In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.
Indication
In August 2012, vinCRIStine sulfate LIPOSOME injection (Marqibo) was granted accelerated approval for the treatment of adult patients with Philadelphia chromosome–negative (Ph–) acute lymphoblastic leukemia (ALL) in second or greater relapse or whose disease has progressed following two or more antileukemia therapies.1,2 Approval was based on the rate of complete remission plus the rate of complete remission with incomplete blood count recovery in a single-arm, single-agent trial of liposomal vincristine in adults in second or greater relapse of ALL. As a condition of the accelerated approval, the manufacturer (Talon Therapeutics, Inc), must evaluate the effect of liposomal vincristine on overall survival in a randomized controlled trial in adult patients with ALL.
In the single-arm trial (HBS407 trial),2 65 patients aged ≥ 18 years with Ph– ALL in second or greater relapse or whose disease had progressed after at least two antileukemia treatments received liposomal vincristine via IV infusion at 2.25 mg/m2 over 60 minutes every 7 days. Patients had to have achieved complete remission from one of the prior antileukemia chemotherapies, defined as a leukemia-free interval of at least 90 days. Patients were not eligible for immediate hematopoietic stem cell transplantation at the start of the study. All patients had received prior vincristine sulfate; 22 (34%) had not received asparaginase products. Fifty-one percent of patients were male, 45% were aged > 30 years, and 11% were aged ≥ 65 years; 85% had precursor B-cell ALL, and 15% had precursor T-cell ALL. Concomitant corticosteroid treatment was not permitted beyond day 5 of the study.
The complete remission rate was 4.6% (3/65 patients), and the rate of complete remission with incomplete blood count recovery was 10.8% (7/65 patients). Among the 10 patients achieving complete remission or complete remission with incomplete blood count recovery, the median remission duration was 28 days (95% CI = 7–36 days), and the median duration to first event (relapse, death, or subsequent chemotherapy) was 56 days (95% CI = 9–65 days).
How It Works
The newly approved vincristine product is a sphingomyelin/cholesterol liposome-encapsulated formulation of vincristine sulfate.2,3 Vincristine induces cell cycle–specific cytotoxicity by binding to tubulin during mitosis, resulting in microtubule depolymerization and metaphase arrest and thus apoptosis. The degree of killing increases with higher drug concentration and longer duration of exposure. Since free vincristine undergoes rapid cellular uptake and extensive tissue binding, it has a half-life of minutes and low levels of free drug are present in plasma. Dosing of conventional vincristine is limited by significant neurotoxicity due to binding to neuronal tubulin, with such toxicity occurring at doses higher than 1.4 mg/m2 and leading to capping of the total dose of vincrsitine.
Liposomal encapsulation of vincristine prolongs circulation of active drug and passively targets it to tissues with fenestrated vasculature (eg, bone marrow, lymph nodes, spleen, liver, and solid tumors), resulting in increased penetration and accumulation in tumor tissue and potentially reducing levels in neural tissue compared with free vincristine.
Liposomal vincristine has shown greater antitumor activity in vitro and in animal models compared with conventional vincristine at equivalent (mg/kg) doses, and was more likely to be curative in mouse models using leukemia cell lines.
How It Is Given
Liposomal vincristine is given at 2.25 mg/m2 via IV infusion over 1 hour once every 7 days. It is for IV use only; administration by any other route is fatal. The liposomal formulation of this drug has different dosage recommendations than vincristine sulfate injection. The final drug product is prepared on site from components in the supplied Marqibo Kit; extensive careful preparation is required.
Contraindications to liposomal vincristine use include demyelinating conditions (including Charcot-Marie-Tooth syndrome) and intrathecal use; intrathecal use is fatal.
Dose interruption and reduction are required for peripheral neuropathy. Treatment should be interrupted for grade 3 or persistent grade 2 neuropathy, discontinued if neuropathy remains at or worsens to grade 3 or 4, and restarted at 2.00 mg/m2 if it recovers to grade 1 or 2. For persistent grade 2 neuropathy after the initial dose reduction, treatment should be interrupted and then resumed at 1.825 mg/m2 and subsequently 1.5 mg/m2 if neuropathy recovers to grade 1 and should be discontinued for neuropathy of grade 3 or 4.
Safety Profile
The safety of liposomal vincristine at 2.25 mg/m2 weekly was evaluated in two single-arm trials (HBS407 and VSLI-06 trials) including a total of 83 patients with ALL in second or greater relapse.2 Adverse events occurred in 100% of patients, with the most common (> 30% of patients) being constipation (57%), nausea (52%), pyrexia (43%), fatigue (41%), peripheral neuropathy (39%), febrile neutropenia (38%), diarrhea (37%), anemia (34%), decreased appetite (33%), and insomnia (32%).
Adverse events of grade 3 or higher occurred in 96% of patients, with the most common (> 10%) being infections (40%, including pneumonia, septic shock, and staphylococcal bacteremia), neuropathy (32.5%, including peripheral motor and sensory neuropathy in 17%), febrile neutropenia (31%), neutropenia (18%), anemia (17%), thrombocytopenia (17%), pyrexia (14.5%), and fatigue (12%).
Dose reduction or delay occurred in 53% of patients during treatment. Treatment was discontinued due to adverse events in 28% of patients, with the most common non–leukemia-related causes being peripheral neuropathy (10%) and tumor lysis syndrome (2%). Neuropathy-related adverse events leading to discontinuation included decreased vibratory sense, facial palsy, hyporeflexia, constipation, asthenia, fatigue, and musculoskeletal pain.
Death occurred in 23% of patients (n = 15) in the HBS407 trial. Causes of deaths were respiratory failure in 4 patients, pneumonia and septic shock in 3, intracerebral hemorrhage and multisystem organ failure in 2 each, and brain infarct, liver failure, pulmonary hemorrhage, and sudden cardiac death in 1 each.
Liposomal vincristine carries a boxed warning regarding appropriate use, emphasizing that the formulation is for IV use only and is fatal if given by other routes, that death has occurred with intrathecal use, and that it has different dose recommendations than vincristine sulfate injection. It also carries warnings/precautions for intrathecal administration; extravasation; neurologic toxicity; myelosuppression; tumor lysis syndrome; constipation, bowel obstruction, and paralytic ileus; fatigue; hepatic toxicity; and embryofetal toxicity. ■
References
1. U.S. Food and Drug Administration: VinCRIStine sulfate LIPOSOMAL injection. Available at http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm315111.htm. Accessed August 20, 2012.
2. MARQIBO® (vinCRIStine sulfate LIPOSOME injection) for intravenous use prescribing information. Talon Therapeutics, Inc, August 2012. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202497s000lbl.pdf. Accessed August 20, 2012.
3. Thomas DA, Kantarjian HM, Stock W, et al: Phase 1 multicenter study of vincristine sulfate liposomes injection and dexamethasone in adults with relapsed or refractory acute lymphoblastic leukemia. Cancer 115:5490-5498, 2009.
