General AML|FLT3

Phase I study of cabozantinib in patients with R/R AML

Cabozantinib, a multi-targeted tyrosine kinase inhibitor, is a potent inhibitor of Fms Like Tyrosine Kinase 3 (FLT3), Vascular Endothelia Growth Factor Receptor 2 (VEGFR2), MET, and KIT. Cabozantinib has been studied in many malignancies and is approved by the US Food and Drug Administration (FDA) for use in medullary thyroid and renal carcinoma. However, there is a paucity of studies of cabozantinib in Acute Myeloid Leukemia (AML).

Amir T. Fathi, MD from the Dana-Farber Cancer Institute, Boston, and colleagues aimed to assess the safety and tolerability of cabozantinib in patients with AML in a phase I dose-escalation study (NCT01961765). The results of the study were published in Cancer on 28th September 2017.

Eighteen newly-diagnosed (n = 2) and Relapsed/Refractory (R/R [n = 16]) AML patients with a median age of 68 years (range, 27–85) were enrolled in this study. FLT3-Internal Tandem Duplication (FLT3-ITD) were detected in five patients with one patient having a concurrent FLT3/Tyrosine Kinase Domain (FLT3/TKD) D835 mutation. Patients were administered oral cabozantinib in 28-day cycles and dose-escalation occurred via three cohorts including 40 mg (n = 15), 60 mg (n = 3), and 80 mg daily. The primary endpoint of the study was to determine the Maximum Tolerated Dose (MTD) of cabozantinib in patients.  

The key findings of the study were:
  • Safety
    • At dose level 1 (40 mg daily), there was no Dose Limiting Toxicity (DLT) detected
    • At dose level 2 (60 mg daily), DLT of grade 3 pancreatitis and grade 3 transaminitis occurred in two patients respectively
    • MTD was determined at 40 mg cabozantinib daily
    • Grade 2 or higher non-hematologic toxicities occurred including nausea (28%), fatigue (6%), hypertension (28%), oral mucositis (11%), anorexia (11%), constipation (6%) and transaminitis (11%)
  • Response
    • No marrow response according to the formal criteria
    • Peripheral blasts reduction occurred in four patients
      • Two patients transiently cleared circulating blasts
      • One patient experienced a reduction in marrow blasts
      • One patient experienced stable marrow disease

The study also aimed to assess the serial plasma samples of patients for the pharmacodynamic effects of cabozantinib on FLT3 inhibitory activity using Plasma Inhibitory Assay (PIA).

  • Cabozantinib inhibited FLT3 auto-phosphorylation in FLT3/ITD mutant cell lines by day 8 of cycle 1
  • Cabozantinib was potently active against FLT3/TKD/F691- mutant BAF3 cell line

In summary, cabozantinib was “well-tolerated in patients with AML with an MTD of 40 mg daily”. Additionally, the interpretation of the study findings suggested that cabozantinib can effectively inhibit FLT3/TKD/F691 resistance mutation.

Fathi et al. noted that their study is limited by “small size and scope” and suggested that a “larger efficacy trial of cabozantinib” should be carried out in order to further explore the therapeutic promise of cabozantinib by “specifically studying patients with FLT3-mutant AML”.

Abstract
BACKGROUND

Cabozantinib, a tyrosine kinase inhibitor of FMS-like tyrosine kinase 3 (FLT3), MET, AXL, vascular endothelial growth factor receptor, and KIT, is approved for use in multiple malignancies. We assessed the safety and tolerability of cabozantinib in AML, given up-regulation of multiple relevant pathways.

METHODS

Adults were eligible if they were 18 years old or older with relapsed/refractory AML or if they were 70 years old or older with newly diagnosed AML but were ineligible for conventional therapy. Cabozantinib was administered in 28-day cycles, and dose escalation occurred via cohorts. A pharmacodynamic evaluation of serial plasma samples via a plasma inhibitory assay (PIA) was used to assess FLT3-inhibitory activity in FLT3-mutant cell lines.

RESULTS

Among 18 patients enrolled, 5 were found to harbor FLT3/ITD mutations. Sixteen patients (89%) had relapsed/refractory AML, and most were treated with 2 or more lines of prior treatment. No dose-limiting toxicities (DLTs) were detected at the first dose level (40 mg daily), but 2 patients experienced DLTs at the next level (60 mg daily). The remaining patients were then dosed at 40 mg daily, the maximum tolerated dose (MTD). Additional grade 2 or higher toxicities, possibly/probably related to cabozantinib, included fatigue, nausea, transaminitis, and electrolyte imbalance. No patients had a marrow response according to formal criteria, but 4 had peripheral blast reductions; 2 of these 4 patients transiently cleared circulating blasts. One patient experienced a reduction in marrow blasts, and 1 had stable disease. The FLT3-inhibitory activity of plasma samples, as assessed with the PIA, revealed potent and sustained inhibition in FLT3/ITD and, notably, F691 tyrosine kinase domain (TKD)–mutant cells.

CONCLUSIONS

Cabozantinib is well tolerated in AML patients at an MTD of 40 mg daily and is a potent inhibitor of FLT3/ITD- and F691 TKD–altered tyrosine kinases.

References
  1. Fathi A. T., et al. Cabozantinib is well tolerated in acute myeloid leukemia and effectively inhibits the resistance-conferring FLT3/tyrosine kinase domain/F691 mutation. Cancer. 2017 Sep 28. DOI: 10.1002/cncr.31038. [Epub ahead of print].