A Phase I Study of the Multi-Targeted Tyrosine Kinase Inhibitor Cabozantinib in Patients with Acute Myeloid Leukemia
Authors: Fathi Amir T. , Blonquist Traci M. , Levis Mark J. , Hernandez Daniela , Ballen Karen K. , Avigan David E. , Joyce Robin , McMasters Malgorzata , Logan Emma , Hobbs Gabriela S. , Brunner Andrew M. , Connolly Christine , Perry Ashley M. , Joseph Christelle , Som Tina T. , Ramos Aura Y. , Neuberg Donna S. , Amrein Philip C. 
Published: October 2019

Cabozantinib is a multi-targeted tyrosine kinase inhibitor (TKI) of FLT3, MET, AXL, VEGFR, and KIT, all of which are implicated in the pathogenesis of acute myeloid leukemia (AML). Cabozantinib has been studied in clinical trials of solid tumors, and is FDA approved for use in medullary thyroid and renal cell carcinoma. Despite multiple relevant targets, cabozantinib has not been previously studied in AML. Given up-regulation of these key enzymes and related pathways in AML, we sought to assess the safety and tolerability of cabozantinib in this population.

The primary objective of this phase I, 3+3 cohort dose-escalation study was to define the maximum tolerated dose (MTD) of cabozantinib in patients with AML. Eligibility included adults ≥ age 18, with relapsed or refractory (R/R) AML, or those aged ≥ 70, with new diagnosed AML but ineligible for or declining conventional therapy. Study treatment required a white blood cell count (WBC) of < 30,000/mm3, but concurrent treatment with hydroxyurea was allowed to control WBC during the first 15 days of cycle 1. The first dose level was 40MG by mouth daily (QD), a dose previously demonstrated to be well-tolerated in solid tumor malignancies. Cabozantinib was administered in 28 day cycles, and dose escalation occurred via 3 cohorts (40MG QD, 60MG QD, 80MG QD). Escalation to each successive dose level was guided by incidence of dose limiting toxicity (DLT) during cycle 1 of study treatment. Pharmacodynamic evaluation of serial plasma samples obtained from patients, by use of a plasma inhibitory assay (PIA), was used to assess FLT3 inhibitory activity in FLT3-ITDcell lines. Response was determined by bone marrow biopsy after the first cycle of treatment, and those achieving complete or partial remission, or with stable disease and clinical benefit, could continue on study until disease progression, intolerable toxicity, or upon receipt of 12 cycles.

18 patients were enrolled on study. The median age was 68 (range 27-85); 12 (67%) were male, and 14 (78%) were Caucasian. FLT3-ITD mutations were detected in 5 (23%) patients, and NPM1 mutations in none. 16 patients (89%) had R/R AML, and 2 patients (11%) had newly diagnosed disease. The majority (75%) of those with R/R AML had been treated with two or more lines of prior treatment. 3 patients were enrolled at the first dose level (40MG QD), of whom one experienced >G3 transaminitis, thought unrelated to cabozantinib, but could not be dosed for this reason and was therefore replaced. No DLTs were detected at the first dose level among the 4 studied patients. However, two of the three patients enrolled at the second dose level (60MG QD) experienced DLT, one with grade 3 pancreatitis and the other with grade 3 transaminitis. Three patients were then enrolled at the next lower level, dose level 1 (40MG QD), of whom two could not complete the DLT period, one because of disease progression and the other due to an infected aortic ulceration unrelated to study treatment. These two patients were replaced, and no additional DLTs were noted. 40MG daily was therefore determined to be the MTD, and 6 patients were subsequently treated in an expansion cohort at this dose. Additional ≥ grade 2 toxicities, possibly or probably related to cabozantinib, each affected 3 or less patients, and included fatigue, nausea, anorexia, constipation, oral mucositis, palmar-plantar erythrodysesthesia, transaminitis, and electrolyte imbalance. Fifteen patients could be assessed for response on study. No patients had a marrow response per formal criteria. Four patients had a reduction in peripheral blasts during treatment, of whom 2 transiently cleared their circulating blasts (one with FLT3-ITD). One patient experienced a reduction in marrow blasts, and one had stable marrow disease. FLT3 inhibitory activity of serially collected patient plasma samples, as determined by the ex vivo PIA, consistently revealed potent and sustained inhibition of FLT3 auto-phosphorylation in FLT3-ITDmutant cell lines by day 8 of cycle 1.

Cabozantinib, a multi-targeted TKI, is well-tolerated in patients with AML at the MTD of 40 MG daily. In this molecularly heterogeneous, heavily pre-treated population of AML patients, clinical response to cabozantinib monotherapy was limited. However, we found that cabozantinib inhibits FLT3-ITD tyrosine kinase in a potent and sustained fashion. Additional clinical study of cabozantinib among patients with FLT3 mutant AML is therefore warranted.

Disclosures

Fathi: Celgene: Consultancy, Research Funding; Merck: Other: Advisory Board participation; Seattle Genetics: Consultancy, Other: Advisory Board participation, Research Funding; Agios Pharmaceuticals: Other: Advisory Board participation; Bexalata: Other: Advisory Board participation. Levis:Millennium: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi-Sankyo: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Research Funding. Avigan:Astex: Research Funding; DCPrime: Research Funding. Hobbs:Constellation: Other: Advisory Board participation; Incyte: Other: Advisory Board participation.