Phase II Pilot Clinical Trial of Pazopanib in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) or at Initial Diagnosis When No Intensive Treatment Is Possible

Background: Patients with AML who are not eligible for intensive therapy or stem cell transplantation have a dismal prognosis. Autocrine and paracrine secretion of angiogenic and hematopoietic growth factors such as vascular endothelial growth factor in the bone marrow (BM) microenvironment may promote proliferation and survival of leukemic blasts. The oral multikinase inhibitor pazopanib was reported to exert growth inhibitory and proapoptotic effects in myeloid cells. Methods: This phase II study evaluated pazopanib (800 mg orally once daily) in patients with relapsed or refractory AML or at initial diagnosis when no intensive treatment is possible. All patients who received pazopanib for 14 days or longer were included into the analysis of safety, tolerability and efficacy. Response criteria are defined according to the Revised Recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. Co-primary endpoints were cumulative response rate (CR, CRp, CRi, PR) within up to one year and reduction of BM microvessel density (MVD) on day 28. Overall survival (OS) and progression free survival (PFS, time from first dose until progression or death from any cause) were measured from the first day of treatment until death of any cause or progression of disease. Results: Between February 2012 and September 2015, 20 AML patients with a median (range) age of 76 (52 - 86) years were treated with pazopanib. The majority of patients (n = 15, 75%) had relapsed (n = 7) or refractory (n = 8) AML, five patients (25%) were enrolled with newly diagnosed AML. Median (range) ECOG performance status was 1 (1 - 3). According to ELN 2010 criteria, four patients (20%) had adverse risk, 15 (75%) had intermediate risk, and one patient (5%) had favorable cytogenetic/molecular risk. Overall, the safety profile of pazopanib was similar to that reported in previous studies. The most common AEs of any grade, related to pazopanib as assessed by the investigator, were gastrointestinal AEs, including nausea (n = 8), diarrhea (n = 6), inappetence (n = 5) and vomiting (n = 3). Two out of 20 treated patients (10%) had a partial remission (reduction of blast count > 50%) and 14 (70%) a stable disease (SD) while on pazopanib. Four patients (20%) experienced initial PD. Median PFS was 65 days (95% CI 29 - 105). After the end of study period three remarkable responses occurred on subsequent therapies such as demethylating agents resulting in one CRi and one CRp and one CR after secondary BM transplantation. All these patients had SD while on pazopanib and improved general condition allowing escalation of therapy. However, at the time of OS evaluation all patients had died due to PD and/or infections. Median OS of the treated study cohort was 191 days (95% CI 87 - 435), and 1-year survival altogether was 35%. There was no significant change in BM MVD between day 1 and day 28. Conclusion: Pazopanib was found to be safe in patients with AML not eligible for intensive therapy. The survival data are encouraging but clearly necessitate a controlled randomized clinical trial for confirmation. Clinical trial information: NCT01361334.