The US Food and Drug Administration (FDA) has approved Talon Therapeutics' Marqibo (vinCRIStine sulfate LIPOSOME injection) for the treatment of adult patients with Philadelphia chromosome negative (Ph-) acute lymphoblastic leukaemia (ALL) in second or greater relapse or whose disease has progressed following two or more anti-leukaemia therapies.
This indication is based on overall response rate. Clinical benefit such as improvement in overall survival has not been verified. Marqibo is administered at a dose of 2.25 mg/m2 intravenously over one hour once every seven days. Marqibo has different dosage recommendations than non-liposomal vincristine sulfate.
"We are delighted that Marqibo will be available to a patient population with an underserved hematologic malignancy," stated Steven R Deitcher MD, president, chief executive officer and Board Member of Talon Therapeutics. "This represents a transformational event for Talon and fulfillment of our most important corporate goal, to date."
Marqibo is a novel, sphingomyelin/cholesterol liposome-encapsulated, formulation of vincristine sulfate. Vincristine, a microtubule inhibitor, is FDA-approved for ALL and Non-Hodgkin's Lymphoma (NHL) and is widely used in combination regimens for treatment for a variety of adult and pediatric hematologic and solid tumour malignancies. The Optisome nanoparticle encapsulation technology, utilized by Talon, has been shown to provide prolonged circulation of vincristine in the blood.
Marqibo has received orphan drug designation for the treatment of ALL from the FDA and from the European Medicines Agency (EMA). Talon intends to submit a Marketing Authorization Application to the EMA in 2013.
Marqibo is a liposomal vinca alkaloid indicated for the treatment of adult patients with Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukaemia (ALL) in second or greater relapse or whose disease has progresses following two or more anti-leukaemia therapies. This indication is based on overall response rate. Clinical benefit such as improvement in overall survival has not been verified.
Marqibo is contraindicated in patients with demyelinating conditions including Charcot-Marie-Tooth syndrome. Marqibo is contraindicated in patients with hypersensitivity to vincristine sulfate or any of the other components of Marqibo (vinCRIStine sulfate LIPOSOME injection). Marqibo is contraindicated for intrathecal administration.
Marqibo (vinCRIStine sulfate LIPOSOME injection) has different dosage recommendations than vinCRIStine sulfate injection. Verify drug name and dose prior to preparation and administration to avoid overdosage.
Only administer through a secure and free-flowing venous access line. If extravasation is suspected, discontinue infusion immediately and consider local treatment measures.
Sensory and motor neuropathies are common and are cumulative. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, hyporeflexia, areflexia, neuralgia, jaw pain, decreased vibratory sense, cranial neuropathy, ileus, burning sensation, arthralgia, myalgia, muscle spasm, or weakness, both before and during treatment. Orthostatic hypotension may occur. The risk of neurologic toxicity is greater if Marqibo is administered to patients with preexisting neuromuscular disorders or when other drugs with risk of neurologic toxicity are being given. In the studies of relapsed and/or refractory adult ALL patients, Grade = 3 neuropathy events occurred in 32.5 per cent of patients. Worsening neuropathy requires dose delay, reduction, or discontinuation of Marqibo.
Monitor complete blood counts prior to each dose of Marqibo. If Grade 3 or 4 neutropenia, thrombocytopenia, or anaemia develops, consider Marqibo dose modification or reduction as well as supportive care measures.
Tumour lysis syndrome (TLS) may occur in patients with ALL receiving Marqibo. Anticipate, monitor for, and manage.
Ileus, bowel obstruction, and colonic pseudo-obstruction have occurred. Marqibo can cause constipation. Institute a prophylactic bowel regimen to mitigate potential constipation, bowel obstruction, and/or paralytic ileus, considering adequate dietary fiber intake, hydration, and routine use of stool softeners, such as docusate. Additional treatments, such as senna, bisacodyl, milk of magnesia, magnesium citrate, and lactulose may be considered.
Marqibo can cause severe fatigue. Marqibo dose delay, reduction, or discontinuation may be necessary.
Fatal liver toxicity and elevated levels of aspartate aminotransferase have occurred. Elevated levels of aspartate aminotransferase of Grade =3 occurred in six to 11 per cent of patients in clinical trials. Monitor hepatic function tests. Reduce or interrupt Marqibo for hepatic toxicity.
Marqibo can cause fetal harm when administered to a pregnant woman. Vincristine sulfate liposome injection was teratogenic or caused embryo-fetal death in animals. Women of childbearing potential should avoid becoming pregnant while being treated with Marqibo. There are no adequate and well-controlled studies of Marqibo in pregnant women and there were no reports of pregnancy in any of the clinical studies in the Marqibo clinical development program. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
The most common adverse reactions ( > 30 per cent) were constipation (57 per cent), nausea (52 per cent), pyrexia (43 per cent), fatigue (41 per cent), peripheral neuropathy (39 per cent), febrile neutropenia (38 per cent), diarrhoea (37 per cent), anaemia (34 per cent), decreased appetite (33 per cent), and insomnia (32 per cent).
The most commonly reported SAEs included febrile neutropenia (20.5 per cent), pyrexia (13.3 per cent), hypotension (7.2 per cent), respiratory distress (6.0 per cent), and cardiac arrest (6.0 per cent).
Twenty-eight percent of patients experienced adverse reactions leading to treatment discontinuation. The most common adverse reactions that caused treatment discontinuation were peripheral neuropathy (10 per cent), leukaemia-related (seven per cent), and tumour lysis syndrome (two per cent).
Deaths occurred in 23 per cent of patients in study 1. The non-leukaemia related causes of deaths were brain infarct, intracerebral haemorrhage, liver failure, multi-system organ failure, pneumonia and septic shock, respiratory failure, pulmonary haemorrhage, and sudden cardiac death.
No formal drug interaction studies have been conducted with Marqibo. Marqibo is expected to interact with drugs known to interact with non-liposomal vincristine sulfate.
Simultaneous oral or intravenous administration of phenytoin and antineoplastic chemotherapy combinations that included non-liposomal vincristine sulfate has been reported to reduce blood levels of phenytoin and to increase seizure activity.
Vincristine sulfate, the active agent in Marqibo, is a substrate for cytochrome P450 3A isozymes (CYP3A); therefore, the concomitant use of strong CYP3A inhibitors should be avoided (e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin). Similarly, the concomitant use of strong CYP3A inducers should be avoided (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, St. John's Wort).
Vincristine sulfate, the active agent in Marqibo, is also a substrate for P-glycoprotein (P-gp). The effect of concomitant use of potent P-gp inhibitors or inducers has not been investigated; it is likely that these agents will alter the pharmacokinetics or pharmacodynamics of Marqibo. Therefore the concomitant use of potent P-gp inhibitors or inducers should be avoided.
Based on its mechanism of action and findings from animal studies, Marqibo can cause fetal harm when administered to pregnant women.
If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. In an embryofetal developmental study, pregnant rats were administered vincristine sulfate liposome injection intravenously during the period of organogenesis at vincristine sulfate doses of 0.022 to 0.09 mg/kg/day. Drug-related adverse effects included fetal malformations (skeletal and visceral), decreases in fetal weights, increased numbers of early resorptions and post-implantation losses, and decreased maternal body weights Malformations were observed at doses = 0.044 mg/kg/day in animals at systemic exposures approximately 20-40 per cent of those reported in patients at the recommended dose.
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug taking into account the importance of the drug to the mother.
The safety and effectiveness of Marqibo in pediatric patients have not been established.
Safety and effectiveness in elderly individuals have not been established. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
The influence of renal impairment on the safety, efficacy, and pharmacokinetics of Marqibo has not been evaluated.
Non-liposomal vincristine sulfate is excreted primarily by the liver. The influence of severe hepatic impairment on the safety and efficacy of Marqibo has not been evaluated. The pharmacokinetics of Marqibo was evaluated in patients with moderate hepatic dysfunction (Child-Pugh B) secondary to melanoma liver metastases. The dose-adjusted maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) of Marqibo in patients with moderate hepatic impairment was comparable to the Cmax and AUC of patients with ALL who had otherwise normal hepatic function.
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