On November 27, 2018 Generex Biotechnology Corporation (OTCMKTS:GNBT) reported that it has signed a clinical trial agreement (CTA) with the NSABP Foundation, Inc. (NSABP), to manage a Phase II clinical trial of Pembrolizumab (Keytruda) in combination with the AE37 Peptide Vaccine in Patients with Metastatic Triple Negative Breast Cancer (Press release, Generex, NOV 27, 2018, View Source [SID1234531648]).

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The clinical trial, sponsored by Generex and conducted in conjunction with Merck, is currently being reviewed by the FDA, and clinical operations including site qualification, drug shipment and packaging, and IRB review and approval are underway, with plans to enroll patients in the first quarter of 2019.

Eric von Hofe, President of Generex’s wholly-owned subsidiary Antigen Express, commented, "We are very pleased to be working with the NSABP Foundation on this important trial combining AE37 and Keytruda in triple-negative breast cancer patients. The extensive expertise of the NSABP Foundation and their network of sites and investigators will be a great asset in this development effort."

Generex EVP of R&D Richard Purcell commented, "This contract with our research partners at the NSABP Foundation provides cost and timeline certainty to our AE37 development program in combination with Keytruda. We look forward to our continued collaboration with Merck and the NSABP Foundation research team."

Previously, the Company reported that it filed an investigational new drug application (IND) with the U.S. Food & Drug Administration (FDA) to initiate A Phase II Clinical Trial of Pembrolizumab (Keytruda) in Combination with the AE37 Peptide Vaccine in Patients with Metastatic Triple Negative Breast Cancer.

About AE37

AE37 is an investigational therapeutic cancer vaccine being developed to treat cancer in women with certain types of breast cancer. It is a combination of portions of two proteins that together stimulate the immune system to fight cancer cells.

Up to 80 percent of breast cancers express some level of a protein called HER2. While treatments exist to target HER2 in breast cancer patients with the highest level of HER2 expression (roughly 25%), the majority of patients who have lower levels of expression have more limited treatment options. AE37 consists of a protein derived from the HER2 protein combined with a portion of the MHC class II associated invariant chain which has been termed Ii-Key.

AE37 does not directly target HER2, but instead acts as a vaccine to activate the immune system to recognize the HER2 protein that is expressed on cancer cells as foreign.

AE37 ensures activation of CD4-positive lymphocytes, immune cells that are important in stimulating both the antibody response (antibodies against HER2) and cellular responses directed against the HER2 protein in breast cancer cells. The Ii-Key peptide is coupled with the HER2 protein to ensure a more robust and long-lasting response

On November 27, 2018 BioClin Therapeutics, Inc., a privately-held clinical stage drug development company focused on helping patients in the high unmet need of bladder cancer, reported the company is changing its name to Rainier Therapeutics, Inc (Press release, BioClin Therapeutics, NOV 27, 2018, View Source [SID1234531647]).

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The new name, which will be implemented immediately, comes as the company prepares for late-stage, pivotal studies of its lead therapeutic candidate, vofatamab, which the company plans to initiate in 2019. Vofatamab (B-701) is an antibody specifically targeted against the FGFR3 receptor being developed for the treatment of patients in both early and late-stage bladder cancer.

"Our new logo incorporates the awe-inspiring image of a mountain and is designed to be symbolic for how we are striving to help our patients and caregivers, just as mountaineers strive to reach a summit. It also illustrates the challenging journey our patients face with this disease," commented Scott Myers, Chairman and CEO of Rainier Therapeutics. "We look forward to supporting late-stage clinical development efforts for vofatamab and are assembling an experienced, fully integrated team to provide support in multiple facets of operations."

On November 27, 2018 Takeda Pharmaceutical Company Limited (TSE: 4502) reported that the European Commission (EC) granted marketing authorization for 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, NOV 27, 2018, View Source [SID1234531645]). The decision follows a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) on September 20, 2018.

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"The introduction of targeted therapies has greatly improved the treatment of ALK+ NSCLC, yet for the approximately 70 percent of patients who progress on crizotinib with brain metastases, additional therapeutic options are needed," said Enriqueta Felip, M.D., PhD., Head of the Thoracic Oncology Unit, Oncology Department at Vall d’Hebron University Hospital in Barcelona. "Data from the ALTA trial investigating ALUNBRIG showed sustained systemic and intracranial efficacy results and a manageable safety profile, leading to the longest progression-free survival and overall survival reported in this setting. This approval gives physicians in the European Union another choice in addressing ALK+ NSCLC patients previously treated with crizotinib."

"The European Commission’s decision to approve ALUNBRIG for patients with ALK+ NSCLC is a significant advancement for European patients impacted by this life-threatening disease," said Jesús Gómez-Navarro, M.D., Vice President, Head of Oncology Clinical Research and Development, Takeda. "This is the first time a median progression-free survival of over 16 months as assessed by an independent review committee and median overall survival of 34 months have been reported in the post-crizotinib setting, which highlights the strength of the ALTA trial data. The authorization of ALUNBRIG in the EU speaks to our ongoing commitment to developing innovative solutions to improve the lives of the approximately 40,000 patients diagnosed with this disease worldwide each year."

"Many people are unaware of ALK+ NSCLC and its nuances, including the fact this type of lung cancer tends to affect people at a younger age, and it is not associated with smoking," said Stefania Vallone, President, Lung Cancer Europe. "These younger patients are often in the prime of their lives and in the middle of raising their families, focusing on their careers, and contributing to their community. The availability of new treatments to potentially extend time without disease progression is very important and cannot be underestimated."

The European Commission’s approval is based on data from the global Phase 2 ALTA trial, in which patients were randomized to receive one of two dosing regimens of ALUNBRIG: 90 mg once daily (n=112) or the recommended dosing regimen of 180 mg once daily with seven-day lead-in at 90 mg once daily (n=110). Results showed that of the patients who received the recommended dosing regimen, 56 percent achieved an objective response rate (ORR), and the median duration of response (DOR) was 15.7 months as assessed by independent review committee (IRC). ALUNBRIG demonstrated a median progression-free survival (PFS) of 16.7 months by IRC assessment and overall survival of 34.1 months for patients with locally advanced or metastatic ALK+ NSCLC who had progressed on crizotinib.

The most common adverse reactions (≥25%) reported in patients treated with ALUNBRIG at the recommended 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. The most common serious adverse reactions (≥ 2 percent) reported in patients treated with ALUNBRIG at the recommended dosing regimen other than events related to neoplasm progression were pneumonitis, pneumonia, and dyspnea.

This decision by the European Commission means that ALUNBRIG is now approved for marketing of this indication in the 28 member states of the European Union, and applicable in Norway, Liechtenstein and Iceland. For further details about the European Commission decision, please visit the European Medicines Agency website: www.ema.europe.eu/ema.

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.

Among patients who received the 90 mg dosing regimen, 46 percent achieved an ORR as assessed by investigator and 51 percent as assessed by IRC. The median DOR was 12.0 months as assessed by investigator and 16.4 months by IRC assessment. Median PFS was 9.2 months as assessed by both investigator and IRC assessment. Additionally, of the patients with measurable brain metastases at baseline (n=26), 50 percent achieved an intracranial ORR by IRC assessment; median duration of intracranial response was 9.4 months by IRC assessment. Median overall survival was 29.5 months.

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.

ALUNBRIG (brigatinib): EUROPEAN IMPORTANT SAFETY INFORMATION

SPECIAL WARNINGS AND PRECAUTIONS FOR USE

Pulmonary Adverse Reactions: Severe, life-threatening, and fatal pulmonary adverse reactions, including those with features consistent with ILD/pneumonitis, can occur. Most pulmonary adverse reactions were observed within the first 7 days of treatment. Grade 1-2 pulmonary adverse reactions resolved with interruption of treatment or dose modification. Increased age and shorter interval (less than 7 days) between the last dose of crizotinib and the first dose of ALUNBRIG were independently associated with an increased rate of these pulmonary adverse reactions. Consider these factors when initiating treatment with ALUNBRIG. Some patients experienced pneumonitis later in treatment with ALUNBRIG. Patients should be monitored for new or worsening respiratory symptoms (e.g., dyspnoea, cough, etc.), particularly in the first week of treatment. Evidence of pneumonitis in any patient with worsening respiratory symptoms should be promptly investigated. If pneumonitis is suspected, the dose of ALUNBRIG should be withheld, and the patient evaluated for other causes of symptoms (e.g., pulmonary embolism, tumour progression, and infectious pneumonia). The dose should be modified accordingly.

Hypertension has occurred. Blood pressure should be monitored regularly during treatment with ALUNBRIG. Hypertension should be treated according to standard guidelines to control blood pressure. Heart rate should be monitored more frequently in patients if concomitant use of a medication known to cause bradycardia cannot be avoided. For severe hypertension (≥ Grade 3), ALUNBRIG should be withheld until hypertension has recovered to Grade 1 or to baseline. The dose should be modified accordingly.

Bradycardia has occurred. Caution should be exercised when administering ALUNBRIG in combination with other agents known to cause bradycardia. Heart rate and blood pressure should be monitored regularly. Treatment with ALUNBRIG should be withheld if symptomatic bradycardia occurs. Concomitant medications known to cause bradycardia should be evaluated. Upon recovery, dose should be modified accordingly. In case of life-threatening bradycardia, permanently discontinue ALUNBRIG if no contributing concomitant medication is identified or in the case of recurrence. If contributing concomitant medication is identified, modify dose accordingly.

Visual Disturbance has occurred with ALUNBRIG. Patients should be advised to report any visual symptoms. For new or worsening severe visual symptoms, an ophthalmologic evaluation and dose reduction should be considered.

Creatine Phosphokinase (CPK) Elevation has been reported. Advise patients to report any unexplained muscle pain, tenderness, or weakness. Monitor CPK levels regularly during treatment. Based on the severity of the CPK elevation, withhold treatment with ALUNBRIG and modify dose accordingly.

Pancreatic Enzyme Elevation: Elevations of amylase and lipase have occurred. Lipase and amylase should be monitored regularly during treatment with ALUNBRIG. Based on the severity of the laboratory abnormalities, withhold ALUNBRIG and modify dose accordingly.

Hepatotoxicity: Elevations of hepatic enzymes (aspartate aminotransferase, alanine aminotransferase) and bilirubin have occurred. Liver function, including AST, ALT and total bilirubin should be assessed prior to the initiation of ALUNBRIG and then every 2 weeks during the first 3 months of treatment. Thereafter, monitoring should be performed periodically. Based on the severity of the laboratory abnormalities, withhold ALUNBRIG and modify dose accordingly.

Hyperglycemia: Elevations of serum glucose have occurred. Fasting serum glucose should be assessed prior to initiation of ALUNBRIG and monitored periodically thereafter. Antihyperglycaemic treatment should be initiated or optimised as needed. If adequate hyperglycaemic control cannot be achieved with optimal medical management, ALUNBRIG should be withheld until adequate hyperglycaemic control is achieved; upon recovery reducing the dose may be considered or ALUNBRIG may be permanently discontinued.

Drug drug interactions: Concomitant use of ALUNBRIG with strong CYP3A inhibitors should be avoided. If concomitant use of strong CYP3A inhibitors cannot be avoided, reduce dose of ALUNBRIG from 180 mg to 90 mg, or from 90 mg to 60 mg. After discontinuation of a strong CYP3A inhibitor, ALUNBRIG should be resumed at the dose that was tolerated prior to the initiation of the strong CYP3A inhibitor. The concomitant use of ALUNBRIG with strong and moderate CYP3A inducers should be avoided.

Fertility: Women of childbearing potential should be advised to use effective non-hormonal contraception during treatment with ALUNBRIG and for at least 4 months following the final dose. Men with female partners of childbearing potential should be advised to use effective contraception during treatment and for at least 3 months after the last dose of ALUNBRIG

Lactose: ALUNBRIG contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medication.

UNDESIRABLE EFFECTS
The most common adverse reactions (≥ 25%) reported in patients treated with ALUNBRIG at the recommended dosing regimen were increased AST, hyperglycaemia, hyperinsulinaemia, anaemia, increased CPK, nausea, increased lipase, decreased lymphocyte count, increased ALT, diarrhoea, increased amylase, fatigue, cough, headache, increased alkaline phosphatase, hypophosphataemia, increased APTT, rash, vomiting, dyspnoea, hypertension, decreased white blood cell count, myalgia, and peripheral neuropathy.

The most common serious adverse reactions (≥ 2%) reported in patients treated with ALUNBRIG at the recommended dosing regimen other than events related to neoplasm progression were pneumonitis, pneumonia, and dyspnoea.

SPECIAL POPULATIONS

Elderly patients: The limited data on the safety and efficacy of ALUNBRIG in patients aged 65 years and older suggest that a dose adjustment is not required in elderly patients. There are no available data on patients over 85 years of age.

Hepatic impairment: No dose adjustment of ALUNBRIG is required for patients with mild hepatic impairment (Child-Pugh class A) or moderate hepatic impairment (Child-Pugh class B). A reduced starting dose of 60 mg once daily for the first 7 days, then 120 mg once daily is recommended for patients with severe hepatic impairment (Child-Pugh class C).

Renal impairment: No dose adjustment of ALUNBRIG is required for patients with mild or moderate renal impairment (estimated glomerular filtration rate (eGFR) ≥ 30 mL/min). A reduced starting dose of 60 mg once daily for the first 7 days, then 90 mg once daily is recommended for patients with severe renal impairment (eGFR < 30 mL/min). Patients with severe renal impairment should be closely monitored for new or worsening respiratory symptoms that may indicate ILD/pneumonitis (e.g., dyspnoea, cough, etc.) particularly in the first week.

Paediatric population: The safety and efficacy of ALUNBRIG in patients less than 18 years of age have not been established. No data are available.

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 November 27, 2018 Acceleron Pharma Inc. (NASDAQ:XLRN), a leading biopharmaceutical company in the discovery and development of TGF-beta therapeutics to treat serious and rare diseases, reported it will host a conference call and live audio webcast on Monday, December 3, 2018 at 9:00 a.m. EST to review the MEDALIST and BELIEVE Phase 3 trial presentations of luspatercept at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition taking place on December 1-4, 2018 in San Diego, California (Press release, Acceleron Pharma, NOV 27, 2018, View Source [SID1234531644]).

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Guest Presenters:

Alan F. List, M.D., President and CEO of Moffitt Cancer Center, Senior member in the Department of Malignant Hematology and the Experimental Therapeutics Program, Professor of Internal Medicine and Oncology at the University of South Florida Morsani College of Medicine
Maria Domenica Cappellini, M.D., Chief of the Internal Medicine Unit, Professor of Internal Medicine, University of Milan, Chief of the Rare Disease Centre at the Policlinico Hospital IRCCS Foundation Ca’ Granda, Milan, Italy
Participants can access the live conference call by dialing 877-312-5848 (domestic) or 253-237-1155 (international) and referring to the "Acceleron ASH (Free ASH Whitepaper) 2018 Conference Call."

The live webcast can be accessed under "Events & Presentations" in the Investors/Media page of the company’s website at www.acceleronpharma.com.

A replay of the webcast will be available approximately two hours after the event on the Acceleron website.

On November 27, 2018 AstraZeneca, together with Acerta Pharma, its hematology research and development center of excellence, and MedImmune, its global biologics research and development arm, reported that it will present 27 abstracts, including six oral presentations, at the 2018 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition in San Diego, CA, December 1-4 (Press release, AstraZeneca, NOV 27, 2018, View Source [SID1234531643]).

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

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New data include presentations on CALQUENCE (acalabrutinib) and LUMOXITI (moxetumomab pasudotox-tdfk), as well as research findings from AstraZeneca’s early pipeline, across a variety of blood cancers.

Dave Fredrickson, Executive Vice President, Head of Oncology Business Unit, said: "In less than a year, we have launched two innovative medicines to treat blood cancers. At this year’s ASH (Free ASH Whitepaper), we will continue our momentum by presenting new results from two important trials of CALQUENCE in mantle cell lymphoma and chronic lymphocytic leukemia, and further showcase our broad pipeline with data from our novel MCL1 and CDK9 inhibitors."

Updated results for acalabrutinib in chronic lymphocytic leukemia (CLL)

An oral presentation will focus on new three-year follow-up efficacy and safety results (median 33 months) from the ongoing Phase I/II ACE-CL-001 clinical trial, assessing acalabrutinib monotherapy in a cohort of treatment-naive patients with CLL (Abstract #692).

These data expand on findings previously reported and highlight the promising overall and durable response rates and safety profile in this patient population. Trial data continue to be collected and analyzed.

New long-term CALQUENCE data in previously-treated mantle cell lymphoma (MCL)

Long-term follow up data (median 26.3 months) being presented for CALQUENCE further confirm results from the registrational Phase II ACE-LY-004 clinical trial in relapsed or refractory MCL (Abstract #2876). Initial analysis of this trial served as the basis for the accelerated approval of CALQUENCE for the treatment of adult patients with MCL who have received at least one prior therapy by the US Food and Drug Administration (FDA) in October 2017.

New data from recently approved LUMOXITI

Results will be presented from trials of LUMOXITI in relapsed or refractory hairy cell leukemia which evaluated whether minimal residual disease eradication, as measured by different quantitative testing approaches, is associated with improved complete response duration (Abstract #1861).

Early pipeline offers new insights into MCL1 inhibition and resistance

New data from AstraZeneca’s early hematology pipeline will be presented, including four oral presentations, on different potential new medicines across multiple blood cancers. The presentations feature new insights into the therapeutic potential of inhibiting the anti-apoptotic protein, myeloid cell leukemia-1 (MCL1) target.

Key pipeline data that will be presented includes preclinical activity of the novel MCL1 inhibitor AZD5991 in multiple myeloma (Abstract #952), findings on the potential to overcome MCL1 resistance in multiple myeloma (Abstract #472), and data on the influence of myeloma patient-derived MCL1 point mutations in MCL1-inhibitor function (Abstract #951). Data will also be presented on MCL1/CDK9 targeting by AZD5991 and the CDK9 inhibitor AZD4573 (Abstract #768).

Key AstraZeneca, Acerta and MedImmune presentations at ASH (Free ASH Whitepaper) 2018:

Lead author Title Presentation details
Acalabrutinib
Wang, M
Long-Term Follow-Up of
Acalabrutinib Monotherapy in
Patients With Relapsed/Refractory
Mantle Cell Lymphoma

Poster session
Sunday, December 2, 6:00-8:00 PM
Location: San Diego Convention
Center, Hall GH
Abstract #2876

Byrd, J
Acalabrutinib in Treatment-Naïve
(TN) Chronic Lymphocytic
Leukemia (CLL): Updated Results
from the Phase 1/2 ACE-CL-001
Study

Oral session
Monday, December 3
Presentation time: 10:45 AM
Location: San Diego Convention
Center, Ballroom 20A
Abstract #692

Kabadi, S
Real World Treatment Patterns,
Adverse Events and Healthcare
Resource Utilization and Costs
Among Chronic Lymphocytic
Leukemia (CLL) Patients in the
United States

Oral session
Monday, December 3
Presentation time: 3:15 PM
Location: San Diego Convention
Center, Room 25B
Abstract #837

Moxetumomab pasudotox
Arons, E
Molecular Remissions with Anti-
CD22 Recombinant Immunotoxin
Moxetumomab Pasudotox are
Associated with Improved
Complete Remission Durations
During Phase I and III Testing

Poster session
Saturday December 1, 6:15-8:15 PM
Location: San Diego Convention
Center, Hall GH
Abstract #1861

Early pipeline
Siu, K
Overcoming MCL1 Resistance in
Multiple Myeloma

Oral session
Sunday, December 2
Presentation time: 5:15 PM
Location: Marriott Marquis San
Diego Marina, Grand Ballroom 7
Abstract #472

Carter, B
MCL-1/CDK9 Targeting by
AZD5991/AZD4573 Overcomes
Intrinsic and Acquired Venetoclax
Resistance in Vitro and in Vivo in PDX
Model of AML Through
Modulation of Cell Death and
Novel Metabolic Functions

Oral session
Monday, December 3
Presentation time: 4:00 PM
Location: Manchester Grand Hyatt
San Diego, Seaport Ballroom F
Abstract #768

Chen, B
Myeloma Patient-Derived MCL1
Point Mutations can Influence
MCL1-Inhibitor Function

Oral session
Monday, December 3
Presentation time: 5:00 PM
Location: San Diego Convention
Center, Ballroom 20D
Abstract #951

Matulis, S
Preclinical Activity of Novel MCL1
Inhibitor AZD5991 in Multiple
Myeloma

Oral session
Monday, December 3
Presentation time: 5:15 PM
Location: San Diego Convention
Center, Ballroom 20D
Abstract #952

CALQUENCE (acalabrutinib) Important Safety Information

Hemorrhage

Serious hemorrhagic events, including fatal events, have occurred in the combined safety database of 612 patients with hematologic malignancies treated with CALQUENCE monotherapy. Grade 3 or higher bleeding events, including gastrointestinal, intracranial, and epistaxis, have been reported in 2% of patients. Overall, bleeding events, including bruising and petechiae of any grade, occurred in approximately 50% of patients with hematological malignancies.

The mechanism for the bleeding events is not well understood.

CALQUENCE may further increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies, and patients should be monitored for signs of bleeding.

Consider the benefit-risk of withholding CALQUENCE for 3 to 7 days pre- and post-surgery, depending upon the type of surgery and the risk of bleeding.

Infection

Serious infections (bacterial, viral, or fungal), including fatal events and opportunistic infections, have occurred in the combined safety database of 612 patients with hematologic malignancies treated with CALQUENCE monotherapy. Grade 3 or higher infections occurred in 18% of these patients. The most frequently reported Grade 3 or 4 infection was pneumonia. Infections due to hepatitis B virus (HBV) reactivation and progressive multifocal leukoencephalopathy (PML) have occurred.

Monitor patients for signs and symptoms of infection and treat as medically appropriate. Consider prophylaxis in patients who are at increased risk for opportunistic infections.

Cytopenias

In the combined safety database of 612 patients with hematologic malignancies, patients treated with CALQUENCE monotherapy experienced Grade 3 or 4 cytopenias, including neutropenia (23%), anemia (11%), and thrombocytopenia (8%), based on laboratory measurements. Monitor complete blood counts monthly during treatment.

Second Primary Malignancies

Second primary malignancies, including non-skin carcinomas, have occurred in 11% of patients with hematologic malignancies treated with CALQUENCE monotherapy in the combined safety database of 612 patients. The most frequent second primary malignancy was skin cancer, reported in 7% of patients. Advise protection from sun exposure.

Atrial Fibrillation and Flutter

In the combined safety database of 612 patients with hematologic malignancies treated with CALQUENCE monotherapy, atrial fibrillation and atrial flutter of any grade occurred in 3% of patients, and Grade 3 in 1% of patients. Monitor for atrial fibrillation and atrial flutter and manage as appropriate.

ADVERSE REACTIONS

The most common adverse reactions (≥20%) of any grade were anemia,* thrombocytopenia,* headache (39%), neutropenia,* diarrhea (31%), fatigue (28%), myalgia (21%), and bruising (21%).

*Treatment-emergent decreases (all grades) of hemoglobin (46%), platelets (44%), and neutrophils (36%) were based on laboratory measurements and adverse reactions.

The most common Grade ≥ 3 non-hematological adverse reaction (reported in at least 2% of patients) was diarrhea (3.2%).

Dosage reductions or discontinuations due to any adverse reaction were reported in 1.6% and 6.5% of patients, respectively.

Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 4.8% of patients.

DRUG INTERACTIONS

Strong CYP3A Inhibitors: Avoid co-administration with a strong CYP3A inhibitor. If a strong CYP3A inhibitor will be used short-term, interrupt CALQUENCE.

Moderate CYP3A Inhibitors: When CALQUENCE is co-administered with a moderate CYP3A inhibitor, reduce CALQUENCE dose to 100 mg once daily.

Strong CYP3A Inducers: Avoid co-administration with a strong CYP3A inducer. If a strong CYP3A inducer cannot be avoided, increase the CALQUENCE dose to 200 mg twice daily.

Gastric Acid Reducing Agents: If treatment with a gastric acid reducing agent is required, consider using an H2-receptor antagonist or an antacid. Take CALQUENCE 2 hours before taking an H2-receptor antagonist. Separate dosing with an antacid by at least 2 hours.

Avoid co-administration with proton pump inhibitors. Due to the long-lasting effect of proton pump inhibitors, separation of doses may not eliminate the interaction with CALQUENCE.

SPECIFIC POPULATIONS

There is insufficient clinical data on CALQUENCE use in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. Advise women of the potential risk to a fetus.

It is not known if CALQUENCE is present in human milk. Advise lactating women not to breastfeed while taking CALQUENCE and for at least 2 weeks after the final dose.

INDICATIONS

CALQUENCE is a Bruton tyrosine kinase (BTK) inhibitor indicated for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.

This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Please see complete Prescribing Information including Patient Information.

LUMOXITI (moxetumomab pasudotox-tdfk) Important Safety Information, INCLUDING BOXED WARNING

WARNING: CAPILLARY LEAK SYNDROME and HEMOLYTIC UREMIC SYNDROME

Capillary Leak Syndrome (CLS), including life-threatening cases, occurred in patients receiving LUMOXITI. Monitor weight and blood pressure; check labs, including albumin, if CLS is suspected. Delay dosing or discontinue LUMOXITI as recommended
Hemolytic Uremic Syndrome (HUS), including life-threatening cases, occurred in patients receiving LUMOXITI. Monitor hemoglobin, platelet count, serum creatinine, and ensure adequate hydration. Discontinue LUMOXITI in patients with HUS
WARNINGS AND PRECAUTIONS

Capillary leak syndrome (CLS), including life-threatening cases, has been reported among patients treated with LUMOXITI and is characterized by hypoalbuminemia, hypotension, symptoms of fluid overload, and hemoconcentration. In the combined safety database of HCL patients treated with LUMOXITI, CLS occurred in 34% (44/129) of patients, including Grade 2 in 23% (30/129), Grade 3 in 1.6% (2/129), and Grade 4 in 2% (3/129).
Most cases of CLS occurred in the first 8 days (range: 1 to 19) of a treatment cycle, however, cases have also been reported on other days throughout the cycle. The median time to resolution of CLS was 12 days (range: 1 to 53).

Monitor patient weight and blood pressure prior to each LUMOXITI infusion and as clinically indicated during treatment. Assess patients for signs and symptoms of CLS, including weight gain (increase in 5.5 pounds (2.5 kg) or ≥ 5% from Day 1 of current cycle), hypotension, peripheral edema, shortness of breath or cough, and pulmonary edema and/or serosal effusions. In addition, the following changes in laboratory parameters may help identify CLS: hypoalbuminemia, elevated hematocrit, leukocytosis, and thrombocytosis.

CLS may be life-threatening or fatal if treatment is delayed. Counsel patients to seek immediate medical attention should signs or symptoms of CLS occur at any time. Patients who develop CLS should receive appropriate supportive measures, including concomitant oral or intravenous corticosteroids, and hospitalization as clinically indicated. Withhold LUMOXITI for Grade 2 CLS until resolution, and permanently discontinue for Grade ≥ 3 CLS.

Hemolytic Uremic Syndrome (HUS), including life threatening cases, has been reported in patients treated with LUMOXITI and is characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and progressive renal failure. In the combined safety database of HCL patients treated with LUMOXITI, HUS occurred in 7% (9/129) of patients, including Grade 3 in 3% (4/129) and Grade 4 in 0.8% (1/129).
Most cases of HUS occurred in the first 9 days (range: 1 to 16) of a treatment cycle, however, cases have also been reported on other days throughout the cycle. The median time to resolution of HUS was 11.5 days (range: 2 to 44). All cases resolved, including those who discontinued LUMOXITI.

Avoid LUMOXITI in patients with prior history of severe thrombotic microangiopathy (TMA) or HUS. Administer prophylactic intravenous fluids before and after LUMOXITI infusions. In Study 1053, patients with a platelet count ≥ 100,000/mm3 received low-dose aspirin on Days 1 through 8 of each 28-day cycle for prophylaxis of thrombosis.

Monitor blood chemistry and complete blood counts prior to each dose and on Day 8 of each treatment cycle. Monitoring mid-cycle is also recommended. Consider the diagnosis of HUS in patients who develop hemolytic anemia, worsening or sudden onset of thrombocytopenia, increase in creatinine levels, elevation of bilirubin and/or LDH, and have evidence of hemolysis based on peripheral blood smear schistocytes.

The events of HUS may be life-threatening if treatment is delayed with increased risk of progressive renal failure requiring dialysis. If HUS is suspected initiate appropriate supportive measures, including fluid repletion, hemodynamic monitoring, and consider hospitalization as clinically indicated. Discontinue LUMOXITI in patients with HUS.

Renal Toxicity has been reported in patients treated with LUMOXITI therapy. In the combined safety database of HCL patients treated with LUMOXITI, 26% (34/129) reported adverse events of renal toxicity, including acute kidney injury (2.3%), renal failure (2.3%), renal impairment (1.6%), serum creatinine increased (17%), and proteinuria (8%). Grade 3 acute kidney injury occurred in 1.6% (2/129) of patients.
Based on laboratory findings, during treatment, serum creatinine increased by two or more grades from baseline in 22% (29/129) of patients, including increases of Grade 3 in 1.6% (2/129) of patients. At the end of treatment, serum creatinine levels remained elevated at 1.5- to 3-times the upper limit of normal in 5% of patients. Patients who experience HUS, those ≥ 65 years of age, or those with baseline renal impairment may be at increased risk for worsening of renal function following treatment with LUMOXITI.

Monitor renal function prior to each infusion of LUMOXITI, and as clinically indicated throughout treatment. Delay LUMOXITI dosing in patients with Grade ≥ 3 elevations in creatinine, or upon worsening from baseline by ≥ 2 grades.

Infusion Related Reactions occurred in patients treated with LUMOXITI, and were defined as the occurrence of any one of the following events on the day of study drug infusion: chills, cough, dizziness, dyspnea, feeling hot, flushing, headache, hypertension, hypotension, infusion related reaction, myalgia, nausea, pyrexia, sinus tachycardia, tachycardia, vomiting, or wheezing. In Study 1053, infusion related reactions occurred in 50% (40/80) of patients, including Grade 3 events in 11% (9/80) of patients. The most frequently reported infusion related events were nausea (15%), pyrexia (14%), chills (14%), vomiting (11%), headache (9%), and infusion related reaction (9%).
Infusion related reactions may occur during any cycle of treatment with LUMOXITI. Premedicate with antihistamines and antipyretics prior to each LUMOXITI dose. If a severe infusion related reaction occurs, interrupt the LUMOXITI infusion and institute appropriate medical management. Administer an oral or intravenous corticosteroid approximately 30 minutes before resuming, or before the next LUMOXITI infusion.

Electrolyte Abnormalities: In the combined safety database of HCL patients treated with LUMOXITI, electrolyte abnormalities occurred in 57% (73/129) of patients with the most common electrolyte abnormality being hypocalcemia occurring in 25% of patients. Grade 3 electrolyte abnormalities occurred in 14% (18/129) of patients and Grade 4 electrolyte abnormalities occurred in 0.8% (1/129) of patients. Electrolyte abnormalities co-occurred in the same treatment cycle with CLS, HUS, fluid retention, or renal toxicity in 37% (48/129) of patients.
Monitor serum electrolytes prior to each dose and on Day 8 of each treatment cycle. Monitoring mid-cycle is also recommended.

ADVERSE REACTIONS

Most common non-laboratory adverse reactions (≥ 20%) of any grade were infusion related reactions (50%), edema peripheral (39%), nausea (35%), fatigue (34%), headache (33%), pyrexia (31%), constipation (23%), anemia (21%), and diarrhea (21%). The most common Grade 3 or 4 adverse reactions (reported in at least ≥ 5% of patients) were hypertension, febrile neutropenia, and HUS.
Most common laboratory abnormalities (≥ 20%) of any grade were creatinine increased, ALT increased, hypoalbuminemia, AST increased, hypocalcemia, hypophosphatemia, hemoglobin decreased, neutrophil count decreased, hyponatremia, blood bilirubin increased, hypokalemia, GGT increased, hypomagnesemia, platelet count decreased, hyperuricemia, and alkaline phosphate increased.
Adverse reactions resulting in permanent discontinuation of LUMOXITI occurred in 15% (12/80) of patients. The most common adverse reaction leading to LUMOXITI discontinuation was HUS (5%). The most common adverse reaction resulting in dose delays, omissions, or interruptions was pyrexia (3.8%).
SPECIFIC POPULATIONS

Pregnancy: There are no available data on LUMOXITI use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. Advise pregnant women of the potential risk to a fetus.
Lactation: Advise women not to breastfeed.
Geriatric Use: Exploratory analyses suggest a higher incidence of adverse reactions leading to drug discontinuation (23% versus 7%) and renal toxicity (40% versus 20%) for patients 65 years of age or older as compared to those younger than 65 years.
Please see full Prescribing Information, including Boxed WARNING, Patient Information (Medication Guide), and Instructions for Use

NOTES TO EDITORS

About AstraZeneca in Hematology

Leveraging its strength in oncology, AstraZeneca has established hematology as one of four key oncology disease areas of focus. The company’s hematology franchise includes two US FDA-approved medicines and a robust global development program for a broad portfolio of potential blood cancer treatments. Acerta Pharma serves as AstraZeneca’s hematology research and development center of excellence. AstraZeneca partners with like-minded science-led companies to advance the discovery and development of therapies to address unmet need.

In October 2018, AstraZeneca and Innate Pharma announced a global strategic collaboration that included Innate Pharma licensing the US commercial rights of LUMOXITI, and with support from AstraZeneca, will continue EU development and commercialization, pending regulatory submission and approval.