XL184

Stage

Phase 3

Status

A phase 1 trial of XL184 in patients with advanced malignancies for whom there are no available therapies known to prolong survival is ongoing. At the maximum tolerated dose, an additional cohort enrolling subjects with medullary thyroid cancer (MTC) is ongoing. View Data Summary.

A phase 1b/2 trial of XL184 with erlotinib in non-small cell lung cancer (NSCLC) patients who have progressed after prior benefit from erlotinib is ongoing.

A phase 2 trial of XL184 in subjects with progressive or recurrent glioblastoma multiforme in first or second relapse is ongoing.

A phase 3 trial of XL184 was initiated in July of 2008. The phase 3 trial is a randomized, placebo-controlled, double-blinded study of XL184 as single-agent therapy in 315 patients with unresectable, locally advanced, or metastatic MTC. Patients will be randomized in a 2:1 ratio to receive XL184 or placebo administered as a daily oral dose. The primary endpoint will be duration of progression-free survival. In a planned event-driven analysis, the study size provides 90% power to detect a 75% increase in progression-free survival in patients with documented progressive disease prior to study entry.

Secondary endpoints will include overall survival, objective tumor response rate, and changes in serum biomarkers (carcinoembryonic antigen and calcitonin). Additional secondary endpoints will be assessment of the potential relationship between germline and/or tumor DNA sequence alterations and the efficacy of XL184, as well as assessment of pharmacodynamics and pharmacokinetics of XL184. It is expected that up to 100 sites in up to 20 countries will participate in this study.

Indications

MTC, NSCLC, Glioblastoma

Principal Targets

Cell growth and migration: MET, RET
Angiogenesis: MET and VEGFR2

MET is mutationally activated in hereditary papillary renal cell carcinoma and in some NSCLC tumors, activated or over-expressed in head and neck cancer, glioma, and other solid tumors, and amplified in subsets of gastric and lung cancers.
VEGF and HGF (the ligand for MET) act synergistically to stimulate angiogenesis.
In response to hypoxia, tumor cells upregulate VEGF to stimulate angiogenesis and MET to promote survival and stimulate migration to better-oxygenated tissue. Dual targeting of MET and VEGFR2 therefore blocks two of the major mechanisms tumors use to overcome hypoxia.
MET plays an important role in the development of resistance to EGFR-inhibitor therapy in some patients with NSCLC.
RET is mutationally activated in hereditary forms of MTC and in sporadic forms of both medullary and papillary thyroid cancer.

Preclinical Data

XL184 inhibits VEGFR2, MET, and RET, which are key drivers of tumor formation, growth, and metastasis. In pharmacodynamic studies in mice, oral administration of XL184 resulted in balanced and durable inhibition of these targets. XL184 has demonstrated dose-dependent tumor growth inhibition and tumor regression in a variety of tumor models, including breast cancer, colon cancer, MTC, NSCLC, and glioblastoma.

Clinical Data

Data from an ongoing phase 1 clinical trial of XL184, in patients (pts) with advanced malignancies were reported at the EORTC-NCI-AACR International Conference on Molecular Targets and Cancer Therapeutics, in October 2008 in Geneva, Switzerland.

A total of 84 pts have been treated in the study, including 36 with medullary thyroid cancer (MTC). The results showed a disease control rate of 84% and a response rate of 55% in evaluable pts with MTC.
In the ongoing phase 1 trial, the maximum tolerated dose (MTD) for XL184 had previously been determined to be 175 mg/day given orally once-daily.
Based on initial signs of clinical activity in a number of pts with MTC during the dose-escalation phase, the trial had been expanded to treat additional pts with MTC at the MTD.
- In the expanded trial, 22 MTC pts had received treatment with XL184 for at least 3 months and were evaluable for tumor response. In these pts, the data presented at the EORTC-NCI-AACR meeting showed a disease control rate (percentage of pts with partial responses or prolonged stable disease >3 months) of 84%, with 55% of the response-evaluable MTC pts experiencing partial responses as determined by RECIST criteria. Four of these partial responses were seen after only 28 days of dosing. With only two exceptions, the evaluated MTC pts had reductions in the MTC-associated plasma marker calcitonin.
XL184 was generally well tolerated at the MTD of 175 mg QD (capsule).
- Adverse events related to the study drug included diarrhea, nausea, fatigue, mucositis, anorexia, elevation of liver enzymes, hypertension, vomiting, hair hypopigmentation, and palmar-plantar erythema.
- Dose-limiting toxicities included palmar-plantar erythema, elevation of liver enzymes, lipase elevation, and mucositis.
Pharmacokinetic analyses indicated that the half-life of XL184 is approximately 100 hours (range 59-136 hours), with exposure at the MTD exceeding that required for efficacy in preclinical models.
Pharmacodynamic analyses demonstrated statistically significant changes at the MTD in plasma markers including VEGF-A, placental growth factor (PlGF), and soluble VEGFR2, similar to the effects of other anti-angiogenic agents, and consistent with the anti-VEGFR activity of XL184.
- In addition, increases in soluble MET were measured in 4 of 7 pts at the MTD who were analyzed for this endpoint.
In an ongoing analysis of the RET mutational status of MTC pts, all pts with a known RET mutation were found to show clinical improvement in response to XL184. However, most pts without detectable RET mutations also showed clinical improvement, suggesting that the activity of XL184 in MTC may be independent of RET mutational status. Only one MTC patient showed disease progression by RECIST criteria after at least one post-baseline radiographic evaluation, and this patient was determined to have an activating BRAF mutation.

View Poster

About Medullary Thyroid Cancer
The American Cancer Society estimates that MTC accounts for 5% of all thyroid cancers. MTC occurs in sporadic and inherited forms (approximately 80% and 20% of MTC, respectively). Patients with the inherited form of MTC invariably have an activating mutation in RET in their germline DNA. Activating mutations in RET are also present in the tumor DNA of up to 50% of sporadic MTC patients with no familial history of thyroid cancer. MTC may metastasize to lymph nodes or other organs before it is ever diagnosed. Additionally, MTC does not take up radioactive iodine, which is commonly used to treat other types of thyroid cancers and to diagnose metastases. As a result, MTC is more difficult to treat than other thyroid cancers. There are no approved therapies for MTC; however, common treatments for MTC include surgery to remove malignant tissue, radiation therapy, and chemotherapy, all of which are associated with potential side effects, some of which may be long-term.

Information on Clinical Trials

Information about ongoing clinical trials of Exelixis' investigational product candidates is available at ClinicalTrials.gov, a service of the U.S. National Institutes of Health. General information about clinical trials and issues related to participating in clinical trials also is available at ClinicalTrials.gov.

Related Publications

For publication information related to this compound, please see the Related Publications page.