6 ADVERSE REACTIONS

The following adverse reactions have been associated with COPIKTRA in clinical trials and are discussed in greater detail in other sections of the prescribing information:

Infections [see Warnings and Precautions (5.1)]
Diarrhea or Colitis [see Warnings and Precautions (5.2)]
Cutaneous Reactions [see Warnings and Precautions (5.3)]
Pneumonitis [see Warnings and Precautions (5.4)]
Hepatotoxicity [see Warnings and Precautions (5.5)]
Neutropenia [see Warnings and Precautions (5.6)]

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely variable conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared with rates in clinical trials of another drug and may not reflect the rates observed in practice.

Summary of Clinical Trial Experience in B-cell Malignancies

The data described below reflect exposure to COPIKTRA in two single-arm, open-label clinical trials, one open-label extension clinical trial, and one randomized, open-label, actively controlled clinical trial totaling 442 patients with previously treated hematologic malignancies primarily including CLL/SLL (69%) and FL (22%). Patients were treated with COPIKTRA 25 mg BID until unacceptable toxicity or progressive disease. The median duration of exposure was 9 months (range: 0.1 to 53 months), with 36% (160/442) of patients having at least 12 months of exposure.

For the 442 patients, the median age was 67 years (range: 30 to 90 years), 65% were male, 92% were White, and 93% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Patients had a median of 2 prior therapies. The trials required hepatic transaminases at least ≤ 3 times upper limit of normal (ULN), total bilirubin ≤ 1.5 times ULN, and serum creatinine ≤ 1.5 times ULN. Patients were excluded for prior exposure to a PI3K inhibitor within 4 weeks.

Fatal adverse reactions within 30 days of the last dose occurred in 36 patients (8%) treated with COPIKTRA 25 mg BID.

Serious adverse reactions were reported in 289 patients (65%). The most frequent serious adverse reactions that occurred were infection (31%), diarrhea or colitis (18%), pneumonia (17%), rash (5%), and pneumonitis (5%).

Adverse reactions resulted in treatment discontinuation in 156 patients (35%), most often due to diarrhea or colitis, infection, and rash. COPIKTRA was dose reduced in 104 patients (24%) due to adverse reactions, most often due to diarrhea or colitis and transaminase elevation. The median time to first dose modification or discontinuation was 4 months (range: 0.1 to 27 months), with 75% of patients having their first dose modification or discontinuation within 7 months.

Common Adverse Reactions

Table 4 summarizes common adverse reactions in patients receiving COPIKTRA 25 mg BID, and Table 5 summarizes the treatment-emergent laboratory abnormalities. The most common adverse reactions (reported in ≥ 20% of patients) were diarrhea or colitis, neutropenia, rash, fatigue, pyrexia, cough, nausea, upper respiratory infection, pneumonia, musculoskeletal pain, and anemia.

Table 4. Common Adverse Reactions (≥ 10% Incidence) in Patients with B-cell Malignancies Receiving COPIKTRA
a Diarrhea or colitis includes the preferred terms: colitis, enterocolitis, colitis microscopic, colitis ulcerative, diarrhea, diarrhea hemorrhagic
b Transaminase elevation includes the preferred terms: alanine aminotransferase increased, aspartate aminotransferase increased, transaminases increased, hypertransaminasemia, hepatocellular injury, hepatotoxicity
c Pneumonia includes the preferred terms: All preferred terms containing "pneumonia" except for "pneumonia aspiration"; bronchopneumonia, bronchopulmonary aspergillosis
d Rash includes the preferred terms: dermatitis (including allergic, exfoliative, perivascular), erythema (including multiforme), rash (including exfoliative, erythematous, follicular, generalized, macular & papular, pruritic, pustular), toxic epidermal necrolysis and toxic skin eruption, drug reaction with eosinophilia and systemic symptoms, drug eruption, Stevens-Johnson syndrome
Adverse Reactions	COPIKTRA 25 mg BID (N = 442)
Adverse Reactions	Any Grade n (%)	Grade ≥ 3 n (%)
Blood and lymphatic system disorders
Neutropenia † Anemia † Thrombocytopenia †	151 (34) 90 (20) 74 (17)	132 (30) 48 (11) 46 (10)
Gastrointestinal disorders
Diarrhea or colitis †a Nausea † Abdominal pain Vomiting Mucositis Constipation	222 (50) 104 (24) 78 (18) 69 (16) 61 (14) 57 (13)	101 (23) 4 (< 1) 9 (2) 6 (1) 6 (1) 1 (< 1)
General disorders and administration site conditions
Fatigue † Pyrexia	126 (29) 115 (26)	22 (5) 7 (2)
Hepatobiliary disorders
Transaminase elevation †b	67 (15)	34 (8)
Infections and infestations
Upper respiratory tract infection † Pneumonia †c Lower respiratory tract infection †	94 (21) 91 (21) 46 (10)	2 (< 1) 67 (15) 11 (3)
Metabolism and nutrition disorders
Decreased appetite Edema † Hypokalemia †	63 (14) 60 (14) 45 (10)	2 (< 1) 6 (1) 17 (4)
Musculoskeletal and connective tissue disorders
Musculoskeletal pain † Arthralgia	90 (20) 46 (10)	6 (1) 1 (< 1)
Nervous system disorders
Headache †	55 (12)	1 (< 1)
Respiratory, thoracic and mediastinal disorders
Cough † Dyspnea †	111 (25) 52 (12)	2 (< 1) 8 (2)
Skin and subcutaneous tissue disorders
Rash †d	136 (31)	41 (9)

Grade 4 adverse reactions occurring in ≥ 2% of recipients of COPIKTRA included neutropenia (18%), thrombocytopenia (6%), sepsis (3%), hypokalemia and increased lipase (2% each), and pneumonia and pneumonitis (2% each).

Table 5. Most Common New or Worsening Laboratory Abnormalities (≥ 20% Any Grade) in Patients with B-cell Malignancies Receiving COPIKTRA
a Includes laboratory abnormalities that are new or worsening in grade or with worsening from baseline unknown.
b Percentages are based on number of patients with at least one post-baseline assessment; not all patients were evaluable.
Laboratory Parameter a	COPIKTRA 25 mg BID (N = 442)
Laboratory Parameter a	Any Grade n (%)b	Grade ≥ 3 n (%)b
Hematology abnormalities
Neutropenia Anemia Thrombocytopenia Lymphocytosis Leukopenia Lymphopenia	276 (63) 198 (45) 170 (39) 132 (30) 129 (29) 90 (21)	184 (42) 66 (15) 65 (15) 92 (21) 34 (8) 39 (9)
Chemistry abnormalities
ALT increased AST increased Lipase increased Hypophosphatemia ALP increased Serum amylase increased Hyponatremia Hyperkalemia Hypoalbuminemia Creatinine increased Hypocalcemia	177 (40) 163 (37) 133 (36) 136 (31) 128 (29) 101 (28) 116 (27) 114 (26) 111 (25) 106 (24) 100 (23)	34 (8) 24 (6) 58 (16) 23 (5) 7 (2) 16 (4) 30 (7) 14 (3) 7 (2) 7 (2) 12 (3)

Grade 4 laboratory abnormalities developing in ≥ 2% of patients included neutropenia (24%), thrombocytopenia (7%), lipase increase (4%), lymphocytopenia (3%), and leukopenia (2%).

Summary of Clinical Trial Experience in CLL/SLL

Study 1

The safety data below reflects exposure in a randomized, open-label, actively controlled clinical trial for adult patients with CLL or SLL who received at least one prior therapy. Of 313 patients treated, 158 received COPIKTRA monotherapy and 155 received ofatumumab. The 442-patient safety analysis above includes patients from Study 1.

COPIKTRA was administered at 25 mg BID in 28-day treatment cycles until unacceptable toxicity or progressive disease. The comparator group received 12 doses of ofatumumab with an initial dose of 300 mg intravenous (IV) on Day 1 followed a week later by 7 weekly doses of 2000 mg IV, followed 4 weeks later by 2000 mg IV every 4 weeks for 4 doses.

In the total study population, the median age was 69 years (range: 39 to 90 years), 60% were male, 92% were White, and 91% had an ECOG performance status of 0 to 1. Patients had a median of 2 prior therapies, with 61% of patients having received 2 or more prior therapies. The trial required a hemoglobin ≥ 8 g/dL and platelets ≥ 10,000 µL with or without transfusion support, hepatic transaminases ≤ 3 times upper limit of normal (ULN), total bilirubin ≤ 1.5 times ULN, and serum creatinine ≤ 2 times ULN. The trial excluded patients with prior autologous transplant within 6 months or allogeneic transplant, prior exposure to a PI3K inhibitor or a Bruton's tyrosine kinase (BTK) inhibitor, and uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura.[see Clinical Studies (14)]

During randomized treatment, the median duration of exposure to COPIKTRA was 11.6 months with 72% (114/158) exposed for ≥ 6 months and 49% (77/158) exposed for ≥ 1 year. The median duration of exposure to ofatumumab was 5.3 months, with 77% (120/155) receiving at least 10 of 12 doses.

Fatal adverse reactions within 30 days of the last dose occurred in 12% (19/158) of patients treated with COPIKTRA and in 4% (7/155) of patients treated with ofatumumab.

Serious adverse reactions were reported in 73% (115/158) of patients treated with COPIKTRA and most often involved infection (38% of patients; 60/158) and diarrhea or colitis (23% of patients; 36/158).

COPIKTRA was discontinued in 57 patients (36%), most often due to diarrhea or colitis, infection, and rash. COPIKTRA was dose reduced in 46 patients (29%) due to adverse reactions, most often due to diarrhea or colitis and rash.

Common Adverse Reactions

Table 6 summarizes selected adverse reactions in Study 1, and Table 7 summarizes treatment-emergent laboratory abnormalities. The most common adverse reactions with COPIKTRA (reported in ≥ 20% of patients) were diarrhea or colitis, neutropenia, pyrexia, upper respiratory tract infection, pneumonia, rash, fatigue, nausea, anemia and cough.

Table 6. Common Nonhematologic Adverse Reactions (≥ 10% Incidence) in Patients with CLL/SLL Receiving COPIKTRA (Study 1)
Grades were obtained per CTCAE version 4.03.
† Grouped term for reactions with multiple preferred terms
a Diarrhea or colitis includes the preferred terms: colitis, enterocolitis, colitis microscopic, colitis ulcerative, diarrhea
b Pneumonia includes the preferred terms: All preferred term containing "pneumonia" except for "pneumonia aspiration"; bronchopneumonia, bronchopulmonary aspergillosis
c Rash includes the preferred terms: dermatitis (including allergic, exfoliative, perivascular), erythema (including multiforme), rash (including exfoliative, erythematous, follicular, generalized, macular & papular, pruritic, pustular), toxic skin eruption, drug eruption
d Transaminase elevation includes the preferred terms: alanine aminotransferase increased, aspartate aminotransferase increased, transaminases increased, hepatotoxicity
Adverse Reactions	COPIKTRA N = 158		Ofatumumab N = 155
Adverse Reactions	Any Grade (%)	Grade ≥ 3 (%)	Any Grade (%)	Grade ≥ 3 (%)
Gastrointestinal disorders
Diarrhea or colitis †a Nausea † Constipation Abdominal pain Vomiting	57 23 17 16 15	25 0 <1 3 0	14 11 8 7 7	2 0 0 0 0
General disorders and administration site conditions
Pyrexia Fatigue †	29 25	3 4	10 23	<1 4
Hepatobiliary disorders
Transaminase elevation †d	11	6	4	<1
Infections and infestations
Upper respiratory tract infection † Pneumonia †b Lower respiratory tract infection †	28 27 18	0 22 4	16 8 10	<1 3 1
Investigations
Weight decreased	11	0	2	0
Metabolism and nutrition disorders
Decreased appetite Edema †	13 11	0 1	3 5	<1 0
Musculoskeletal and connective tissue disorders
Musculoskeletal pain †	17	1	12	<1
Respiratory, thoracic and mediastinal disorders
Cough †	23	1	16	0
Dyspnea	12	3	7	0
Skin and subcutaneous tissue disorders
Rash †c	27	11	15	<1

Table 7. Most Common New or Worsening Laboratory Abnormalities (≥ 20% Any Grade) in Patients with CLL/SLL Receiving COPIKTRA (Study 1)
Grades were obtained per CTCAE version 4.03.
Laboratory Parameter	COPIKTRA N = 158		Ofatumumab N = 155
Laboratory Parameter	Any Grade (%)	Grade ≥ 3 (%)	Any Grade (%)	Grade ≥ 3 (%)
Hematology abnormalities
Neutropenia Anemia Thrombocytopenia Lymphocytosis	67 55 43 30	49 20 16 22	52 36 34 11	37 7 8 6
Chemistry abnormalities
ALT increased Lipase increased AST increased Phosphate decreased Hyperkalemia Hyponatremia Amylase increased Hypoalbuminemia Creatinine increased Alkaline phosphatase increased Hypocalcemia Hypokalemia	42 37 36 34 31 31 31 31 29 27 25 20	7 12 3 3 4 7 5 2 1 0 1 8	12 15 14 20 24 18 10 15 31 14 17 8	0 3 1 3 1 3 1 1 0 0 1 0

Grade 4 laboratory abnormalities that developed in ≥ 2% of COPIKTRA treated patients included neutropenia (32%), thrombocytopenia (6%), lymphopenia (3%), and hypokalemia (2%).

The data above are not an adequate basis for comparison of rates between the study drug and the active control.