On June 11, 2015 AVEO Oncology reported that it has received written feedback from the U.S. Food and Drug Administration regarding a potential pivotal study for tivozanib in the treatment of NRP-1 low colorectal cancer (CRC) (Press release, AVEO, JUN 11, 2015, View Source;p=RssLanding&cat=news&id=2058718 [SID:1234505395]). Tivozanib is an oral, potent, selective inhibitor of vascular endothelial growth factor (VEGF) with a long half-life and activity against all three VEGF receptors.

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AVEO recently presented results from the BATON-CRC study, a 265 patient randomized trial exploring the combination of mFOLFOX6 and tivozanib or bevacizumab as first-line treatment in patients with advanced metastatic CRC, at the 2015 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Tumor Angiogenesis and Vascular Normalization Conference. Among the predefined biomarkers explored in this study, neuropilin-1 (NRP-1), a signaling protein known to bind to VEGF-A in serum, was found to be a potential prognostic marker for angiogenesis inhibitor activity and may be predictive of tivozanib activity relative to bevacizumab.

Results from this study and the Company’s ongoing assay development efforts were presented to the FDA. Updated analyses from the Company’s assay development efforts, which are similar to those presented at the AACR (Free AACR Whitepaper) conference, will be presented at the upcoming European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) 17th World Congress on Gastrointestinal Cancer taking place July 1-4, 2015 in Barcelona Spain.

In response to questions from AVEO regarding a proposed pivotal phase 3 trial of tivozanib in CRC, the FDA suggested that the Company continue work on the development of its biomarker assay to address variability between assays presented, and that, at present, "insufficient data exists to determine the appropriateness of this [NRP-1 low] subgroup" for the proposed phase 3 study. This feedback is consistent with the Company’s current clinical strategy and discussions with cancer research cooperative groups. As such, AVEO plans to evaluate options to confirm the activity of tivozanib and FOLFOX in NRP-1 low CRC through a prospectively defined, randomized Phase 2 study, while continuing to work on the development of a commercially viable assay.

"NRP-1 expression is a biomarker of growing interest for malignancies treated with angiogenesis inhibitors," said Michael Bailey, president and chief executive officer of AVEO. "As part of our effort to develop a commercial companion diagnostic, we continue to evaluate alternative NRP-1 assays. Feedback from the FDA reinforces the importance of these ongoing efforts prior to embarking on a pivotal trial. We look forward to continuing our dialogue with the Agency and cooperative groups toward the design and potential conduct of an appropriate confirmatory study and the development of a companion diagnostic."

On June 11, 2015, Cellectar Biosciences reported that, after review of the company’s investigational new drug (IND) application, the U.S. Food and Drug Administration (FDA) has determined that Cellectar’s tumor margin illumination agent, CLR1502, will be evaluated as a combination product and assigned to the Center for Devices and Radiological Health (CDRH) (Filing, 8-K, Cellectar Biosciences, JUN 11, 2015, View Source [SID:1234505396]). As a result of this classification, the FDA has advised Cellectar that it will need to submit a new investigational application for the combination product prior to initiating its planned proof-of-concept trial in breast cancer surgery.

"Our tumor illumination agent shares similar spectral qualities with indocyanine green (ICG), a fluorescent dye commonly used in medical diagnostics, and can therefore use several commercially available fluorescent imaging devices. Current labeling for such devices is limited to FDA approved applications such as cardiac, circulatory, hepatic and ophthalmic conditions," said Dr. Simon Pedder, president and chief executive officer of Cellectar Biosciences. "Because of the groundbreaking nature of our overall technology and the potential for an agent like CLR1502 to dramatically expand the utility of such imaging devices, we appreciate the agency’s perspective and current interest in evaluating CLR1502 in combination with a light source technology. As previously disclosed, in the course of our discussions FDA regarding the CLR1502 registration program, the FDA has stressed that a combination product designation is not binding, can be revised later in our development program, and that we are not necessarily precluded from filing a standalone NDA in the future."

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About CLR1502

CLR1502 is a small-molecule, broad-spectrum, cancer-targeted, non-radioactive optical imaging agent developed by Cellectar to be the first of its kind for broad spectrum intraoperative tumor margin illumination and non-invasive tumor imaging. CLR1502 is comprised of a proprietary phospholipid ether (PLE) analog, acting as a cancer-targeted delivery and retention vehicle attached to a fluorophore to enable real-time visualization of malignant tissue under near-infrared light.

CLR1502 is being developed for intraoperative imaging of cancer that will aid in the identification of malignant tissue during diagnostic, staging, debulking and curative cancer surgeries. In particular, the potential of CLR1502 in tumor margin illumination during oncologic resections raises the possibility that this operative aid may improve surgical outcomes.

On June 11, 2015 Merrimack reported the initiation of clinical imaging assessing the use of a potential marker for delivery of MM-398 (irinotecan liposome injection), also known as "nal-IRI," to metastatic breast cancer (Press release, Merrimack, JUN 11, 2015, View Source [SID:1234505397]). This study is an expansion of a Phase 1 pilot study which assessed the feasibility of using ferumoxytol*, an iron oxide nanoparticle, to act as a marker for MM-398 tumor response prediction. The study will now enroll patients who have metastatic breast cancer which is either hormone receptor-positive, triple-negative, or where active brain metastases are present.

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"We were encouraged by the results of the initial pilot phase of the study, particularly the data that suggest a relationship between high levels of ferumoxytol uptake and shrinkage of tumor lesions after MM-398 treatment," said Dr. Jasgit Sachdev, MD, Virginia G Piper Cancer Center. "We are excited to continue to evaluate the activity of MM-398 and the predictive value of this imaging approach in additional patients with metastatic breast cancer."

The data from the initial pilot study (n=31 lesions comprising 9 patients) showed a relationship between ferumoxytol levels in individual tumor lesions, as measured using magnetic resonance imaging, and corresponding change in individual tumor lesion size following treatment with MM-398. Results observed in several patients with metastatic breast cancer in the pilot study warranted further expansion of the study to additional patients in this population. Adverse events from MM-398 therapy were consistent with previous studies. Reported grade 3 and above adverse events related to MM-398 treatment included diarrhea, hypokalemia, abdominal pain, anemia, nausea and neutropenia.

"We look forward to expanding this study and aim to use it to support our biomarker hypothesis and further our strategy to use diagnostic imaging to identify the patients who are most likely to derive benefit from treatment with MM-398," said Bart Hendriks, Ph.D., Director of Imaging Diagnostics at Merrimack.

As part of this expansion, 30 patients with metastatic breast cancer will be imaged with ferumoxytol followed by treatment with MM-398. Ten patients will be enrolled in each of three cohorts as follows: ER and/or PR-positive metastatic breast cancer, triple-negative metastatic breast cancer or metastatic breast cancer with active brain metastases. Eligible patients for the trial must have received less than four prior lines of chemotherapy for the treatment of metastatic disease. The primary objectives of this study are to investigate the feasibility of ferumoxytol quantitation in tumor lesions and to characterize the relationship between ferumoxytol uptake in the tumor and tumor response to MM-398 in patients with advanced metastatic breast cancer. Merrimack plans to conduct the trial at multiple sites in the United States. The Virginia G Piper Cancer Center in Scottsdale, Arizona is now open to screen patients. For more information, please visit clinicaltrials.gov (Identifier: NCT01770353).

About MM-398

MM-398 (irinotecan liposome injection), is an encapsulation of irinotecan in a long-circulating liposomal formulation. The activated form of irinotecan is SN-38, which functions by inhibiting topoisomerase I (an essential enzyme involved in DNA transcription and replication) and promoting cell death. Merrimack and Baxter International’s biopharmaceutical business (NYSE: BAX) have an exclusive licensing agreement to develop and commercialize MM-398 outside of the United States. PharmaEngine, Inc. (Taipei, Taiwan) holds the rights to commercialize MM-398 in Taiwan.

On June 11, 2015 Cyclenium Pharma Inc., an emerging pharmaceutical company specializing in the discovery and development of novel drug candidates based on proprietary macrocyclic chemistry and McGill University, one of the world’s leading post-secondary institutions, have entered into multiple research agreements designed to discover novel modulators for promising biological targets of pharmacological interest (Press release, Cyclenium, JUN 11, 2015, View Source [SID1234517246]). Involving investigators from the Rosalind and Morris Goodman Cancer Research Centre (GCRC), the Departments of Biochemistry and Physiology, and the McGill High Throughput Screening (HTS) facility, these collaborations will provide McGill researchers with immediate access to Cyclenium’s proprietary QUEST Library of next generation macrocyclic molecules and associated optimization capabilities. The initial objective of these exploratory efforts is to identify macrocyclic compounds capable of interacting with specific therapeutic targets, including several involving protein-protein interactions, being studied in the various McGill laboratories, thereby providing tools to improve the understanding of their involvement in various disease states, with the longer term goal of discovering novel pharmacological or diagnostic agents acting at these targets.

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"We have been greatly impressed with the nature and quality of the research being pursued within McGill’s laboratories and feel strongly that our macrocyclic compounds will be of significant assistance in advancing their studies," stated Helmut Thomas, Ph.D., President & Chief Executive Officer of Cyclenium. "Coupling the cutting-edge efforts and the world class expertise of their investigators with our CMRT Technology and proven development success in the macrocycle arena offers an excellent opportunity for synergy in the discovery and development of novel therapeutic and diagnostic agents against important, but difficult, pharmacological targets."

"We are excited about our collaboration with Cyclenium," said Dr. Morag Park, Director of the Rosalind and Goodman Cancer Research Centre, McGill University, "as it will continue to create new opportunities to accelerate the translation of basic research and our mechanistic understanding of cancer biology into potential therapies for cancer patients."

"The partnership with Cyclenium will provide our researchers access to new chemical probes with which we can query the mechanics of life at the molecular level," said Dr. Albert Berghuis, Chair of the Biochemistry Department, McGill University. "There is no doubt that the basic insights gained will lead to new avenues for therapy development for a host of diseases. This is therefore a win-win-win scenario for McGill, Cyclenium, and ultimately patients."

"This collaborative venture is a prime example of harnessing the biomedical expertise of publicly funded university researchers with the technical prowess and resources of the biopharmaceutical industry to enhance drug discovery and disease treatment," said Dr. John Orlowski, Chair of the Department of Physiology, McGill University. "Such relationships will ultimately benefit not only the healthcare of Canadians but also individuals world-wide."

On June 11, 2015 TG Therapeutics reported that clinical data for TG-1101 (ublituximab), the Company’s novel glycoengineered anti-CD20 monoclonal antibody, and TGR-1202, the Company’s once-daily PI3K delta inhibitor, will be presented at the 20th Congress of the European Hematology Association (EHA) (Free EHA Whitepaper), being held from June 11 – June 14, 2015 in Vienna, Austria as well as at the 13th International Congress on Malignant Lymphoma (ICML), being held from June 17 – June 20, 2015 in Lugano, Switzerland (Press release, TG Therapeutics, JUN 11, 2015, View Source [SID:1234505398]).

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The Company and its study investigators will present data from the following clinical studies:

TGR-1202 as a single agent in relapsed/refractory B-cell malignancies
TGR-1202 in combination with TG-1101 ("1303 combination") in CLL and NHL
TGR-1202 + TG-1101 + ibrutinib in B-cell malignancies
TG-1101 in combination with ibrutinib in patients with relapsed/refractory CLL

Additional information on the presentations can be found below:

20th Congress of EHA (Free EHA Whitepaper) (Vienna):

Date/Time: Friday, June 12, 2015, 17:15 – 18:45 CEST
Abstract Number: P327 (Poster)
Presentation Title: UBLITUXIMAB + TGR-1202 DEMONSTRATES ACTIVITY AND FAVORABLE SAFETY PROFILE IN RELAPSED/REFRACTORY B-CELL NHL AND HIGH-RISK CLL
Presenter: Matthew Lunning, DO, University of Nebraska, Omaha, NE

Date/Time: Saturday, June 13, 2015, 11:45 – 12:00 CEST
Abstract Number: S432 (Oral Presentation)
Presentation Title: TGR-1202, A NOVEL ONCE DAILY PI3K-DELTA INHIBITOR, DEMONSTRATES CLINICAL ACTIVITY WITH A FAVORABLE SAFETY PROFILE, LACKING HEPATOTOXICITY, IN PATIENTS WITH CLL AND B-CELL LYMPHOMA
Presenter: Owen A. O’Connor, MD, PhD, Columbia Presbyterian Lymphoma Center, New York, NY

ICML Meeting (Lugano):

Date/Time: Wednesday, June 17, 2015, 17:45 CEST
Abstract Number: 038 (Oral Presentation)
Presentation Title: TGR-1202, A NOVEL ONCE DAILY PI3K δ INHIBITOR, DEMONSTRATES CLINICAL ACTIVITY WITH A FAVORABLE SAFETY PROFILE, LACKING HEPATOTOXICITY IN PATIENTS WITH CLL AND B-CELL LYMPHOMA
Presenter: Owen A. O’Connor, MD, PhD, Columbia Presbyterian Lymphoma Center, New York, NY

Date/Time: Thursday, June 18, 2015, 17:15 CEST
Abstract Number: 105 (Oral Presentation)
Presentation Title: UBLITUXIMAB (TG-1101), A NOVEL GLYCOENGINEERED ANTI-CD20 MAB, IN COMBINATION WITH IBRUTINIB ACHIEVES 95% ORR IN PATIENTS WITH HIGHRISK RELAPSED/REFRACTORY CLL
Presenter: John Burke, MD, Rocky Mountain Cancer Center/US Oncology, Aurora, CO

Date/Time: Thursday, June 18, 2015, 17:25 CEST
Abstract Number: 106 (Oral Presentation)
Presentation Title: THE CHEMOTHERAPY-FREE TRIPLET OF UBLITUXIMAB, TGR-1202, AND IBRUTINIB IS SAFE AND HIGHLY ACTIVE IN RELAPSED B-CELL MALIGNANCIES
Presenter: Loretta Nastoupil, MD, MD Anderson Cancer Center, Houston, TX

Date/Time: Thursday, June 18, 2015
Abstract Number: 284 (Poster)
Presentation Title: UBLITUXIMAB + TGR-1202 DEMONSTRATES ACTIVITY AND FAVORABLE SAFETY PROFILE IN RELAPSED/REFRACTORY B-CELL NHL AND HIGH-RISK CLL
Presenter: Matthew Lunning, DO, University of Nebraska, Omaha, NE