ASH Clinical News ACN_5.4s_March_supplement_web - Page 7

IMBRUVICA ® (ibrutinib) IMBRUVICA ® (ibrutinib) Table 1: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with MCL (N=111) (continued) All Grades Grade 3 or 4 Body System Adverse Reaction (%) (%) Respiratory, thoracic Dyspnea 27 4 and mediastinal Cough 19 0 disorders Epistaxis 11 0 Metabolism and Decreased appetite 21 2 nutrition disorders Dehydration 12 4 Nervous system Dizziness 14 0 disorders Headache 13 0 Table 3: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with CLL/SLL (N=51) in Study 1102 (continued) All Grades Grade 3 or 4 Body System Adverse Reaction (%) (%) General disorders and Fatigue 33 6 administration site Pyrexia 24 2 conditions Peripheral edema 22 0 Asthenia 14 6 Chills 12 0 Skin and Bruising 51 2 subcutaneous tissue Rash 25 0 disorders Petechiae 16 0 Respiratory, thoracic Cough 22 0 and mediastinal Oropharyngeal pain 14 0 disorders Dyspnea 12 0 Musculoskeletal and Musculoskeletal pain 25 6 connective tissue Arthralgia 24 0 disorders Muscle spasms 18 2 Nervous system Dizziness 20 0 disorders Headache 18 2 Metabolism and Decreased appetite 16 2 nutrition disorders Neoplasms benign, Second malignancies* 12* 0 malignant, unspecified Vascular disorders Hypertension 16 8 * One patient death due to histiocytic sarcoma. Table 2: Treatment-Emergent* Hematologic Laboratory Abnormalities in Patients with MCL (N=111) Percent of Patients (N=111) All Grades Grade 3 or 4 (%) (%) Platelets Decreased 57 17 Neutrophils Decreased 47 29 Hemoglobin Decreased 41 9 * Based on laboratory measurements and adverse reactions Ten patients (9%) discontinued treatment due to adverse reactions in the trial (N=111). The most frequent adverse reaction leading to treatment discontinuation was subdural hematoma (1.8%). Adverse reactions leading to dose reduction occurred in 14% of patients. Patients with MCL who develop lymphocytosis greater than 400,000/mcL have developed intracranial hemorrhage, lethargy, gait instability, and headache. However, some of these cases were in the setting of disease progression. Forty percent of patients had elevated uric acid levels on study including 13% with values above 10 mg/dL. Adverse reaction of hyperuricemia was reported for 15% of patients. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: The data described below reflect exposure in one single-arm, open-label clinical trial (Study 1102) and three randomized controlled clinical trials (RESONATE, RESONATE-2, and HELIOS) in patients with CLL/SLL (n=1278 total and n=668 patients exposed to IMBRUVICA). Study 1102 included 51 patients with previously treated CLL/SLL, RESONATE included 391 randomized patients with previously treated CLL or SLL who received single agent IMBRUVICA or ofatumumab, RESONATE-2 included 269  randomized patients 65 years or older with treatment naïve-CLL or SLL who received single agent IMBRUVICA or chlorambucil, and HELIOS included 578 randomized patients with previously treated CLL or SLL who received IMBRUVICA in combination with bendamustine and rituximab or placebo in combination with bendamustine and rituximab. The most commonly occurring adverse reactions in Studies 1102, RESONATE, RESONATE-2, and HELIOS in patients with CLL/SLL receiving IMBRUVICA (≥ 20%) were neutropenia, thrombocytopenia, anemia, diarrhea, musculoskeletal pain, nausea, rash, bruising, fatigue, pyrexia and hemorrhage. Four to 10 percent of patients receiving IMBRUVICA in Studies 1102, RESONATE, RESONATE-2, and HELIOS discontinued treatment due to adverse reactions. These included pneumonia, hemorrhage, atrial fibrillation, rash and neutropenia (1% each). Adverse reactions leading to dose reduction occurred in approximately 6% of patients. Study 1102: Adverse reactions and laboratory abnormalities from the CLL/ SLL trial (N=51) using single agent IMBRUVICA 420  mg daily in patients with previously treated CLL/SLL occurring at a rate of ≥ 10% with a median duration of treatment of 15.6 months are presented in Tables 3 and 4. Table 3: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with CLL/SLL (N=51) in Study 1102 All Grades Grade 3 or 4 Body System Adverse Reaction (%) (%) 4 59 Gastrointestinal Diarrhea 2 22 disorders Constipation 2 20 Nausea 0 20 Stomatitis 2 18 Vomiting 0 14 Abdominal pain 0 12 Dyspepsia 2 47 Infections and Upper respiratory tract infestations infection 6 22 Sinusitis 6 16 Skin infection 10 12 Pneumonia 2 12 Urinary tract infection Table 4: Treatment-Emergent* Hematologic Laboratory Abnormalities in Patients with CLL/SLL (N=51) in Study 1102 Percent of Patients (N=51) All Grades (%) Grade 3 or 4 (%) Platelets Decreased 69 12 Neutrophils Decreased 53 26 Hemoglobin Decreased 43 0 * Based on laboratory measurements per IWCLL criteria and adverse reactions. RESONATE: Adverse reactions and laboratory abnormalities described below in Tables 5 and 6 reflect exposure to IMBRUVICA with a median duration of 8.6 months and exposure to ofatumumab with a median of 5.3 months in RESONATE in patients with previously treated CLL/SLL. Table 5: Adverse Reactions Reported in ≥ 10% of Patients and at Least 2% Greater in the IMBRUVICA Treated Arm in Patients with CLL/SLL in RESONATE IMBRUVICA Ofatumumab (N=195) (N=191) Body System All Grades Grade 3 or 4 All Grades Grade 3 or 4 Adverse Reaction (%) (%) (%) (%) Gastrointestinal disorders Diarrhea 48 4 18 2 Nausea 26 2 18 0 Stomatitis* 17 1 6 1 Constipation 15 0 9 0 Vomiting 14 0 6 1 General disorders and administration site conditions Pyrexia 24 2 15 1 Infections and infestations Upper respiratory 16 1 11 2 tract infection Pneumonia* 15 10 13 9 Sinusitis* 11 1 6 0 Urinary tract 10 4 5 1 infection Skin and subcutaneous tissue disorders Rash* 24 3 13 0 Petechiae 14 0 1 0 Bruising* 12 0 1 0