Copanlisib 60 mg vial for Injection for with relapsed follicular lymphoma after two prior systemic therapies.
First approved of an intravenous phosphatidylinositol-3-kinase (PI3K) inhibitor.
It is an inhibitor of phosphatidylinositol-3-kinase (PI3K) with inhibitory activity predominantly against PI3K-α and PI3K-δ isoforms expressed in malignant B-cells.
It induces tumor cell death by apoptosis and inhibition of proliferation of primary malignant B cell lines.
PI3K is linked to cellular proliferation, motility, and survival of malignant B-cells in non-Hodgkin’s lymphoma
For the treatment of adult patients with relapsed follicular lymphoma who have received at least two prior systemic therapies.
Approval based on overall response rate of 104 adult patients with relapsed follicular lymphoma from the Phase II CHRONOS-1 study.
It achieved a 59% overall response rate in patients with relapsed follicular lymphoma, with a complete response rate of 12%.
Copanlisib has been shown to have an effect against survival and spread of cancerous B-cells.
In Phase 2 clinical trials, 59 percent had a complete or partial shrinkage of their tumors that lasted about 12 months.
It is administered as intravenous infusion on a weekly but intermittent schedule.
Copanlisib can cause serious side effects including: infections, hyperglycemia, hypertension, pneumonitis, neutropenia and skin rashes.
Most common side effects: hyperglycemia, diarrhea, decreased general strength and energy, hypertension, leukopenia, neutropenia, nausea, lower respiratory tract infections and thrombocytopenia.
It can cause harm to unborn babies, and
lactating patients are advised to not breastfeed.
Approval for the treatment of adult patients experiencing relapsed follicular lymphoma who have received at least two prior systemic therapies.
Follicular lymphoma is the most common subtype of indolent, or slow-growing, NHL, comprising approximately one out of five lymphomas.
Response rates and duration of response decline with each line of therapy, underscoring the need for patients whose disease has already progressed.
The PI3K pathway is activated in many tumor types, including lymphoma.
Also granted orphan drug status for the treatment of splenic, nodal and extranodal subtypes of marginal zone lymphoma.
Phase II clinical trials are in progress for treatment of endometrial cancer, diffuse large B-cell lymphoma, cholangiocarcinoma, and non-Hodgkin lymphoma.
Copanlisib in combination with R-CHOP or R-B (rituximab and bendamustine) is in a phase III trial for relapsed indolent non-Hodgkin lymphoma (NHL).
Two separate phase III trials are investigating the use of copanlisib in combination with rituximab for indolent NHL and the other using copanlisib alone in cases of rituximab-refractory indolent NHL.
Copanlisib is an intravenously administered pan‐class I PI3K inhibitor for patients with relapsed FL who have received ≥2 prior systemic therapies.
In the phase II CHRONOS‐1 trial in patients with indolent BCL (73% had FL) relapsing after or refractory to ≥2 prior therapies and who had received prior treatment with rituximab and an alkylating agent: After a median treatment duration of 6 months, ORR was 60.6% in the full population and 58.7% in patients with FL; overall median duration of response was 14.1 months, and median PFS was 12.5 months
It is effective in inhibiting HER2+ breast cancer cells with acquired resistance to the HER2-inhibitors trastuzumab and/or lapatinib.
Protein binding 84.2%.
Metabolism:CYP3A4/5 about 90% and CYP1A1 about 10%.
Elimination half-life 39.
Excretion- Feces (64%), Urine (22%.
It is associated with: serious, including fatal, infections, Grade 3 or 4 hyperglycemia, Grade 3 hypertension, non-infectious pneumonitis, Grade 3 or 4 neutropenia, Grade 3 or 4 cutaneous reactions, and embryo-fetal toxicity.
Serious adverse reactions were reported in 26% of patients.
The most frequent serious adverse reactions that occurred were pneumonia (8%), pneumonitis (5%) and hyperglycemia (5%).
Most adverse effects were of low severity and resolved with dose reduction, or discontinuation.
Adverse reactions resulted in dose reduction in 21% and discontinuation in 16% patients.
The most frequently observed adverse drug reactions (≥20%) in treated patients are: hyperglycemia (54%), leukopenia (36%), diarrhea (36%), decreased general strength and energy (36%), hypertension (35%), neutropenia (32%), nausea (26%), thrombocytopenia (22%), and lower respiratory tract infections (21%).
The safety profile differs from that of daily oral PI3K inhibitors, with low rates of liver toxicity, colitis, pneumonitis, and opportunistic infections.
Dose 60 mg or 0.8 mg/kg in clinical trials.
The PI3K pathway is involved in cell growth, survival and metabolism.
The PI3K pathway’s dysregulation plays an important role in FL.
Induces tumor cell death by apoptosis and inhibition of proliferation of primary malignant B cell lines.
It inhibits several key cell-signaling pathways, including B cell receptor signaling, CXCR12 mediated chemotaxis of malignant B cells, and NFκB signaling in lymphoma cell lines.
Administered as a 1-hour intravenous infusion of 60 mg on days 1, 8, and 15 of a 28-day treatment cycle on an intermittent schedule.
Routes of administration intravenous infusion only.
Treatment should be continued until disease progression or unacceptable toxicity.
Serious, including fatal, infections occurred in 19% patients treated with monotherapy.
The most common serious infection is pneumonia.
Serious pneumocystis jiroveci pneumonia (PJP) infection occurred in 0.6% of patients treated with monotherapy.
Considering PJP prophylaxis for populations at risk.
Withhold drug in patients with suspected PJP infection of any grade. If confirmed, treat infection until resolution, then resume at previous dose with concomitant PJP prophylaxis.
Hyperglycemia glucose occurs in 41% of patients, with
serious hyperglycemic events occurred in 2.8% of patients.
Blood glucose levels typically peak 5 to 8 hours post-infusion and subsequently decline to baseline levels.
Grade 3 hypertension occurred in 26% of patients, with serious hypertensive events occurring in 0.9% of patients.
Treatment may result in infusion-related hypertension.
Non-infectious pneumonitis occurs in 5% of patients.
Patients with pneumonitis have been managed by withholding the drug and administration of systemic corticosteroids.
Grade 3 or 4 neutropenia occurs in 24% of patients treated, while serious neutropenic events occurred in 1.3%.
Blood counts should be monitored at least weekly during treatment
The drug should be withheld, reduction in dose dose, or discontinued depending on the severity and persistence of neutropenia.
Severe cutaneous reactions Grade 3 and 4 occurred in 2.8% and 0.6% of patients treated.
Serious cutaneous reaction events were reported in 0.9% and include: dermatitis exfoliative, exfoliative rash, pruritus, and rash, including maculo-papular rash.
Can cause fetal harm when administered to a pregnant woman.
Women are advised not to breastfeed.
Serious adverse reactions reported to occur in 26%) patients.
The most frequent serious adverse reactions are pneumonia (8%), pneumonitis (5%) and hyperglycemia (5%).
The most frequently observed adverse drug reactions of 20% are hyperglycemia (54%), leukopenia (36%), diarrhea (36%), decreased general strength and energy (36%), hypertension (35%), neutropenia (32%), nausea (26%), thrombocytopenia (22%), and lower respiratory tract infections (21%).
Should avoid concomitant use with strong CYP3A inducers, and the dose should be reduced to 45 mg when concomitantly administered with strong CYP3A inhibitors.