Duvelisib

COPIKTRA is indicated for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after at least two prior lines of systemic therapy. Limitations of Use: COPIKTRA is not indicated or recommended for the treatment of any patients with CLL or SLL as initial or second line treatment due to an increased risk of treatment-related mortality. COPIKTRA is a kinase inhibitor indicated for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after at least two prior lines lines of systemic therapy. ( 1 ) Limitations of Use : COPIKTRA is not indicated or recommended for the treatment of any patients with CLL or SLL as initial or second line treatment due to an increased risk of treatment-related mortality. ( 1 )

Strength Description 25 mg White to off-white opaque and Swedish orange opaque capsule printed in black ink with "duv 25 mg" 15 mg Pink opaque capsule printed in black ink with "duv 15 mg" Capsules: 25 mg, 15 mg. ( 3 )

None. None.

Hepatotoxicity: Monitor hepatic function. ( 5.6 ) Neutropenia: Monitor blood counts. ( 5.7 ) Embryo-Fetal toxicity: COPIKTRA can cause fetal harm. Advise females of reproductive potential and males with female partners of reproductive potential of potential risk to a fetus and to use effective contraception. ( 5.8 )

5.1 Treatment-related Mortality In a randomized controlled study in patients with relapsed or refractory CLL or SLL, treatment with COPIKTRA caused increased treatment-related mortality [see Clinical Studies ( 14 )] . With extended follow-up with a median of 63 months, treatment-related deaths occurred in 15% (23/158) of those patients in the overall population. In the indicated patient population, patients with relapsed or refractory CLL or SLL after at least two prior lines of systemic therapy, treatment-related deaths following treatment with COPIKTRA occurred in 14% (13/93) of patients. The most common cause of the treatment-related deaths were infections, which occurred in 9% and 11% of patients with relapsed or refractory CLL following at least one or two prior systemic therapies, respectively [see Adverse Reactions ( 6.1 )] . COPIKTRA is not indicated and is not recommended for any patients in the initial or second-line treatment setting [see Indications and Usage ( 1 )] .

5.2 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 )] .

5.3 Diarrhea or Colitis Serious, including fatal (1/442; 0.2%), 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 )] .

5.4 Cutaneous Reactions Serious, including fatal (2/442; 0.5%), 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 )].

5.5 Pneumonitis Serious, including fatal (1/442; 0.2%), 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 )] .

5.6 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). […]

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: Treatment-related Mortality [see Warnings and Precautions ( 5.1 )] Infections [see Warnings and Precautions ( 5.2 )] Diarrhea or Colitis [see Warnings and Precautions ( 5.3 )] Cutaneous Reactions [see Warnings and Precautions ( 5.4 )] Pneumonitis [see Warnings and Precautions ( 5.5 )] Hepatotoxicity [see Warnings and Precautions ( 5.6 )] Neutropenia [see Warnings and Precautions ( 5.7 )] 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 Secura Bio, Inc. (Secura Bio) at 1-844-973-2872, 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 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 (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) 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 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 [see Clinical Studies ( 14 )] . COPIKTRA was administered at 25 mg BID in 28-day treatment cycles until unacceptable toxicity or progressive disease. […]

CYP3A4 inhibitors: Reduce COPIKTRA dose to 15 mg twice daily when co-administered with strong CYP3A4 inhibitors. ( 2.4 , 7.1 , 12.3 ) Strong CYP3A4 inducers: Avoid coadministration. ( 2.5 , 7.1 , 12.3 ) Moderate CYP3A4 inducers: Avoid coadministration. If coadministration cannot be avoided, increase the dose of COPIKTRA. ( 2.5 , 7.1 , 12.3 ) CYP3A4 substrates: Monitor for signs of toxicities when co-administering COPIKTRA with sensitive CYP3A substrates. ( 7.2 )

7.1 Effects of Other Drugs on COPIKTRA Strong CYP3A4 Inhibitors Coadministration with a strong CYP3A4 inhibitor increases duvelisib AUC [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of COPIKTRA toxicities. Reduce COPIKTRA dosage when co-administered with a strong CYP3A4 inhibitor [see Dosage and Administration ( 2.4 )] . Strong and Moderate CYP3A4 Inducers Coadministration with a strong or moderate CYP3A4 inducer decreases duvelisib area under the curve (AUC) [see Clinical Pharmacology ( 12.3 )] , 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. [see Dosage and Administration ( 2.5 ), Clinical Pharmacology ( 12.3 )].

7.2 Effects of COPIKTRA on Other Drugs CYP3A4 Substrates Coadministration with COPIKTRA increases AUC of a sensitive CYP3A4 substrate [see Clinical Pharmacology ( 12.3 )] 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.

Lactation: Advise women not to breastfeed. ( 8.2 )

8.1 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 [see Clinical Pharmacology ( 12.1 )] . 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.

8.2 Lactation Risk Summary There are no data on the presence of duvelisib and/or its metabolites in human milk, the effects on the breastfed child, or on milk production. Because of the potential for serious adverse reactions from duvelisib in a breastfed child, advise lactating women not to breastfeed while taking COPIKTRA and for 1 month after the last dose.

8.3 Females and Males of Reproductive Potential COPIKTRA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1 )]. Pregnancy Testing Conduct pregnancy testing before initiation of COPIKTRA treatment. Contraception Females Based on animal studies, COPIKTRA can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with COPIKTRA and for 1 month after the last dose. Males Advise male patients with female partners of reproductive potential to use effective contraception during treatment with COPIKTRA and for 1 month after the last dose. Infertility Based on testicular findings in animals, male fertility may be impaired by treatment with COPIKTRA [see Nonclinical Toxicology ( 13.1 )] . There are no data on the effect of COPIKTRA on human fertility.

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

8.5 Geriatric Use Clinical trials of COPIKTRA included 270 patients (61%) that were 65 years of age and older and 104 (24%) that were 75 years of age and older. No major differences in efficacy or safety were observed between patients less than 65 years of age and patients 65 years of age and older.

Duvelisib is an inhibitor of PI3K with inhibitory activity predominantly against PI3K-δ and PI3K-γ isoforms expressed in normal and malignant B-cells. Duvelisib induced growth inhibition and reduced viability in cell lines derived from malignant B-cells and in primary CLL tumor cells. Duvelisib inhibits several key cell-signaling pathways, including B-cell receptor signaling and CXCR12-mediated chemotaxis of malignant B-cells. Additionally, duvelisib inhibits CXCL12-induced T cell migration and M-CSF and IL-4 driven M2 polarization of macrophages.