Personalized Kinase Inhibitor Therapy for Patients With AML

A Phase II Pilot Study of Kinase Inhibition in Relapsed/Refractory Acute Leukemias: Using a Comprehensive In Vitro Kinase Inhibitor Panel to Select Individualized, Targeted Therapies

NCT01620216

Oregon Health & Science University (OHSU) Knight Cancer Institute

National Cancer Institute, Bristol-Myers Squibb

OHSU

24 patients

Leukemia cells from patients over 21 years of age with relapsed/refractory disease after at least one cycle of salvage therapy will be tested to evaluate sensitivity to a panel of kinase inhibitors. Based on those results, one of the study’s FDA-approved drugs (dasatinib, nilotinib, sorafenib, or sunitinib) is selected for treatment of each individual patient. A change in leukemic burden over time is the primary endpoint. The underlying concept is that the kinase inhibitor screen targets leukemia cell function that is a property distinct from conventional classification strategies based on karyotype, cell count, and molecular markers. Although the available drug panel is small, the trial will help identify new therapeutic targets and permit monitoring of kinase pathway activation.

Effective options for treatment of refractory or relapsed AML and ALL are limited, especially for older patients who often have co-morbid conditions that compromise performance status. With median survival in elderly patients of around 10 months for AML and five months for ALL, alternatives to high-toxicity, cytotoxic chemotherapy regimens are needed. Leukemogenesis is frequently driven by aberrant kinase signaling, and the successful treatment of BCR-ABL kinase expressing CML with imatinib provides a blueprint for combining leukemia eradication with minimal toxicity. However, unlike CML, acute leukemias are genetically and functionally heterogeneous, with no single signaling pathway dominating. The tyrosine kinase inhibitor screen used in this trial targets the majority of the tyrosine kinome and identifies at least one effective FDA-approved kinase inhibitor in 35 percent of relapsed patients.

Owing to pathobiologic heterogeneity, developing effective, minimally toxic treatment regimens for patients with acute leukemia remains an unmet challenge. The mainstay of current treatment for acute leukemia is combination cytotoxic therapy using a “one-size-fits-all” format. Drug development and approval processes are slow and expensive. Moreover, interventional drug trials are population-based, leaving little room for individualized approaches. Struggling with a wide spectrum of drug treatment responses, several leukemia study groups have attempted to tailor treatment based on measures of minimal residual disease (MRD). By their very nature, such trials are reactive whereby the MRD marker tracks patient response in vivo, and MRD failure prompts a treatment change to a potentially more suitable drug. Such an approach comes at a cost of months of drug exposure that can induce drug resistance and promote clonal evolution. Despite the exciting discovery of tyrosine kinase signaling pathways, identification of specific targets within these pathways, and development of narrowly targeted and well-tolerated drugs, AML and ALL patients have benefited little from these accomplishments. Leukemia cell kinase signaling pathway activity can vary between disease subtypes, over time, within clones, and, importantly, among individual patients. As knowledge of leukemia signaling  abnormalities has grown, clinical trial design has not always kept up. The current trial aims to move innovative bench approaches more seamlessly to the bedside, thereby enabling a more personalized approach to the treatment of acute leukemia. In contrast to simple MRD approaches, the failure of a drug to kill a patient’s leukemia cells is revealed in vitro, combining the advantages of choosing the most promising drug with the appeal of tracking disease response directly.

While this is an early-phase pilot trial, the kinase inhibitor screen in combination with an innovative trial design may help translate our understanding of leukemia biology into treatment approaches that address the individual needs of patients with acute leukemia.