XL184 (BMS-907351)

Co-developed with Bristol-Myers Squibb Company.

Development Status

A phase 3 trial of XL184 is ongoing. 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 medullary thyroid cancer (MTC). Patients are randomized in a 2:1 ratio to receive XL184 or placebo administered as a daily oral dose. The primary endpoint is duration of progression-free survival. Secondary endpoints will include overall survival, objective tumor response rate, and changes in serum biomarkers (carcinoembryonic antigen and calcitonin). It is expected that up to 100 sites in up to 20 countries will participate in this study.

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

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 1 trial in patients with advanced malignancies is ongoing.

Indications

MTC, Glioblastoma, NSCLC

Principal Targets

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

MET is a receptor tyrosine kinase that plays a key role in cellular proliferation, migration and angiogenesis. These biological processes contribute to the transformation, progression, survival and metastasis of cancer cells.
MET is mutationally activated in some tumor types, such as hereditary and sporadic papillary renal cell carcinoma and some head and neck cancers. More frequently, MET is either overexpressed or activated in the absence of mutation in glioblastomas, breast carcinomas, colorectal carcinomas, some gastric cancers, and other solid tumors. MET amplification has been demonstrated in some colorectal tumors, gastric tumors, gliomas, and NSCLCs.
Expression of VEGF has been observed in a variety of cancers and has been associated with prognostic significance. Targeting the VEGF receptor has been recognized as a potential anti-cancer strategy in multiple tumors.
Targeting of MET and VEGFR2 blocks invasive and angiogenic mechanismsthat tumors use to overcome hypoxia.
Activated RET is involved in cell signaling cascades that regulate cell proliferation, migration, differentiation, and survival. RET is mutationally activated in papillary thyroid cancer (PTC) and in both familial and sporadic forms of medullary thyroid cancer (MTC).

XL184 targets

Preclinical Data

XL184 inhibits MET, VEGFR2, 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 MTC, glioblastoma, NSCLC, breast cancer, and pancreatic cancer.

Clinical Data

Most recently, data from an ongoing phase 2 clinical trial of XL184 in patients (pts) with previously treated glioblastoma multiforme (GBM) were presented at the American Society of Clinical Oncology Annual Meeting in May 2009.

To date, 46 patients who make up the intent to treat (ITT) population have been enrolled in the trial, including 30 (65%) in first relapse and 16 (35%) in second or third relapse. Importantly, the trial did not exclude patients previously treated with an antiangiogenic agent.
Tumor response, as determined by an independent radiology facility (IRF), using MacDonald criteria were reported. By ITT analysis, 7 of 35 (20%) of the antiangiogenic naïve patients had a confirmed partial response. The overall rate of response in all patients, including the refractory population of previously treated patients with an antiangiogenic therapy, was 15%.
In the anti-angiogenic naïve population, 7 of 31 (23%) of efficacy evaluable patients had a confirmed partial response by IRF.
The median duration of response by IRF was 2.9 months (range = 1.9-8.6 months).
In an exploratory analysis, among 35 patients with at least one post baseline MRI scan, 12 (34%) had tumor shrinkage ≥50% as their best response as determined by investigator, including 1 patient who had received prior antiangiogenic therapy.
The 6-month progression-free survival (PFS) rate in patients receiving no prior antiangiogenic therapy was 23%, with 10 patients censored for PFS at the time of analysis, and the median PFS interval was 3.6 months.
All 46 patients were evaluated for safety. Most adverse events were of Grade 1 or 2 severity. The most frequently occurring Grade 3 and Grade 4 adverse events were: fatigue (30%), alanine aminotransferase increase (9%), confusional state (9%), lipase increase (9%), lymphopenia (9%), convulsion (7%), headache (7%), and hypophosphatemia (7%). Adverse events of special interest were: hypertension (all incidences, 39%; Grade 3/4, 7%), palmar-plantar erythrodysesthesia (30%; 7%), bleeding events (28%; 9%), proteinuria (26%; 0%), pulmonary embolism (9%; 7%) and craniotomy wound dehiscence (4%; 2%).
In the study, 87% of patients had a dose interruption of XL184, and the median average daily dose was 122 mg/day.

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Additionally, data from an ongoing phase 1 clinical trial of XL184, in patients 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. 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.

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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.