Copiktra Drug Information

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 † 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 90 74 132 48 46 Gastrointestinal disorders Diarrhea or colitis † a Nausea † Abdominal pain Vomiting Mucositis Constipation 222 104 78 69 61 57 101 4 (< 1) 9 6 6 1 (< 1) General disorders and administration site conditions Fatigue † Pyrexia 126 115 22 7 Hepatobiliary disorders Transaminase elevation † b 67 34 Infections and infestations Upper respiratory tract infection † Pneumonia † c Lower respiratory tract infection † 94 91 46 2 (< 1) 67 11 Metabolism and nutrition disorders Decreased appetite Edema † Hypokalemia † 63 60 45 2 (< 1) 6 17 Musculoskeletal and connective tissue disorders Musculoskeletal pain † Arthralgia 90 46 6 1 (< 1) Nervous system disorders Headache † 55 1 (< 1) Respiratory, thoracic and mediastinal disorders Cough † Dyspnea † 111 52 2 (< 1) 8 Skin and subcutaneous tissue disorders Rash † d 136 41 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) Any Grade n (%) b Grade ≥ 3 n (%) b Hematology abnormalities Neutropenia Anemia Thrombocytopenia Lymphocytosis Leukopenia Lymphopenia 276 198 170 132 129 90 184 66 65 92 34 39 Chemistry abnormalities ALT increased AST increased Lipase increased Hypophosphatemia ALP increased Serum amylase increased Hyponatremia Hyperkalemia Hypoalbuminemia Creatinine increased Hypocalcemia 177 163 133 136 128 101 116 114 111 106 100 34 24 58 23 7 16 30 14 7 7 12 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 DUO Study 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 DUO . 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 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 (DUO) 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 † 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 (DUO) 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.

Long-Term Safety Follow-Up The comparative safety data from the 5 year follow up in those treated with either COPIKTRA (n=158) or ofatumumab (n=155) were analyzed in adult patients with CLL or SLL as part of a randomized, open-label, actively controlled clinical trial (DUO) . Fatal adverse reactions occurred in 15% (23/158) of patients treated with COPIKTRA and in 3% (5/155) of patients treated with ofatumumab. The most common fatal adverse reactions in the COPIKTRA arm were infections and respiratory adverse reactions, occurring in 9% and 3% of patients, respectively.

Effects of Other Drugs on

COPIKTRA Strong CYP3A4 Inhibitors Coadministration with a strong CYP3A4 inhibitor increases duvelisib AUC , which may increase the risk of COPIKTRA toxicities. Reduce COPIKTRA dosage when co-administered with a strong CYP3A4 inhibitor . Strong and Moderate CYP3A4 Inducers Coadministration with a strong or moderate CYP3A4 inducer decreases duvelisib area under the curve (AUC) , which may reduce COPIKTRA efficacy. Avoid coadministration of strong or moderate CYP3A4 inducers with COPIKTRA. If coadministration with a moderate CYP3A4 inducer cannot be avoided, increase the COPIKTRA dose..

Effects of

COPIKTRA on Other Drugs CYP3A4 Substrates Coadministration with COPIKTRA increases AUC of a sensitive CYP3A4 substrate which may increase the risk of toxicities of these drugs. Consider reducing the dose of the sensitive CYP3A4 substrate and monitor for signs of toxicities of the co-administered sensitive CYP3A4 substrate.

Pregnancy Risk Summary Based on findings from animal studies and the mechanism of action, COPIKTRA can cause fetal harm when administered to a pregnant woman . There are no available data in pregnant women to inform the drug-associated risk. 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 10 times and 39 times the MRHD of 25 mg BID in rats and rabbits, respectively (see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data In an embryo-fetal development study in rats, pregnant animals received daily oral doses of duvelisib of 0, 10, 50, 150 and 275 mg/kg/day during the period of organogenesis. Administration of duvelisib at doses ≥ 50 mg/kg/day resulted in adverse developmental outcomes including reduced fetal weights and external abnormalities (bent tail and fetal anasarca), and doses ≥ 150 mg/kg/day resulted in maternal toxicity including mortality and no live fetuses (100% resorption) in surviving dams.

In another study in pregnant rats receiving oral doses of duvelisib up to 35 mg/kg/day during the period of organogenesis, no maternal or embryo-fetal effects were observed. The dose of 50 mg/kg/day in rats is approximately 10 -times the MRHD of 25 mg BID. In an embryo-fetal development study in rabbits, pregnant animals received daily oral doses of duvelisib of 0, 25, 100, and 200 mg/kg/day during the period of organogenesis. Administration of duvelisib at doses ≥ 100 mg/kg/day resulted in maternal toxicity (body weight losses or lower mean body weights and increased mortality) and adverse developmental outcomes (increased resorptions and post-implantation loss, abortion, and decreased numbers of viable fetuses). In another study in pregnant rabbits receiving oral doses of duvelisib up to 75 mg/kg/day, no maternal or embryo-fetal effects were observed.

The dose of 100 mg/kg/day in rabbits is approximately 39 times the MRHD of 25 mg BID.

Pediatric Use Safety and effectiveness of COPIKTRA have not been established in pediatric patients. Pediatric studies have not been conducted.