On November 13, 2017 Array BioPharma Inc. (Nasdaq: ARRY), a biopharmaceutical company focused on the discovery, development and commercialization of targeted small molecule cancer therapies, reported data from the Phase 1b clinical trial evaluating the immunotherapy combination of ARRY-382, with Merck’s KEYTRUDA (pembrolizumab), an anti-PD-1 antibody, in patients with certain advanced solid tumors, at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 32nd Annual Meeting, being held Nov. 8-12, 2017 in National Harbor, Maryland (Press release, Array BioPharma, NOV 13, 2017, View Source;p=RssLanding&cat=news&id=2316453 [SID1234521957]). ARRY-382 is a highly selective oral inhibitor of the CSF1R kinase and would be among the first investigational compounds targeting this pathway.

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"We are pleased to announce completion of the Phase 1b clinical study of ARRY-382 in combination with KEYTRUDA. In addition to establishing an appropriate Phase 2 dose for the combination, we are encouraged by the early signs of activity in patients with tumor types that have been historically unresponsive to anti-PD1 therapies," said Ron Squarer, Chief Executive Officer, Array BioPharma.

In the Phase 1b dose escalation trial, the recommended Phase 2 dose of ARRY-382 was determined to be 300 mg daily in combination with KEYTRUDA 2 mg/kg given intravenously every 3 weeks.

Nineteen patients, with a median of two prior lines of therapy and 42% with ≥3 prior regimens, were treated in the study. Patients with pancreatic (n=6), colorectal (n=5), ovarian (n=3), gastric and melanoma (n=2, each), and triple negative breast cancer (n=1) were enrolled. Investigators noted that ARRY-382 had a manageable safety profile when administered with KEYTRUDA in this study, and the most common grade 3/4 adverse events (AEs) (>10%), regardless of causality, included increased AST, increased blood creatine kinase (CK), rash, increased lipase, increased alkaline phosphatase (ALP), increased alanine aminotransferase (ALT) and anemia.

The combination of ARRY-382 and KEYTRUDA demonstrated early signs of activity, with 11% (n=2) of patients achieving a confirmed partial response, based on RECIST version 1.1 guidelines The first responder, who was treated with ARRY-382 at 200 mg, had Stage III pancreatic ductal adenocarcinoma. As of the data cut-off, this patient was on study treatment in cycle 14 (42 weeks). The second responder, who was treated with ARRY-382 at 300 mg, had stage IV ovarian cancer with liver metastasis. As of the data cut-off, this patient was on study treatment in cycle 8 (24 weeks).

The current trial was designed to enroll Phase 2 cohorts in both melanoma and non-small cell lung cancer patients, and now Array plans to expand the study to include other patient populations, including a cohort of pancreatic cancer patients. The Phase 2 portion of the study is currently active and enrolling patients.

About CSF1R and ARRY-382

Colony-stimulating factor 1 receptor (CSF1R) is a cell-surface receptor for its ligands, colony-stimulating factor 1 (CSF1) and IL-34.[1, 2] CSF1R is thought to play an important role as regulator of the development, morphology, survival, and functions of tissue macrophages as well as tumor-associated macrophages (TAMs). TAMs play a role in modulating anti-tumor adaptive immunity and CSF1 is believed to be a driver of TAM differentiation towards an immunosuppressive tumor promoting phenotype. Increased CSF1 expression is implicated in tumor progression and metastasis, and is associated with poor prognosis in some cancers.[3] Combining a PD-1 inhibitor with a CSF1R inhibitor in preclinical models shows enhanced antitumor activity. ARRY-382 is a highly selective, oral inhibitor of CSF1R.

On November 13, 2017 Mirati Therapeutics, Inc. (Nasdaq: MRTX) (the Company or Mirati), a clinical-stage targeted oncology company, reported that it is reprioritizing its development programs to capitalize on encouraging data and development opportunities in its sitravatinib and KRAS programs (Press release, Mirati, NOV 13, 2017, View Source [SID1234522006]). In addition, the Company announced that it has selected a clinical lead and backup compounds in its KRAS program that potently target KRAS G12C mutations. An Investigational New Drug (IND) Application submission is expected by the fourth quarter of 2018. The Company also announced it will deprioritize further investment in glesatinib and will pursue opportunities to partner the program. The reallocation of resources will support the acceleration and expansion of the sitravatinib and KRAS programs and is expected to provide funding for operations into late 2019.

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"We are very encouraged by the early results from our sitravatinib immuno-oncology program. The combination of sitravatinib and nivolumab has demonstrated durable responses and prolonged stable disease in patients with non-small cell lung cancer that have documented progression on prior checkpoint therapy. This is a patient population with poor prognosis and limited treatment options. We are focusing on accelerating this promising opportunity with sitravatinib and advancing our potentially first-in-class KRAS program, both of which address large underserved patient populations with significant market potential," said Charles M. Baum, M.D., Ph.D., President and Chief Executive Officer.

Program updates the Company expects to provide in 2018 include:
•
Phase 2 data from the immuno-oncology combination of sitravatinib and nivolumab in patients with checkpoint refractory non-small cell lung cancer (NSCLC) by mid-2018.
•
Advancement of the potentially first-in-class KRAS G12C inhibitor program to an IND submission by the fourth quarter of 2018.
•
Phase 1b proof-of-concept data from the study of sitravatinib as a single agent in genetically selected patients with NSCLC and other solid tumors by mid-2018.

•
Phase 2 data from the immuno-oncology combination of mocetinostat and durvalumab in patients with checkpoint refractory NSCLC in the first quarter of 2018.

Mirati’s Development Programs

Sitravatinib

Sitravatinib is a spectrum-selective kinase inhibitor that potently inhibits receptor tyrosine kinases (RTKs), including TAM family receptors (TYRO3, Axl, Mer), split family receptors (VEGFR2, KIT) and RET. As an immuno-oncology agent, sitravatinib is being tested in combination with the anti-PD-1 checkpoint inhibitor, nivolumab (OPDIVO), in NSCLC patients who have experienced documented disease progression following treatment with a checkpoint inhibitor. The majority of NSCLC patients either do not respond to checkpoint therapy or experience disease progression following treatment. Sitravatinib’s potent inhibition of TAM and split family RTKs may overcome resistance to checkpoint inhibitor therapy through targeted reversal of an immunosuppressive tumor microenvironment, enhancing antigen-specific T cell response and expanding dendritic cell-dependent antigen presentation.

As previously reported at the IASLC 18th World Conference on Lung Cancer, initial data from the ongoing Phase 2 study of sitravatinib in combination with nivolumab included three confirmed Partial Responses (PRs) in the first 11 evaluable patients. Eight of these patients exhibited tumor reduction. Seven patients (including all three patients with PRs) remained on study, with treatment duration ranging from four months to 10.5 months. These initial results are encouraging and may extend to other tumor types, including renal cell, bladder and liver cancer, where checkpoint inhibitors have demonstrated efficacy that may potentially be expanded by combining with sitravatinib. The Company plans to provide an update on the first two stages of this trial in up to 34 patients by mid-2018.

Sitravatinib is also being evaluated as a single agent in a Phase 1b expansion trial enrolling patients whose tumors harbor CBL, CHR4Q12 and RET genetic alterations in NSCLC and other tumor types. In the ongoing Phase 1b study of sitravatinib as a single agent, an objective response with tumor reduction of 77% was observed in the first evaluable NSCLC patient with a CBL mutation. The Company continues to enroll patients in this trial to confirm this early promising activity and will provide a further update across all cohorts by mid-2018.

KRAS Program Advancing Towards IND in 2018

The Company has selected a clinical lead and backup compounds for advancement to IND in its potential first-in-class KRAS program. The KRAS program emerged from a joint drug discovery collaboration with Array BioPharma, where over 100 co-crystal structures provided critical insight toward the design of potent and selective KRAS inhibitors. The clinical lead and backups are orally-available small molecule inhibitors of KRAS G12C mutations, with potencies of 1 to 20 nM (cellular IC50) and selectivity of greater than 1,000-fold for target inhibition in tumor cells harboring KRAS G12C mutations compared with cells exhibiting wild-type KRAS. In addition, the clinical lead and backups demonstrated complete regression of KRAS G12C-positive tumors implanted in mice. IND-enabling preclinical studies are underway, and an IND submission is expected by the fourth quarter of 2018, with early clinical proof-of-concept anticipated in 2019.

Historically, KRAS has been extremely difficult to directly inhibit due to its high affinity for GTP, and its lack of a defined binding pocket. Tumors characterized by KRAS mutations are commonly associated with poor prognosis and resistance to therapy. KRAS G12C driver mutations occur in approximately 14% of NSCLC adenocarcinoma patients and 5% of colorectal cancer patients, who

have few treatment options. The Company’s KRAS program has the potential to be the first direct inhibitor of this important and challenging tumor driver mutation.

Mocetinostat

Mocetinostat is a selective Class I and IV HDAC inhibitor. Inhibition of histone acetylation is predicted to enhance the recognition of tumor cells by anti-tumor T cells and reverse immunosuppressive factors in the tumor microenvironment. The Company is conducting a Phase 2 study of mocetinostat in combination with durvalumab (IMFINZI) in NSCLC patients who have experienced disease progression after prior treatment with checkpoint inhibitor therapy. Patients are stratified into two cohorts based upon their best response to prior checkpoint therapy. Stage 1 of the study is currently enrolling nine patients in each cohort. As previously reported, one cohort has already met the prespecified criteria for expansion into stage 2 with at least one confirmed partial response. The Company will provide an update on this trial in the first quarter of 2018.

Glesatinib
Glesatinib has demonstrated clinical activity and acceptable tolerability in MET-altered NSCLC patients. However, in light of superior investment opportunities in its pipeline, the Company will suspend further investment in glesatinib and will pursue opportunities to partner the program. The Company intends to present glesatinib data at a future medical conference.

LSD1 Preclinical Program
The Company has elected to suspend further development of its preclinical LSD1 inhibitor program as part of its reprioritization. In light of superior investment opportunities in its pipeline, the Company will seek a partner to continue development of the program.

Fennec Pharmaceuticals has filed a 10-Q – Quarterly report [Sections 13 or 15(d)] with the U.S. Securities and Exchange Commission (Filing, 10-Q, Fennec Pharmaceuticals, 2017, NOV 13, 2017, View Source [SID1234521990]).

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On November 13, 2017 Galectin Therapeutics Inc. (NASDAQ: GALT), the leading developer of therapeutics that target galectin proteins, and Providence Cancer Institute reported the presentation of preclinical and early clinical data from an investigator-initiated Phase 1 clinical trial of GR-MD-02 used in combination with pembrolizumab (KEYTRUDA). Data of two complimentary abstracts were presented Nov. 11, 2017 at the Annual Meeting of the Society for Cancer Immunotherapy in National Harbor, Md., by William L. Redmond, Ph.D., Earle A. Chiles Research Institute, a division of Providence Cancer Institute (data posted) (Press release, Galectin Therapeutics, NOV 13, 2017, View Source [SID1234521962]).

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Three patients in cohort 2 (4 mg/kg GR-MD-02) have now been completed to add to the six patients in dose cohort 1 (2 mg/kg GR-MD-02). One patient in the first cohort had head and neck cancer, while the remaining eight patients had advanced melanoma. Five patients with advanced melanoma had objective responses after five courses of every three-week therapy, with three partial responses and two complete responses. All the patients in the second cohort had an objective response. Please refer to the posted data to review additional information on the patients who responded.

"In addition to the encouraging clinical responses seen in this study, we are making progress on identifying immunological markers that may predict clinical responses to the combination therapy," said Redmond, associate member, Laboratory of Cancer Immunotherapy, and director, Immune Monitoring Laboratory. "In this regard, we have shown that clinical responders to the combination of GR-MD-02 and pembrolizumab may have reduced myeloid-derived suppressor cells following treatment."
The Providence Cancer Institute translational medicine team conducted two phase 1 clinical trials, initiated under direction of principal investigator Brendan D. Curti, M.D., director, Genitourinary Oncology Research and Immunotherapy Clinical Program, and co-director, Melanoma Program.

GR-MD-02 was also combined in an investigator-led trial with ipilimumab (Yervoy) in patients with advanced melanoma (View Source;rank=6). Seven subjects treated with the lowest two dose cohorts of GR-MD-02 (1 and 2 mg/kg) have been completed with no safety signals identified due to GR-MD-02. In these low dose initial cohorts, there were no notable changes in the peripheral immune signature. Due to changes in the standard of care for metastatic melanoma (i.e., approval of KEYTRUDA), recruitment has been slowed significantly.

"We are encouraged by these early safety and efficacy results and look forward to further data on GR-MD-02 used in combination with pembrolizumab in patients with metastatic melanoma or head and neck cancer," said Curti. "An objective response rate of five out of eight patients (62.5%) with advanced melanoma, including two complete responses, is very encouraging and compares favorably with the known response rates with pembrolizumab alone (ORR of ~ 33%). We have begun enrolling cohort 3 (GR-MD-02 8 mg/kg), which will include at least 10 patients with melanoma to provide a larger group of patients to evaluate. We hope to report additional data in mid-2018 when we anticipate a decision on progressing to phase 2. This decision will be based on the response rate of the combination with GR-MD-02 as compared to historical response rates to pembrolizumab alone."

"Galectin Therapeutics is delighted with our collaboration and the excellent work by Providence Cancer Institute," said Peter Traber, M.D., CEO and CMO of Galectin Therapeutics. "It is known that galectin-3 produced by tumors is important in avoidance of immune recognition by cancer cells, and we are gratified by the large body of pre-clinical work and these early clinical trials that may support the combination of our galectin-3 inhibitor, GR-MD-02, with immune checkpoint inhibitors. It is important to note that not all galectin-3 inhibitors may be effective, as we have shown that a previous drug GM-CT-01 (DAVANAT) had no effect in the same pre-clinical models. Finally, the use of combination immunotherapy with GR-MD-02 is covered by a joint Galectin-Providence U.S. patent with exclusive rights granted to Galectin."

About GR-MD-02
GR-MD-02 is a complex carbohydrate drug that targets galectin-3, a critical protein in the pathogenesis of fatty liver disease and fibrosis. Galectin-3 plays a major role in diseases that involve scarring of organs including fibrotic disorders of the liver, lung, kidney, heart and vascular system. The drug binds to galectin proteins and disrupts their function. Preclinical data in animals have shown that GR-MD-02 has robust treatment effects in reversing liver fibrosis and cirrhosis.

On November 13, 2017 Diffusion Pharmaceuticals Inc. (Nasdaq: DFFN) ("Diffusion" or "the Company"), a clinical-stage biotechnology company focused on extending the life expectancy of cancer patients using the novel small molecule trans sodium crocetinate (TSC) in conjunction with standard radiation and chemotherapy, reported financial results for the three and nine months ended September 30, 2017 and provided a business update (Press release, RestorGenex, NOV 13, 2017, View Source [SID1234522010]).

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David Kalergis, Chairman and Chief Executive Officer of Diffusion Pharmaceuticals, stated, "The FDA’s authorization of patient enrollment in our TSC Glioblastoma (GBM) Phase 3 pivotal study marks a major milestone, and the Agency’s agreement with our focus on inoperable GBM patients allows a greatly improved trial design. Because the inoperable GBM patients treated with TSC in the Phase 2 study showed a remarkable four-fold increase in overall survival at two years, the approved trial design can enroll fewer patients than the previous Phase 3 design and have a greater chance of reaching its overall survival endpoint. The thousands of patients diagnosed with inoperable GBM who are currently excluded from participation in most newly-diagnosed GBM clinical trials can now have renewed hope, with a novel treatment being developed specifically for them, to be used in conjunction with their standard of care radiation and chemotherapy treatments. We are ready to begin our GBM trial with a highly-regarded CRO engaged, sites identified and enough drug product on hand to conduct the entire trial. We are currently working with the sites’ Institutional Review Boards and remain on track to begin enrolling patients by the end of 2017."

"In an effort to bring the Company into compliance with Nasdaq’s listing requirements, our shareholders voted to modify the terms of our Series A Convertible Preferred Stock to allow dividends to be paid in either cash or common stock, thus allowing the common stock purchase warrants issued with our Series A Convertible Preferred Stock to be classified, for accounting purposes, as permanent equity rather than as a liability. We believe this change, which occurred subsequent to the close of the quarter, brings us into compliance with Nasdaq’s $2.5 million stockholders’ equity requirement. We are now awaiting confirmation from Nasdaq that we have demonstrated compliance with all applicable requirements for continued listing. This modification also permits additional financial flexibility as we advance our programs."

Mr. Kalergis continued, "We’ve also made important additions to our board and management during the third quarter. Robert Ruffolo, Jr. joined our board of directors, bringing comprehensive pharmaceutical industry experience and drug development knowledge, honed at Wyeth (now Pfizer) and SmithKline Beecham (now GlaxoSmithKline). William Hornung joined us as Chief Business Officer, with more than 20 years of finance and operations leadership experience in the biopharmaceutical industry with such companies as PTC Therapeutics, Elan Pharmaceuticals, The Liposome Company and Contravir Pharmaceuticals. Bill has already had a positive impact on our business development activities."

Recent Highlights

Research and Development

●
Diffusion received final protocol guidance from the U.S. Food and Drug Administration ("FDA") for the Phase 3 trial with its lead compound trans sodium crocetinate ("TSC") in patients newly diagnosed with inoperable glioblastoma multiforme ("GBM"), a type of brain cancer.

●
Diffusion selected the first 17 clinical trial sites in the U.S. under one Institutional Review Board, with 100 sites planned for the Phase 3 GBM trial. We anticipate our first patient dosing for the Phase 3 GBM before the end of 2017.

●
We engaged a contract research organization and completed a major TSC production run, providing sufficient Phase 3 drug product to conduct the entire trial.

Key Personnel and Other

●
Appointed Robert Ruffolo, Jr. Ph.D. to the Company’s Board of Directors.

●
Named William "Bill" Hornung as the Company’s Chief Business Officer, a new position.

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In an effort to regain Company compliance with Nasdaq’s stockholders’ equity requirement, obtained shareholder approval to amend a provision of our Certificate of Incorporation relating to the Series A convertible preferred stock, enabling the Company to revalue and re-classify Series A warrants from liabilities to stockholders’ equity.

●
Participated in multiple investor conferences to present the Company’s business and interface with the investment community.

Financial Results for the Three Months Ended September 30, 2017

We had cash, cash equivalents and a certificate of deposit totaling $11.2 million as of September 30, 2017.

We recognized $1.8 million in research and development expenses during the three months ended September 30, 2017 compared to $1.9 million during the three months ended September 30, 2016. The decrease in research and development expense was attributable to a $1.0 million non-cash impairment charge recognized in the third quarter of 2016, a $0.2 million decrease in expense associated with animal toxicology studies and a $0.1 million decrease in stock-based compensation expense. These amounts were partially offset by a $0.9 million increase in costs associated with our GBM trials, a $0.1 million increase in API and drug manufacturing costs and a $0.1 million increase in salary related expenses.

General and administrative expenses were $1.6 million during the three months ended September 30, 2017 compared to $3.9 million during the three months ended September 30, 2016. The decrease in general and administrative expense was primarily due to a $2.5 million decrease in non-cash litigation settlement fees, partially offset by an increase in salary and stock-based compensation expense of $0.1 million and an increase in professional fees of $0.1 million.

In connection with the private placement of our Series A convertible preferred stock and common stock warrants, we determined the warrants to be classified as liabilities and subject to remeasurement at each reporting period. As a result of the liability classification, during the three months ended September 30, 2017, we recorded a $8.4 million non-cash gain for the change in fair value of our common stock warrant liabilities which was primarily attributable to the decrease in the market price for our common stock.

As noted above, at a Special Stockholders meeting held on November 1, 2017, holders of both our common stock and Series A convertible preferred stock approved an amendment to our Certificate of Incorporation to permit us to pay dividends on the Series A convertible preferred stock in either cash or shares of our common stock, rather than just shares. This amendment allowed us to revalue our Series A warrant liability on November 1, 2017 and reclassify the liability, for accounting purposes, to stockholders’ equity. As a result of the non-cash gain relating to the change in fair value of the warrant liabilities referred to above, we believe that this Certificate of Incorporation amendment will allow us to maintain our Nasdaq compliant status with respect to stockholders’ equity for the foreseeable future. See Note 12 of our unaudited condensed consolidated financial statements filed in Form 10-Q as of September 30, 2017 for further details.