On June 24, 2015 Tokai Pharmaceuticals reported the initiation of ARMOR3-SV, Tokai’s pivotal Phase 3 clinical trial of galeterone in men with metastatic castration-resistant prostate cancer (mCRPC) whose tumors express the AR-V7 splice variant, which is a truncated form of the androgen receptor (AR) that has been associated with non-responsiveness to commonly-used oral therapies for mCRPC (Press release, Tokai Pharmaceuticals, JUN 24, 2015, View Source [SID:1234505799]).

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Tokai also announced today that the components of the AR-V7 clinical trial assay have been finalized by its collaborator, Qiagen (NASDAQ: QGEN; Frankfurt Prime Standard: QIA), and that global deployment of the assay is now underway.

"ARMOR3-SV represents an important step forward in bringing precision medicine to patients with prostate cancer, and we are pleased with the progress made by our valued collaborator Qiagen in readying the AR-V7 clinical assay for global implementation," said Jodie Morrison, President and Chief Executive Officer of Tokai. "With worldwide commercial rights to galeterone, our pivotal clinical trial on track to read out by the end of 2016, and a strong financial position, Tokai is well positioned to realize its mission of bringing new therapeutic treatment options to patients with prostate cancer."

"Based on the evidence reported thus far, a diagnostic tool that can predict patient responsiveness to certain therapies should lead to more informed treatment decisions and ultimately better care for prostate cancer patients," said Mary Ellen Taplin, M.D., Director of Clinical Research, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute and lead U.S. investigator of ARMOR3-SV. "Given the encouraging clinical data reported to date for galeterone and the precision medicine approach being employed in Tokai’s pivotal trial, this study has the opportunity to alter the treatment landscape for metastatic CPRC patients."

ARMOR3-SV will compare galeterone to Xtandi (enzalutamide) in 148 mCRPC treatment-naïve patients whose prostate tumors express the AR-V7 splice variant. These truncated ARs are missing the C-terminal end of the AR that contains the ligand-binding domain, which is known as C-terminal loss. AR-V7 is the most common form of C-terminal loss. The pivotal trial will employ a precision medicine approach for selection of patients with the AR-V7 splice variant by using an AR-V7 clinical trial assay successfully optimized for global use by Qiagen. The primary endpoint of ARMOR3-SV is radiographic progression-free survival assessed by blinded independent central review. The design of ARMOR3-SV is aligned with feedback obtained from the U.S. Food and Drug Administration and the European Medicines Agency.

ARMOR3-SV has been initiated at more than 15 sites in the United States, with site initiations in Canada and the United Kingdom anticipated later in June. Additional study centers throughout North America, Western Europe and Australia are expected to join the study in the coming months. In addition, with recent finalization of the components of the AR-V7 clinical trial assay, technology transfer activities and training of the global central laboratories are underway, and screening of eligible patients for the splice variant is expected to begin in July. The company expects topline data from ARMOR3-SV to be available by the end of 2016.

On June 24, 2015 Agios Pharmaceuticals reported dose administration for the first patient in a Phase 1, open-label, dose-escalation and expansion study of single agent AG-881, a small molecule that has shown in preclinical studies to fully penetrate the blood-brain barrier and inhibit isocitrate dehydrogenase-1 (IDH1) and IDH2 mutations in cancer models (Press release, Agios Pharmaceuticals, JUN 24, 2015, View Source [SID:1234505798]).

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"The initiation of this study represents a significant milestone for Agios, as it marks the third program from our portfolio of IDH inhibitors to enter the clinic in less than two years," said Chris Bowden, M.D., chief medical officer of Agios. "We look forward to producing important early data to guide our future development plans and continuing to demonstrate Agios’ leadership in cancer metabolism and drug development for IDH inhibitors."

"We are eager to explore the profile of AG-881 as we continue to investigate the role of IDH inhibitors for the treatment of patients with IDH mutant-positive tumors," said Howard Burris, M.D., Sarah Cannon Research Institute, an investigator for the study. "The Phase 1 study of this second-generation IDH inhibitor expands the opportunities for clinical development in the genetically defined spectrum of IDH1 or IDH2 mutant-positive tumors."

About the AG-881 Phase 1 Study in Advanced Solid Tumors, including Gliomas, with an IDH1 or IDH2 Mutation

The purpose of the Phase 1 multi-center, open-label study is to evaluate the safety, pharmacokinetics, pharmacodynamics and clinical activity of AG-881 in advanced solid tumors. AG-881 will be administered continuously as a single agent dosed orally in a 28-day cycle. The first portion of the study includes a dose-escalation phase in which cohorts of patients will receive ascending oral doses of AG-881 to determine the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose based on safety and tolerability. The second portion of the study is a dose expansion phase where patients will receive AG-881 to further evaluate the safety, tolerability and clinical activity of the recommended Phase 2 dose. Please refer to www.clinicaltrials.gov for additional clinical trial information.

Upcoming Milestones for AG-881

A second dose-escalating and expansion trial, for patients with advanced IDH1 or IDH2 mutant-positive hematologic malignancies whose cancer has progressed on a prior IDH inhibitor therapy, is expected to begin shortly.

About IDH Mutations and Cancer

IDH1 and IDH2 are two metabolic enzymes that are mutated in a wide range of hematologic and solid tumor malignancies, including acute myeloid leukemia (AML) and gliomas. Normally, IDH enzymes help to break down nutrients and generate energy for cells. When mutated, IDH increases production of an oncometabolite 2-hydroxyglutarate (2HG) that alters the cells’ epigenetic programming, thereby promoting cancer. 2HG has been found to be elevated in several tumor types. Agios believes that inhibition of the mutated IDH proteins may lead to clinical benefit for the subset of cancer patients whose tumors carry them.

Summary of Agios and Celgene Collaboration on IDH Mutant Inhibitors

Agios and Celgene entered a global, strategic collaboration in April 2010, and to date, three potential new distinct investigational medicines have emerged – the IDH2 mutant inhibitor, AG-221; the IDH1 mutant inhibitor, AG-120; and the pan-IDH mutant inhibitor, AG-881, which was recently announced as part of a new collaboration between the companies. These three investigational medicines aim to improve treatment outcomes for patients whose cancers carry IDH mutations, including difficult-to-treat AML and glioma, a type of aggressive brain tumor with a poor prognosis.

Each of these investigational medicines carries different financial terms and rights under the collaboration:

AG-221: Celgene has worldwide development and commercialization rights for AG-221. Agios is eligible for up to $120 million in milestone payments and royalties on any net sales.
AG-120: Agios retains U.S. development and commercialization rights, while Celgene has development and commercialization rights outside the U.S. Agios is eligible to receive royalties on any net sales outside the U.S. and up to $120 million in milestone payments. Celgene is eligible to receive royalties on any net sales in the U.S.
AG-881: Joint worldwide development and 50/50 profit share collaboration. Agios is eligible to receive regulatory milestone payments up to $70 million.

On June 24, 2015 Spectrum Pharmaceuticals reported the publication of results from the pivotal BELIEF (CLN-19) Study, which was selected as a Rapid Communication in the Journal of Clinical Oncology (JCO), the journal of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) (Press release, Spectrum Pharmaceuticals, JUN 24, 2015, View Source [SID:1234505796]).

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The study, led by Dr. Owen O’Connor from the Center for Lymphoid Malignancies, Department of Medicine, Columbia University Medical Center, New York, NY, showed that monotherapy with Beleodaq produced complete and durable responses with manageable toxicity in patients with R/R PTCL across the major subtypes, irrespective of the number or type of prior therapies.

Beleodaq, previously known as belinostat, is a histone deacetylase (HDAC) inhibitor indicated for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). This indication is approved under accelerated approval based on tumor Response Rate and Duration of Response. An improvement in survival or disease-related symptoms has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial.

Peripheral T-cell lymphomas are a diverse group of non-Hodgkin lymphomas with a poor prognosis and no accepted standard of care for relapsed or refractory patients. Unfortunately, current treatment options for most of these patients induce responses in only a minority of cases ( < 30%), and thus long-term survival is relatively poor. The BELIEF study evaluated the efficacy and tolerability of Beleodaq as a single agent in R/R PTCL. This study was an open-label, single-arm, non-randomized, international trial conducted at 62 centers that enrolled 129 patients with R/R PTCL, who had progressed following ≥1 prior therapy with a median number of prior therapies of two (1-8). These patients received Beleodaq (1,000 mg/m2) as daily 30-minute infusions on Days 1-5 every 21 days until disease progression or unacceptable toxicity.

The primary endpoint of the BELIEF study was ORR as assessed centrally by an Independent Review Committee using the International Working Group (IWG) criteria. The ORR in the 120 evaluable patients was 25.8% (31 patients) (95% CI 18.3 – 34.6), including 13 Complete Responses (10.8%) (95% CI 5.9 – 17.8) and 18 Partial Responses (15%) (95% CI 9.1 – 22.7). Secondary endpoints included a median DoR of 13.6 months by IWG criteria and 8.4 months to disease progression or death, with the longest ongoing patient at ≥36 months. The most common Grade 3/4 adverse events were anemia (10.8%), thrombocytopenia (7%), dyspnea (6.2%), and neutropenia. No clinically relevant ECG changes were identified, and cardiovascular monitoring of ECGs is not required at baseline or during treatment. In this pivotal study, monotherapy with Beleodaq produced complete and durable responses with manageable toxicity in patients with R/R PTCL across the major disease subtypes, irrespective of the number or type of prior therapies and with a low incidence of Grade 3/4 thrombocytopenia.

"We are pleased to have the results of the pivotal Beleodaq study selected for publication as a Rapid Communication in such a prominent journal," said Rajesh C. Shrotriya, MD, Chairman and Chief Executive Officer of Spectrum Pharmaceuticals. "This is a highly distinguished category that JCO reserves for papers judged to have special impact to their broad clinical readership. Spectrum has a unique PTCL franchise, marketing two FDA approved drugs for this indication, Folotyn (pralatrexate injection) and Beleodaq. We are very proud to be able to offer patients and clinicians more treatment options with two approved treatments for R/R PTCL."

"This is a very exciting time in the treatment of patients with PTCL," said Dr. Owen A. O’Connor, MD, PhD, Director of the Center for Lymphoid Malignancies, Professor of Medicine and Experimental Therapeutics at Columbia Medical Center, New York Presbyterian Medical Center, one of the lead investigators in the BELIEF study. "At long last we finally have tools in the therapeutic armamentarium to help our patients. Belinostat represents the latest drug approved for patients with R/R PTCL that has relatively few side effects and produces long durations of benefit, even in patients who have received multiple conventional treatments in the past. Now that we have several new options to treat the disease when it comes back, we need to use these drugs to make better up-front treatment platforms; Belinostat will be an important part of that future."