Press Release
Press Release
Exelixis Announces Positive Preliminary Data From an Investigator-Sponsored Phase 1 Trial of XL888 and Vemurafenib
– Combination Generally Well Tolerated; 92% Objective Response Rate Observed –
– Investigators Plan Phase 1b Triple-combination Trial of XL888, Vemurafenib, and Cobimetinib –
The trial results were presented today by
“The BRAF inhibitor vemurafenib is active in BRAF-mutated malignant
melanoma, but development of resistance is common. Preclinical studies
led by
“About half of metastatic melanoma patients whose tumors harbor a BRAF
V600 mutation respond to vemurafenib, but most of them develop
resistance and their tumors begin to regrow,” said
Study Design
The phase 1 multi-cohort study is designed to evaluate the combination of vemurafenib plus escalating doses of XL888 in patients with unresectable stage III/IV BRAF V600 mutation-positive melanoma. The trial enrolls four cohorts; patients receive 960 mg of vemurafenib BID along with XL888 BIW at one of four dose levels: 30 mg (cohort 1), 45 mg (cohort 2), 90 mg (cohort 3), or 135 mg (cohort 4). Eligible patients must have a confirmed BRAF V600 mutation and have not received treatment with a BRAF or HSP90 inhibitor. The primary endpoint of the trial is to determine the safety and tolerability of the combination, including a maximum tolerated dose (MTD). Secondary endpoints include objective response rate (RECIST-1 criteria), estimates of progression-free survival (PFS) and overall survival, and analysis of pharmacodynamic biomarkers.
Study Results
The trial had enrolled fifteen subjects (cohorts 1-3, n=3; cohort 4, n=6), and the median age was 60 years. Seventy-three percent of the subjects were male, and the majority of subjects (14/15) were assessed as having the stage IV metastatic form of their disease.
The most common adverse events were consistent with previous studies of vemurafenib and included anorexia, fatigue, arthralgia, and rash. Diarrhea and vision changes were seen at all dose levels, with the highest rates being seen in cohort 4. These events resolved upon dose interruption. Dose-limiting toxicities only occurred in cohort 4 (grade 3 diarrhea and pancreatitis), and an MTD has not yet been established. The trial also reported fewer secondary cutaneous neoplasms in higher XL888 dose cohorts.
At the time of data cut-off, objective tumor regression was observed in 11 of 12 response-evaluable patients (two complete responses and nine partial responses), for an objective response rate of 92%. Additionally, one stage IIIC patient with a partial response underwent resection of residual disease and pathology showed no viable tumor cells. Three patients who did not have post baseline tumor assessments were excluded from the response analysis; two patients elected alternative treatment prior to the first post baseline scan, and the third patient was still in the first cycle of study treatment. The estimated PFS at 6- and 12-months was 63% (95% CI: 28 - 84%) and 39% (95% CI: 11 - 68%), respectively.
About XL888
XL888 is a highly potent and selective ATP-competitive inhibitor of
HSP90, a molecular chaperone protein that affects the activity and
stability of a range of key regulatory proteins, including kinases such
as BRAF, MET, and VEGFR2. In preclinical studies, XL888 has been shown
to inhibit the proliferation of a broad panel of human tumor cell lines
and induce marked degradation of HSP90 client proteins, which include a
number of kinases implicated in cancer cell growth and survival. After
completing phase 1 testing,
About
Forward-Looking Statements
This press release contains forward-looking statements, including,
without limitation, statements related to: the planned phase 1b
triple-combination trial of XL888, vemurafenib and cobimetinib;
potential future combination studies with XL888; the clinical and
therapeutic potential of XL888; and Exelixis’ continued support of the
Moffitt team evaluating XL888. Words such as “plan,” “further,” “would,”
“can” “look forward,” “suggest,” “potential,” or other similar
expressions, identify forward-looking statements, but the absence of
these words does not necessarily mean that a statement is not
forward-looking. In addition, any statements that refer to expectations
or other characterizations of future events or circumstances are
forward-looking statements. These forward-looking statements are based
upon Exelixis’ current plans, assumptions, beliefs, expectations,
estimates and projections. Forward-looking statements involve risks and
uncertainties. Exelixis’ actual results and the timing of events could
differ materially from those anticipated in the forward-looking
statements as a result of these risks and uncertainties, which include,
without limitation: risks related to the potential failure of XL888 to
demonstrate safety and efficacy in clinical testing; the clinical,
therapeutic and commercial value of XL888; the general sufficiency of
Exelixis’ capital and other resources; the uncertainty of regulatory
approval processes; market competition; changes in economic and business
conditions; and other factors discussed under the caption “Risk Factors”
in Exelixis’ quarterly report on Form 10-Q filed with the
Source:
Exelixis, Inc.
Susan Hubbard, 650-837-8194
Investor
Relations & Corporate Communications
shubbard@exelixis.com