On November 17, 2014 Deciphera Pharmaceuticals reported the presentation of preclinical data that demonstrated that altiratinib (DCC-2701) inhibited tumor growth and invasion in a bevacizumab resistant glioblastoma mouse model (Press release Deciphera Pharmaceuticals, NOV 17, 2014, View Source [SID:1234500972]). Altiratinib, a kinase inhibitor that targets multiple selected kinases MET, TIE2, VEGFR2 and TRK, is currently in Phase 1 clinical development for the treatment of invasive solid tumors and received Orphan Drug Status from the U.S. Food and Drug Administration for the treatment of glioblastoma. The data on altiratinib were presented at the 19th Annual Scientific Meeting and Education Day of The Society for Neuro-Oncology held November 13-16, 2014, in Miami.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"Altiratinib is differentiated in its ability to inhibit MET and TRK kinases while also providing balanced inhibition of the tumor microenvironment within a single oral therapeutic," said Michael D. Taylor, PhD, Deciphera’s President and Chief Executive Officer. "This balanced inhibitory profile demonstrates the power of Deciphera’s switch pocket technology to design advanced kinase inhibitor therapies to simultaneously block multiple cancer signaling mechanisms in the tumor cell and the tumor microenvironment to prevent growth and spread of cancer."
"These data demonstrated that altiratinib inhibited tumor growth and invasion both in vitro and in vivo. Based on these results, we believe the combination of altiratinib and anti-VEGF therapy may provide a new strategy to overcome antiangiogenic therapy resistance and prolong overall survival in patients with glioblastoma," said John F. de Groot MD, Associate Professor, Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center and presenting author. "We look forward to further exploring the potential of altiratinib in refractory glioblastoma, an area of significant unmet medical need."

In an oral presentation titled, "The Novel c-MET inhibitor altiratinib (DCC-2701) inhibits tumor growth and invasion in a bevacizumab resistant glioblastoma mouse model," John F. de Groot, MD and colleagues from the Brain Tumor Center at MD Anderson Cancer Center described data that demonstrated altiratinib, either alone or in combination with anti-VEGF therapy (bevacizumab), inhibited tumor growth, epithelial-mesenchymal transition (EMT) progression and invasion both in vitro and in vivo, compared with anti-VEGF therapy alone:

• Altiratinib, alone or in combination with bevacizumab treatment, dramatically suppressed EMT and tumor invasion in vivo. This anti-invasive effect correlated with decreased N-cadherin and vimentin levels.

• In vivo, microvascular density associated with evasive revascularization induced by bevacizumab, was significantly inhibited in the groups treated with altiratinib and altiratinib plus bevacizumab, compared with control or the group treated with bevacizumab alone.

• Similarly, F4/80+ bone marrow derived macrophage cell infiltration was significantly suppressed in the groups treated with altiratinib and altiratinib plus bevacizumab, compared to control or the group treated with bevacizumab alone.

On November 16, 2014 Exelixis reported preliminary results from a phase 1 investigator-sponsored trial (IST) evaluating the safety and activity of XL888, an Exelixis-discovered small molecule oral inhibitor of Heat Shock Protein 90 (HSP90), in combination with vemurafenib in patients with unresectable stage III/IV BRAF V600 mutation-positive melanoma (Press release, Exelixis, NOV 16, 2014, View Source;p=irol-newsArticle&ID=1990028 [SID1234517436]). Safety and efficacy results support the further investigation of 90 mg of XL888 twice weekly (BIW) and vemurafenib 960 mg twice daily (BID) in additional studies that would include a third agent.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The trial results were presented today by Keiran Smalley, Ph.D., an investigator on the trial and an associate professor at H. Lee Moffitt Cancer Center, Tampa, Florida, in a late-breaking oral presentation session at the Society for Melanoma Research 2014 International Congress, which is taking place November 13-16, 2014, in Zurich, Switzerland. Based on these results, as well as findings from coBRIM, the phase 3 pivotal trial of cobimetinib, an Exelixis-discovered MEK inhibitor, and vemurafenib in previously untreated metastatic melanoma patients with a BRAF V600 mutation, the Moffitt Center plans to initiate a phase 1b IST of the triple combination of vemurafenib, cobimetinib, and XL888 in a similar patient population.

"The BRAF inhibitor vemurafenib is active in BRAF-mutated malignant melanoma, but development of resistance is common. Preclinical studies led by Keiran Smalley, Ph.D. suggested that most BRAF inhibitor resistance mechanisms involve proteins that are clients of HSP90, and the preclinical evaluation of XL888 showed that it is highly active in vemurafenib-resistant melanoma models," said Jeffrey Weber, MD, Ph.D., director of the Donald A. Adam Comprehensive Melanoma Research Center at the Moffitt Cancer Center and Research Institute in Tampa, FL. "The current phase 1 data show that both drugs can be given together, and compelling initial response results suggest potential cooperative activity."

"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 Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis. "Multiple mechanisms drive this resistance, and the team at Moffitt found that many of them involve upregulation of HSP90 client proteins that are sensitive to XL888. We look forward to supporting the Moffitt team as they continue to evaluate XL888 as part of our IST program."

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, Exelixis deprioritized XL888 and its other pipeline assets to focus its limited resources on the company’s lead compound, cabozantinib. Investigators at the Moffitt Cancer Center conducted preclinical work showing activity of XL888 in vemurafenib-resistant melanoma models. These preclinical results provided the rationale for the current investigator-sponsored phase 1 trial.