On November 17, 2014 Kite Pharma reported that the European Medicines Agency (EMA) Committee for Orphan Medicinal Products (COMP) has adopted a positive opinion recommending KTE-C19 for designation as an orphan medicinal product for the treatment of diffuse large B cell lymphoma (DLBCL) (Press release Kite Pharma, NOV 17, 2014, View Source [SID:1234501041]). KTE-C19 is an anti-CD19 CAR T cell therapy that involves genetically modifying a patient’s T cells to express a CAR that is designed to target CD19, a protein expressed on the cell surface of B cell lymphomas and leukemias.

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The COMP, a committee of the EMA, adopts an opinion on the granting of orphan drug designation, after which the opinion is submitted to the European Commission for endorsement of the opinion. Orphan drug designation by the European Commission provides regulatory and financial incentives for companies to develop and market therapies that treat a life-threatening or chronically debilitating condition affecting no more than five in 10,000 persons in the European Union (EU), and where no satisfactory treatment is available. In addition to a 10-year period of marketing exclusivity in the EU after product approval, orphan drug designation provides incentives for companies seeking protocol assistance from the EMA during the product development phase, and direct access to the centralized authorization procedure.

DLBCL is an aggressive type of non-Hodgkin lymphoma for which the treatment options include chemotherapy, anti-CD20 antibodies, and, in selected patients, autologous transplant. Although most patients with DLBCL can be cured by either chemotherapy or transplant, a significant proportion of patients have disease that is resistant to chemotherapy or that relapses after transplant. For these patients with refractory DLBCL, there is a substantial unmet need for more effective therapies.

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.

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"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 17, 2014 Clovis Oncology reported that they have entered into a clinical trial collaboration with GlaxoSmithKline to evaluate a novel combination therapy targeting mutant epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC) (Press release Clovis Oncology, NOV 17, 2014, View Source;p=RssLanding&cat=news&id=1990475 [SID:1234500975]). The Phase 1/2 trial of rociletinib given in combination with trametinib is planned to start in 1H 2015. The trial is designed to assess the safety and activity of the combination in patients with EGFR mutant NSCLC who were previously treated with an EGFR tyrosine kinase inhibitor (TKI).

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"We have seen significant activity in EGFR mutant NSCLC patients treated with rociletinib monotherapy, and so an important next step in our research is to examine rociletinib in combination with other targeted therapies that may also impact acquired resistance to EGFR inhibitors," said Lecia V. Sequist, MD, MPH, Massachusetts General Hospital Cancer Center and Associate Professor of Medicine at Harvard Medical School and the lead investigator for this combination study.

"As we continue to see compelling activity for rociletinib single-agent therapy at our selected dose, we look forward to exploring combination trials in both T790M-positive and T790M-negative patients," said Patrick J. Mahaffy, President and CEO of Clovis Oncology. "We believe that given the tolerability profile of rociletinib, particularly its lack of cutaneous toxicity, it may be a good candidate for combination therapy with trametinib, and other relevant targeted therapies. We intend to announce additional combination studies over the next few months."

All patients with EGFR mutant NSCLC eventually develop resistance to EGFR TKI therapy and T790M is the primary resistance mutation, occurring in 60 percent of patients treated with first- and second-generation EGFR inhibitors. Rociletinib targets the activating mutations of EGFR (L858R and Del19) and the T790M mutation, and has demonstrated encouraging clinical activity and tolerability in Phase 1/2 studies of patients with EGFR mutant NSCLC.

Another mechanism of acquired resistance in EGFR mutant NSCLC is through the activation of the mitogen-activated protein kinase (MAPK) pathway. Trametinib is an orally active inhibitor of mitogen-activated protein kinase (MEK), which plays a key role in downstream MAPK pathway signaling, and it thereby inhibits growth factor-mediated signaling and cellular proliferation. Trametinib as a single agent has been approved by the FDA for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test.

In preclinical models of T790M+ EGFR mutant NSCLC, acquired resistance to T790M inhibitors can occur through MAPK pathway activation, and the combination of rociletinib and trametinib has been shown to restore MAPK pathway suppression, resulting in increased anti-tumor activity.

This clinical trial is designed to test the hypothesis that the combination of two oral drugs targeting different cellular growth pathways, both often active in EGFR mutant NSCLC, will lead to augmented clinical benefit. Rociletinib is the core drug of the combination, and trametinib will be titrated in to first assess safety and then explore efficacy. Extensive tumor sampling will be performed to enable detailed molecular characterization of each patient’s tumor load, together with pharmacodynamic assessment of pathway inhibition. Integration of clinical data with molecular tumor data, both on and off drug(s), will enable robust understanding of observed clinical outcomes.

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.

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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.

On November 14, 2014 ImmunoCellular Therapeutics reported the presentation of updated efficacy data from the Phase II trial of dendritic cell-based immunotherapeutic vaccine ICT-107 at the 19th Annual Scientific Meeting and Education Day of the Society for Neuro-Oncology, being held in Miami, FL (Press release ImmunoCellular Therapeutics, NOV 14, 2014, View Source [SID:1234500964]). Patrick Y. Wen, MD, Director of the Center for Neuro-Oncology at Dana Farber Cancer Institute and Professor of Neurology at Harvard Medical School, and principal investigator on the trial, will present the maturing data set in patients with newly diagnosed glioblastoma multiforme (GBM) in an oral presentation.

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Consistent with prior data presentations in December 2013 and June 2014, the results demonstrate a statistically significant progression-free survival (PFS) benefit, and a numeric overall survival (OS) benefit in ICT-107 treated patients compared to the control group. The ICT-107 treatment effect continues to be strongest in the pre-defined HLA-A2 subgroup of patients in which the MGMT methylated patients showed the largest treatment effect, with a significant PFS advantage over the control group, and continued potential for the OS advantage to move toward significance as more events occur. There were no differences in adverse events between the ICT-107 treated group and the control group.

"ICT-107 continues to hold promise for patients with newly diagnosed glioblastoma, as no other immunotherapy has shown statistical benefit for a clinical outcome in a controlled trial in this patient population," said Dr. Wen. "I think that the data from the phase II trial strongly support advancing to a registrational program."

"With this second update of the original trial results, we remain confident that there is a meaningful treatment benefit in HLA-A2 patients. In the per-protocol population, OS hazard ratios are in the 0.6-0.7 range for all HLA-A2 patients as a group as well as for each of the MGMT subgroups. If our upcoming phase III program generates statistically significant results in this range, ICT-107 could represent a clinically meaningful advance for GBM patients," said Andrew Gengos, ImmunoCellular’s Chief Executive Officer. "The US FDA and three national European regulators have indicated support for phase III testing. We anticipate hearing shortly from the EMA, and then expect to be in position to finalize our phase III design and move into trial execution in 2015."

Updated ICT-107 Phase II OS and PFS Results

As of October 2014, a total of 88 events (patient deaths) had been recorded from the 124 randomized patients, representing 9 additional events since these data from the phase II trial were last updated in June 2014. There were 25 active and 11 control patients alive for a total of 36 patients available for additional follow-up.
Median PFS for the HLA-A2 methylated MGMT per-protocol (PP) population was 24.1 months for the ICT-107 treated group and 8.5 months for control, representing a statistically significant 15.6-month PFS benefit for the ICT-107 treated group (age stratified HR = 0.257 [0.095-0.697], p = 0.004).
Median OS for the HLA-A2 methylated MGMT PP population was 23.9 months for the control group, and the median has not yet been reached for the ICT-107 treated group. At the time of the analysis, 65% of ICT-107 patients and 50% of the control patients were alive (age stratified HR = 0.631 [0.212-1.880], p = 0.404), suggesting the potential for long-term survival with ICT-107 treatment.
Median PFS for the HLA-A2 unmethylated MGMT PP population was 10.5 months for the ICT-107 treated group and 6.0 months for the control group, representing a 4.5-month median PFS benefit for the ICT-107 treated group (age stratified HR = 0.720 [0.351-1.474], p = 0.364).
Median OS for the HLA-A2 unmethylated MGMT PP population, was 15.8 months for ICT-107 patients, and 11.8 months for the control group, representing a 4-month median OS benefit for the ICT-107 treated group (age stratified HR = 0.652 [0.320-1.325], p = 0.233).
Median PFS in the intent-to-treat (ITT) population (all phase II patients) was 11.4 months for the ICT-107 treated group and 10.1 months for the control group, representing a statistically significant benefit in the ICT-107 treated group (age stratified HR = 0.640 [0.423-0.968], p = 0.033).
Median OS in the ITT population was 18.3 months for the ICT-107 treated group and 16.7 for the control group, representing a numeric, but not statistically significant, advantage for the treatment group (age stratified HR = 0.854 [0.547-1.334], p = 0.487).

The Company is utilizing all available information from the controlled phase II trial to design phase III testing in order to increase its probability of success, including the timing of randomization within the standard-of-care treatment these patients receive, in an attempt to limit the number of patients who are "early progressors" and unlikely to respond to therapy.