ASH News Daily 2013 - Day 2 - (Page B-27)

ASH News Daily Sunday, December 8, 2013 Page B-27 ® medicine, the PhD can develop the skills to participate in and lead translational research teams to improve human health. FocuS on traineeS Trainee Events Monday, December 9 12:15 - 1:15 p.m. tion is the cultural difference between basic science investigators and physician scientists. Although a bidirectional understanding of this difference is essential, the perspective of the non-clinician PhD will be emphasized in this session. Working at the intersection of biomedical science and clinical Giving a Scientific Presentation Speaker: Theodore Warkentin, MD, McMaster University, Hamilton, Ontario, Canada Presentation of one's scholarly work is an essential task for an academic career and the effective communication techniques that allow for engaging presentations need to be learned and honed over time. «« From Page B-23 reported (<  1%). KYPROLIS can cause elevations of serum transaminases and bilirubin. Withhold KYPROLIS in patients experiencing Grade 3 or greater elevations of transaminases, bilirubin, or other liver abnormalities until resolved or returned to baseline. After resolution, consider if restarting KYPROLIS is appropriate. Monitor liver enzymes frequently [see Dosage and Administration and Adverse Reactions]. Embryo-fetal Toxicity. KYPROLIS can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. There are no adequate and well‑controlled studies in pregnant women using KYPROLIS. Carfilzomib caused embryo‑fetal toxicity in pregnant rabbits at doses that were lower than in patients receiving the recommended dose. Females of reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations]. ADVERSE REACTIONS: The following adverse reactions are discussed in greater detail in other sections of the labeling: * Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia [see Warnings and Precautions] * Pulmonary Hypertension [see Warnings and Precautions] * Pulmonary Complications [see Warnings and Precautions] * Infusion Reactions [see Warnings and Precautions] * Tumor Lysis Syndrome [see Warnings and Precautions] * Thrombocytopenia [see Warnings and Precautions] * Hepatic Toxicity and Hepatic Failure [see Warnings and Precautions] The most common adverse reactions (incidence of 30% or greater) to KYPROLIS observed in clinical trials of patients with multiple myeloma were fatigue, anemia, nausea, thrombocytopenia, dyspnea, diarrhea, and pyrexia. Clinical Trials Safety Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug, and may not reflect the rates observed in medical practice. A total of 526 patients with relapsed and/or refractory multiple myeloma received KYPROLIS as monotherapy or with pre‑dose dexamethasone. Patients received a median of four treatment cycles with a median cumulative KYPROLIS dose of 993.4 mg. Deaths due to all causes within 30 days of the last dose of KYPROLIS occurred in 37/526 (7%) of patients. Deaths not attributed to disease progression were cardiac in 5 patients (acute coronary syndrome, cardiac arrest, cardiac disorder), end‑organ failure in 4 patients (multi‑organ failure, hepatic failure, renal failure), infection in 4 patients (sepsis, pneumonia, respiratory tract bacterial infection), dyspnea and intracranial hemorrhage in 1 patient each, and 1 patient found dead of unknown causes. Serious adverse reactions were reported in 45% patients. The most common serious adverse reactions were pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%). Adverse reactions leading to discontinuation of KYPROLIS occurred in 15% of patients and included congestive heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, and acute renal failure (1% each). Adverse reactions occurring at a rate of 10% or greater are presented in Table 4. Table 4: Incidence of Adverse Reactions Occurring in ≥ 10% of Multiple Myeloma Patients Treated with KYPROLIS Event Fatigue Anemia Nausea Thrombocytopenia Dyspnea Diarrhea Pyrexia Upper respiratory tract infection Headache Cough Blood creatinine increased Lymphopenia Edema peripheral Vomiting Constipation Neutropenia Back pain Insomnia Chills Arthralgia Muscle spasms Hypertension Asthenia Hypokalemia Hypomagnesemia Leukopenia Pain in extremity Pneumonia Aspartate aminotransferase increased Dizziness Hypoesthesia Anorexia Pain Hyperglycemia Chest wall pain Hypercalcemia Hypophosphatemia Hyponatremia All Gradesa 292 (55.5) 246 (46.8) 236 (44.9) 191 (36.3) 182 (34.6) 172 (32.7) 160 (30.4) 149 (28.3) 145 (27.6) 137 (26.0) 127 (24.1) 126 (24.0) 126 (24.0) 117 (22.2) 110 (20.9) 109 (20.7) 106 (20.2) 94 (17.9) 84 (16.0) 83 (15.8) 76 (14.4) 75 (14.3) 73 (13.9) 72 (13.7) 71 (13.5) 71 (13.5) 70 (13.3) 67 (12.7) 66 (12.5) 66 (12.5) 64 (12.2) 63 (12.0) 63 (12.0) 62 (11.8) 60 (11.4) 58 (11.0) 55 (10.5) 54 (10.3) Patients (N = 526) [n (%)] Grade 3 Events 38 (7.2) 111 (21.1) 7 (1.3) 69 (13.1) 25 (4.8) 4 (0.8) 7 (1.3) 17 (3.2) 7 (1.3) 1 (0.2) 13 (2.5) 84 (16.0) 3 (0.6) 5 (1.0) 1 (0.2) 50 (9.5) 15 (2.9) 0 1 (0.2) 7 (1.3) 2 (0.4) 15 (2.9) 12 (2.3) 14 (2.7) 2 (0.4) 27 (5.1) 7 (1.3) 52 (9.9) 15 (2.9) 5 (1.0) 3 (0.6) 1 (0.2) 12 (2.3) 16 (3.0) 3 (0.6) 13 (2.5) 24 (4.6) 31 (5.9) Grade 4 Events 2 (0.4) 7 (1.3) 0 54 (10.3) 1 (0.2)b 1 (0.2) 2 (0.4) 0 0 0 1 (0.2) 11 (2.1) 0 0 0 4 (0.8) 0 0 0 0 0 2 (0.4) 1 (0.2) 3 (0.6) 0 1 (0.2) 0 3 (0.6)b 1 (0.2) 1 (0.2) 0 0 0 3 (0.6) 0 8 (1.5) 3 (0.6) 3 (0.6) National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0. b One event was Grade 5 severity. a This session will cover presentation styles and proper construction of slides and posters, highlighting common presentation pitfalls as well as tactics to help engage an audience. Attendees will learn how to make the most of opportunities to present their scholarly work and receive valuable feedback. Practical Biostatistics 101 Speaker: Lillian Sung, MD, PhD, The Hospital for Sick Children, Toronto, Ontario, Canada This session is designed to help translate the complexities of statistics into relevant clinical applications and will provide a practical Description of Selected Adverse Drug Reactions. Renal Events: The most common renal adverse reactions were increase in blood creatinine (24%) and renal failure (9%), which were mostly Grade  1 or Grade  2 in severity. Grade  3 renal adverse reactions occurred in 6% of patients and Grade 4 events occurred in 1%. Discontinuations due to increased blood creatinine and acute renal failure were 1% each. In one patient, death occurred with concurrent sepsis and worsening renal function [see Dosage and Administration]. Peripheral Neuropathy: Peripheral neuropathy (including all events of peripheral sensory neuropathy and peripheral motor neuropathy) occurred in 14% of patients enrolled in clinical trials. Grade 3 peripheral neuropathy occurred in 1% of patients. Serious peripheral neuropathy events occurred in < 1% of patients, which resulted in dose reduction in < 1% and treatment discontinuation in < 1%. Withhold or discontinue treatment as recommended [see Dosage and Administration]. Herpes Virus Infection: Herpes zoster reactivation was reported in 2% of patients. Consider antiviral prophylaxis for patients who have a history of herpes zoster infection. DRUG INTERACTIONS: Carfilzomib is primarily metabolized via peptidase and epoxide hydrolase activities, and as a result, the pharmacokinetic profile of carfilzomib is unlikely to be affected by concomitant administration of cytochrome P450 inhibitors and inducers. Carfilzomib is not expected to influence exposure of other drugs [see Clinical Pharmacology section of full PI]. USE IN SPECIFIC POPULATIONS: Pregnancy. Pregnancy Category D [see Warnings and Precautions]. Females of reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS. Based on its mechanism of action and findings in animals, KYPROLIS can cause fetal harm when administered to a pregnant woman. Carfilzomib caused embryo‑fetal toxicity in pregnant rabbits at doses that were lower than in patients receiving the recommended dose. If KYPROLIS is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Carfilzomib was administered intravenously to pregnant rats and rabbits during the period of organogenesis at doses of 0.5, 1, and 2 mg/kg/day in rats and 0.2, 0.4, and 0.8 mg/kg/day in rabbits. Carfilzomib was not teratogenic at any dose tested. In rabbits, there was an increase in pre‑implantation loss at ≥ 0.4 mg/kg/day and an increase in early resorptions and post‑implantation loss and a decrease in fetal weight at the maternally toxic dose of 0.8  mg/kg/day. The doses of 0.4 and 0.8 mg/kg/day in rabbits are approximately 20% and 40%, respectively, of the recommended dose in humans of 27 mg/m2 based on body surface area. Nursing Mothers. It is not known whether KYPROLIS is excreted in human milk. Since many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from KYPROLIS, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use. The safety and effectiveness of KYPROLIS in pediatric patients have not been established. Geriatric Use. In studies of KYPROLIS there were no clinically significant differences observed in safety and efficacy between patients less than 65 years of age and patients 65 years of age and older. Renal Impairment. The pharmacokinetics and safety of KYPROLIS were evaluated in a Phase 2 trial in patients with normal renal function and those with mild, moderate, and severe renal impairment and patients on chronic dialysis. On average, patients were treated for 5.5 cycles using KYPROLIS doses of 15 mg/m2 on Cycle 1, 20 mg/m2 on Cycle 2, and 27 mg/m2 on Cycles  3 and beyond. The pharmacokinetics and safety of KYPROLIS were not influenced by the degree of baseline renal impairment, including the patients on dialysis. Since dialysis clearance of KYPROLIS concentrations has not been studied, the drug should be administered after the dialysis procedure [see Clinical Pharmacology section of full PI]. Hepatic Impairment. The safety, efficacy and pharmacokinetics of KYPROLIS have not been evaluated in patients with baseline hepatic impairment. Patients with the following laboratory values were excluded from the KYPROLIS clinical trials: ALT/AST ≥ 3 × upper limit of normal (ULN) and bilirubin ≥ 2 × ULN [see Clinical Pharmacology section of full PI]. Cardiac Impairment. Patients with New York Heart Association Class III and IV heart failure were not eligible for the clinical trials. Safety in this population has not been evaluated. OVERDOSAGE: There is no known specific antidote for KYPROLIS overdosage. In the event of an overdosage, monitor the patient and provide appropriate supportive care. NONCLINICAL TOXICOLOGY: Carcinogenesis, Mutagenesis, and Impairment of Fertility. Carcinogenicity studies have not been conducted with carfilzomib. Carfilzomib was clastogenic in the in vitro chromosomal aberration test in peripheral blood lymphocytes. Carfilzomib was not mutagenic in the in vitro bacterial reverse mutation (Ames) test and was not clastogenic in the in vivo mouse bone marrow micronucleus assay. Fertility studies with carfilzomib have not been conducted. No effects on reproductive tissues were noted during 28‑day repeat‑dose rat and monkey toxicity studies or in 6‑month rat and 9‑month monkey chronic toxicity studies. Animal Toxicology and/ or Pharmacology. Monkeys administered a single bolus intravenous dose of carfilzomib at 3 mg/kg (approximately 1.3 times recommended dose in humans of 27 mg/m2 based on body surface area) experienced hypotension, increased heart rate, and increased serum levels of troponin‑T. The repeated bolus intravenous administration of carfilzomib at ≥ 2 mg/kg/dose in rats and 2  mg/kg/dose in monkeys using dosing schedules similar to those used clinically resulted in mortalities that were due to toxicities occurring in the cardiovascular (cardiac failure, cardiac fibrosis, pericardial fluid accumulation, cardiac hemorrhage/degeneration), gastrointestinal (necrosis/hemorrhage), renal (glomerulonephropathy, tubular necrosis, dysfunction), and pulmonary (hemorrhage/inflammation) systems. The dose of 2 mg/kg/dose in rats is approximately half the recommended dose in humans of 27 mg/m2 based on body surface area. The dose of 2 mg/kg/dose in monkeys is approximately equivalent to the recommended dose in humans based on body surface area. PATIENT COUNSELING INFORMATION: Discuss the following with patients prior to treatment with KYPROLIS: Instruct patients to contact their physician if they develop any of the following symptoms: fever, chills, rigors, chest pain, cough, or swelling of the feet or legs. Advise patients that KYPROLIS may cause fatigue, dizziness, fainting, and/or drop in blood pressure. Advise patients not to drive or operate machinery if they experience any of these symptoms. Advise patients that they may experience shortness of breath (dyspnea) during treatment with KYPROLIS. This most commonly occurs within a day of dosing. Advise patients to contact their physicians if they experience shortness of breath. Counsel patients to avoid dehydration, since patients receiving KYPROLIS therapy may experience vomiting and/or diarrhea. Instruct patients to seek medical advice if they experience symptoms of dizziness, lightheadedness, or fainting spells. Counsel females of reproductive potential to use effective contraceptive measures to prevent pregnancy during treatment with KYPROLIS. Advise the patient that if she becomes pregnant during treatment, to contact her physician immediately. Advise patients not to take KYPROLIS treatment while pregnant or breastfeeding. If a patient wishes to restart breastfeeding after treatment, advise her to discuss the appropriate timing with her physician. Advise patients to discuss with their physician any medication they are currently taking prior to starting treatment with KYPROLIS, or prior to starting any new medication(s) during treatment with KYPROLIS. Manufactured for: Onyx Pharmaceuticals, Inc., 249 East Grand Avenue, South San Francisco, CA 94080 U.S. Patent Numbers: 7,232,818; 7,417,042; 7,491,704; 7,737,112 05-1088-00 ©2012 Onyx Pharmaceuticals, Inc. 1012-CARF-409 September 2012 clinician perspective on key biostatistical concepts and terms as well as basic study designs, touching on relevant clinical endpoints with an emphasis on clinical examples. Are You a Postdoctoral Fellow Residing Outside North America? Consider participating in ASH's International Post-Doctoral Fellows (IPDF) program, which allows postdoctoral fellows to access valuable ASH resources at no charge for up to four years. The program is open to postdoctoral fellows with a PhD, MD, or equivalent medical degree, who reside outside Canada, Mexico, or the United States; register for the ASH annual meeting as a non-member in training; and are enrolled in an approved hematology or oncology training program. Benefits include a complimentary online subscription to Blood, online access to Hematology (the Education Program), and online access to ASH's award-winning member newsletter, The Hematologist. Are You a North American Undergraduate or Trainee, But Not a Member of ASH? Fellows: ASH offers a deeply discounted Associate membership for those in approved hematology or hematology/oncology training programs. Medical Students, Graduate Students, and Residents: ASH now offers a complimentary student membership. Undergraduate Students: Consider participating in ASH's North American Undergraduate Student Benefit program designed for trainees in the United States, Canada, and Mexico who are undergraduate or graduate students, residents (in post-graduate years 1-3 for Canadians), or PhD candidates. This program provides undergraduate students with a complimentary online subscription to Blood, advance annual meeting notifications, and eligibility for reduced meeting registration at the non-member-intraining rate. See Section C for: * Exhibit Hall map and Exhibitor directory * Detailed convention center map * Poster Hall maps * Hilton Riverside Hotel map 

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ASH News Daily 2013 - Day 2

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