On April 14, 2016 Myriad Genetics, Inc. (NASDAQ:MYGN), a leader in molecular diagnostics and personalized medicine, reported that the company and its scientific collaborators will present two studies at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) annual meeting, April 16-20, in New Orleans, La (Press release, Myriad Genetics, APR 14, 2016, View Source [SID:1234510815]). The data will highlight early clinical trials of PARP inhibitors targeting the DNA repair pathway and the use of novel biomarkers to select patients for treatment.

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"Myriad is a leader in developing companion diagnostics for promising new medicines like the PARP inhibitors currently in clinical development," said Richard Wenstrup, M.D., chief medical officer, Myriad Genetics. "Our successful collaborations demonstrate our collective goal of improving patient care through precision medicine. Our growing portfolio of companion diagnostics will achieve that objective by helping physicians select the right treatments for their patients with cancer."

The studies to be presented are described below, and the abstracts are now available at: View Source Follow Myriad on Twitter via @MyriadGenetics to stay informed about news and updates from the Company.

Featured AACR (Free AACR Whitepaper) Mini-Symposia

Title: Safety and efficacy results from a Phase 1 dose-escalation trial of the PARP inhibitor talazoparib (BMN-673) in combination with either temozolomide or irinotecan in patients with advanced malignancies.
Date: Sunday, April 17, 2016: 4:30—4:45 p.m. CDT.
Location: Podium CT011.
Presenter: Zev A. Wainberg, M.D., UCLA Medical Center

Title: Preclinical evaluation of the PARP inhibitor niraparib and cytotoxic chemotherapy alone in combination in a panel of 25 triple-negative breast cancer PDX models: relevance of BRCA mutations, HRD status and other biomarkers.
Date: Tuesday, April 19, 2016: 3:20—3:35 p.m. CDT.
Location: Podium 4353.
Presenter: Olivier Deas, Ph.D., XenTech SAS.

AMPK is a master regulator of cellular metabolism that exerts either oncogenic or tumor suppressor activity depending on context. Here, we report that the specific AMPK agonist GSK621 selectively kills acute myeloid leukemia (AML) cells but spares normal hematopoietic progenitors. This differential sensitivity results from a unique synthetic lethal interaction involving concurrent activation of AMPK and mTORC1. Strikingly, the lethality of GSK621 in primary AML cells and AML cell lines is abrogated by chemical or genetic ablation of mTORC1 signaling. The same synthetic lethality between AMPK and mTORC1 activation is established in CD34-positive hematopoietic progenitors by constitutive activation of AKT or enhanced in AML cells by deletion of TSC2. Finally, cytotoxicity in AML cells from GSK621 involves the eIF2α/ATF4 signaling pathway that specifically results from mTORC1 activation. AMPK activation may represent a therapeutic opportunity in mTORC1-overactivated cancers.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

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On April 14, 2016 Portola Pharmaceuticals (Nasdaq:PTLA) reported that new data from a pharmacokinetic modeling study designed to identify the dose of cerdulatinib for expansion cohorts in a Phase 2 study will be presented in a poster session at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016, which is taking place from April 16-20 in New Orleans (Press release, Portola Pharmaceuticals, APR 14, 2016, View Source;p=RssLanding&cat=news&id=2157123 [SID:1234510817]).

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Cerdulatinib is an oral, dual Syk/JAK kinase inhibitor in development to treat patients with resistant or relapsed hematologic cancer. Cerdulatinib inhibits two key cell signaling pathways that promote cancer cell growth in certain hematologic malignancies. Portola is evaluating cerdulatinib in an ongoing Phase 1/2 study in patients with relapsed/refractory B-cell malignancies who have failed multiple therapies.

The abstract will be made available at www.AACR.org.

Poster Presentation Details

Abstract Title (#CT144): Preclinical and clinical studies and modeling and simulation to identify Phase 2 dose for cerdulatinib: a dual SYK/JAK inhibitor for the treatment of B-cell malignancies
Presenting Author: Janet M. Leeds, Ph.D., Senior Director, Drug Metabolism and Pharmacokinetics, Portola Pharmaceuticals

Poster Session Title: Phase I Clinical Trials 2
Presentation Date and Time: Wednesday, April 20, 7:30 a.m. – 11 a.m. Central Time
Location: Ernest N. Morial Convention Center, Halls G-J, Poster Section 13

While proteasome inhibition is a validated therapeutic approach for multiple myeloma (MM), inhibition of individual constitutive proteasome (c20S) and immunoproteasome (i20S) subunits has not been fully explored owing to a lack of effective tools. We utilized the novel proteasome constitutive/immunoproteasome subunit enzyme-linked immunosorbent (ProCISE) assay to quantify proteasome subunit occupancy in samples from five phase I/II and II trials before and after treatment with the proteasome inhibitor carfilzomib. Following the first carfilzomib dose (15-56 mg/m(2) ), dose-dependent inhibition of c20S and i20S chymotrypsin-like active sites was observed [whole blood: ≥67%; peripheral blood mononuclear cells (PBMCs): ≥75%]. A similar inhibition profile was observed in bone marrow-derived CD138(+) tumour cells. Carfilzomib-induced proteasome inhibition was durable, with minimal recovery in PBMCs after 24 h but near-complete recovery between cycles. Importantly, the ProCISE assay can be used to quantify occupancy of individual c20S and i20S subunits. We observed a relationship between MM patient response (n = 29), carfilzomib dose and occupancy of multiple i20S subunits, where greater occupancy was associated with an increased likelihood of achieving a clinical response at higher doses. ProCISE represents a new tool for measuring proteasome inhibitor activity in clinical trials and relating drug action to patient outcomes.
© 2016 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd.

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Pegfilgrastim is a pegylated form of the granulocyte-colony stimulating factor, filgrastim. Herein, we report the results of a multicentre, randomized, double-blind phase III trial comparing the efficacy and safety of pegfilgrastim with filgrastim in patients with malignant lymphoma. Patients were randomized to receive either a single subcutaneous dose of pegfilgrastim or daily subcutaneous doses of filgrastim on day 4 after the completion of cyclophosphamide, cytarabine, etoposide and dexamethasone ± rituximab (CHASE(R); day 1-3) chemotherapy. The primary endpoint was the duration of severe neutropenia (DSN), defined as the number of days with neutrophil count <0·5 × 10(9) /l in the first cycle of chemotherapy. A total of 111 lymphoma patients were randomized to either the pegfilgrastim or filgrastim group. 109 patients received either pegfilgrastim (n = 54) or filgrastim (n = 55). Efficacy data were available for 107 patients (pegfilgrastim: n = 53, filgrastim: n = 54). Both groups were well balanced in terms of gender, age, performance status and other variables. The mean DSN (±S.D.) was 4·5 (±1·2) and 4·7 (±1·3) d in the pegfilgrastim and filgrastim groups. No significant difference in safety was observed. This trial verified the non-inferiority of a single subcutaneous dose of pegfilgrastim compared with daily subcutaneous doses of filgrastim, considering DSN as an indicator.
© 2016 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd.

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