On January 20, 2017 FibroGen, Inc. (Nasdaq:FGEN) reported that updated results from an ongoing clinical study of pamrevlumab (FG-3019) in combination with standard-of-care chemotherapy in patients with locally advanced pancreatic ductal adenocarcinoma (PDAC) were presented in a poster session during the ASCO (Free ASCO Whitepaper) 2017 Gastrointestinal Cancers Symposium in San Francisco (Press release, FibroGen, JAN 20, 2017, View Source;p=IROL-news&nyo=0 [SID1234517531]). Pamrevlumab is a fully human monoclonal therapeutic antibody that inhibits connective tissue growth factor (CTGF), a common factor in chronic fibrotic and proliferative disorders.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"I am very encouraged by these additional results from this clinical trial of pamrevlumab evaluated in combination with standard-of-care chemotherapy in patients with locally advanced pancreatic ductal adenocarcinoma," said Vincent J. Picozzi, Jr., M.D., Director of the Pancreas Center, Virginia Mason Hospital & Seattle Medical Center, and principal investigator. "Based on our participation in this trial, and a previous clinical study (FGCL- MC3019-028), I believe pamrevlumab has the potential to provide meaningful benefit for pancreatic cancer patients with locally advanced and/or metastatic disease."

Of the 33 subjects enrolled to date:

Twenty-two have been randomized to pamrevlumab plus chemotherapy, 10 remain on treatment
– Three discontinued treatment due to complications not related to pamrevlumab, and nine completed treatment
– Seven subjects who completed treatment met protocol defined criteria eligible for tumor resection and were considered operable following treatment. Three subjects had complete tumor removal (R0), and one subject had microscopic tumor remaining after surgery (R1)
Of the 11 subjects randomized to chemotherapy alone, five subjects discontinued treatment due to various reasons, and six subjects completed treatment
– Of the six subjects who received chemotherapy alone, one subject met protocol defined criteria eligible for tumor resection and had a complete tumor removal (R0)
Differences in overall survival (OS) between subjects treated with and without pamrevlumab look encouraging
There were no complications from laparoscopy or biopsies that were clinically significant or delayed dosing, and, to date, there have been no safety imbalances between treatment arms.
In this open-label, randomized study, pamrevlumab in combination with gemcitabine and nab-paclitaxel is compared to chemotherapy alone for the treatment of patients with locally advanced pancreatic ductal adenocarcinoma who have failed resection scoring and were characterized as inoperable assessed by histology, CT scans, and laparoscopy. Subjects are randomized to six cycles of chemotherapy with gemcitabine and nab-paclitaxel, with or without pamrevlumab. The study has enrolled 33 patients, and is targeted to enroll up to 42 subjects.

About Pancreatic Ductal Adenocarcinoma and Connective Tissue Growth Factor

Pancreatic ductal adenocarcinoma (PDAC), or pancreatic cancer, is the fourth leading cause of cancer deaths in the United States. According to the National Cancer Institute, in 2016, there were approximately 53,000 new cases of pancreatic cancer projected in the United States alone. Pancreatic cancer is aggressive and typically not diagnosed until it is largely incurable. Most patients are diagnosed after the age of 45, and overall five-year survival is about 7%, due to many factors, including advanced stage at diagnosis and limited response to currently available therapies (View Source). PDAC tumors often exhibit a high degree of desmoplasia, characterized by extensive connective tissue stroma and elevated levels of Connective Tissue Growth Factor (CTGF). Cancer-stroma interactions affect tumorigenesis, angiogenesis, resistance to therapy and metastatic spread of tumor cells. CTGF is overexpressed in PDAC and facilitates local desmoplasia, tumor progression and metastasis in animal models.

About Pamrevlumab

Pamrevlumab (FG-3019) is an investigational therapeutic antibody developed by FibroGen to inhibit the activity of CTGF, a common factor in chronic fibrotic and proliferative disorders characterized by persistent and excessive scarring that can lead to organ dysfunction and failure. FibroGen is currently conducting clinical studies of pamrevlumab in idiopathic pulmonary fibrosis, pancreatic cancer, and Duchenne muscular dystrophy.

In desmoplastic, or fibrotic, cancers such as pancreatic cancer, CTGF in the extensive fibrous stroma associated with the tumor promotes abnormal proliferation of stromal cells and tumor cells. Studies in a transgenic mouse model of pancreatic cancer indicate that treatment with pamrevlumab in combination with chemotherapy may enhance the efficacy of chemotherapy and improve survival.

On January 20, 2017 Bayer reported that the Japanese Ministry of Health, Labour and Welfare (MHLW) has granted priority review to Bayer Yakuhin, Ltd., Osaka, Japan, for regorafenib in the second-line treatment of patients with unresectable hepatocellular carcinoma (HCC) (Press release, , JAN 20, 2017, View Source;sessionID=1485224246 [SID1234517530]). Regorafenib was submitted for marketing approval in HCC in Japan in October 2016. The MHLW grants priority review to medicines on the basis of their clinical usefulness and severity of the disease. Regorafenib is already approved under the brand name Stivarga in many countries, including Japan, to treat metastatic colorectal cancer and unresectable and/or metastatic gastrointestinal stromal tumors.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"Liver cancer is one of the leading cancer-related causes of death in Japan. Nexavar as the first and only approved systemic treatment for HCC has been a major advance in this field, but effective second-line treatment options are urgently needed for patients", said Dr. Joerg Moeller, member of the Executive Committee of Bayer AG’s Pharmaceutical Division and Head of Development. "We welcome the priority review for regorafenib in Japan as it supports our efforts to make the compound available as early as possible in the second-line setting for HCC in Japan."

The regulatory submission for regorafenib is based on data from the international, multicenter, placebo-controlled Phase III RESORCE [REgorafenib after SORafenib in patients with hepatoCEllular carcinoma] trial. The trial investigated regorafenib in patients with unresectable hepatocellular carcinoma (HCC) whose disease had progressed during treatment with sorafenib (Nexavar) tablets. Results showed that regorafenib significantly improved overall survival (OS) compared to placebo (HR 0.63; 95% CI 0.50-0.79; p<0.001), which over the trial period represents a 37 percent reduction in the risk of death for patients who received regorafenib plus best supportive care (BSC) compared to patients treated with placebo plus BSC. The median OS was 10.6 months in patients treated with regorafenib, compared to 7.8 months in patients who received placebo plus BSC. The safety and tolerability was generally consistent with the known profile of regorafenib, with no clinically meaningful differences in health-related quality of life (HRQoL) between the regorafenib and placebo plus BSC groups. Data from the study were first presented at the 18th World Congress on Gastrointestinal Cancer (WCGC) in June 2016 and published online on December 5, 2016 in the peer-reviewed journal The Lancet.

Regorafenib has also been submitted to the regulatory authorities in the US and EU for the treatment of second-line HCC.

About the RESORCE trial
The Phase III RESORCE [REgorafenib after SORafenib in patients with hepatoCEllular carcinoma] clinical trial enrolled 573 patients whose disease had progressed during treatment with sorafenib. Patients were randomized in a 2:1 ratio to receive either regorafenib or placebo plus best supportive care.

Patients received 160 mg regorafenib once daily or placebo, for 3 weeks on/1week off, with 28 days constituting one full treatment cycle. The primary endpoint of the study was overall survival, and secondary endpoints were time to progression, progression-free survival, objective tumor response rate and disease control rate. Health-related quality of life was assessed by the FACT-Hep and EQ-5D questionnaires. Safety and tolerability were also continuously monitored.

About Hepatocellular Carcinoma
Hepatocellular carcinoma (HCC) is the most common form of liver cancer and represents approximately 70-85 percent of liver cancer worldwide. Liver cancer is the sixth most common cancer in the world and the second leading cause of cancer-related deaths globally. More than 780,000 cases of liver cancer are diagnosed worldwide each year (52,000 in the European Union, 501,000 in the Western Pacific region and 30,000 in the United States) and the incidence rate is increasing. In 2012, approximately 746,000 people died of liver cancer including approximately 48,000 in the European Union, 477,000 in the Western Pacific region and 24,000 in the United States.

About Regorafenib (Stivarga)
Regorafenib is an oral multi-kinase inhibitor that potently blocks multiple protein kinases involved in tumor angiogenesis (VEGFR1, -2, -3, TIE2), oncogenesis (KIT, RET, RAF-1, BRAF), metastasis (VEGFR3, PDGFR, FGFR) and tumor immunity (CSF1R).

Regorafenib is approved under the brand name Stivarga in more than 90 countries worldwide, including the U.S., countries of the EU and Japan for the treatment of metastatic colorectal cancer (mCRC). The product is also approved in over 80 countries, including the U.S., countries of the EU and Japan, for the treatment of metastatic gastrointestinal stromal tumors (GIST). In the EU, Stivarga is indicated for the treatment of adult patients with mCRC who have been previously treated with, or are not considered candidates for, available therapies including fluoropyrimidine-based chemotherapy, an anti-VEGF therapy and an anti-EGFR therapy, as well as for the treatment of adult patients with unresectable or metastatic GIST who progressed on or are intolerant to prior treatment with imatinib and sunitinib.

Regorafenib is a compound developed by Bayer. In 2011, Bayer entered into an agreement with Onyx, now an Amgen subsidiary, under which Onyx receives a royalty on all global net sales of regorafenib in oncology.

On January. 20, 2017 Mateon Therapeutics, Inc. (OTCQX:MATN), a biopharmaceutical company developing vascular disrupting agents (VDAs) for the treatment of orphan oncology indications, reported the presentation of final data from Study OX4218 in patients with neuroendocrine tumors (NETs) at a poster session at the ASCO (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium being held today in San Francisco.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Study OX4218 was a multi-center, open label, phase 2 clinical trial to investigate the safety and activity of combretastatin A4-phosphate (CA4P) in the treatment of well-differentiated, low-to-intermediate-grade unresectable, recurrent or metastatic pancreatic or gastrointestinal neuroendocrine tumors/carcinoid (PNETs or GI-NETs) with elevated biomarkers. Following patients’ completion of Study OX4218, patients were eligible to enroll in Study OX4219, a long term extension study, if they achieved a biomarker or symptom response. In OX4218 patients were treated with CA4P 60 mg/m2 on Days 1, 8, and 15 of a 21-day cycle for 3 cycles, and in OX4219 patients received CA4P maintenance on Day 1 of a 21-day cycle until disease progression or up to one year.

A total of 18 patients were enrolled in OX4218. One patient (6%) experienced significant symptomatic improvement as measured by ECOG Status and had a partial response per investigator-assessed RECIST and an additional 7 patients (39%) had stable disease. In addition, a majority of patients (53%) experienced an improvement in patient-reported quality of life. A statistically significant mean change in biomarkers from baseline, the primary endpoint of the study, was not achieved in OX4218 due to the small sample size along with a high intra- and inter-patient variability observed in the biomarkers. A total of 7 patients were enrolled in OX4219, of which 5 patients (71%) had stable disease, including one that continued for 14 months. The partial response and stable disease analyses, as well as other measures from the trial, suggest that CA4P monotherapy has activity in this indication.

"The results of OX4218 and OX4219 confirm that CA4P monotherapy has efficacy in the indications studied, as we have seen with the investigational drug in a number of other monotherapy trials," said William D. Schwieterman, M.D., President and Chief Executive Officer of Mateon. "However, we believe that the efficacy of CA4P only becomes compelling when it is used in combination with an anti-angiogenic agent, due to the complementary mechanisms of action for the two agents. Based on the evidence of efficacy observed in this trial, plus an understanding of the benefits of combination therapy, a lead investigator in this trial is sponsoring a 20 patient study in NETs using CA4P in combination with everolimus (AFINITOR, marketed by Novartis), an anti-angiogenic agent which is already approved and commonly used in this indication."

Overall CA4P monotherapy was well tolerated. Treatment related adverse events were reported in 77% of subjects. The most common Grade 3-5 AEs ( > 10%) included: anemia, abdominal pain, fatigue, hypertension, and ALT and AST increases. One Grade 5 adverse event, carcinoid syndrome, was reported and attributed to the underlying disease.

On January 20, 2017 Merck (NYSE:MRK), known as MSD outside the United States and Canada), and certain of its affiliates, reported it agreed to enter into a settlement and license agreement with Bristol-Myers Squibb Company and Ono Pharmaceutical Co., Ltd., resolving the worldwide patent infringement litigation related to the use of an anti-PD-1 antibody for the treatment of cancer, such as KEYTRUDA (pembrolizumab) (Press release, Merck & Co, JAN 20, 2017, View Source [SID1234517483]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Under the settlement and license agreement, the company will make a one-time payment of $625 million to Bristol-Myers Squibb and provide royalties on the worldwide sales of KEYTRUDA for a non-exclusive license to market KEYTRUDA in any market in which it is approved. For global net sales of KEYTRUDA, the company will pay Bristol-Myers Squibb royalties as follows:

6.5 percent of net sales occurring from Jan. 1, 2017 through and including Dec. 31, 2023; and
2.5 percent of net sales occurring Jan. 1, 2024 through and including Dec. 31, 2026.
The parties also agreed to dismiss all claims in the relevant legal proceedings.

"Today’s announcement eliminates uncertainty and enables us to continue to focus on KEYTRUDA, our immuno-oncology medicine, which is already helping thousands of patients around the world and becoming a foundation for the treatment of cancer through our industry-leading clinical development program," said Kenneth C. Frazier, chairman and chief executive officer, Merck.

The $625 million payment will be recorded in the company’s fourth-quarter and full-year 2016 results. This expense will be excluded from Merck’s non-GAAP results.

On January 20, 2017 Today, during a plenary session at the Keystone Symposia Conference, "PI3K Pathways in Immunology, Growth Disorders and Cancer," Infinity Pharmaceuticals, Inc. (NASDAQ: INFI) reportted preclinical data for IPI-549, an oral immuno-oncology development candidate that selectively inhibits phosphoinositide-3-kinase-gamma (PI3K-gamma) (Press release, Infinity Pharmaceuticals, JAN 20, 2017, View Source;p=RssLanding&cat=news&id=2238789 [SID1234517482]). Preclinical data showed that IPI-549 is able to help overcome resistance to checkpoint inhibition by remodeling the immune-suppressive tumor microenvironment primarily through its effects on myeloid cells, a type of cell considered to be involved in suppressing immune response against tumors. Initial Phase 1 monotherapy data from nine patients with advanced solid tumors were also summarized and showed that the safety, pharmacokinetics and pharmacodynamics of IPI-549 monotherapy treatment appeared favorable. IPI-549 is believed to be the only PI3K-gamma inhibitor in clinical development.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

These preclinical data provide a compelling rationale for Infinity’s ongoing Phase 1 clinical study designed to evaluate IPI-549 as a monotherapy and in combination with Opdivo (nivolumab), a PD-1 immune checkpoint inhibitor, in patients with advanced solid tumors. The combination portion of the Phase 1 study will include patients with non-small cell lung cancer (NSCLC), melanoma, and squamous cell carcinoma of the head and neck (SCCHN) whose tumors show initial resistance or subsequently develop resistance to immune checkpoint therapy. There is a great need for additional treatment options for the growing number of patients living with these cancers, which account for more than 17 percent of all new cancer cases in the U.S.1,2

"While new immunotherapies, such as T cell checkpoint inhibitors, are showing great promise in the treatment of various cancers, there are multiple mechanisms of immune tolerance in tumors. Additional treatment options are needed for patients who relapse or do not respond to currently available therapies," stated Jeffery Kutok, M.D., Ph.D., vice president of biology and translational science at Infinity Pharmaceuticals and a plenary speaker at the conference. "The data presented suggest that targeting PI3K-gamma by IPI-549 within immune-suppressive myeloid cells in the tumor microenvironment could offer a unique way to both enhance the activity of checkpoint inhibition in sensitive tumors, as well as to overcome tumor resistance to checkpoint inhibition. Infinity is excited to be at the forefront of developing a potentially transformative approach within immuno-oncology, and we look forward to reporting additional data from our Phase 1 study of IPI-549 later this year."

The tumor microenvironment, or TME, refers to the non-cancerous cells present in the tumor. Cells within the TME, including immune-suppressive myeloid cells, can provide growth signals to tumor cells, as well as signals that inhibit an anti-tumor immune response. The presence of the supportive TME is believed to be one reason why some cancer therapies do not provide durable or effective results. Targeting the immune-suppressive myeloid cells represents an emerging approach within the field of cancer immunotherapy, and inhibition of PI3K-gamma represents a novel approach to targeting the immune-suppressive microenvironment.

Summary of Today’s Presentation
In a presentation entitled "The PI3K-gamma inhibitor, IPI-549, increases antitumor immunity by targeting tumor-associated myeloid cells and overcomes immune checkpoint blockade resistance in preclinical models," Dr. Kutok reviewed data previously published in two Nature articles3,4 and presented at the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference (CIMT) (Free CIMT Whitepaper).5,6

Preclinical data showed that macrophage PI3K-gamma signaling promotes immune suppression by inhibiting activation of anti-tumor T cells. Blocking PI3K-gamma activated the immune response and significantly suppressed growth of tumors in preclinical models. These data demonstrate that PI3K-gamma plays a key role in cancer growth and also help to further elucidate the mechanism of action for IPI-549.

Preclinical data also demonstrated that resistance to immune checkpoint blockade is directly mediated by the suppressive activity of tumor-infiltrating myeloid cells in a number of preclinical tumor models and confirmed that immune-suppressive myeloid cells play a critical role in resistance to checkpoint inhibitors. Furthermore, the data showed that inhibition of PI3K-gamma by IPI-549 switched the activation of myeloid cells from an immune-suppressive state to a pro-inflammatory state, leading to enhanced anti-tumor cytotoxic T cell activity, particularly when combined with checkpoint inhibitors. Thus, in preclinical models, IPI-549 treatment is able to overcome resistance to checkpoint inhibition. These findings provide further rationale for the ongoing Phase 1 study of IPI-549 in combination with checkpoint inhibitors.

Phase 1 clinical data from nine patients treated with IPI-549 administered as a monotherapy at doses ranging from 10 mg once daily (QD) to 20 mg QD were also summarized during the presentation. As of the September 2016 data cutoff, no dose limiting toxicities and no serious adverse events were observed. Pharmacokinetic and pharmacodynamic data supported once daily dosing of IPI-549 based on the observed half-life and inhibition of the PI3K-gamma pathway.

About the IPI-549 Phase 1 Study
The ongoing Phase 1 clinical study of IPI-549 is designed to explore the activity, safety, tolerability, pharmacokinetics and pharmacodynamics of IPI-549 as a monotherapy and in combination with Opdivo in patients with advanced solid tumors. The study includes monotherapy and combination dose-escalation phases, in addition to expansion cohorts, and is expected to enroll approximately 175 patients.

The IPI-549 monotherapy dose-escalation phase is expected to be completed in the first half of 2017, and the monotherapy expansion phase in patients with advanced solid tumors is anticipated to begin in the second half of the year. Once the dose-escalation phase evaluating IPI-549 plus Opdivo is completed, an expansion phase is planned to evaluate the combination in patients with select solid tumors, including non-small cell lung cancer (NSCLC), melanoma and squamous cell carcinoma of the head and neck (SCCHN). Patients enrolled in expansion cohorts evaluating IPI-549 plus Opdivo represent a difficult-to-treat population, as they must have demonstrated initial resistance or subsequently develop resistance to a PD-1 or PD-L1 therapy immediately prior to enrolling in the study.

About IPI-549
IPI-549 is an investigational, orally administered immuno-oncology development candidate that selectively inhibits PI3K-gamma. In preclinical studies, IPI-549 increases antitumor immunity by targeting tumor-associated myeloid cells and overcomes immune checkpoint blockade resistance in preclinical tumor models. As such, IPI-549 may have the potential to treat a broad range of solid tumors and represents a potentially complementary approach to restoring anti-tumor immunity in combination with other immunotherapies such as checkpoint inhibitors. A Phase 1 study of IPI-549 in patients with advanced solid tumors is ongoing.7

IPI-549 is an investigational compound and its safety and efficacy has not been evaluated by the U.S. Food and Drug Administration or any other health authority.