin lymphoma. The future studies should explore mechanism-based combinations (clinicaltrials.gov NCT01258998).

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Combined Modality Therapy; Cytokines; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Eruptions; Feedback, Physiological; Female; Gastrointestinal Diseases; Hematologic Diseases; Hematopoietic Stem Cell Transplantation; Heterocyclic Compounds, 3-Ring; Hodgkin Disease; Humans; Hyperglycemia; Kaplan-Meier Estimate; Lymphoma; Male; Middle Aged; Neoplasm Proteins; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Recurrence; Salvage Therapy; Transplantation, Autologous; Treatment Outcome; Tumor Burden; Young Adult