On September 21, 2018 Takeda Pharmaceutical Company Limited (TSE: 4502) reported that the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion, recommending the full approval of ALUNBRIG (brigatinib) as a monotherapy for the treatment of adult patients with anaplastic lymphoma kinase-positive (ALK+) advanced non-small cell lung cancer (NSCLC) previously treated with crizotinib (Press release, Takeda SEP 21, 2018, View Source [SID1234529516]). ALUNBRIG is a tyrosine kinase inhibitor (TKI) designed to target and inhibit the ALK mutation in NSCLC. Approximately three to five percent of NSCLC patients globally have the ALK mutation. If the CHMP opinion is affirmed, and the European Commission approves ALUNBRIG, it will become the only ALK inhibitor available in the European Union as a one tablet per day dose that can be taken with or without food.

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The randomized, global Phase 2 ALTA trial was designed to investigate the efficacy and safety of ALUNBRIG in patients with locally advanced or metastatic ALK+ NSCLC who had progressed on crizotinib. Patients were randomized to receive one of two regimens of ALUNBRIG: 90 mg of ALUNBRIG once daily (n=112) or 180 mg once daily with seven-day lead-in at 90 mg once daily (n=110).

"ALK+ NSCLC is a serious and life-threatening disease that affects approximately 40,000 people worldwide every year, and many patients will progress on or stop responding to first-line treatment," said Stefania Vallone, President, Lung Cancer Europe. "For European people with ALK+ NSCLC, there remains a significant unmet need for new and effective treatment options."

"While ALK inhibitors have demonstrated tremendous growth in this treatment space over the past decade, having an additional targeted therapy option available for the treatment of ALK+ NSCLC has been eagerly anticipated," said Enriqueta Felip, M.D., PhD, Head of the Thoracic Oncology Unit, Oncology Department at Vall d’Hebron University Hospital in Barcelona. "With a median progression-free survival of 16.7 months and overall survival of 34.1 months, ALUNBRIG has shown impressive results, representing new progress for ALK+ NSCLC treatment in this setting."

"The ALTA trial has established ALUNBRIG as a potential second-line treatment option for ALK+ NSCLC, by demonstrating significant efficacy with a manageable safety profile," said Jesús Gómez-Navarro, M.D., Vice President, Head of Oncology Clinical Research and Development, Takeda. "With 16.7 months median progression-free survival, the longest of any ALK inhibitor to be reported in this setting, ALUNBRIG offers great potential for patients who progressed on crizotinib. Today’s positive opinion brings us closer toward the ultimate goal of advancing the treatment paradigm for the considerable number of crizotinib-treated ALK+ NSCLC patients living in Europe. We look forward to the European Commission’s review of the CHMP positive opinion and introducing ALUNBRIG to patients and healthcare professionals in the European Union if approved."

As part of this submission, the CHMP also reviewed data from the first interim analysis of the Phase 3 ALTA-1L trial, which met its primary endpoint, as supportive evidence. In ALTA-1L, treatment with ALUNBRIG resulted in a statistically and clinically significant improvement in PFS versus crizotinib as assessed by a blinded independent review committee. The safety profile associated with ALUNBRIG was generally consistent with prior studies and approved U.S. and Canadian labeling.

The CHMP positive opinion for ALUNBRIG will now be reviewed by the European Commission, which has the authority to approve medicines for use in the 28 member states of the European Union, as well as Norway, Liechtenstein and Iceland.

About the ALTA Trial

The Phase 2 ALTA (ALK in Lung Cancer Trial of AP26113) trial of ALUNBRIG in adults is a global, ongoing, two-arm, open-label, multicenter trial, which enrolled 222 patients with locally advanced or metastatic ALK+ NSCLC who had progressed on crizotinib. Patients received either 90 mg of ALUNBRIG once daily (n=112) or 180 mg once daily with seven-day lead-in at 90 mg once daily regimen (n=110). Investigator-assessed confirmed objective response rate (ORR) per RECIST v1.1 was the primary endpoint. Key additional endpoints included Independent Review Committee (IRC)-assessed ORR, duration of response (DOR), progression-free survival (PFS), intracranial ORR, intracranial DOR, safety and tolerability.

Results of the ALTA trial demonstrated that of the patients who received the 180 mg dosing regimen, 56 percent achieved an ORR as assessed by investigator and 56 percent as assessed by IRC. The median DOR was 13.8 months as assessed by investigator and 15.7 months by IRC assessment. Median PFS was 15.6 months as assessed by investigator and 16.7 months by IRC assessment. Additionally, of the patients with measurable brain metastases at baseline (n=18), 67 percent achieved an intracranial ORR by IRC assessment; median duration of intracranial response was 16.6 months by IRC assessment. Median overall survival was 34.1 months as assessed by investigator.

The most common adverse reactions (≥25%) reported in patients treated with ALUNBRIG at the 180 mg dosing regimen were increased aspartate aminotransferase (AST), hyperglycemia, hyperinsulinemia, anemia, increased creatine phosphokinase (CPK), nausea, increased lipase, decreased lymphocyte count, increased alanine aminotransferase (ALT), diarrhea, increased amylase, fatigue, cough, headache, increased alkaline phosphatase, hypophosphatemia, increased abnormal activated partial thromboplastin time (APTT), rash, vomiting, dyspnea, hypertension, decreased blood cell count, myalgia, and peripheral neuropathy.

About the ALTA-1L Trial

The Phase 3 ALTA-1L (ALK in Lung Cancer Trial of BrigAtinib in 1st Line) trial of ALUNBRIG in adults is a global, ongoing, randomized, open-label, comparative, multicenter trial, which enrolled 275 patients with ALK+ locally advanced or metastatic NSCLC who have not received prior treatment with an ALK inhibitor. Patients received either ALUNBRIG, 180 mg once daily with seven-day lead-in at 90 mg once daily, or crizotinib, 250 mg twice daily. Independent Review Committee (IRC)-assessed progression-free survival (PFS) was the primary endpoint. Secondary endpoints included objective response rate (ORR) per RECIST v1.1, intracranial ORR, intracranial PFS, overall survival (OS), safety and tolerability. A total of approximately 198 PFS events are planned at the final analysis of the primary endpoint in order to demonstrate a minimum of six months PFS improvement over crizotinib. The trial is designed with two pre-specified interim analyses for the primary endpoint – one at approximately 50 percent of planned PFS events and one at approximately 75 percent of planned PFS events.

About ALK+ NSCLC

Non-small cell lung cancer (NSCLC) is the most common form of lung cancer, accounting for approximately 85 percent of the estimated 1.8 million new cases of lung cancer diagnosed each year worldwide, according to the World Health Organization. Genetic studies indicate that chromosomal rearrangements in anaplastic lymphoma kinase (ALK) are key drivers in a subset of NSCLC patients. Approximately three to five percent of patients with metastatic NSCLC have a rearrangement in the ALK gene.

Takeda is committed to continuing research and development in NSCLC to improve the lives of the approximately 40,000 patients diagnosed with this serious and rare form of lung cancer worldwide each year.

About ALUNBRIG (brigatinib)

ALUNBRIG is a targeted cancer medicine discovered by ARIAD Pharmaceuticals, Inc., which was acquired by Takeda in February 2017. In April 2017, ALUNBRIG received Accelerated Approval from the U.S. Food and Drug Administration (FDA) for ALK+ metastatic NSCLC patients who have progressed on or are intolerant to crizotinib. This indication is approved under Accelerated Approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. In July 2018, Health Canada approved ALUNBRIG for the treatment of adult patients with ALK+ metastatic NSCLC who have progressed on or who were intolerant to an ALK inhibitor (crizotinib). The FDA and Health Canada approvals of ALUNBRIG were primarily based on results from the pivotal Phase 2 ALTA (ALK in Lung Cancer Trial of AP26113) trial.

ALUNBRIG received Breakthrough Therapy Designation from the FDA for the treatment of patients with ALK+ NSCLC whose tumors are resistant to crizotinib and was granted Orphan Drug Designation by the FDA for the treatment of ALK+ NSCLC, ROS1+ and EGFR+ NSCLC.

The brigatinib clinical development program further reinforces Takeda’s ongoing commitment to developing innovative therapies for people living with ALK+ NSCLC worldwide and the healthcare professionals who treat them. The comprehensive program includes the following clinical trials:

Phase 1/2 trial, which was designed to evaluate the safety, tolerability, pharmacokinetics and preliminary anti-tumor activity of ALUNBRIG
Pivotal Phase 2 ALTA trial investigating the efficacy and safety of ALUNBRIG at two dosing regimens in patients with ALK+ locally advanced or metastatic NSCLC who had progressed on crizotinib
Phase 3 ALTA-1L, a global randomized trial assessing the efficacy and safety of ALUNBRIG in comparison to crizotinib in patients with ALK+ locally advanced or metastatic NSCLC who have not received prior treatment with an ALK inhibitor
Phase 2 single-arm, multicenter trial in Japanese patients with ALK+ NSCLC, focusing on patients who have progressed on alectinib
Phase 2 global, single arm trial evaluating ALUNBRIG in patients with advanced ALK+ NSCLC who have progressed on alectinib or ceritinib
Phase 3 global randomized trial comparing the efficacy and safety of ALUNBRIG versus alectinib in participants with ALK+ NSCLC who have progressed on crizotinib
For additional information on the brigatinib clinical trials, please visit www.clinicaltrials.gov.

IMPORTANT SAFETY INFORMATION (U.S.)

WARNINGS AND PRECAUTIONS

Interstitial Lung Disease (ILD)/Pneumonitis: Severe, life-threatening, and fatal pulmonary adverse reactions consistent with interstitial lung disease (ILD)/pneumonitis have occurred with ALUNBRIG. In Trial ALTA (ALTA), ILD/pneumonitis occurred in 3.7% of patients in the 90 mg group (90 mg once daily) and 9.1% of patients in the 90→180 mg group (180 mg once daily with 7-day lead-in at 90 mg once daily). Adverse reactions consistent with possible ILD/pneumonitis occurred early (within 9 days of initiation of ALUNBRIG; median onset was 2 days) in 6.4% of patients, with Grade 3 to 4 reactions occurring in 2.7%. Monitor for new or worsening respiratory symptoms (e.g., dyspnea, cough, etc.), particularly during the first week of initiating ALUNBRIG. Withhold ALUNBRIG in any patient with new or worsening respiratory symptoms, and promptly evaluate for ILD/pneumonitis or other causes of respiratory symptoms (e.g., pulmonary embolism, tumor progression, and infectious pneumonia). For Grade 1 or 2 ILD/pneumonitis, either resume ALUNBRIG with dose reduction after recovery to baseline or permanently discontinue ALUNBRIG. Permanently discontinue ALUNBRIG for Grade 3 or 4 ILD/pneumonitis or recurrence of Grade 1 or 2 ILD/pneumonitis.

Hypertension: In ALTA, hypertension was reported in 11% of patients in the 90 mg group who received ALUNBRIG and 21% of patients in the 90→180 mg group. Grade 3 hypertension occurred in 5.9% of patients overall. Control blood pressure prior to treatment with ALUNBRIG. Monitor blood pressure after 2 weeks and at least monthly thereafter during treatment with ALUNBRIG. Withhold ALUNBRIG for Grade 3 hypertension despite optimal antihypertensive therapy. Upon resolution or improvement to Grade 1 severity, resume ALUNBRIG at a reduced dose. Consider permanent discontinuation of treatment with ALUNBRIG for Grade 4 hypertension or recurrence of Grade 3 hypertension. Use caution when administering ALUNBRIG in combination with antihypertensive agents that cause bradycardia.

Bradycardia: Bradycardia can occur with ALUNBRIG. In ALTA, heart rates less than 50 beats per minute (bpm) occurred in 5.7% of patients in the 90 mg group and 7.6% of patients in the 90→180 mg group. Grade 2 bradycardia occurred in 1 (0.9%) patient in the 90 mg group. Monitor heart rate and blood pressure during treatment with ALUNBRIG. Monitor patients more frequently if concomitant use of drug known to cause bradycardia cannot be avoided. For symptomatic bradycardia, withhold ALUNBRIG and review concomitant medications for those known to cause bradycardia. If a concomitant medication known to cause bradycardia is identified and discontinued or dose adjusted, resume ALUNBRIG at the same dose following resolution of symptomatic bradycardia; otherwise, reduce the dose of ALUNBRIG following resolution of symptomatic bradycardia. Discontinue ALUNBRIG for life-threatening bradycardia if no contributing concomitant medication is identified.

Visual Disturbance: In ALTA, adverse reactions leading to visual disturbance including blurred vision, diplopia, and reduced visual acuity, were reported in 7.3% of patients treated with ALUNBRIG in the 90 mg group and 10% of patients in the 90→180 mg group. Grade 3 macular edema and cataract occurred in one patient each in the 90→180 mg group. Advise patients to report any visual symptoms. Withhold ALUNBRIG and obtain an ophthalmologic evaluation in patients with new or worsening visual symptoms of Grade 2 or greater severity. Upon recovery of Grade 2 or Grade 3 visual disturbances to Grade 1 severity or baseline, resume ALUNBRIG at a reduced dose. Permanently discontinue treatment with ALUNBRIG for Grade 4 visual disturbances.

Creatine Phosphokinase (CPK) Elevation: In ALTA, creatine phosphokinase (CPK) elevation occurred in 27% of patients receiving ALUNBRIG in the 90 mg group and 48% of patients in the 90 mg→180 mg group. The incidence of Grade 3-4 CPK elevation was 2.8% in the 90 mg group and 12% in the 90→180 mg group. Dose reduction for CPK elevation occurred in 1.8% of patients in the 90 mg group and 4.5% in the 90→180 mg group. Advise patients to report any unexplained muscle pain, tenderness, or weakness. Monitor CPK levels during ALUNBRIG treatment. Withhold ALUNBRIG for Grade 3 or 4 CPK elevation. Upon resolution or recovery to Grade 1 or baseline, resume ALUNBRIG at the same dose or at a reduced dose.

Pancreatic Enzyme Elevation: In ALTA, amylase elevation occurred in 27% of patients in the 90 mg group and 39% of patients in the 90→180 mg group. Lipase elevations occurred in 21% of patients in the 90 mg group and 45% of patients in the 90→180 mg group. Grade 3 or 4 amylase elevation occurred in 3.7% of patients in the 90 mg group and 2.7% of patients in the 90→180 mg group. Grade 3 or 4 lipase elevation occurred in 4.6% of patients in the 90 mg group and 5.5% of patients in the 90→180 mg group. Monitor lipase and amylase during treatment with ALUNBRIG. Withhold ALUNBRIG for Grade 3 or 4 pancreatic enzyme elevation. Upon resolution or recovery to Grade 1 or baseline, resume ALUNBRIG at the same dose or at a reduced dose.

Hyperglycemia: In ALTA, 43% of patients who received ALUNBRIG experienced new or worsening hyperglycemia. Grade 3 hyperglycemia, based on laboratory assessment of serum fasting glucose levels, occurred in 3.7% of patients. Two of 20 (10%) patients with diabetes or glucose intolerance at baseline required initiation of insulin while receiving ALUNBRIG. Assess fasting serum glucose prior to initiation of ALUNBRIG and monitor periodically thereafter. Initiate or optimize anti-hyperglycemic medications as needed. If adequate hyperglycemic control cannot be achieved with optimal medical management, withhold ALUNBRIG until adequate hyperglycemic control is achieved and consider reducing the dose of ALUNBRIG or permanently discontinuing ALUNBRIG.

Embryo-Fetal Toxicity: Based on its mechanism of action and findings in animals, ALUNBRIG can cause fetal harm when administered to pregnant women. There are no clinical data on the use of ALUNBRIG in pregnant women. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with ALUNBRIG and for at least 4 months following the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for at least 3 months after the last dose of ALUNBRIG.

ADVERSE REACTIONS

Serious adverse reactions occurred in 38% of patients in the 90 mg group and 40% of patients in the 90→180 mg group. The most common serious adverse reactions were pneumonia (5.5% overall, 3.7% in the 90 mg group, and 7.3% in the 90→180 mg group) and ILD/pneumonitis (4.6% overall, 1.8% in the 90 mg group and 7.3% in the 90→180 mg group). Fatal adverse reactions occurred in 3.7% of patients and consisted of pneumonia (2 patients), sudden death, dyspnea, respiratory failure, pulmonary embolism, bacterial meningitis and urosepsis (1 patient each).

The most common adverse reactions (≥25%) in the 90 mg group were nausea (33%), fatigue (29%), headache (28%), and dyspnea (27%) and in the 90→180 mg group were nausea (40%), diarrhea (38%), fatigue (36%), cough (34%), and headache (27%).

DRUG INTERACTIONS

CYP3A Inhibitors: Avoid concomitant use of ALUNBRIG with strong CYP3A inhibitors. Avoid grapefruit or grapefruit juice as it may also increase plasma concentrations of brigatinib. If concomitant use of a strong CYP3A inhibitor is unavoidable, reduce the dose of ALUNBRIG.

CYP3A Inducers: Avoid concomitant use of ALUNBRIG with strong CYP3A inducers.

CYP3A Substrates: Coadministration of ALUNBRIG with CYP3A substrates, including hormonal contraceptives, can result in decreased concentrations and loss of efficacy of CYP3A substrates.

USE IN SPECIFIC POPULATIONS

Pregnancy: ALUNBRIG can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus.

Lactation: There are no data regarding the secretion of brigatinib in human milk or its effects on the breastfed infant or milk production. Because of the potential adverse reactions in breastfed infants, advise lactating women not to breastfeed during treatment with ALUNBRIG.

Females and Males of Reproductive Potential:

Contraception: Advise females of reproductive potential to use effective non-hormonal contraception during treatment with ALUNBRIG and for at least 4 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with ALUNBRIG and for at least 3 months after the final dose.

Infertility: ALUNBRIG may cause reduced fertility in males.

Pediatric Use: The safety and efficacy of ALUNBRIG in pediatric patients have not been established.

Geriatric Use: Clinical studies of ALUNBRIG did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. Of the 222 patients in ALTA, 19.4% were 65-74 years and 4.1% were 75 years or older. No clinically relevant differences in safety or efficacy were observed between patients ≥65 and younger patients.

Hepatic or Renal Impairment: No dose adjustment is recommended for patients with mild hepatic impairment or mild or moderate renal impairment. The safety of ALUNBRIG in patients with moderate or severe hepatic impairment or severe renal impairment has not been studied.

On September 21, 2018 Exelixis, Inc. (NASDAQ:EXEL) reported that its partner Ipsen received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP), the scientific committee of the European Medicines Agency (EMA), for CABOMETYX (cabozantinib) tablets as a monotherapy for the treatment of hepatocellular carcinoma (HCC) in adults who have been previously treated with sorafenib (Press release, Exelixis, SEP 21, 2018, View Source;p=irol-newsArticle&ID=2368377 [SID1234529514]). The positive CHMP opinion will now be reviewed by the European Commission, which has the authority to approve medicines for the European Union.

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"This positive CHMP opinion represents significant progress for patients in Europe with this aggressive form of liver cancer who progress on prior systemic therapy, a large underserved patient population that currently only has one approved second-line treatment option," said Michael M. Morrissey, Ph.D., President and Chief Executive Officer of Exelixis. "We are excited about the potential therapeutic benefits CABOMETYX may offer the liver cancer community and look forward to the European Commission’s decision."

Under the terms of the Collaboration Agreement with Ipsen, Exelixis is eligible to receive a milestone payment of $40 million for the approval of the second-line treatment of HCC. This milestone would be paid by Ipsen within 70 days of the approval decision by the European Commission.

CABOMETYX is currently approved in the European Union for the treatment of advanced renal cell carcinoma (RCC) in adults who have received prior VEGF-targeted therapy and for previously untreated intermediate- or poor-risk advanced RCC. The CHMP recommendation to expand the indication is based on results from the CELESTIAL trial of CABOMETYX in patients with advanced HCC who received prior sorafenib. In this phase 3 pivotal trial, CABOMETYX demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) versus placebo.

On May 29, 2018, Exelixis announced that the U.S. Food and Drug Administration (FDA) accepted for filing the supplemental New Drug Application (sNDA) for CABOMETYX for previously treated advanced HCC and assigned a Prescription Drug User Fee Act (PDUFA) action date of January 14, 2019. An sNDA is an application to the FDA that, if approved, will allow a drug sponsor to make changes to a previously approved product label, including modifications to the indication.

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

About the CELESTIAL Study

CELESTIAL is a randomized, double-blind, placebo-controlled study of cabozantinib in patients with advanced HCC conducted at more than 100 sites globally in 19 countries. The trial was designed to enroll 760 patients with advanced HCC who received prior sorafenib and may have received up to two prior systemic cancer therapies for HCC and had adequate liver function. Enrollment of the trial was completed in September 2017. Patients were randomized 2:1 to receive 60 mg of cabozantinib once daily or placebo and were stratified based on etiology of the disease (hepatitis C, hepatitis B or other), geographic region (Asia versus other regions) and presence of extrahepatic spread and/or macrovascular invasion (yes or no). No cross-over was allowed between the study arms during the blinded treatment phase of the trial. The primary endpoint for the trial is OS, and secondary endpoints include objective response rate and PFS. Exploratory endpoints include patient-reported outcomes, biomarkers and safety.

In October 2017, Exelixis announced that the independent data monitoring committee for the CELESTIAL study recommended that the trial be stopped for efficacy following review at the second planned interim analysis, with cabozantinib providing a statistically significant and clinically meaningful improvement in OS compared with placebo in patients with previously treated advanced HCC. The data, originally presented at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper)’s Gastrointestinal Cancers Symposium (ASCO-GI) in January 2018, were published in The New England Journal of Medicine in July 2018.1

About HCC

Liver cancer is the second-leading cause of cancer death worldwide, accounting for more than 700,000 deaths and 800,000 new cases each year.2 In the U.S., the incidence of liver cancer has more than tripled since 1980.3 HCC is the most common form of liver cancer, making up about three-fourths of the estimated nearly 42,000 new cases in the U.S. in 2018.4 HCC is the fastest-rising cause of cancer-related death in U.S.1 Without treatment, patients with advanced HCC usually survive less than 6 months.4

About CABOMETYX (cabozantinib)

CABOMETYX tablets are approved in the United States for the treatment of patients with advanced RCC. CABOMETYX tablets are also approved in: the European Union, Norway, Iceland, Australia, Switzerland and South Korea for the treatment of advanced RCC in adults who have received prior VEGF-targeted therapy; in the European Union for previously untreated intermediate- or poor-risk advanced RCC; and in Canada for adult patients with advanced RCC who have received prior VEGF targeted therapy. In March 2017, the FDA granted orphan drug designation to cabozantinib for the treatment of advanced HCC. On March 28, 2018, Ipsen announced that the European Medicines Agency validated its application for a new indication for cabozantinib as a treatment for previously treated advanced HCC in the European Union; on September 20, 2018 the CHMP provided a positive opinion for CABOMETYX as a monotherapy for the treatment of HCC in adults who have been previously treated with sorafenib. 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.

U.S. Important Safety Information

Hemorrhage: Severe and fatal hemorrhages have occurred with CABOMETYX. In two RCC studies, the incidence of Grade ≥ 3 hemorrhagic events was 3% in CABOMETYX-treated patients. Do not administer CABOMETYX to patients that have or are at risk for severe hemorrhage.
Gastrointestinal (GI) Perforations and Fistulas: In RCC studies, fistulas were reported in 1% of CABOMETYX-treated patients. Fatal perforations occurred in patients treated with CABOMETYX. In RCC studies, gastrointestinal (GI) perforations were reported in 1% of CABOMETYX-treated patients. Monitor patients for symptoms of fistulas and perforations, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a fistula which cannot be appropriately managed or a GI perforation.
Thrombotic Events: CABOMETYX treatment results in an increased incidence of thrombotic events. In RCC studies, venous thromboembolism occurred in 9% (including 5% pulmonary embolism) and arterial thromboembolism occurred in 1% of CABOMETYX-treated patients. Fatal thrombotic events occurred in the cabozantinib clinical program. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or any other arterial thromboembolic complication.
Hypertension and Hypertensive Crisis: CABOMETYX treatment results in an increased incidence of treatment-emergent hypertension, including hypertensive crisis. In RCC studies, hypertension was reported in 44% (18% Grade ≥ 3) of CABOMETYX-treated patients. Monitor blood pressure prior to initiation and regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume CABOMETYX at a reduced dose. Discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy. Discontinue CABOMETYX if there is evidence of hypertensive crisis or severe hypertension despite optimal medical management.
Diarrhea: In RCC studies, diarrhea occurred in 74% of patients treated with CABOMETYX. Grade 3 diarrhea occurred in 11% of patients treated with CABOMETYX. Withhold CABOMETYX in patients who develop intolerable Grade 2 diarrhea or Grade 3-4 diarrhea that cannot be managed with standard antidiarrheal treatments until improvement to Grade 1; resume CABOMETYX at a reduced dose.
Palmar-Plantar Erythrodysesthesia (PPE): In RCC studies, palmar-plantar erythrodysesthesia (PPE) occurred in 42% of patients treated with CABOMETYX. Grade 3 PPE occurred in 8% of patients treated with CABOMETYX. Withhold CABOMETYX in patients who develop intolerable Grade 2 PPE or Grade 3 PPE until improvement to Grade 1; resume CABOMETYX at a reduced dose.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in the cabozantinib clinical program. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.
Embryo-fetal Toxicity may be associated with CABOMETYX. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during CABOMETYX treatment and for 4 months after the last dose.
Adverse Reactions: The most commonly reported (≥25%) adverse reactions are: diarrhea, fatigue, nausea, decreased appetite, hypertension, PPE, weight decreased, vomiting, dysgeusia, and stomatitis.
Strong CYP3A4 Inhibitors: If concomitant use with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage.
Strong CYP3A4 Inducers: If concomitant use with strong CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage.
Lactation: Advise women not to breastfeed while taking CABOMETYX and for 4 months after the final dose.
Hepatic Impairment: In patients with mild to moderate hepatic impairment, reduce the CABOMETYX dosage. CABOMETYX is not recommended for use in patients with severe hepatic impairment.

On September 21, 2018 BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160), a commercial-stage biopharmaceutical company focused on developing and commercializing innovative molecularly-targeted and immuno-oncology drugs for the treatment of cancer, reported its preliminary results from the Phase 1 trial of its investigational BTK inhibitor zanubrutinib in Chinese patients with B-cell lymphoma in an oral presentation at the 21st Annual Meeting of the Chinese Society of Clinical Oncology (CSCO) in Xiamen, China (Press release, BeiGene, SEP 21, 2018, View Source;p=irol-newsArticle&ID=2368471 [SID1234529513]).

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"We continue to be encouraged by clinical data on zanubrutinib, including these results, which we believe support its broad global clinical development. Our recent new drug application filing for zanubrutinib in China for patients with relapsed/refractory mantle cell lymphoma (MCL), a type of B-cell lymphoma, is currently under review by the National Medical Products Administration of China, and we are hopeful that it will give patients in China, and across the world, a new treatment option where it is so greatly needed," said Jane Huang, M.D., Chief Medical Officer, Hematology, at BeiGene.

Summary of Preliminary Results from the Phase 1 Trial of Zanubrutinib in Chinese Patients with B-Cell Lymphoma

An ongoing Phase 1 trial of zanubrutinib as a monotherapy in patients with different subtypes of B-cell malignancies, including Waldenström macroglobulinemia (WM), chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and other non-Hodgkin’s lymphomas (NHL), is being conducted in China. The trial is fully enrolled and comprised of two parts – a dose escalation phase involving 21 patients and a dose-expansion phase of 23 patients treated with zanubrutinib at the recommended Phase 2 dose of 160 mg taken orally twice daily.

Preliminary findings suggested that there was no significant difference in the pharmacokinetic profile of zanubrutinib between Chinese and non-Chinese patients. Preliminary findings also showed complete or greater than 80 percent sustained BTK occupancy was achieved among these patients with both single- and multiple-dose administrations.

As of June 15, 2018, after a median follow-up of 9.5 months (2.3 months–23.4 months), 21 patients (47%) remained on treatment. With 44 patients enrolled in the trial, 34 were evaluable for response. Of the nine patients with CLL/SLL, the overall response rate (ORR) was 100 percent, with two complete responses (CRs), six partial responses (PRs), and a PR with lymphocytosis (PR-L). Of the two patients with mantle cell lymphoma (MCL), there was one CR and one stable disease (SD). Of the two patients with WM, there was one PR and one SD. Of the 26 patients with follicular lymphoma (FL), the ORR was 42 percent with two CRs and nine PRs. There were three patients with FL who were not evaluable at the time of the data cutoff. Of the five patients with marginal zone lymphoma (MZL), there were three SDs and two patients who were not evaluable.

At the time of data cutoff, no dose-limiting toxicities occurred during dose escalation portion of the trial and there were no unexpected safety signals identified in the trial. No deaths related to adverse events were observed in the trial. The most common adverse events (occurring in ≥ 20% of patients) of any attribution among all 44 patients were neutrophil count decreased (50%), anemia (32%), upper respiratory tract infection (25%), white blood cell count decreased (25%), platelet count decreased (23%), rash (23%), hematuria (20%), and hyperuricemia (20%).

"These preliminary safety, tolerability and pharmacokinetics data of zanubrutinib support its ongoing clinical study. In this study, the preliminary results suggest zanubrutinib has a high rate of activity and is generally well-tolerated, which we believe is based on its potency and high-degree of selectivity," said Jun Zhu, M.D., Medical Department Chief at the Beijing Cancer Hospital and study presenter.

About B-Cell Lymphomas
Lymphoma is a diverse group of malignancies that originates from B, T or NK cells. The most common type of B-cell lymphomas are non-Hodgkin’s lymphoma, of which diffuse large B-cell lymphoma (DLBCL) is the most common. Other types of B-cell non-Hodgkin’s lymphoma include FL, CLL/SLL, MCL, MZL, and WM.

About Zanubrutinib
Zanubrutinib (BGB-3111) is an investigational small molecule inhibitor of Bruton’s tyrosine kinase (BTK) that is currently being evaluated in a broad pivotal clinical program globally and in China as a monotherapy and in combination with other therapies to treat various B-cell malignancies.

On September 20, 2018 Galectin Therapeutics Inc. (NASDAQ:GALT), the leading developer of therapeutics that target galectin proteins, and Providence Cancer Institute, reported additional preliminary clinical data from cohort 3 of an investigator-initiated Phase 1b clinical trial of GR-MD-02 used in combination with KEYTRUDA (pembrolizumab) in patients with metastatic melanoma for which KEYTRUDA is indicated or those patients whose melanoma progressed during or recently after KEYTRUDA monotherapy (Press release, Galectin Therapeutics, SEP 20, 2018, View Source [SID1234530280]).

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The Providence Cancer Institute (Portland, OR) translational medicine team is conducting this phase 1b clinical trial, initiated under direction of principal investigator Brendan D. Curti, M.D., Director, Providence Melanoma Program. The objectives of this study were to determine a safe dose of GR-MD-02 used in combination with KEYTRUDA and to measure the response rate to combined therapy. "We are very encouraged by the objective response rate and the disease control rate observed in patients with advanced melanoma. These response rates were higher than expected with KEYTRUDA alone," said Dr. Curti. "An objective response rate of seven out of fourteen patients (50%) and a disease control rate of nine out of fourteen patients (64%) with advanced melanoma is very encouraging. The published objective response rates in randomized studies using KEYTRUDA in patients with advanced melanoma range from 21% in patients who have had prior therapy to 39% in patients who had not received prior systemic therapy. Importantly, the combination was also very well tolerated, and treatment appears to be associated with fewer adverse events than expected with KEYTRUDA alone."

When aggregated with the cohorts previously reported, the data shows a 50% objective response rate in advanced melanoma with GR-MD-02 in combination with KEYTRUDA and a significant decrease in the frequency of suppressive myeloid-derived suppressor cells (MDSC) following treatment in the responding patients (on day 85 post-treatment) was observed. The published data on KEYTRUDA alone have shown an objective response rate of 33% in this patient population.

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Fourteen advanced melanoma patients across three dose cohorts now have Objective Response Rate (ORR) and Disease Control Rate (DCR) data. Six patients in cohort 3 (8 mg/kg GR-MD-02) have now been added to the three patients in cohort 2 (4 mg/kg GR-MD-02) and the five patients in cohort 1 (2 mg/kg GR-MD-02). Cohorts 1 and 3 each had two patients with an objective response. All three patients in cohort 2 had an objective response.
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N=13; 1 patient in cohort 3 not depicted due to clinical progression prior to scans. Dotted line at -30% change from baseline indicates the RECIST 1.1 threshold for definition of partial response.

Generally, the U.S. Food and Drug Administration has defined objective response rate as the sum of partial responses plus complete responses. Disease control rate is the objective responses plus those with stable disease.

In addition to the fourteen advanced melanoma patients, six patients with head and neck cancer were enrolled in this phase 1b trial with a 33% objective response rate and a 67% disease control rate. Dr. Curti states "the response rates observed overall in advanced melanoma and head and neck cancer patients were better than expected with KEYTRUDA alone and are the basis for moving forward with both tumor types, particularly given the low response rates of anti-PD-1 monotherapy in head and neck cancer. There is a significant clinical need for better options for these patients and our initial objective response rates were encouraging enough to warrant inclusion of additional patients to help determine whether we should also pursue these challenging patient populations in a phase 2 trial. Taken together with the observed favorable safety and tolerability of the combination, these results provide a compelling rationale to move forward with this approach." Given that all three melanoma patients (100%) were responders at 4 mg/kg dose, the investigators plan to continue the trial with expansion of the 4 mg/kg GR-MD-02 and KEYTRUDA cohort to include additional advanced melanoma patients and additional head and neck cancer patients.

"In addition to the encouraging clinical responses seen thus far, we continue to make progress on identifying immunological biomarkers that correlate with favorable responses," said William L. Redmond, Ph.D., Associate Member, Laboratory of Cancer Immunotherapy, and Director, Immune Monitoring Laboratory at the Earle A. Chiles Research Institute, a division of Providence Cancer Institute. "We have observed a significant decrease in the frequency of suppressive myeloid-derived suppressor cells (MDSC) following treatment in the responding patients (on day 85 post-treatment). Comprehensive laboratory studies are being performed to further identify the biological mechanisms associated with this response."

"Galectin Therapeutics is very pleased with our continuing collaboration with Providence Cancer Institute, and we are encouraged that Dr. Curti and his team are expanding the trial to include additional patients," said Harold Shlevin, Ph.D., CEO and President of Galectin Therapeutics. "The planned expansion of the size of the 4 mg/kg dose cohort, and inclusion of both advanced melanoma patients and patients with head and neck cancer, will permit further evaluation that the use of GR-MD-02 in combination with KEYTRUDA has a better objective response rate and fewer adverse events than KEYTRUDA alone. We believe this collaboration with Providence to be a fruitful approach to helping to determine the potential of GR-MD-02 in combination immuno-therapy, and it also leverages our ability to collect additional data related to the immunological monitoring of these patients before potentially proceeding to the next phase of development."

Additional information about this clinical trial may be found at www.clinicaltrials.gov/ct2/show/NCT02575404

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-3 proteins and disrupts its function. Preclinical data in animals have shown that GR-MD-02 has robust treatment effects in reversing liver fibrosis and cirrhosis. GR-MD-02 also has robust efficacy in pre-clinical cancer models in combination with immunotherapy agents.

On September 20, 2018 Cell Medica reported the treatment of the first patient world-wide to receive CMD-501, an autologous CAR-NKT therapy targeting pediatric neuroblastoma (Press release, Cell Medica, SEP 20, 2018, View Source [SID1234530199]). This is the first time an engineered NKT cell therapy has been used in humans. Cell Medica is a clinical-stage biopharmaceutical company that is transforming the treatment of solid and hematological cancer by developing the next generation of CAR therapies.

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This open-label Phase 1 study, GINAKIT2, is being carried out in collaboration with both Baylor College of Medicine (BCM) and Texas Children’s Hospital.

Dr. Andras Heczey, Principal Investigator, Assistant Professor, Pediatrics-Oncology at Baylor College of Medicine and Physician-Scientist, Texas Children’s Cancer Center commented: "Dosing the first patient with this novel CAR-NKT therapy is an important milestone for all pediatric patients with neuroblastoma. CAR-NKTs may offer an exciting new therapeutic option for these patients and potentially for others with solid and hematological cancers. I am extremely grateful to the patients and families participating in this ground-breaking study."

Chris Nowers, Cell Medica’s CEO, said: "We believe that our CAR-NKT platform has a unique profile, with a potential to target solid and hematological tumors, as well as the possibility of a subsequent allogeneic "off the shelf" CAR-NKT therapy that could address some challenges of current autologous CAR-T therapies. This study marks an important step forward for Cell Medica and we are proud to be leading the development of this innovative class of next generation CAR therapies with our colleagues at BCM and Texas Children’s."

Innovative CAR-NKT Platform
CMD-501 is based on Cell Medica’s novel CAR-NKT platform, a next-generation technology of engineered immune cells with enhanced functions for the treatment of hematological and solid tumors, utilizing the unique properties of NKT cells, a specialized type of innate lymphocytes, sharing properties of T and NK cells. CMD-501 is the initial study from Cell Medica’s CAR-NKT pipeline and utilizes an autologous approach. The patient’s own NKT cells are genetically engineered with a CAR targeting GD2, a molecule expressed on the surface of nearly all neuroblastoma cells. In collaboration with its partners at BCM and Texas Children’s, Cell Medica designed this CAR-NKT cell therapy to also secrete the cytokine IL-15, which has been shown in pre-clinical studies to increase the persistence of CAR-NKT cells and improve their efficacy within the immunosuppressive tumor microenvironment.

Dr. Leonid Metelitsa, Professor of Pediatrics, Hematology-Oncology, Baylor College of Medicine and Co-Director, Neuroblastoma Program, Texas Children’s Cancer Center added: "It has been a great pleasure leading the multi-disciplinary team in the development of this versatile CAR-NKT platform. NKT cells effectively traffic to the tumor site, so expressing tumor-specific CARs in these cells ensures delivery to the site of disease for maximum efficacy. We’re now exploiting another natural feature of NKT cells, their lack of allo-reactivity and we are developing allogeneic, "off the shelf", therapies that will further harness the unique advantages of NKT cells."

First-in-Human Study
GINAKIT2 is a first-in-human, dose escalation evaluation of CMD-501 in children with relapsed or refractory (R/R) high-risk neuroblastoma, (NCT03294954). Neuroblastomas occur primarily in children and account for 7-10 percent of all pediatric cancers. Ninety percent of patients are younger than 5 years at diagnosis. R/R high risk neuroblastoma is one of the deadliest types of childhood cancer and the current median survival is around 1-3 years. Almost all neuroblastomas express GD2, which is targeted by CMD-501. This study is supported by a grant from Alex’s Lemonade Stand Foundation (ALSF), awarded to BCM investigators, Drs. Heczey and Metelitsa.

About Neuroblastoma and GD2
Neuroblastoma is a cancer of the sympathetic nervous system which can occur in the chest, neck, abdomen and adrenal glands, and can metastasize to the bone marrow and other organs. Children with low or intermediate risk neuroblastoma can be cured through surgical intervention and/or chemotherapy, however, at least half of all children with neuroblastoma have high risk disease, which often requires combined surgical, radio-, immuno-, and chemotherapy, in addition to autologous stem cell transplantation. Patients with relapsed/refractory high-risk neuroblastoma have one of the deadliest types of childhood cancer and a poor prognosis, with median survival of 1-3 years.

GD2 is a molecule expressed on tumors of neuroectodermal origin, including almost all neuroblastomas, and a substantial fraction of small cell lung cancer and melanoma, with restricted expression on normal tissues, making it a good target for CAR-NKT cell therapy.

About CMD-501
CMD-501 is an innovative autologous product in which NKT cells are genetically engineered with a CAR targeting GD2. NKT cells are a subset of T lymphocyte with the cytotoxic and anti-tumor properties of conventional T cells, but with other biological attributes that are expected to improve their ability to attack tumors. GD2 is a molecule expressed on the surface of most neuroblastoma cells.

In collaboration with its partners at BCM, Cell Medica has engineered a GD2-specific CAR construct that is additionally designed to secrete the cytokine IL-15, which has been shown in pre-clinical studies to increase the persistence of CAR-NKT cells and improve their efficacy within the immunosuppressive tumor microenvironment. CMD-501 is an autologous product, meaning that each patient’s own cells are collected, modified and activated outside the body, and then infused back into the same patient. However, NKT cells also have significant potential for so-called off-the-shelf use, where cells from a healthy donor could be prepared in large quantities in advance and used to treat many different patients. Cell Medica is collaborating with BCM to bring an off-the-shelf CAR-NKT cell product into the clinic in the near future.