FDA label d839b833-df53-337e-e053-2995a90a9f8b

WARNING: FATAL AND SERIOUS TOXICITIES: INFECTIONS, DIARRHEA OR COLITIS, CUTANEOUS REACTIONS, and PNEUMONITIS Fatal and/or serious infections occurred in 31% of COPIKTRA-treated patients. Monitor for signs and symptoms of infection. Withhold COPIKTRA if infection is suspected [see Warnings and Precautions ( 5.1 )]. Fatal and/or serious diarrhea or colitis occurred in 18% of COPIKTRA-treated patients. Monitor for the development of severe diarrhea or colitis. Withhold COPIKTRA [see Warnings and Precautions ( 5.2 )] . Fatal and/or serious cutaneous reactions occurred in 5% of COPIKTRA-treated patients. Withhold COPIKTRA [see Warnings and Precautions ( 5.3 )] . Fatal and/or serious pneumonitis occurred in 5% of COPIKTRA-treated patients. Monitor for pulmonary symptoms and interstitial infiltrates. Withhold COPIKTRA [see Warnings and Precautions ( 5.4 )]. WARNING: FATAL AND SERIOUS TOXICITIES: INFECTIONS, DIARRHEA OR COLITIS, CUTANEOUS REACTIONS, and PNEUMONITIS See full prescribing information for complete boxed warning. Fatal and/or serious infections occurred in 31% of COPIKTRA-treated patients. Monitor for signs and symptoms of infection. Withhold COPIKTRA if infection is suspected. ( 5.1 ) Fatal and/or serious diarrhea or colitis occurred in 18% of COPIKTRA-treated patients. Monitor for the development of severe diarrhea or colitis. Withhold COPIKTRA. ( 5.2 ) Fatal and/or serious cutaneous reactions occurred in 5% of COPIKTRA-treated patients. Withhold COPIKTRA. ( 5.3 ) Fatal and/or serious pneumonitis occurred in 5% of COPIKTRA-treated patients. Monitor for pulmonary symptoms and interstitial infiltrates. Withhold COPIKTRA. ( 5.4 )

5 WARNINGS AND PRECAUTIONS Hepatotoxicity: Monitor hepatic function. ( 5.5 ) Neutropenia: Monitor blood counts. ( 5.6 ) Embryo-Fetal toxicity: COPIKTRA can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception. ( 5.7 ) 5.1 Infections Serious, including fatal (18/442; 4%), infections occurred in 31% of patients receiving COPIKTRA 25 mg BID (N = 442). The most common serious infections were pneumonia, sepsis, and lower respiratory infections. Median time to onset of any grade infection was 3 months (range: 1 day to 32 months), with 75% of cases occurring within 6 months. Treat infections prior to initiation of COPIKTRA. Advise patients to report any new or worsening signs and symptoms of infection. For grade 3 or higher infection, withhold COPIKTRA until infection has resolved. Resume COPIKTRA at the same or reduced dose [see Dosage and Administration ( 2.3 )] . Serious, including fatal, Pneumocystis jirovecii pneumonia (PJP) occurred in 1% of patients taking COPIKTRA. Provide prophylaxis for PJP during treatment with COPIKTRA. Following completion of COPIKTRA treatment, continue PJP prophylaxis until the absolute CD4+ T cell count is greater than 200 cells/µL. Withhold COPIKTRA in patients with suspected PJP of any grade, and permanently discontinue if PJP is confirmed. CMV reactivation/infection occurred in 1% of patients taking COPIKTRA. Consider prophylactic antivirals during COPIKTRA treatment to prevent CMV infection including CMV reactivation. For clinical CMV infection or viremia, withhold COPIKTRA until infection or viremia resolves. If COPIKTRA is resumed, administer the same or reduced dose and monitor patients for CMV reactivation by PCR or antigen test at least monthly [see Dosage and Administration ( 2.3 )] . 5.2 Diarrhea or Colitis Serious, including fatal (1/442; <1%), diarrhea or colitis occurred in 18% of patients receiving COPIKTRA 25 mg BID (N = 442). The median time to onset of any grade diarrhea or colitis was 4 months (range: 1 day to 33 months), with 75% of cases occurring by 8 months. The median event duration was 0.5 months (range: 1 day to 29 months; 75 th percentile: 1 month). Advise patients to report any new or worsening diarrhea. For non-infectious diarrhea or colitis, follow the guidelines below: For patients presenting with mild or moderate diarrhea (Grade 1-2) (i.e. up to 6 stools per day over baseline) or asymptomatic (Grade 1) colitis, initiate supportive care with antidiarrheal agents as appropriate, continue COPIKTRA at the current dose, and monitor the patient at least weekly until the event resolves. If the diarrhea is unresponsive to antidiarrheal therapy, withhold COPIKTRA and initiate supportive therapy with enteric acting steroids (e.g. budesonide). Monitor the patient at least weekly. Upon resolution of the diarrhea, consider restarting COPIKTRA at a reduced dose. For patients presenting with abdominal pain, stool with mucus or blood, change in bowel habits, peritoneal signs, or with severe diarrhea (Grade 3) (i.e. > 6 stools per day over baseline) withhold COPIKTRA and initiate supportive therapy with enteric acting steroids (e.g. budesonide) or systemic steroids. A diagnostic work-up to determine etiology, including colonoscopy, should be performed. Monitor at least weekly. Upon resolution of the diarrhea or colitis, restart COPIKTRA at a reduced dose. For recurrent Grade 3 diarrhea or recurrent colitis of any grade, discontinue COPIKTRA. Discontinue COPIKTRA for life-threatening diarrhea or colitis [see Dosage and Administration ( 2.3 )] . 5.3 Cutaneous Reactions Serious, including fatal (2/442; < 1%), cutaneous reactions occurred in 5% of patients receiving COPIKTRA 25 mg BID (N = 442). Fatal cases included drug reaction with eosinophilia and systemic symptoms (DRESS) and toxic epidermal necrolysis (TEN). Median time to onset of any grade cutaneous reaction was 3 months (range: 1 day to 29 months, 75th percentile: 6 months), with a median event duration of 1 month (range: 1 day to 37 months, 75th percentile: 2 months). Presenting features for the serious events were primarily described as pruritic, erythematous, or maculo-papular. Less common presenting features include exanthem, desquamation, erythroderma, skin exfoliation, keratinocyte necrosis, and papular rash. Advise patients to report any new or worsening cutaneous reactions. Review all concomitant medications and discontinue any medications potentially contributing to the event. For patients presenting with mild or moderate (Grade 1-2) cutaneous reactions, continue COPIKTRA at the current dose, initiate supportive care with emollients, anti-histamines (for pruritus), or topical steroids, and monitor the patient closely. Withhold COPIKTRA for severe (Grade 3) cutaneous reaction until resolution. Initiate supportive care with steroids (topical or systemic) or anti-histamines (for pruritus). Monitor at least weekly until resolved. Upon resolution of the event, restart COPIKTRA at a reduced dose. Discontinue COPIKTRA if severe cutaneous reaction does not improve, worsens, or recurs. For life-threatening cutaneous reactions, discontinue COPIKTRA. In patients with SJS, TEN, or DRESS of any grade, discontinue COPIKTRA [see Dosage and Administration ( 2.3 )]. 5.4 Pneumonitis Serious, including fatal (1/442; < 1%), pneumonitis without an apparent infectious cause occurred in 5% of patients receiving COPIKTRA 25 mg BID (N = 442). Median time to onset of any grade pneumonitis was 4 months (range: 9 days to 27 months), with 75% of cases occurring within 9 months). The median event duration was 1 month, with 75% of cases resolving by 2 months. Withhold COPIKTRA in patients who present with new or progressive pulmonary signs and symptoms such as cough, dyspnea, hypoxia, interstitial infiltrates on a radiologic exam, or a decline by more than 5% in oxygen saturation and evaluate for etiology. If the pneumonitis is infectious, patients may be restarted on COPIKTRA at the previous dose once the infection, pulmonary signs and symptoms resolve. For moderate non-infectious pneumonitis (Grade 2), treat with systemic corticosteroids, and resume COPIKTRA at a reduced dose upon resolution. If non-infectious pneumonitis recurs or does not respond to steroid therapy, discontinue COPIKTRA. For severe or life-threatening non-infectious pneumonitis, discontinue COPIKTRA and treat with systemic steroids [see Dosage and Administration ( 2.3 )] . 5.5 Hepatotoxicity Grade 3 and 4 ALT and/or AST elevation developed in 8% and 2%, respectively, in patients receiving COPIKTRA 25 mg BID (N = 442). Two percent of patients had both an ALT or AST greater than 3 x ULN and total bilirubin greater than 2 x ULN. Median time to onset of any grade transaminase elevation was 2 months (range: 3 days to 26 months), with a median event duration of 1 month (range: 1 day to 16 months). Monitor hepatic function during treatment with COPIKTRA. For Grade 2 ALT/AST elevation (greater than 3 to 5 × ULN), maintain COPIKTRA dose and monitor at least weekly until return to less than 3 × ULN. For Grade 3 ALT/AST elevation (greater than 5 to 20 × ULN), withhold COPIKTRA and monitor at least weekly until return to less than 3 × ULN. Resume COPIKTRA at the same dose (first occurrence) or at a reduced dose for subsequent occurrence. For grade 4 ALT/AST elevation (greater than 20 × ULN) discontinue COPIKTRA [see Dosage and Administration ( 2.3 )] . 5.6 Neutropenia Grade 3 or 4 neutropenia occurred in 42% of patients receiving COPIKTRA 25 mg BID (N = 442), with Grade 4 neutropenia occurring in 24% of all patients. The median time to onset of Grade ≥ 3 neutropenia was 2 months (range: 3 days to 31 months), with 75% of cases occurring within 4 months. Monitor neutrophil counts at least every 2 weeks for the first 2 months of COPIKTRA therapy, and at least weekly in patients with neutrophil counts < 1.0 Gi/L (Grade 3-4). Withhold COPIKTRA in patients presenting with neutrophil counts < 0.5 Gi/L (Grade 4). Monitor until ANC is > 0.5 Gi/L, resume COPIKTRA at same dose for the first occurrence or a reduced dose for subsequent occurrence [see Dosage and Administration ( 2.3 )] . 5.7 Embryo-Fetal Toxicity Based on findings in animals and its mechanism of action, COPIKTRA can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of duvelisib to pregnant rats and rabbits during organogenesis caused adverse developmental outcomes including embryo-fetal mortality (resorptions, post-implantation loss, and decreased viable fetuses), alterations to growth (lower fetal weights) and structural abnormalities (malformations) at maternal doses approximately 10 times and 39 times the maximum recommended human dose (MRHD) of 25 mg BID in rats and rabbits, respectively. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment and for at least 1 month after the last dose [see Use in Specific Populations ( 8.1 , 8.3 ) and Clinical Pharmacology ( 12.1 , 12.3 )].

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 )] The most common adverse reactions (≥20%) are diarrhea or colitis, neutropenia, rash, fatigue, pyrexia, cough, nausea, upper respiratory infection, pneumonia, musculoskeletal pain, and anemia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Verastem, Inc. (Verastem) at 877-7RXVSTM or 1-877-779-8786, or U.S. Food and Drug Administration (FDA) at 1-800-FDA-1088 or www.fda.gov/medwatch . 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 3 summarizes common adverse reactions in patients receiving COPIKTRA 25 mg BID, and Table 4 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 3. Common Adverse Reactions (≥ 10% Incidence) in Patients with B-cell Malignancies Receiving COPIKTRA † Grouped term for reactions with multiple preferred terms 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) 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 4. 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) 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. 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 5 summarizes selected adverse reactions in Study 1, and Table 6 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 5. 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 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 † Dyspnea 23 12 1 3 16 7 0 0 Skin and subcutaneous tissue disorders Rash †c 27 11 15 <1 Table 6. 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 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. Summary of Clinical Trial Experience in FL The data described below reflect the exposure to COPIKTRA 25 mg BID in 96 patients with relapsed or refractory FL. These patients were included in the 442-patient safety analysis presented above. The median duration of treatment was 24 weeks, with 46% of patients exposed for ≥ 6 months and 19% exposed for ≥ 1 year. The median age was 64 years (range: 30 to 82 years), and 93% had an ECOG performance status of 0 to 1. Patients had a median of 3 prior systemic therapies. Serious adverse reactions were reported in 58% and most often involved diarrhea or colitis, pneumonia, renal insufficiency, rash, and sepsis. The most common adverse reactions (≥ 20% of patients) were diarrhea or colitis, nausea, fatigue, musculoskeletal pain, rash, neutropenia, cough, anemia, pyrexia, headache, mucositis, abdominal pain, vomiting, transaminase elevation, and thrombocytopenia. Adverse reactions resulted in COPIKTRA discontinuation in 29% of patients, most often due to diarrhea or colitis and rash. COPIKTRA was dose reduced in 23% due to adverse reactions, most often due to transaminase elevation, diarrhea or colitis, lipase increased, and infection.

<table width="700" ID="table3" styleCode="Noautorules"><caption>Table 3. Common Adverse Reactions (&#x2265; 10% Incidence) in Patients with B-cell Malignancies Receiving COPIKTRA</caption><colgroup><col align="left" width="50%"/><col align="center" width="25%"/><col align="center" width="25%"/></colgroup><tfoot><tr><td align="left" colspan="3">^&#x2020; Grouped term for reactions with multiple preferred terms ^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 &quot;pneumonia&quot; except for &quot;pneumonia aspiration&quot;; bronchopneumonia, bronchopulmonary aspergillosis ^d Rash includes the preferred terms: dermatitis (including allergic, exfoliative, perivascular), erythema (including multiforme), rash (including exfoliative, erythematous, follicular, generalized, macular &amp; papular, pruritic, pustular), toxic epidermal necrolysis and toxic skin eruption, drug reaction with eosinophilia and systemic symptoms, drug eruption, Stevens-Johnson syndrome </td></tr></tfoot><tbody><tr valign="top"><td align="center" rowspan="2" styleCode="Toprule Botrule Lrule Rrule"> <content styleCode="bold">Adverse Reactions </content></td><td colspan="3" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">COPIKTRA 25 mg BID (N = 442) </content></td></tr><tr><td align="center" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Any Grade n (%) </content></td><td styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Grade &#x2265; 3 n (%) </content></td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Blood and lymphatic system disorders</content> Neutropenia &#x2020; Anemia &#x2020; Thrombocytopenia &#x2020; </td><td styleCode="Toprule Botrule Lrule Rrule"> 151 (34) 90 (20) 74 (17) </td><td styleCode="Toprule Botrule Lrule Rrule"> 132 (30) 48 (11) 46 (10) </td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Gastrointestinal disorders</content> Diarrhea or colitis ^&#x2020;a Nausea ^&#x2020; Abdominal pain Vomiting Mucositis Constipation </td><td styleCode="Toprule Botrule Lrule Rrule"> 222 (50) 104 (24) 78 (18) 69 (16) 61 (14) 57 (13) </td><td styleCode="Toprule Botrule Lrule Rrule"> 101 (23) 4 (&lt; 1) 9 (2) 6 (1) 6 (1) 1 (&lt; 1) </td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">General disorders and administration site conditions</content> Fatigue ^&#x2020; Pyrexia </td><td styleCode="Toprule Botrule Lrule Rrule"> 126 (29) 115 (26) </td><td styleCode="Toprule Botrule Lrule Rrule"> 22 (5) 7 (2) </td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Hepatobiliary disorders</content> Transaminase elevation ^&#x2020;b</td><td styleCode="Toprule Botrule Lrule Rrule"> 67 (15) </td><td styleCode="Toprule Botrule Lrule Rrule"> 34 (8) </td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Infections and infestations</content> Upper respiratory tract infection ^&#x2020; Pneumonia ^&#x2020;c Lower respiratory tract infection ^&#x2020;</td><td styleCode="Toprule Botrule Lrule Rrule"> 94 (21) 91 (21) 46 (10) </td><td styleCode="Toprule Botrule Lrule Rrule"> 2 (&lt; 1) 67 (15) 11 (3) </td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Metabolism and nutrition disorders</content> Decreased appetite Edema ^&#x2020; Hypokalemia ^&#x2020;</td><td styleCode="Toprule Botrule Lrule Rrule"> 63 (14) 60 (14) 45 (10) </td><td styleCode="Toprule Botrule Lrule Rrule"> 2 (&lt; 1) 6 (1) 17 (4) </td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Musculoskeletal and connective tissue disorders</content> Musculoskeletal pain ^&#x2020; Arthralgia </td><td styleCode="Toprule Botrule Lrule Rrule"> 90 (20) 46 (10) </td><td styleCode="Toprule Botrule Lrule Rrule"> 6 (1) 1 (&lt; 1) </td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Nervous system disorders</content> Headache ^&#x2020;</td><td styleCode="Toprule Botrule Lrule Rrule"> 55 (12) </td><td styleCode="Toprule Botrule Lrule Rrule"> 1 (&lt; 1) </td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Respiratory, thoracic and mediastinal disorders</content> Cough ^&#x2020; Dyspnea ^&#x2020;</td><td styleCode="Toprule Botrule Lrule Rrule"> 111 (25) 52 (12) </td><td styleCode="Toprule Botrule Lrule Rrule"> 2 (&lt; 1) 8 (2) </td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Skin and subcutaneous tissue disorders</content> Rash ^&#x2020;d</td><td styleCode="Toprule Botrule Lrule Rrule"> 136 (31) </td><td styleCode="Toprule Botrule Lrule Rrule"> 41 (9) </td></tr></tbody></table>

<table width="700" ID="table4" styleCode="Noautorules"><caption>Table 4. Most Common New or Worsening Laboratory Abnormalities (&#x2265; 20% Any Grade) in Patients with B-cell Malignancies Receiving COPIKTRA</caption><colgroup><col align="left" width="50%"/><col align="center" width="25%"/><col align="center" width="25%"/></colgroup><tfoot><tr><td align="left" colspan="3">^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. </td></tr></tfoot><tbody><tr valign="top"><td align="center" rowspan="2" styleCode="Toprule Botrule Lrule Rrule"> <content styleCode="bold">Laboratory Parameter ^a</content></td><td colspan="3" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">COPIKTRA 25 mg BID (N = 442) </content></td></tr><tr><td align="center" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Any Grade n (%) ^b</content></td><td styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Grade &#x2265; 3 n (%) ^b</content></td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Hematology abnormalities</content> Neutropenia Anemia Thrombocytopenia Lymphocytosis Leukopenia Lymphopenia </td><td styleCode="Toprule Botrule Lrule Rrule"> 276 (63) 198 (45) 170 (39) 132 (30) 129 (29) 90 (21) </td><td styleCode="Toprule Botrule Lrule Rrule"> 184 (42) 66 (15) 65 (15) 92 (21) 34 (8) 39 (9) </td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Chemistry abnormalities</content> ALT increased AST increased Lipase increased Hypophosphatemia ALP increased Serum amylase increased Hyponatremia Hyperkalemia Hypoalbuminemia Creatinine increased Hypocalcemia </td><td styleCode="Toprule Botrule Lrule Rrule"> 177 (40) 163 (37) 133 (36) 136 (31) 128 (29) 101 (28) 116 (27) 114 (26) 111 (25) 106 (24) 100 (23) </td><td styleCode="Toprule Botrule Lrule Rrule"> 34 (8) 24 (6) 58 (16) 23 (5) 7 (2) 16 (4) 30 (7) 14 (3) 7 (2) 7 (2) 12 (3) </td></tr></tbody></table>

<table width="775" ID="table5" styleCode="Noautorules"><caption>Table 5. Common Nonhematologic Adverse Reactions (&#x2265; 10% Incidence) in Patients with CLL/SLL Receiving COPIKTRA (Study 1)</caption><colgroup><col align="left" width="40%"/><col align="center" width="15%"/><col align="center" width="15%"/><col align="center" width="15%"/><col align="center" width="15%"/></colgroup><tfoot><tr><td align="left" colspan="5">Grades were obtained per CTCAE version 4.03. ^&#x2020; 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 &quot;pneumonia&quot; except for &quot;pneumonia aspiration&quot;; bronchopneumonia, bronchopulmonary aspergillosis ^c Rash includes the preferred terms: dermatitis (including allergic, exfoliative, perivascular), erythema (including multiforme), rash (including exfoliative, erythematous, follicular, generalized, macular &amp; papular, pruritic, pustular), toxic skin eruption, drug eruption ^d Transaminase elevation includes the preferred terms: alanine aminotransferase increased, aspartate aminotransferase increased, transaminases increased, hepatotoxicity </td></tr></tfoot><tbody><tr valign="bottom"><td align="center" rowspan="2" styleCode="Toprule Botrule Lrule Rrule" valign="middle"><content styleCode="bold">Adverse Reactions</content></td><td colspan="2" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">COPIKTRA N = 158 </content></td><td colspan="2" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Ofatumumab N = 155 </content></td></tr><tr valign="bottom"><td align="center" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Any Grade (%)</content></td><td styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Grade &#x2265; 3 (%)</content></td><td styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Any Grade (%)</content></td><td styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Grade &#x2265; 3 (%)</content></td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Gastrointestinal disorders</content> Diarrhea or colitis ^&#x2020;a Nausea ^&#x2020; Constipation Abdominal pain Vomiting </td><td styleCode="Toprule Botrule Lrule Rrule"> 57 23 17 16 15 </td><td styleCode="Toprule Botrule Lrule Rrule"> 25 0 &lt;1 3 0 </td><td styleCode="Toprule Botrule Lrule Rrule"> 14 11 8 7 7 </td><td styleCode="Toprule Botrule Lrule Rrule"> 2 0 0 0 0 </td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">General disorders and administration site conditions</content> Pyrexia Fatigue ^&#x2020;</td><td styleCode="Toprule Botrule Lrule Rrule"> 29 25 </td><td styleCode="Toprule Botrule Lrule Rrule"> 3 4 </td><td styleCode="Toprule Botrule Lrule Rrule"> 10 23 </td><td styleCode="Toprule Botrule Lrule Rrule"> &lt;1 4 </td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Hepatobiliary disorders</content> Transaminase elevation ^&#x2020;d</td><td styleCode="Toprule Botrule Lrule Rrule"> 11 </td><td styleCode="Toprule Botrule Lrule Rrule"> 6 </td><td styleCode="Toprule Botrule Lrule Rrule"> 4 </td><td styleCode="Toprule Botrule Lrule Rrule"> &lt;1 </td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Infections and infestations</content> Upper respiratory tract infection ^&#x2020; Pneumonia ^&#x2020;b Lower respiratory tract infection ^&#x2020;</td><td styleCode="Toprule Botrule Lrule Rrule"> 28 27 18 </td><td styleCode="Toprule Botrule Lrule Rrule"> 0 22 4 </td><td styleCode="Toprule Botrule Lrule Rrule"> 16 8 10 </td><td styleCode="Toprule Botrule Lrule Rrule"> &lt;1 3 1 </td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Investigations</content> Weight decreased </td><td styleCode="Toprule Botrule Lrule Rrule"> 11 </td><td styleCode="Toprule Botrule Lrule Rrule"> 0 </td><td styleCode="Toprule Botrule Lrule Rrule"> 2 </td><td styleCode="Toprule Botrule Lrule Rrule"> 0 </td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Metabolism and nutrition disorders</content> Decreased appetite Edema ^&#x2020;</td><td styleCode="Toprule Botrule Lrule Rrule"> 13 11 </td><td styleCode="Toprule Botrule Lrule Rrule"> 0 1 </td><td styleCode="Toprule Botrule Lrule Rrule"> 3 5 </td><td styleCode="Toprule Botrule Lrule Rrule"> &lt;1 0 </td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Musculoskeletal and connective tissue disorders</content> Musculoskeletal pain ^&#x2020;</td><td styleCode="Toprule Botrule Lrule Rrule"> 17 </td><td styleCode="Toprule Botrule Lrule Rrule"> 1 </td><td styleCode="Toprule Botrule Lrule Rrule"> 12 </td><td styleCode="Toprule Botrule Lrule Rrule"> &lt;1 </td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Respiratory, thoracic and mediastinal disorders</content> Cough ^&#x2020; Dyspnea </td><td styleCode="Toprule Botrule Lrule Rrule"> 23 12 </td><td styleCode="Toprule Botrule Lrule Rrule"> 1 3 </td><td styleCode="Toprule Botrule Lrule Rrule"> 16 7 </td><td styleCode="Toprule Botrule Lrule Rrule"> 0 0 </td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Skin and subcutaneous tissue disorders</content> Rash ^&#x2020;c</td><td styleCode="Toprule Botrule Lrule Rrule"> 27 </td><td styleCode="Toprule Botrule Lrule Rrule"> 11 </td><td styleCode="Toprule Botrule Lrule Rrule"> 15 </td><td styleCode="Toprule Botrule Lrule Rrule"> &lt;1 </td></tr></tbody></table>