Abstract C26: A phase 1 multiple ascending dose study of cabozantinib (XL184) monotherapy in Japanese patients with advanced solid tumors.
Authors: Yamamoto N. , Nokihara H. , Wakui H. , Yamada Y. , Frye J. , DeCillis A. , Tamura T. 
Published: June 2012

Abstract
Background: Cabozantinib is a potent orally available small molecule inhibitor of multiple receptor tyrosine kinases with growth promoting and angiogenic properties. The primary targets of cabozantinib are MET and VEGFR2. In preclinical models, cabozantinib demonstrated significant tumor growth inhibition in multiple tumor models including human medullary thyroid cancer (MTC), human breast cancer, human lung carcinoma and rat glioblastoma. Anti-tumor activity in patients has been observed across a broad range of tumor types including MTC, prostate, ovarian and breast cancer, non-small cell lung cancer (NSCLC), hepatocellular carcinoma, melanoma and glioblastoma. The primary objectives of this open-label phase 1 study are determination of the maximum tolerated dose (MTD) and recommended phase 2 dose in Japanese patients.
Methods: Patients with advanced solid malignancies are enrolled in successive cohorts to receive escalating doses of cabozantinib in a 3+3 trial design. Patients are treated with continuous 4-week cycles of cabozantinib administered orally (PO) once daily (QD). Dose limiting toxicities (DLTs) are determined using Cycle 1 data. Response is assessed on Day 29 and every 8 weeks thereafter by modified RECIST v1.0 criteria and patients with stable disease (SD) or objective response receive continued therapy. Pharmacokinetic (PK) parameters of cabozantinib and relevant plasma markers including VEGF-A, sVEGFR2 and PlGF are being evaluated.
Results: As of 1 September 2011, 6 patients with advanced malignancies have been enrolled: NSCLC (n=3), colorectal cancer, gastrointestinal stromal tumor (GIST), leiomyosarcoma (n=1 each). Patients were pretreated with a median of 3 prior regimens (range, 2 − 7). Patients have been treated at 2 dose levels of 40mg and 60mg free base equivalents (salt strengths of 50mg and 75mg, respectively) PO QD. There have been no DLTs or serious adverse events reported to date. The MTD has not yet been defined. Observed adverse events were generally mild to moderate and include hypertension, palmer-plantar erythrodysesthesia, diarrhea, mucositis, rash, edema and headache. Laboratory abnormalities include elevated AST/ALT, neutropenia, thrombocytopenia and increases in alkaline phosphatase, LDH, lipase and TSH. Results of preliminary PK analysis at the 40mg QD dose level showed that cabozantinib appeared to reach steady-state plasma concentrations by Day 15 and there was evidence of 6- to 7-fold accumulation on Day 19. One patient with NSCLC has had a confirmed partial response with 38% reduction in the sum of target lesions. Three pretreated patients including 2 with NSCLC and 1 with GIST have had SD with reductions in the sum of target lesions of 20, 13 and 16% respectively, and continue treatment with cabozantinib.
Conclusions: Cabozantinib appears well tolerated at doses tested to date. Early signs of antitumor activity including prolonged stable disease and response have been observed in the initial dosing cohorts. Determination of the MTD is ongoing.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C26.