Copanlisib - Indications, Side Effects, Dosage, and Contraindications

Overview

Copanlisib is a drug used to treat adults with relapsed follicular lymphoma (a slowly progressing blood cancer) who have previously received at least two systemic therapies. On September 14, 2017, the Food and Drug Administration (FDA) granted expedited approval for Copanlisib to treat adult individuals with relapsed follicular lymphoma who had undergone at least two previous systemic therapies.

The approval relied on efficacy data from a phase 2 trial that included 104 patients with recurrent follicular lymphoma. Copanlisib was administered intravenously to participants on days one, eight, and 15 of a 28-day treatment cycle at 0.8 mg/kg (milligram per kilogram) or 60 mg (milligrams) doses.

Copanlisib was generally well tolerated despite common treatment-emergent side effects such as tiredness, diarrhea, and temporary hyperglycemia caused by infusions. Patients with active PI3K/B-cell antigen receptor signaling demonstrated a higher response to Copanlisib.

In a nutshell, Copanlisib is a potential therapy choice for individuals with relapsed or refractory marginal zone lymphoma (MZL) (lymphatic cancer) and follicular lymphoma, with high effectiveness and tolerable toxicity profiles. Its use may assist in avoiding disease recurrence and enhance patient outcomes.

Drug Group

Copanlisib is a selective pan-Class I phosphoinositide 3-kinase (PI3K) inhibitor that targets alpha and delta isoforms. It inhibits the PI3K signaling pathway, which is involved in cell proliferation, survival, and resistance to chemotherapeutic drugs, interfering with downstream signaling pathways that promote cell growth. Copanlisib inhibits tumor growth and promotes apoptosis in various tumor cell lines and xenograft models.

Indications

• Copanlisib is a kinase inhibitor used for the treatment of adult individuals with relapsed follicular lymphoma (FL) who have had at least two previous systemic treatments.

• This indication received accelerated approval because of a high overall response rate. Continued approval for this indication may require a confirmatory trial to demonstrate clinical benefits.

Dosage Forms and Available Strengths

Copanlisib is an injectable in a single-dose vial containing 60 mg of lyophilized solids for reconstitution.

Warnings and Precautions

• Infections: Observe individuals for any signs of infection. Withhold therapy for grade 3 or higher infections until resolved.

• Hyperglycemia: Begin each infusion after ideal blood glucose control is achieved. Treatment options for hyperglycemia include withholding, reducing the dose, or discontinuing.

• Hypertension: Individuals should only receive medication for hypertension (high blood pressure) once their systolic and diastolic blood pressures are less than 150 mmHg (millimeters of mercury) and 90 mmHg, respectively. If antihypertensive medication is essential, consider lowering the dose. Discontinue treatment for individuals with uncontrolled or life-threatening blood pressure.

• Non-infectious Pneumonitis (NIP): Treat non-infectious pneumonitis (NIP) (non-infectious causes of lung inflammation) and lower the dosage. Discontinue medication if grade 2 NIP recurs or in individuals with grade 3 or higher NIP.

• Neutropenia: For neutropenia (low neutrophil levels), check blood counts regularly, at least weekly, during treatment. Withhold therapy until the absolute neutrophil count (ANC) is greater than or equal to 0.5 x 103 cells per mm3 (cells per millimeter cube).

• Severe Cutaneous Reactions: For severe and persistent cutaneous responses, treatment should be withheld, reduced, or discontinued.

• Embryo-Fetal Toxicity: Copanlisib can harm fetuses. Inform individuals about potential risks to the fetus and encourage them to use effective contraception.

For Patients

What Is Follicular Lymphoma?

Follicular lymphoma is a kind of blood cancer caused by the aberrant proliferation of white blood cells (WBCs) in lymph nodes, resulting in the creation of clumps known as follicles. It is the second most frequent type of non-Hodgkin's lymphoma and the most prevalent slow-growing lymphoma. Symptoms can include swollen lymph nodes, fever, and night sweats; however, many people are identified before they notice anything.

Some people might not need immediate treatment and instead be advised to watch and wait. Follicular lymphoma is classified as a chronic illness by healthcare professionals, and it frequently recurs after therapy.

In approximately three percent of cases, follicular lymphoma can evolve into diffuse large B-cell lymphoma (DLBCL), resulting in new and more severe symptoms. It may migrate to other areas of the body. Despite its slow progression, follicular lymphoma may remain a serious and challenging condition.

How Does Copanlisib Work?

Copanlisib, an inhibitor of PI3K, targets the PI3K-alpha and PI3K-delta isoforms in malignant B cell populations. This inhibition of these enzymes disrupts downstream signaling pathways crucial to cell growth and survival. Copanlisib causes tumor cell death by apoptosis and inhibits proliferation in the main malignant B cell populations. It inhibits multiple signaling pathways: B-cell receptor signaling, a chemokine receptor CXCR12-mediated chemotaxis of malignant B cells, and NFκB (Nuclear factor kappa-light-chain-enhancer of activated B cells) signaling in lymphoma lineage cells.

What Are the Clinical Uses of Copanlisib?

Copanlisib has various clinical applications in the therapeutic management of lymphomas and other cancers.

• Follicular Lymphoma: Copanlisib is FDA-approved for treating adult individuals with relapsed follicular lymphoma (FL) after receiving at least two prior systemic treatments. It provides a viable treatment option for FL, a slowly developing blood malignancy characterized by aberrant B-cell proliferation in lymph nodes.

• Endometrial Cancer: Clinical trials in the phase II stage are underway to determine Copanlisib's efficacy in treating endometrial cancer.

• Diffuse Large B-Cell Lymphoma (DLBCL): Clinical investigations look into its potential in DLBCL.

• Cholangiocarcinoma: Studies are underway to determine its efficacy against this type of cancer.

• Non-Hodgkin Lymphoma (NHL): Copanlisib is being examined in conjunction with R-CHOP (Rituximab-Cyclophosphamide-Hydroxydaunorubicin-Oncovin-Prednisone) or R-B (Rituximab and Bendamustine) in a phase III trial for relapsed indolent NHL.

How Is Copanlisib Administered?

1. Copanlisib injection is a powder that is combined with liquids and administered using a needle or catheter inserted into a vein. It is typically administered slowly over 60 minutes on days one, eight, and 15 of a 28-day therapy cycle.

2. Copanlisib injection might produce elevated blood pressure for eight hours after the infusion. The physician will check the blood pressure before the infusion and for several hours after the infusion.

If patients have any of the following symptoms after receiving Copanlisib, contact the physician right away:

• Dizziness.

• Feeling faint.

• Headache.

• Pounding heartbeat.

3. Depending on the response to Copanlisib and any side effects, the physician may reduce the dosage, delay or discontinue Copanlisib injections, or prescribe additional medications. It is necessary to convey to the physician how one feels during the treatment.

4. Ask the doctor or pharmacist for an extra copy of the Copanlisib manufacturer's details for the patient.

What Are the Side Effects of Copanlisib?

Copanlisib injections may have adverse effects. Inform the physician if any of the following symptoms are severe or do not resolve:

• Diarrhea (loose and watery stools).

• Nausea.

• Vomiting.

• Mouth sores, ulcers, or pain.

• Burning, tingling, or numbness on the skin.

• Pain when touched.

• Swelling of the nose, throat, or mouth.

• Loss of strength or energy.

Certain adverse effects of Copanlisib can be severe. If patients suffer any of the following symptoms, call the physician right away:

• Unusual bleeding or bruising.

• New or worsening cough, shortness of breath, or difficulty breathing.

• Rash.

• Fever, sore throat, and chills.

• Feeling extremely hungry or thirsty, headache, or having frequent urination.

Copanlisib injections may produce additional adverse effects. Call the physician if patients experience any odd problems while receiving Copanlisib.

What Are the Things to Inform the Doctor Before Taking Copanlisib?

Before getting a Copanlisib injection,

• Inform the healthcare provider and pharmacist if patients are allergic to Copanlisib or its ingredients. Consult the pharmacist for a list of Copanlisib components.

• Inform the pharmacist and doctor about any prescription and nonprescription drugs, vitamins, nutritional supplements, or herbal products that patients are taking or intend to use any of the following: Boceprevir; Carbamazepine, Clarithromycin, Cobicistat, Conivaptan, Diltiazem, Efavirenz, Enzalutamide, Idelalisib, Indinavir with Ritonavir; Itraconazole, and Ketoconazole, lopinavir with Ritonavir; Mitotane, Nefazodone, Nelfinavir, Nevirapine, Paritaprevir, Ritonavir, Ombitasvir, or Dasabuvir; Phenobarbital, Phenytoin, Posaconazole, Rifabutin, Rifampin, Ritonavir, Saquinavir, and Tipranavir with Ritonavir; and Voriconazole. The healthcare provider may need to adjust the dosages of the drugs or closely monitor for negative effects. Many other drugs may interact with Copanlisib injection, so inform the physician about everything patients are taking, including ones that are not on the list.

• Tell the physician about any herbal supplements that patients are taking, particularly St. John's wort (a plant used to treat depression).

• Inform the physician if patients have an infection or have previously suffered from diabetes (high blood glucose), lung or breathing issues, high blood pressure, or liver illness.

• Inform the physician if patients are pregnant, want to become pregnant, or intend to father a child. Patients should not become pregnant while having Copanlisib injections. Before beginning treatment with Copanlisib, patients must have a negative pregnancy test. Use effective birth control while receiving Copanlisib injections and for one month following the final dosage. If the patient is a male and a woman is capable of becoming pregnant, the patient ought to utilize effective birth control during treatment and for one month following the last injection. If the patient or their partner becomes pregnant while taking Copanlisib, contact the doctor.

• Inform the physician if patients are breastfeeding. Patients should not breastfeed while having Copanlisib injections or for one month following their last dose.

• Patients should be aware that Copanlisib may lower fertility in both men and women. Consult the doctor about the risks of taking Copanlisib injections.

Dietary Considerations:

Avoid drinking grapefruit juice while taking Copanlisib, and maintain the normal diet unless the doctor instructs.

Missed Dose:

Patients who miss a Colpanlisib injection session should contact the doctor for guidance.

Overdose:

Following a single intravenous dose administration, the lethal dose (LD50) of Copanlisib dihydrochloride was greater than 23.0 mg/kg in both male and female rats, corresponding to 20.0 mg/kg of Copanlisib. Information regarding Copanlisib overdose is lacking for humans. In a medical setting, a Copanlisib overdose is usually treated immediately.

Storage and Handling:

To ensure optimal use, keep the Copanlisib vials refrigerated at 2°C (degree Celsius) to 8°C (36°F (degree Fahrenheit) to 46°F). After reconstitution, the reconstituted and diluted solution can be administered immediately or refrigerated for 24 hours. Allow the Copanlisib product to adjust to room temperature before use. Avoid direct sunlight and use only Copanlisib in a sterile 0.9 percent sodium chloride injection, USP (United States Pharmacopeia) solution. Never combine or inject Copanlisib with other medications or diluents.

For Doctors

Pharmacodynamics

Copanlisib is a kinase inhibitor that inhibits tumor growth and promotes apoptosis in numerous tumor cell lines and xenograft models. Copanlisib elevates plasma glucose levels.

Chemical Taxonomy

Copanlisib's IUPAC name is 2-Amino-N-[7-methoxy-8- (3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo [1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide1 and has a chemical formula of C23H28N8O4.

Mechanism of Action

The phosphatidylinositol-3-kinase (PI3K) signaling system is involved in cell proliferation, survival, and resistance to chemotherapy. PI3K isoforms are frequently overexpressed in B-cell malignancies, especially follicular lymphoma. Copanlisib belongs to class I PI3K inhibitors that target PI3K-alpha and PI3K-delta isoforms seen in malignant B cells. It has IC50 (half-maximal inhibitory concentration) values of 0.5, 3.7, 6.4, and 0.7 nmol/L (nanomoles per liter) for class I PI3K-alpha, beta, gamma, and delta isoforms. Copanlisibin causes apoptosis in tumor cells, inhibits cell cycle progression, and prevents the growth of primary malignant B cell lines. Copanlisib inhibits multiple cell signaling pathways, including B-cell receptor (BCR) signaling, CXCR12-mediated chemotaxis of malignant B cells, and NFκB signaling in lymphoma cell lines.

Pharmacokinetics

• Absorption: Copanlisib's area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) increase dose-proportionally over the absolute dose range of 5 to 93 mg (0.08 to 1.55 times the permitted recommended dose), and its pharmacokinetics are linear. Copanlisib's pharmacokinetics show no time dependency or accumulation. The geometric mean (range) of Copanlisib exposure at 0.8 mg/kg (roughly corresponding to the recommended dose of 60 mg) is 463 (range: 105 to 1670; SD (standard deviation): 584) ng/mL (nanogram per milliliter) for Cmax and 1570 (range: 536 to 3410; SD: 338) ng x hr/mL (nanogram x hour per milliliter) for AUC 0-25h (hour).

• Distribution: The average geometrical volume of the distribution is 871 (range: 423 to 2150; standard deviation: 479) L (liters). Copanlisib is 84.2 percent bound to plasma proteins, particularly serum albumin. The in vitro average blood-to-plasma ratio is 1.7, with a range of 1.5 to 2.1.

• Metabolism: Copanlisib is mostly metabolized by CYP3A (greater than 90 percent) and, to a lesser extent, CYP1A1 (less than 10 percent). The M1 metabolite represents five percent of total radioactivity in plasma and exhibits pharmacological activity similar to that of the parent drug.

• Excretion: In humans, approximately half of Copanlisib leaves the body as the unmodified parent molecule, with the remaining half excreted as metabolites. After receiving a single intravenous dose of 12 mg (0.2 times the recommended permitted dose) of radiolabeled Copanlisib, roughly 64 percent of the administered dose was recovered in feces and 22 percent in urine after 20 to 34 days.

Copanlisib remained unchanged in approximately 30 percent of the administered dose in feces and 15 percent in urine. Metabolites formed by CYP450-mediated oxidation comprised 41 percent of the given dosage. Copanlisib has a mean geometric terminal elimination half-life of 39.1 hours (range: 14.6 to 82.4; SD: 15.0). The average geometrical clearance is 17.9 (range: 7.3 to 51.4; SD: 8.5) L/hr (liters per hour).

Non-Clinical Toxicology

• Carcinogenesis, Mutagenesis, and Impairment of Fertility: Copanlisib has not been tested for carcinogenicity or fertility; however, it has been reported to have negative effects on male and female reproductive systems in repeat dosage toxicity tests. Male rats and dogs exhibited effects on the testes, epididymides, and prostate. Still, female rats experienced bleeding, cysts, atrophy, and decreased weight in the ovaries, uterus, and vagina, as well as a dose-related fall in female rats in estrus. Copanlisib was not used in fertility studies.

Drug Interactions

• CYP3A Inducers: Avoid using powerful CYP3A inducers simultaneously.

• CYP3A Inhibitors: When using powerful CYP3A inhibitors, the Copanlisib dose should be reduced to 45 mg.

Clinical Studies

The efficacy of Copanlisib was studied in a phase 2 clinical trial called CHRONOS-1, which included 142 patients with follicular B-cell non-Hodgkin lymphoma who had relapsed following at least two previous treatments. The most prevalent past systemic therapies were chemotherapy combined with anti-CD20 immunotherapy (89 percent), chemotherapy alone (41 percent), and anti-CD20 immunotherapy alone (37 percent).

The experiment enrolled 142 patients who received 60 mg Copanlisib, 130 patients who received a fixed dose of 60 mg Copanlisib, and 12 who received 0.8 mg/kg equivalent Copanlisib. Treatment continued until the disease progressed or there was intolerable toxicity. Tumor response was measured using the International working group response criteria for malignant lymphoma, and an independent review committee evaluated the effectiveness based on the overall response rate (ORR).

Specific Considerations

• Pregnancy: Copanlisib has been shown to induce embryo-fetal mortality and fetal malformations in dosages as low as 12 percent of the approved human dose. It also has negative effects on the male and female reproductive systems, such as the testes, epididymides, prostate, ovaries, uterus, and vagina. There are no controlled studies on human pregnancy or fertility.

Copanlisib's safety during pregnancy has not been confirmed, although animal research indicates that it may cause fetal damage and unfavorable reproductive effects. Pregnant women should be informed of the potential fetal risk and urged to use extremely effective contraception throughout treatment and for at least one month following the final dosage.

• Breastfeeding: Breastfeeding is not recommended throughout therapy or for at least one month following the final dosage. The consequences of nursing infants and milk production are unclear. After giving radiolabeled Copanlisib to breastfeeding animals, two percent of the radioactivity was released into the milk.

• Pediatric Use: The safety and efficacy of Copanlisib in pediatric patients have not been established.

• Geriatric Use: The study indicated that patients over 65 did not require any dose adjustments. Of the 168 patients with follicular lymphoma who received Copanlisib, 48 percent were 65 or older, and 16 percent were 75 or older. There were no significant differences in efficacy between the elderly and younger patients.

• Hepatic Impairment: Copanlisib dosages should be lowered to 45 mg for moderate hepatic impairment patients (Child-Pugh B) and 30 mg for severe hepatic impairment patients (Child-Pugh C). Patients with mild hepatic impairment do not require a dosage change.