April 2013, Vol 2, No 2
Liposomal Vincristine Allows for Greater Dose Density Without Increased NeurotoxicityUncategorized
In August 2012, vincristine sulfate LIPOSOME injection (VSLI; Marqibo) was granted accelerated approval by the FDA for the treatment of adult patients with Philadelphia chromosome–negative acute lymphoblastic leukemia (ALL) in second or greater relapse or whose disease has progressed after 2 or more antileukemia therapies.1 At the 2012 American Society of Hematology (ASH) Annual Meeting, investigators further described the pharmacokinetics and neurotoxicity profiles of the new drug and reported data in pediatric patients.
Standard vincristine sulfate (VCR) is a component of treatment regimens for pediatric and adult hematologic and solid malignancies,2 including ALL, non-Hodgkin lymphoma, Hodgkin lymphoma, Wilms’ tumor, sarcomas, and brain tumors. Dosing of VCR is limited by significant neurotoxicity, which occurs at doses higher than 1.4 mg/m2 and has led to capping of the total dose at 2.0 mg.2
The newly approved vincristine product is a sphingomyelin/cholesterol liposome–encapsulated formulation of VCR.2 Liposomal carriers are capable of increasing the therapeutic index of anticancer drugs by altering the pharmacokinetic behavior of standard agents. VSLI is administered at 2.25 mg/m2 by IV infusion over 1 hour once every 7 days with no dose cap.1
Increased Delivery of Vincristine to Target Tissue
Dose capping is intended to reduce the risk of drug-induced neuropathy but may also limit clinical efficacy, said Jeffrey A. Silverman, PhD, vice president of clinical pharmacology and translational research at Talon Therapeutics.
“In addition to dose capping, standard VCR is limited by a very rapid distribution half-life and large volume of distribution that suggests there is wide and diffuse tissue distribution,” he said.
“VSLI is designed to overcome the dosing and pharmacokinetic limitations of standard VCR. It is intended to take advantage of fenestrated (leaky) vasculature found in bone marrow, lymph nodes, the spleen, and many tumors…to preferentially penetrate, accumulate, and deliver VCR to cancer tissues,” he pointed out.
Silverman described plasma pharmacokinetics in rats that received standard VCR or VSLI 2 mg/m2 by slow IV bolus.3 VSLI increased VCR plasma circulation time and area under the curve, delivered more VCR to tissues that are important in hematologic malignancies, and slowly released VCR in tumors over days, he reported.
Neurotoxicity Profile Stable in Spite of High Doses Delivered
Peripheral neuropathy is the major toxicity associated with the use of VCR, and this limits the individual dose, cumulative exposure, and dose density of the drug.
“Attempts to increase the dose [of standard VCR] have been met with a 100% incidence of peripheral neuropathy,” Silverman said.
Due to VCR’s dose-dependent antitumor activity, it would be beneficial to be able to increase the dose and dose density without increasing neuropathy, he added.
Investigators dosed VSLI at 2.25 mg/m2 (the FDA-approved dose) without a dose cap and evaluated the emergence of neuropathy in 83 adults with relapsed/refractory ALL and prior VCR exposure; 80% of the subjects had residual neuropathy.2 Peripheral neuropathy was proactively assessed weekly with a detailed evaluation of 16 signs and symptoms.
The investigators observed that the occurrence of peripheral neuropathy was consistent with the labeled dose of standard VCR, despite the delivery of larger, normally unachievable individual and cumulative doses of VCR.
Peripheral neuropathy of any grade occurred in 23% of patients, but only 1% was grade 4 and 22% was grade 3 despite a dose density of 4.04 mg/week (2.25 mg/m2/week). This included peripheral motor neuropathy, pain in the extremity, areflexia, decreased vibratory sense, gait disturbance, hypoethesia, muscular weakness, neuralgia, paresthesia, and peripheral sensory neuropathy.
In comparison, previous studies of VCR showed much higher paresthesia rates at much lower dose
- 78% with a dose density of 0.84 mg/week (1.4 mg/m2 every 3 weeks)
- 34% with a dose density of 0.67 mg/week (2 mg every 3 weeks)
- 60% at a dose density of 1.33 mg/week (4 mg every 3 weeks)
VSLI facilitated more than a 2-fold higher dose density without a concomitant increase in paresthesia rate.
“One of the advantages of VSLI is no dose cap, so we can administer more vincristine, and what we saw in this study is that higher dosing does not translate into greater neurotoxicity. With the conventional drug, we see more neurotoxicity even at much lower doses and lower dose density,” Silverman said.
There were no new or unexpected toxicities observed with VSLI dosed at 2.25 mg/m2, he added.
He acknowledged that the study compared neurotoxicity with VSLI to historical data on VCR. “A head-to-head study is ongoing,” he added.
VSLI in Pediatric Patients
“The pediatric experience with VSLI has been limited,” said Nirali N. Shah, MD, of the National Institutes of Health Pediatric Oncology Branch, Bethesda, Maryland.
At ASH, Shah presented the results of a phase 1 single-institution dose escalation trial of 10 children and young adults (2-20 years old) with relapsed or refractory ALL or solid tumors.6 Seven of 10 received a VSLI dose that exceeded the 2-mg dose cap for standard VCR. Of 7 patients evaluable for response, 1 patient achieved a complete remission, 3 had stable disease, 2 had progressive disease, and 1 was too early to assess for response.
“VSLI appears to be safe and tolerable. The toxicity spectrum appears similar in children and adults,” Shah said. “VSLI may allow for intensification of vincristine therapy in children with cancer.”
Most treatment-related adverse events were grade 1 and 2 and reversible, the most common of which were hepatic transaminase elevations, paresthesias, neutropenia, and fatigue. No patient discontinued treatment due to neurotoxicity.“Clearance of total vincristine in our study was approximately 100-fold lower in comparison to previously observed values for the administration of standard vincristine,” she added.
Accrual at the adult recommended dose is ongoing, and an expanded phase 2 cohort in pediatric patients with ALL is being planned.
1. Marqibo [package insert]. South San Francisco, CA: Talon Therapeutics, Inc; August 2012.
2. Deitcher SR, Silverman JA; on behalf of the RALLY Trial investigators. Neurotoxicity profile of vincristine sulfate liposome injection (VSLI, Marqibo®) monotherapy in adults with relapsed acute lymphoblastic leukemia and universal prior standard vincristine exposure. Blood (ASH Annual Meeting Abstracts). 2012;120. Abstract 3568.
3. Silverman JA, Deitcher SR. Vincristine sulfate liposome injection (VSLI, Marqibo®) facilitates increased delivery of vincristine sulfate to target cancer tissues. Blood (ASH Annual Meeting Abstracts). 2012;120. Abstract 2457.
4. Haim N, Epelbaum R, Ben-Shahar M, et al. Full dose vincristine (without 2-mg dose limit) in the treatment of lymphomas. Cancer. 1994;73:2515-2519.
5. Verstappen CC, Koeppen S, Heimans JJ, et al. Dose-related vincristine-induced peripheral neuropathy with unexpected off-therapy worsening. Neurology. 2005;64:1076-1077.
6. Shah NN, Merchant M, Cole D, et al. Vincristine sulfate liposomes injection (VSLI, Marqibo): interim results from a phase I study in children and adolescents with refractory cancer. Blood (ASH Annual Meeting Abstracts). 2012;120. Abstract 1497.
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