Brand Name
Copiktra
Generic Name
Duvelisib
View Brand Information FDA approval date: September 25, 2018
Form: Capsule
What is Copiktra (Duvelisib)?
COPIKTRA is indicated for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic leukemia after at least two prior therapies. 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 or small lymphocytic lymphoma 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.
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Brand Information
COPIKTRA (duvelisib)
WARNING: TREAMENT-RELATED MORTALITY AND SERIOUS TOXICITIES: INFECTIONS, DIARRHEA OR COLITIS, CUTANEOUS REACTIONS, and PNEUMONITIS
- Treatment-related mortality occurred in 15% of COPIKTRA-treated patients
- 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
- 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
- Fatal and/or serious cutaneous reactions occurred in 5% of COPIKTRA-treated patients. Withhold COPIKTRA
- Fatal and/or serious pneumonitis occurred in 5% of COPIKTRA-treated patients. Monitor for pulmonary symptoms and interstitial infiltrates. Withhold COPIKTRA
1INDICATIONS AND USAGE
COPIKTRA is indicated for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL) after at least two prior therapies.
2CONTRAINDICATIONS
None.
3ADVERSE 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:
- Treatment-related Mortality
- Infections
- Diarrhea or Colitis
- Cutaneous Reactions
- Pneumonitis
- Hepatotoxicity
- Neutropenia
3.1Clinical 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.
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).
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
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.
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.
4DESCRIPTION
COPIKTRA (duvelisib) is a kinase inhibitor.
Duvelisib is a white-to-off-white crystalline solid with the empirical formula C
COPIKTRA capsules are for oral administration and are supplied as white to off-white opaque and Swedish orange opaque capsules (25 mg, on anhydrous basis) or pink opaque capsules (15 mg, on anhydrous basis), and contain the following inactive ingredients: colloidal silicon dioxide, crospovidone, magnesium stearate, and microcrystalline cellulose. Capsule shells contain gelatin, titanium dioxide, black ink, and red iron oxide.
5CLINICAL STUDIES
DUO Study
A randomized, multicenter, open-label trial (DUO Study; NCT02004522) compared COPIKTRA versus ofatumumab in 319 adult patients with CLL (N = 312) or SLL (N = 7) after at least one prior therapy. 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. The trial required hepatic transaminases ≤ 3 times upper limit of normal (ULN), total bilirubin ≤ 1.5 times ULN, and serum creatinine ≤ 2 times ULN.
The study randomized patients with a 1:1 ratio to receive either COPIKTRA 25 mg BID until disease progression or unacceptable toxicity or ofatumumab for 7 cycles. Ofatumumab was administered intravenously at an initial dose of 300 mg, followed one week later by 2000 mg once weekly for 7 doses, and then 2000 mg once every 4 weeks for 4 additional doses.
The approval of COPIKTRA was based on efficacy and safety analysis of patients with at least 2 prior lines of therapy, where the benefit:risk appeared greater in this more heavily pretreated population compared to the overall trial population.
In this subset (95 randomized to COPIKTRA, 101 to ofatumumab), the median patient age was 69 years (range: 40 to 90 years), 59% were male, and 88% had an ECOG performance status of 0 or 1. Forty-six percent received 2 prior lines of therapy, and 54% received 3 or more prior lines. At baseline, 52% of patients had at least one tumor ≥ 5 cm, and 22% of patients had a documented 17p deletion.
During randomized treatment, the median duration of exposure to COPIKTRA was 13 months (range: 0.2 to 37), with 80% of patients receiving at least 6 months and 52% receiving at least 12 months of COPIKTRA. The median duration of exposure to ofatumumab was 5 months (range: < 0.1 to 6).
Efficacy was based on progression-free survival (PFS) as assessed by an Independent Review Committee (IRC). Other efficacy measures included overall response rate. Efficacy of COPIKTRA compared to ofatumumab specifically in patients treated with at least two prior therapies is presented in
Figure 1. Kaplan-Meier Curve of PFS per IRC In Patients with at Least 2 Prior Therapies (DUO)
Increased Mortality in Patients with Relapsed or Refractory CLL or SLL Treated with COPIKTRA
Final overall survival (OS) analysis was conducted with a median follow-up time of 63 months. Fifty percent (80/160) of patients in the overall population died in the COPIKTRA arm, and 44% (70/159) of patients died in the ofatumumab arm. Treatment of patients in the overall population with duvelisib compared with ofatumumab demonstrated an OS HR of 1.09 (95% CI: 0.79, 1.51) with a median OS of 52 months (95% CI: 42, 68) in those patients treated with COPIKTRA and a median OS of 63 months (95% CI: 41 mo, NE) in those treated with ofatumumab. In the indicated population, those patients with relapsed or refractory CLL or SLL after at least 2 prior lines of systemic therapy, 56% (53/95) of patients died in the COPIKRA arm and 49% (49/101) of patients died in the ofatumumab arm. Treatment of patients in the indicated population with duvelisib compared with ofatumumab demonstrated an OS HR of 1.06 (95% CI: 0.71, 1.58) with a median OS of 44 months (95% CI: 32, 57) in those patients treated with COPIKTRA and a median OS of 47 months (95% CI: 29,75) in those treated with ofatumumab.
6HOW SUPPLIED/STORAGE AND HANDLING
COPIKTRA (duvelisib) capsules are supplied as follows:
Store at 20° to 25°C (68° to 77°F), with excursions permitted at 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Retain in original package until dispensing. Dispense blister packs in original container.
7PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Physicians and healthcare professionals are advised to discuss the following with patients prior to treatment with COPIKTRA:
●Treatment-related Mortality
Advise patients that COPIKTRA has been associated with increased deaths due to side effects of therapy in a randomized study when compared to standard therapy. The main reason for death was infection
Infections
Advise patients that COPIKTRA can cause serious infections that may be fatal. Advise patients to immediately report symptoms of infection (e.g. fever, chills)
●Diarrhea or Colitis
Advise patients that COPIKTRA can cause serious diarrhea or colitis (inflammation of the gut) that may be fatal, and to notify their healthcare provider immediately about any new or worsening diarrhea, stool with mucus or blood, or abdominal pain
●Cutaneous Reactions
Advise patients that COPIKTRA can cause a serious skin rash that may be fatal, and to notify their healthcare provider immediately if they develop a new or worsening skin rash
●Pneumonitis
Advise patients that COPIKTRA may cause pneumonitis (inflammation of the lungs) that may be fatal, and to report any new or worsening respiratory symptoms including cough or difficulty breathing
●Hepatotoxicity
Advise patients that COPIKTRA may cause significant elevations in liver enzymes, and that monitoring of liver tests is needed. Advise patients to report symptoms of liver dysfunction including jaundice (yellow eyes or yellow skin), abdominal pain, bruising, or bleeding
●Neutropenia
Advise patients of the need for periodic monitoring of blood counts. Advise patients to notify their healthcare provider immediately if they develop a fever or any sign of infection
●Embryo-Fetal Toxicity
Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the risk to a fetus
Advise females of reproductive potential to use effective contraception during treatment and for 1 month after receiving the last dose of COPIKTRA
Advise males with female partners of reproductive potential to use effective contraception during treatment with COPIKTRA and for 1 month after the last dose
●Lactation
Advise lactating women not to breastfeed during treatment with COPIKTRA and for 1 month after the last dose
●Instructions for Taking COPIKTRA
Advise patients to take COPIKTRA exactly as prescribed. COPIKTRA may be taken with or without food; the capsules should be swallowed whole
Advise patients that if a dose is missed by fewer than 6 hours, to take the missed dose right away and take the next dose as usual. If a dose is missed by more than 6 hours, advise patients to wait and take the next dose at the usual time
Advise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products, before and during treatment with COPIKTRA
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USCPR2419001
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