On January 24, 2020 CStone Pharmaceuticals ("CStone" or the "Company", HKEX: 2616) reported that it has dosed the first patient in Australia in a clinical trial of CS1001, an investigational PD-L1 inhibitor developed by CStone, in combination with regorafenib, an oral multi-kinase inhibitor developed by Bayer Healthcare LLC ("Bayer") (Press release, CStone Pharmaceauticals, JAN 24, 2020, View Source [SID1234553543]). This is the first global proof-of-concept study carried out as a collaboration between CStone and Bayer. It is designed to assess the safety, tolerability, pharmacokinetics, and antitumor activity of the CS1001 plus regorafenib combination in patients with advanced solid tumors including gastric cancer, and to determine the recommended dose for subsequent studies.

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CS1001 is an investigational anti-PD-L1 monoclonal antibody discovered by CStone. The drug candidate is being investigated in a number of clinical trials, including one Phase I bridging study in the U.S., one multi-arm Phase Ib study, two Phase II registrational studies and four Phase III studies in China for several tumor types. The Phase Ia/Ib results released at the 2019 Chinese Society of Clinical Oncology (CSCO) Annual Meeting have shown CS1001 to be well tolerated with promising antitumor activities across multiple cancers.

Developed by Bayer, regorafenib is an oral multi-kinase inhibitor that potently blocks protein kinases including VEGFR, FGFR, and CSF1R. Regorafenib has been approved in more than 90 countries, including China, for the second- or later-line treatment of patients with metastatic colorectal cancer, metastatic gastrointestinal stromal tumors, and advanced hepatocellular carcinoma.

In May 2019, CStone and Bayer entered into a global clinical collaboration in which CStone will sponsor clinical studies of the CS1001 in combination with regorafenib. Bayer will provide regorafenib for CStone-sponsored studies.

There is a large body of evidence demonstrating the clinical benefits of monotherapy with kinase inhibitor or anti-PD-1/L1 antibody in multiple malignancies. Preclinical studies revealed that targeted therapies such as regorafenib could bolster the efficacy of immune checkpoint inhibitors in select solid tumors through modulating the tumor immune microenvironment, implicating possible synergistic antitumor effects between the two mechanisms of action.

"Our collaboration with Bayer in this clinical program marks an important milestone in the implementation of CStone’s global strategy I am very pleased that the first patient has been dosed in this combination study.," said Dr. Frank Jiang, Chairman and CEO of CStone. "We hope this clinical program will strengthen CStone’s pipeline, and above all demonstrate the utility of this combination in improving the clinical outcomes for cancer patients who lack effective treatments."

"Preclinical studies in animal models have shown enhanced antitumor activity by the CS1001 plus regorafenib combination, lending evidential support to the design of this proof-of-concept study. In addition, a range of global studies of similar immuno-combination therapies have generated promising results in advanced or metastatic solid tumors," said Dr. Archie Tse, Chief Translational Medicine Officer at CStone. "We hope results from this trial will further validate the combination of multi-kinase inhibitors and immunotherapy in select tumors."

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 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.

Regorafenib is approved under the brand name Stivarga in more than 90 countries worldwide, including the U.S., countries of the EU, China and Japan for the treatment of metastatic colorectal cancer (mCRC) and metastatic gastrointestinal stromal tumors (GIST) and second-line treatment of advanced hepatocellular (HCC).

About CS1001

CS1001 is an investigational monoclonal antibody directed against PD-L1 being developed by CStone. Authorized by the U.S. based Ligand Corporation, CS1001 is developed by the OMT transgenic animal platform, which can generate fully human antibodies in one step. As a fully human, full-length anti-PD-L1 monoclonal antibody, CS1001 mirrors natural G-type immune globulin 4 (IgG4) human antibody, which can reduce the risk of immunogenicity and potential toxicities in patients, potentially representing a unique advantage over similar drugs.

CS1001 has completed a Phase I dose-escalation study in China, in which CS1001 showed good tolerability and produced sustained clinical benefits during the Phase Ia stage of the study.

CS1001 is being investigated in a number of ongoing clinical trials, including one Phase I bridging study in the U.S., one multi-arm Phase Ib study, two Phase II registrational studies and four Phase III studies in China for several tumor types.

On January 24, 2020 BERG, a biopharmaceutical company that merges biology with technology to map and identify drivers of diseases, reported the presentation of initial results from a Phase 2 clinical trial at the Gastrointestinal Cancer Symposium (ASCO-GI), being held in San Francisco from January 23 – 25, 2020 (Press release, Berg, JAN 24, 2020, View Source [SID1234553542]). The presentation provides details on the analysis of a Phase 2 clinical trial using BPM31510 in Pancreatic Ductal Adenocarcinoma (PDAC) refractory to current standard of care. Initial results demonstrated preliminary efficacy in patient’s refractory to chemotherapy regimens and identification of potential biomarkers of survival guided by the use of the BERG Interrogative Biology platform.

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"Interrogative Biology has enabled BERG to unravel unique insight into interconnected pathways that drive cancer by mapping the nature of disease biology through patient data and Bayesian AI," said Dr. Niven R. Narain, BERG Co-founder, President and Chief Executive Officer. "The research presented this week at ASCO (Free ASCO Whitepaper)-GI further demonstrates how the BERG platform can enhance and improve development of treatments for pancreatic cancer through discovery and validation of biomarkers to improve patient outcomes."

"Pancreatic cancer has continually remained elusive to successful development of novel therapeutic compounds. The observation of an efficacy signal and the parallel use of BERG’s platform to identify biomarkers predictive of response significantly increases chances of successful development of BPM31510," said Dr. Madappa Kundranda, Director Gastrointestinal Cancer Program, Banner MD Anderson Cancer Center, AZ and Principal Investigator at his clinical trial site.

For this trial, BERG has collaborated with leading institutions such as Banner MD Anderson, Gilbert, AZ; Bart’s Cancer Institute, Queen Mary University of London, UK; Medical College of Wisconsin, Milwaukee, WI; Mary Crowley Cancer Center, Dallas, TX; Beth Israel Medical Center/Harvard Medical School, Boston, MA, Royal Free London, UK; Mayo Clinic, Phoenix, AZ; Atlantic Health Systems, Morristown, NJ; Global Cancer Research Institute, San Jose, CA; Sarcoma Cancer Center, Santa Monica, CA; and Vita Medical Associates Bethlehem, PA. BERG is grateful to its patients and family partners and their participation in these critical efforts to improve patient care.

Details of the data presentations include:
Abstract Submission ID: 284735
Abstract Number: 723
Poster Board: L12

Abstract Title: Phase II trial of BPM31510-IV plus gemcitabine in advanced pancreatic ductal adenocarcinomas (PDAC).
Session Information:
Poster Session B: Hepatobiliary Cancer, Neuroendocrine/Carcinoid, Pancreatic Cancer, and Small Bowel Cancer
Session Date & Time:
1/24/2020, 12:00 PM-1:30 PM; 4:30 PM-5:30 PM

On January 24, 2020 Onco360, the nation’s largest independent Oncology Pharmacy,reported that it has been selected by Epizyme to be the exclusive specialty pharmacy partner for TAZVERIK (Tazemetostat), a new oral treatment for adult and pediatric patients (aged 16 years and older) with metastatic or locally advanced epithelioid sarcoma not eligible for complete resection (Press release, Onco360, JAN 24, 2020, View Source [SID1234553539]).

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"The approval of TAZVERIK as a first-line therapy option for patients with unresectable metastatic or locally advanced epithelioid sarcoma is an important advancement in fighting this devastating disease"

"The approval of TAZVERIK as a first-line therapy option for patients with unresectable metastatic or locally advanced epithelioid sarcoma is an important advancement in fighting this devastating disease," said Paul Jardina, President and CEO, Onco360. "As a specialty pharmacy dedicated to serving people with cancer, Onco360 is honored to be selected as the exclusive specialty pharmacy partner for TAZVERIK. We are committed to improving the lives of patients suffering from epithelioid sarcoma."

Epithelioid sarcoma is a rare, slow-growing subtype of soft tissue sarcoma which occurs primarily in young adults. According to the National Comprehensive Cancer Network Guidelines, approximately 13,000 patients are diagnosed with soft tissue sarcomas annually, with a corresponding 5,100 deaths. Epithelioid sarcoma is believed to represent 1% of all soft tissue sarcoma diagnoses. Five-year overall survival ranges from 25-60% dependent upon tumor stage upon initial diagnosis. Greater than 90% of epithelioid sarcoma patients are found to have a genetic mutation, known as loss of INI-1 function, rendering them amenable to treatment with TAZVERIK, a novel EZH2 inhibitor.

TAZVERIK is manufactured by Epizyme, a global, commercial-stage, research-based biotechnology company, and was approved by the U.S. Food and Drug Administration (FDA) to treat adult and pediatric patients (aged 16 years and older) with metastatic or locally advanced epithelioid sarcoma not eligible for complete resection. The FDA’s approval of TAZVERIK is based on the results of an open-label, single-arm cohort of patients from the Phase II EZH-202 clinical trial (NCT02601950), which demonstrated a 15% overall rate of response. Prior to the approval of TAZVERIK, there were no medications that were specifically FDA-approved for the treatment of patients with epithelioid sarcoma. For full prescribing information, visit TAZVERIK .com.

On January 24, 2020 Exelixis, Inc. (NASDAQ: EXEL) reported phase 1/2 clinical trial results from the combination of cabozantinib (CABOMETYX) and nivolumab (Opdivo) with or without ipilimumab (Yervoy) in advanced hepatocellular carcinoma (HCC) (Press release, Exelixis, JAN 24, 2020, View Source [SID1234553537]). Data from the cabozantinib combination cohort of the CheckMate 040 trial will be presented on Friday, January 24 during Rapid Abstract Session B from 7:00 – 7:45 a.m. PT at the 2020 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper)’s Gastrointestinal Cancers Symposium (ASCO GI), which is being held in San Francisco, California, January 23-25, 2020. The data will also be included in Poster Session B from 12:00 – 1:30 p.m. PT and 4:30 – 5:30 p.m. PT on January 24.

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CheckMate 040 is a phase 1/2 study that includes an exploratory cohort of patients with advanced HCC who were either treatment naïve (41%) or who were intolerant to or had progressed on prior sorafenib therapy (59%). For the 36 patients treated with the combination of cabozantinib and nivolumab (17 treatment naïve [47%] and 19 with prior sorafenib therapy [53%]), the investigator-assessed objective response rate (ORR) was 19%, and disease control rate (DCR) was 75%. Median progression-free survival (PFS) was 5.4 months, and median overall survival was 21.5 months. For the 35 patients treated with the combination of cabozantinib, nivolumab and ipilimumab (12 treatment naïve [34%] and 23 with prior sorafenib therapy [66%]), the investigator-assessed ORR was 29%, and DCR was 83%. Median PFS was 6.8 months, and median overall survival had not yet been reached.

"We are pleased to report clinically meaningful responses from CheckMate 040 cohort 6 in advanced liver cancer patients treated with these cabozantinib combinations," said Thomas Yau, M.D., Clinical Associate Professor, Department of Medicine, The University of Hong Kong, and a lead investigator of the trial. "Patients with advanced liver cancer need new and effective treatment options. Based on the cohort six findings, cabozantinib in combination with immunotherapy offers a potentially powerful and attractive new treatment approach that warrants further study in advanced liver cancer populations."

No new safety signals were identified in this combination cohort. Treatment-related grade 3 or 4 adverse events were observed in 47% of the cabozantinib and nivolumab group; events occurring in more than 5% of patients were hypertension (11%), diarrhea (11%), aspartate aminotransferase (AST) increase (8%) and lipase increase (6%). Treatment-related grade 3 or 4 adverse events were observed in 71% of the cabozantinib, nivolumab and ipilimumab group; events occurring in more than 5% of patients were AST increase (23%), lipase increase (17%), ALT increase (17%), hypertension (17%) and palmar-plantar erythrodysaesthesia (9%). Discontinuation rates due to treatment-related adverse events were 11% for the cabozantinib and nivolumab group and 20% for the cabozantinib, nivolumab and ipilimumab group.

"As we just marked one year since CABOMETYX was approved for the treatment of patients with advanced hepatocellular cancer who have previously received sorafenib, it’s exciting to be sharing new data featuring cabozantinib as part of a combination with immunotherapies," said Gisela Schwab, M.D., President, Product Development and Medical Affairs and Chief Medical Officer, Exelixis. "The promising clinical activity observed for these cohorts in CheckMate 040 suggests combination therapy with cabozantinib and immunotherapy may potentially benefit patients with this aggressive disease."

More information about this trial is available at ClinicalTrials.gov.

About CheckMate 040

CheckMate 040 is a phase 1/2, open-label trial investigating nivolumab or nivolumab-based combinations in patients with advanced HCC with and without chronic viral hepatitis who are naïve, intolerant to or who have progressed during sorafenib therapy. Patients in the cabozantinib combination cohort were randomized 1:1 to receive either nivolumab plus cabozantinib or nivolumab plus cabozantinib and ipilimumab. Primary endpoints include ORR (investigator assessed using RECIST v1.1) and safety/tolerability. The trial is sponsored by Bristol-Myers Squibb. Exelixis is co-funding the trial and providing cabozantinib. Ipsen has opted in to participate in the trial and is contributing to the funding for this study under the terms of our collaboration agreement.

About HCC

Liver cancer is a leading cause of cancer death worldwide, accounting for more than 700,000 deaths and 800,000 new cases each year.1 In the U.S., the incidence of liver cancer has more than tripled since 1980.2 HCC is the most common form of liver cancer, making up about three-fourths of the estimated 43,000 new cases in the U.S. in 2020.2 HCC is the fastest-rising cause of cancer-related death in the U.S.3 Without treatment, patients with advanced HCC usually survive less than 6 months.4

About CABOMETYX (cabozantinib)

In the U.S., CABOMETYX tablets are approved for the treatment of patients with advanced RCC and for the treatment of patients with HCC who have been previously treated with sorafenib. CABOMETYX tablets have also received regulatory approvals in the European Union and additional countries and regions worldwide. In 2016, Exelixis granted Ipsen exclusive rights for the commercialization and further clinical development of cabozantinib outside of the United States and Japan. In 2017, Exelixis granted exclusive rights to Takeda Pharmaceutical Company Limited for the commercialization and further clinical development of cabozantinib for all future indications in Japan.

Please see Important Safety Information below and full U.S. prescribing information at View Source

U.S. Important Safety Information

Hemorrhage: Severe and fatal hemorrhages occurred with CABOMETYX. The incidence of Grade 3 to 5 hemorrhagic events was 5% in CABOMETYX patients. Discontinue CABOMETYX for Grade 3 or 4 hemorrhage. Do not administer CABOMETYX to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.
Perforations and Fistulas: Gastrointestinal (GI) perforations, including fatal cases, occurred in 1% of CABOMETYX patients. Fistulas, including fatal cases, occurred in 1% of CABOMETYX patients. Monitor patients for signs and symptoms of perforations and fistulas, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a fistula that cannot be appropriately managed or a GI perforation.
Thrombotic Events: CABOMETYX increased the risk of thrombotic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism in 2% of CABOMETYX patients. Fatal thrombotic events occurred in CABOMETYX patients. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic event requiring medical intervention.
Hypertension and Hypertensive Crisis: CABOMETYX can cause hypertension, including hypertensive crisis. Hypertension occurred in 36% (17% Grade 3 and <1% Grade 4) of CABOMETYX patients. Do not initiate CABOMETYX in patients with uncontrolled hypertension. Monitor blood pressure regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume at a reduced dose. Discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis.
Diarrhea: Diarrhea occurred in 63% of CABOMETYX patients. Grade 3 diarrhea occurred in 11% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 diarrhea, Grade 3 diarrhea that cannot be managed with standard antidiarrheal treatments, or Grade 4 diarrhea.
Palmar-Plantar Erythrodysesthesia (PPE): PPE occurred in 44% of CABOMETYX patients. Grade 3 PPE occurred in 13% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.
Proteinuria: Proteinuria occurred in 7% of CABOMETYX patients. Monitor urine protein regularly during CABOMETYX treatment. Discontinue CABOMETYX in patients who develop nephrotic syndrome.
Osteonecrosis of the Jaw (ONJ): ONJ occurred in <1% of CABOMETYX patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain, or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to CABOMETYX initiation and periodically during treatment. Advise patients regarding good oral hygiene practices. Withhold CABOMETYX for at least 28 days prior to scheduled dental surgery or invasive dental procedures. Withhold CABOMETYX for development of ONJ until complete resolution.
Wound Complications: Wound complications were reported with CABOMETYX. Stop CABOMETYX at least 28 days prior to scheduled surgery. Resume CABOMETYX after surgery based on clinical judgment of adequate wound healing. Withhold CABOMETYX in patients with dehiscence or wound healing complications requiring medical intervention.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, can occur with CABOMETYX. Evaluate for RPLS in patients presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.
Embryo-Fetal Toxicity: CABOMETYX can cause fetal harm. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Verify the pregnancy status of females of reproductive potential prior to initiating CABOMETYX and advise them to use effective contraception during treatment and for 4 months after the last dose.
Adverse Reactions: The most commonly reported (≥25%) adverse reactions are: diarrhea, fatigue, decreased appetite, PPE, nausea, hypertension, and vomiting.
Strong CYP3A4 Inhibitors: If coadministration with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage. Avoid grapefruit or grapefruit juice.
Strong CYP3A4 Inducers: If coadministration with strong CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage. Avoid St. John’s wort.
Lactation: Advise women not to breastfeed during CABOMETYX treatment and for 4 months after the final dose.
Hepatic Impairment: In patients with moderate hepatic impairment, reduce the CABOMETYX dosage. CABOMETYX is not recommended for use in patients with severe hepatic impairment.

On January 24, 2020 Bellicum Pharmaceuticals, Inc. (NASDAQ:BLCM), a leader in developing novel, controllable cellular immunotherapies for cancers, reported new Phase 1 translational results for BPX-601 at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium (ASCO GI) in San Francisco (Press release, Bellicum Pharmaceuticals, JAN 24, 2020, View Source [SID1234553536]). The poster titled "Tumor Infiltration and Cytokine Biomarkers of Prostate Stem Cell Antigen (PSCA)-Directed GoCAR-T Cells in Patients with Advanced Pancreatic Tumors" presented new data from a cohort treated with BPX-601 and a single dose of rimiducid that showed immunomodulation in both the periphery and tumor microenvironment and provided additional insights into surrogate biomarkers of iMC-mediated GoCAR-T activity.

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"These translational results further support the potential for BPX-601 and for our GoCAR platform in solid tumors," stated Rick Fair, President and Chief Executive Officer, Bellicum Pharmaceuticals. "We are particularly encouraged by the findings of tumor infiltration and GoCAR-T mediated immunomodulation. We will look to build on these markers of activity in the next cohort of the study, which will evaluate repeat rimiducid dosing to reactivate BPX-601 cells over time. Initial results from this Cohort 5C are expected during the second half of this year."

The poster at ASCO (Free ASCO Whitepaper) GI presented data from Cohort 5B of the study, consisting of 5 pancreatic cancer patients treated with BPX-601 and a single dose of rimiducid. The primary observations were:

BPX-601 GoCAR-T cells exhibited enhanced survival and persistence up to 9 months.
Activation of BPX-601 GoCAR-T cells mediated upregulation of immunomodulatory cytokines in patients.
BPX-601 GoCAR-T cells infiltrated metastatic pancreatic tumors.
Changes in tumor microenvironment gene expression consistent with a productive CAR-T cell immune response were observed in patients treated with BPX-601 GoCAR-T cells activated by rimiducid.
Interim clinical results from the trial—including results from cohort 5B—were reported at ASCO (Free ASCO Whitepaper) on June 1, 2019 and may be found on the Bellicum website under Scientific Publications.

About BPX-601

BPX-601, the company’s first GoCAR-T product candidate, incorporates iMC, Bellicum’s inducible co-activation domain. iMC (inducible MyD88/CD40) is designed to provide a powerful boost to T cell proliferation and persistence, production of immunomodulatory cytokines and enable the CAR-T to override key immune inhibitory mechanisms, including PD-1 and TGF-beta. BPX-601 is being evaluated as a treatment for pancreatic tumors expressing prostate stem cell antigen (PSCA).