On November 19, 2015 Aduro Biotech, Inc. (Nasdaq:ADRO) reported that it has established European subsidiary headquarters at the BioNovion site in Oss, Netherlands now called Aduro Biotech Europe (Press release, Aduro BioTech, NOV 19, 2015, View Source [SID:1234508289]). On October 30, 2015, Aduro acquired BioNovion, a biopharmaceutical antibody discovery and development company, to broaden its technology portfolio and increase its immunotherapy capabilities. Schedule your 30 min Free 1stOncology Demo! "In addition to expanding our pipeline with complementary technologies, we are pleased that this acquisition allows us to integrate a highly experienced scientific team and expand our clinical development presence abroad," said Stephen T. Isaacs, chairman, president and chief executive officer of Aduro. "With our new base in Europe, we look forward to collaborating with the local European medical and business communities as we initiate international clinical research programs."
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In addition to Aduro’s established LADD and CDN technologies, Aduro’s new combined offerings include the B-select monoclonal antibodies (B-select) platform, which is designed to produce first- and best-in-class agonist and antagonist monoclonal antibodies (mAbs) that may be used to create a deep pipeline of products focused on harnessing the immune system of cancer patients. Aduro is an immuno-oncology company that has multiple therapeutic platforms with the potential to yield powerful immunotherapy combinations.
Monoclonal antibody expertise will remain in the Aduro Biotech Europe office in the Netherlands, which will operate as a subsidiary. Andrea van Elsas, Ph.D. and Hans van Eenennaam, Ph.D, chief scientific officer and chief operating officer of BioNovion respectively, will retain their roles and titles at Aduro Biotech Europe.
Near term clinical development plans include the initiation of a global Phase 3 trial to evaluate the combination of CRS-207, a LADD-based immunotherapy, and standard-of-care chemotherapy in patients with unresectable malignant pleural mesothelioma (MPM). Clinical trial sites in Europe will open in 2016. MPM – a rare, difficult to treat cancer that is commonly associated with asbestos exposure – is still a significant health problem throughout Europe, with the highest MPM related mortality rate globally and over 50,000 MPM related deaths between 1994-2008.1,2
The integration of Aduro’s newly acquired B-select technology provides a new platform for Aduro to continue to build a strong oncology research and development pipeline. Aduro’s broad portfolio of immunotherapy candidates positions the company to potentially offer patients around the globe novel therapeutic options and combinations that are alternatives to traditional therapies.
Author: [email protected]
Lilly and Merck Expand Immuno-oncology Collaboration with Phase III Nonsquamous Non-Small Cell Lung Cancer Trial
On November 19, 2015 Eli Lilly and Company (NYSE: LLY) and Merck (NYSE: MRK), known as MSD outside the United States and Canada, reported the extension of an existing collaboration to evaluate the safety and efficacy of the combination of Lilly’s ALIMTA (pemetrexed for injection) and Merck’s KEYTRUDA (pembrolizumab) in a pivotal Phase III study in first-line nonsquamous non-small cell lung cancer (NSCLC) (Press release, Eli Lilly, NOV 19, 2015, View Source [SID:1234508287]). The study will be sponsored by Merck and will be open to patients with NSCLC in the first-line setting, regardless of PD-L1 status. Financial details of the collaboration were not disclosed. Schedule your 30 min Free 1stOncology Demo! The expansion of this oncology clinical trial collaboration comes following the release of encouraging data from a Phase I study, presented earlier this year at the 16th World Congress on Lung Cancer, which evaluated pemetrexed, carboplatin and pembrolizumab in first-line nonsquamous NSCLC.
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Pemetrexed is a leading therapeutic option used in combination with platinum-based therapies in this setting, making it an ideal candidate for combination studies with immunotherapy treatments. Pembrolizumab is a humanized monoclonal antibody that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. Pembrolizumab blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes, which may affect both tumor cells and healthy cells – and is currently approved as a single-agent therapy for certain types of NSCLC.
"The extension of our immuno-oncology collaboration with Merck reinforces our combination-focused strategy, which we believe has the potential to help this patient population where there is a significant unmet need," said Richard Gaynor, M.D., senior vice president, product development and medical affairs for Lilly Oncology. "Building upon this scientific partnership represents our shared, strong commitment to improve the lives of those living with cancer."
"Based on the data for ALIMTA, we believe this collaboration with Lilly has great potential to help even more patients," said Roger Dansey, M.D., therapeutic area head and senior vice president, oncology late stage development, Merck Research Laboratories. "We look forward to continuing our collaboration with Lilly across all of these trials – including the registrational Phase III all-comers trial for NSCLC."
In addition to the studies of pemetrexed and pembrolizumab in first-line nonsquamous NSCLC, other ongoing trials from the original agreement between Lilly and Merck, through a subsidiary, include:
A Phase I/II study examining the combination of ramucirumab with pembrolizumab in multiple tumors.
A Phase I/II study examining the combination of necitumumab with pembrolizumab in NSCLC.
NOTES TO EDITORS
About KEYTRUDA (pembrolizumab) Injection 100 mg
KEYTRUDA is indicated in the United States at a dose of 2 mg/kg administered as an intravenous infusion over 30 minutes every three weeks for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 as determined by an FDA-approved test with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA. KEYTRUDA is also indicated at the same dosing for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. These indications are approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for these indications may be contingent upon verification and description of clinical benefit in the confirmatory trials.
Selected Important Safety Information for KEYTRUDA (pembrolizumab)
Pneumonitis, including fatal cases, occurred in patients receiving KEYTRUDA. Pneumonitis occurred in 12 (2.9%) of 411 melanoma patients, including Grade 2 or 3 cases in 8 (1.9%) and 1 (0.2%) patients, respectively, receiving KEYTRUDA. Pneumonitis occurred in 19 (3.5%) of 550 patients with NSCLC, including Grade 2 (1.1%), 3 (1.3%), 4 (0.4%), or 5 (0.2%) pneumonitis in patients, receiving KEYTRUDA. Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.
Colitis (including microscopic colitis) occurred in 4 (1%) of 411 patients with melanoma, including Grade 2 or 3 cases in 1 (0.2%) and 2 (0.5%) patients, respectively, receiving KEYTRUDA.
Colitis occurred in 4 (0.7 %) of 550 patients with NSCLC, including Grade 2 (0.2%) or 3 (0.4%) colitis in patients receiving KEYTRUDA. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.
Hepatitis occurred in patients receiving KEYTRUDA. Hepatitis (including autoimmune hepatitis) occurred in 2 (0.5%) of 411 patients with melanoma, including a Grade 4 case in 1 (0.2%) patient, receiving KEYTRUDA. Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.
Hypophysitis occurred in 2 (0.5%) of 411 patients with melanoma, including a Grade 2 case in 1 and a Grade 4 case in 1 (0.2% each) patient, receiving KEYTRUDA. Hypophysitis occurred in 1 (0.2 %) of 550 patients with NSCLC, which was Grade 3 in severity. Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids and hormone replacement as indicated. Withhold KEYTRUDA for Grade 2 and withhold or discontinue for Grade 3 or Grade 4 hypophysitis.
Hyperthyroidism occurred in 5 (1.2%) of 411 patients with melanoma, including Grade 2 or 3 cases in 2 (0.5%) and 1 (0.2%) patients, respectively, receiving KEYTRUDA. Hypothyroidism occurred in 34 (8.3%) of 411 patients with melanoma, including a Grade 3 case in 1 (0.2%) patient, receiving KEYTRUDA. Hyperthyroidism occurred in 10 (1.8%) of 550 patients with NSCLC, including Grade 2 (0.7%) or 3 (0.3%). Hypothyroidism occurred in 38 (6.9%) of 550 patients with NSCLC, including Grade 2 (5.5%) or 3 (0.2%). Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer replacement hormones for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or Grade 4 hyperthyroidism.
Type 1 diabetes mellitus, including diabetic ketoacidosis, has occurred in patients receiving KEYTRUDA. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer anti-hyperglycemics in patients with severe hyperglycemia.
Nephritis occurred in patients receiving KEYTRUDA. Nephritis occurred in 3 (0.7%) patients with melanoma, consisting of one case of Grade 2 autoimmune nephritis (0.2%) and two cases of interstitial nephritis with renal failure (0.5%), one Grade 3 and one Grade 4. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis.
Other clinically important immune-mediated adverse reactions can occur. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement of the adverse reaction to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following steroid taper. Permanently discontinue KEYTRUDA for any severe or Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.
Across clinical studies with KEYTRUDA, the following clinically significant, immune-mediated adverse reactions have occurred: bullous pemphigoid and Guillain-Barré syndrome. The following clinically significant, immune-mediated adverse reactions occurred in less than 1% of patients with melanoma treated with KEYTRUDA: exfoliative dermatitis, uveitis, arthritis, myositis, pancreatitis, hemolytic anemia, and partial seizures arising in a patient with inflammatory foci in brain parenchyma. The following clinically significant, immune-mediated adverse reactions occurred in less than 1% of 550 patients with NSCLC treated with KEYTRUDA: rash, vasculitis, hemolytic anemia, serum sickness, and myasthenia gravis.
Infusion-related reactions, including severe and life-threatening reactions, have occurred in patients receiving KEYTRUDA. Monitor patients for signs and symptoms of infusion related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For severe or life-threatening reactions, stop infusion and permanently discontinue KEYTRUDA.
Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of KEYTRUDA.
Among the 411 patients with metastatic melanoma, KEYTRUDA was discontinued for adverse reactions in 9% of 411 patients. Adverse reactions, reported in at least two patients, that led to discontinuation of KEYTRUDA were: pneumonitis, renal failure, and pain. Serious adverse reactions occurred in 36% of patients. The most frequent serious adverse reactions, reported in 2% or more of patients, were renal failure, dyspnea, pneumonia, and cellulitis. The most common adverse reactions (reported in at least 20% of patients) were fatigue (47%), cough (30%), nausea (30%), pruritus (30%), rash (29%), decreased appetite (26%), constipation (21%), arthralgia (20%), and diarrhea (20%).
Among the 550 patients with metastatic NSCLC, KEYTRUDA was discontinued due to adverse reactions in 14% of patients. Serious adverse reactions occurred in 38% of patients. The most frequent serious adverse reactions reported in 2% or more of patients were pleural effusion, pneumonia, dyspnea, pulmonary embolism, and pneumonitis. The most common adverse reactions (reported in at least 20% of patients) were fatigue (44%), decreased appetite (25%), dyspnea (23%), and cough (29%).
No formal pharmacokinetic drug interaction studies have been conducted with KEYTRUDA.
It is not known whether KEYTRUDA is excreted in human milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA and for 4 months after the final dose.
Safety and effectiveness of KEYTRUDA have not been established in pediatric patients.
About ALIMTA (pemetrexed)
In 2004, ALIMTA received consecutive approvals: it was the first agent to be approved in combination with cisplatin as a treatment for patients with malignant pleural mesothelioma, whose disease is unresectable or who are otherwise not candidates for curative surgery, and then as a single agent for the second-line treatment of patients with locally advanced or metastatic NSCLC after prior chemotherapy treatment.
In 2008, ALIMTA, in combination with cisplatin, was approved as a first-line treatment for locally advanced or metastatic NSCLC for patients with nonsquamous histology. At the time of the first-line approval, the FDA also approved a change to the second-line indication. ALIMTA is now indicated as a single agent for the treatment of patients with locally advanced or metastatic, nonsquamous NSCLC after prior chemotherapy.
In 2009, ALIMTA was approved as a maintenance therapy for locally advanced or metastatic NSCLC, specifically for patients with a nonsquamous histology whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.
In 2012, ALIMTA was approved by the FDA as a continuation maintenance therapy for locally-advanced or metastatic NSCLC, following first-line ALIMTA plus cisplatin for locally advanced or metastatic nonsquamous NSCLC.
ALIMTA is not indicated for treatment of patients with squamous cell NSCLC. Myelosuppression is usually the dose-limiting toxicity with ALIMTA therapy.
Important Safety Information for ALIMTA (pemetrexed for injection)
What is the most important information that I should know about ALIMTA?
ALIMTA can suppress bone marrow function, which may cause low blood cell counts.
ALIMTA may not be appropriate for some patients.
If you are allergic to ALIMTA, tell your doctor because you should not receive it.
If you have liver or kidney problems, be sure to tell your doctor. Your dose of ALIMTA may have to be changed, or ALIMTA may not be right for you.
It is very important to take the following medications prior to and during your treatment with ALIMTA to lower your chances of harmful side effects:
You must take folic acid every day by mouth beginning 7 days before your first dose of ALIMTA. You must keep taking folic acid every day during the time you are being treated with ALIMTA, and every day for 21 days after you receive your last dose of ALIMTA.
Your doctor will give you vitamin B12 injections while you are getting treatment with ALIMTA. You will get your first vitamin B12 injection one week before your first dose of ALIMTA, and then about every 9 weeks during treatment.
Your doctor will prescribe a medicine called a "corticosteroid" which you must take the day before, the day of, and the day after each treatment with ALIMTA to reduce rash.
You will have regular blood tests before and during your treatment with ALIMTA. Your doctor may adjust your dose of ALIMTA or delay your treatment based on the results of your blood test and on your general condition.
What should I tell my doctor before receiving ALIMTA?
If you think you are pregnant, are planning to become pregnant, or are nursing, please tell your healthcare team. ALIMTA may harm your unborn or nursing baby. Your physician may advise you to use effective contraception (birth control) to prevent pregnancy while you are being treated with ALIMTA.
Tell your doctor if you are taking other medicines, including prescription and nonprescription medicines, vitamins, and herbal supplements. ALIMTA and other medicines may affect each other, causing serious side effects. Especially, tell your doctor if you are taking medicines called "nonsteroidal anti-inflammatory drugs" (NSAIDs) for pain or swelling.
What are the possible side effects of ALIMTA?
Most patients taking ALIMTA will have side effects. Sometimes it is not always possible to tell whether ALIMTA, another medicine, or the cancer itself is causing these side effects.
Call your doctor right away if you have a fever, chills, diarrhea, or mouth sores. These symptoms could mean you have an infection, which may be severe and could lead to death.
The most common side effects of ALIMTA when given alone or in combination with cisplatin are:
Stomach upset, including nausea, vomiting, diarrhea, or constipation. You can obtain medicines to help control some of these symptoms. Call your doctor if you get any of these symptoms.
Low blood cell counts:
Low red blood cells. Low red blood cells may make you feel tired, get tired easily, appear pale, and become short of breath.
Low white blood cells. Low white blood cells may give you a greater chance for infection. If you have a fever (temperature above 100.4°F) or other signs of infection, call your doctor right away.
Low platelets. Low platelets give you a greater chance for bleeding. Your doctor will do blood tests to check your blood counts before and during treatment with ALIMTA.
Tiredness. You may feel tired or weak for a few days after your ALIMTA treatments. If you have severe weakness or tiredness, call your doctor.
Redness or sores in your mouth, throat, on your lips or in the tube that connects your throat and stomach (esophagus). You may get redness or sores in your mouth, throat, on your lips, or in your esophagus (stomatitis, pharyngitis, esophagitis) or you may feel pain or have difficulty when drinking or swallowing food. These symptoms may happen a few days after ALIMTA treatment. Talk with your doctor if you get any of these symptoms.
Loss of appetite. You may lose your appetite and lose weight during your treatment. Talk to your doctor if this is a problem for you.
Rash. You may get a rash or itching during treatment. These reactions usually appear between treatments with ALIMTA and usually go away before the next treatment. Skin reactions or rashes that include blistering or peeling may be severe and could lead to death. Call your doctor if you have any of these symptoms.
Talk with your doctor, nurse, or pharmacist about any side effect that bothers you or that doesn’t go away.
These are not all the side effects of ALIMTA. For more information, ask your doctor, nurse, or pharmacist.
Servier Exercises Exclusive Worldwide Licensing Option with Cellectis for UCART19, an Allogeneic CAR-T Cell Therapy for Hematological Malignancies
On November 19, 2015 Cellectis (Alternext: ALCLS; Nasdaq: CLLS) and Servier reported that they signed an amendment to their existing collaboration agreement from February 2014 especially for UCART19, a TALEN gene-edited allogeneic Chimeric Antigen Receptor T-cell (CAR-T) immunotherapy (Press release, Cellectis, NOV 18, 2015, View Source [SID:1234508285]).
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Under this amendment, Servier early exercises its option to acquire the exclusive worldwide rights to further develop and commercialize UCART19, which is about to enter Phase 1 development for chronic lymphocytic leukemia (CLL) and acute lymphoblastic leukemia (ALL).
In addition, Pfizer Inc. (NYSE: PFE) and Servier have entered into an exclusive global license and collaboration agreement to co-develop and commercialize UCART19. Under the terms of the agreement, Pfizer and Servier will work together on a joint clinical development program for UCART19 and share development costs. Pfizer will be responsible for potential commercialization of UCART19 in the United States, and Servier will retain marketing rights in countries outside the United States. Pfizer’s collaboration with Servier on UCART19 is distinct from the collaboration with Cellectis that Pfizer announced in June 2014, which did not include UCART19.
UCART19 utilizes Cellectis’ proprietary, allogeneic approach to develop CAR-T therapies that engineer T-cells from non-patient donors for use in multiple patients. This is different from autologous approaches, which engineer a patient’s own T-cells.
Cellectis will receive from Servier a payment of $38.2 million upon signature. In addition, Cellectis is eligible for over $300 million of milestone payments, R&D financing, and royalties on sales from Servier, based on annual net sales of commercialized products. Financial terms for the Servier agreement with Pfizer were not disclosed.
"Servier’s early option exercise is a strong recognition of the potential value of UCART19 for patients, as the first allogeneic CAR-T therapy expected to move into clinical development that utilizes Cellectis’ TALEN gene editing technologies," said Dr. André Choulika, Ph.D., chairman and chief executive officer of Cellectis. "Cellectis aims to provide cancer patients with highly innovative best-in-class allogeneic CAR-T therapies across all geographies, and we are proud to collaborate on this license agreement with Servier and Pfizer to foster access for patients."
"The partnership between Pfizer and Servier is a major step in the development of UCART19 and our ambition to provide innovative drugs for patients in oncology, as it has been envisioned by Servier’s president, Olivier Laureau," said Emmanuel Canet, M.D., president, Research and Development at Servier.
"This collaboration on the development of the UCART19 asset builds on Pfizer’s position in the CAR-T space and our growing portfolio of investigational immuno-oncology assets, which is a major priority for our oncology business," said Mikael Dolsten, M.D., Ph.D., president, Worldwide Research and Development at Pfizer. "This work with Servier and Cellectis underscores our companies’ shared commitment to developing unique cancer therapies that may benefit patients around the world."
Pfizer Reports Positive Topline Results from Phase 3 Trial Comparing XALKORI® (crizotinib) to Chemotherapy in Previously Untreated East Asian Patients with ALK-Positive Advanced Non-Small Cell Lung Cancer (NSCLC)
On November 18, 2015 Pfizer Inc. reported that PROFILE 1029, a Phase 3 study of anaplastic lymphoma kinase (ALK) inhibitor XALKORI (crizotinib), met its primary objective of significantly prolonging progression-free survival (PFS) in previously untreated East Asian patients with ALK-positive advanced non-small cell lung cancer (NSCLC) when compared to a standard chemotherapy doublet (Press release, Pfizer, NOV 18, 2015, View Source [SID:1234508282]). In this study, XALKORI was used as the first systemic therapy for patients with advanced ALK-positive NSCLC, and patients could have received therapy and/or surgery for early stage disease before they were diagnosed with metastatic disease.
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The adverse events observed with XALKORI in the study were generally consistent with findings from previous trials. No unexpected adverse events were observed. Efficacy and safety data from PROFILE 1029 will be submitted for presentation at a future medical meeting.
PROFILE 1029 is the second positive Phase 3 study for XALKORI in the first-line setting and the third positive Phase 3 study for XALKORI in ALK-positive NSCLC. The PROFILE 1014 and PROFILE 1007 trials demonstrated that XALKORI was superior to chemotherapy in the first-line and the second-line settings, respectively.
"When evaluated specifically in East Asian patients with ALK-positive NSCLC, XALKORI was demonstrated to be superior to chemotherapy in terms of prolonging progression-free survival. This is consistent with the results of previous global randomized clinical trials that included Asian and Western patients, which also demonstrated an improvement in progression-free survival compared to standard-of-care chemotherapy" said Dr. Mace Rothenberg, senior vice president of Clinical Development and Medical Affairs and chief medical officer for Pfizer Oncology. "These results also underscore the importance of early and routine biomarker testing in patients with advanced NSCLC so that these patients can be identified and treated appropriately."
XALKORI was the first ALK inhibitor approved by regulatory authorities in the United States (U.S.), European Union, China and Japan, and it is now approved in more than 85 countries. XALKORI is widely recognized as a standard of care for patients with ALK-positive advanced NSCLC. To date, more than 20,000 patients have been treated with XALKORI worldwide.1
About Non-Small Cell Lung Cancer
Worldwide, lung cancer is the leading cause of cancer death in both men and women.2 NSCLC accounts for about 85 percent of lung cancer cases and remains difficult to treat, particularly in the metastatic setting.3 Approximately 57 percent of NSCLC patients are diagnosed late with metastatic, or advanced, disease where the five-year survival rate is only 5 percent.4
XALKORI (crizotinib) Indication and Important Safety Information (as per U.S. Prescribing Information)
XALKORI is a kinase inhibitor indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test.
Hepatotoxicity: Drug-induced hepatotoxicity with fatal outcome occurred in 0.1% of patients treated with XALKORI across clinical trials (n=1669). Transaminase elevations generally occurred within the first 2 months. Monitor with liver function tests including ALT and total bilirubin every 2 weeks during the first 2 months of treatment, then once a month and as clinically indicated, with more frequent repeat testing for increased liver transaminases, alkaline phosphatase, or total bilirubin in patients who develop transaminase elevations. Permanently discontinue for ALT/AST elevation >3 times ULN with concurrent total bilirubin elevation >1.5 times ULN (in the absence of cholestasis or hemolysis); otherwise, temporarily suspend and dose-reduce XALKORI as indicated.
Interstitial Lung Disease (Pneumonitis): Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis can occur. Across clinical trials (n=1669), 2.9% of XALKORI-treated patients had any grade ILD, 1.1% had Grade 3/4, and 0.5% had fatal ILD. These cases generally occurred within 3 months after initiation of treatment. Monitor for pulmonary symptoms indicative of ILD/pneumonitis. Exclude other potential causes and permanently discontinue XALKORI in patients with drug-related ILD/pneumonitis.
QT Interval Prolongation: QTc prolongation can occur. Across clinical trials (n=1560), 2.1% of patients had QTcF (corrected QT by the Fridericia method) ≥500 ms and 5.0% had an increase from baseline QTcF ≥60 ms by automated machine-read evaluation of ECG. Avoid use in patients with congenital long QT syndrome. Consider periodic monitoring with ECGs and electrolytes in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications that prolong the QT interval. Permanently discontinue XALKORI in patients who develop QTc >500 ms or ≥60 ms change from baseline with Torsade de pointes, polymorphic ventricular tachycardia, or signs/symptoms of serious arrhythmia. Withhold XALKORI in patients who develop QTc >500 ms on at least 2 separate ECGs until recovery to a QTc ≤480 ms, then resume at a reduced dose.
Bradycardia: Symptomatic bradycardia can occur. Across clinical trials, bradycardia occurred in 12.3% of patients treated with XALKORI (N=1669). Avoid use in combination with other agents known to cause bradycardia. Monitor heart rate and blood pressure regularly. In cases of symptomatic bradycardia that is not life-threatening, hold XALKORI until recovery to asymptomatic bradycardia or to a heart rate of ≥60 bpm, re-evaluate the use of concomitant medications, and adjust the dose of XALKORI. Permanently discontinue for life-threatening bradycardia due to XALKORI; however, if associated with concomitant medications known to cause bradycardia or hypotension, hold XALKORI until recovery to asymptomatic bradycardia or to a heart rate of ≥60 bpm. If concomitant medications can be adjusted or discontinued, restart XALKORI at 250 mg once daily with frequent monitoring.
Vision Disorders: Most commonly visual impairment, photopsia, blurred vision or vitreous floaters, occurred in 62% of 1669 patients. The majority (95%) of these patients had Grade 1 visual adverse reactions. 0.8% of patients had Grade 3 and 0.2% had Grade 4 visual impairment. The majority of patients on the XALKORI arms in Studies 1 and 2 (>50%) reported visual disturbances which occurred at a frequency of 4-7 days each week, lasted up to 1 minute, and had mild or no impact on daily activities.
Severe Visual Loss: Across clinical trials, the incidence of Grade 4 visual field defect with vision loss was 0.2% (N=1669). Discontinue XALKORI in patients with new onset of severe visual loss (best corrected vision less than 20/200 in one or both eyes). Perform an ophthalmological evaluation. There is insufficient information to characterize the risks of resumption of XALKORI in patients with a severe visual loss; a decision to resume should consider the potential benefits to the patient.
Embryofetal Toxicity: XALKORI can cause fetal harm when administered to a pregnant woman. Advise of the potential risk to the fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment and for at least 45 days (females) or 90 days (males) respectively, following the final dose of XALKORI.
Adverse Reactions: Safety was evaluated in a phase 3 study in previously untreated patients with ALK-positive metastatic NSCLC randomized to XALKORI (n=171) or chemotherapy (n=169). Serious adverse events were reported in 34% of patients treated with XALKORI, the most frequent were dyspnea (4.1%) and pulmonary embolism (2.9%). Fatal adverse events in XALKORI-treated patients occurred in 2.3% of patients, consisting of septic shock, acute respiratory failure, and diabetic ketoacidosis. Common adverse reactions (all grades) occurring in ≥25% and more commonly (≥5%) in patients treated with XALKORI vs chemotherapy were vision disorder (71% vs 10%), diarrhea (61% vs 13%), edema (49% vs 12%), vomiting (46% vs 36%), constipation (43% vs 30%), upper respiratory infection (32% vs 12%), dysgeusia (26% vs 5%), and abdominal pain (26% vs 12%). Grade 3/4 reactions occurring at a ≥2% higher incidence with XALKORI vs chemotherapy were QT prolongation (2% vs 0%), and constipation (2% vs 0%). In patients treated with XALKORI vs chemotherapy, the following occurred: elevation of ALT (any grade [79% vs 33%] or Grade 3/4 [15% vs 2%]); elevation of AST (any grade [66% vs 28%] or Grade 3/4 [8% vs 1%]); neutropenia (any grade [52% vs 59%] or Grade 3/4 [11% vs 16%]); lymphopenia (any grade [48% vs 53%] or Grade 3/4 [7% vs 13%]); hypophosphatemia (any grade [32% vs 21%] or Grade 3/4 [10% vs 6%]). In patients treated with XALKORI vs chemotherapy, renal cysts occurred (5% vs 1%). Nausea (56%) decreased appetite (30%), fatigue (29%), and neuropathy (21%) also occurred in patients taking XALKORI.
Drug Interactions: Exercise caution with concomitant use of moderate CYP3A inhibitors. Avoid grapefruit or grapefruit juice which may increase plasma concentrations of crizotinib. Avoid concomitant use of strong CYP3A inducers and inhibitors. Avoid concomitant use of CYP3A substrates with narrow therapeutic range in patients taking XALKORI. If concomitant use of CYP3A substrates with narrow therapeutic range is required in patients taking XALKORI, dose reductions of the CYP3A substrates may be required due to adverse reactions.
Lactation: Because of the potential for adverse reactions in breastfed infants, advise females not to breast feed during treatment with XALKORI and for 45 days after the final dose.
Hepatic Impairment: XALKORI has not been studied in patients with hepatic impairment. As crizotinib is extensively metabolized in the liver, hepatic impairment is likely to increase plasma crizotinib concentrations. Use caution in patients with hepatic impairment.
Renal Impairment: Administer XALKORI at a starting dose of 250 mg taken orally once daily in patients with severe renal impairment (CLcr <30 mL/min) not requiring dialysis. No starting dose adjustment is needed for patients with mild and moderate renal impairment.
MAJOR DRUG DISCOVERY FEASIBILITY STUDY WITH MERCK SERONO
On November 18, 2015 Cancer Research Technology (CRT) is pleased to reported that a major drug discovery feasibility study with Merck Serono, the biopharmaceutical business of Merck, focused on the role of the Hippo pathway in cancer (Press release, Cancer Research Technology, NOV 18, 2015, View Source [SID1234523508]).
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Under normal circumstances the Hippo pathway regulates cell size, controlling the growth of tissues during development and regeneration. Deregulation of the Hippo pathway has been implicated in inducing tumours in a broad range of cancers, making it a potentially attractive target for cancer therapy.
Scientists from CRT Discovery Laboratories (CRT-DL) will work together with Merck Serono scientists to validate the target, using CRT-DL’s expertise in building cell screening assays.
The establishment of this relationship exemplifies CRT-DL’s drug discovery model of bringing together complementary skills from academia and industry to build on novel insights within an exciting area of biology, which we hope will lead to new therapies for cancer patients.