Liposomal Vincristine 'Appears to Be a Step Forward'

A new formulation of an old drug — vincristine encapsulated in liposomes — offers oncologists a new tool, and "appears to be a step forward in the successful use of vincristine, which still has utility and widespread use after half a century."

So concludes an editorial by Jane Liesveld, MD, BS, professor of medicine and hematology/oncology, and Barbara Asselin, MD, professor of pediatrics, both from the University of Rochester in New York, published online January 14 in the Journal of Clinical Oncology.

The new product, vincristine sulfate liposomal injection (VSLI), marketed as Marqibo by Talon Therapeutics, was approved by the US Food and Drug Administration last year.

The approval was accelerated for the narrow indication of adults with Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) who are in second or greater relapse that has progressed after 2 or more lines of antileukemia therapy. This is "a very rare patient population with a grave prognosis and no current standard of treatment," the company noted at the time.

The approval was based on a pivotal open-label phase 2 study of 65 heavily pretreated ALL patients, known as RALLY, which was published online November 19, 2012 in the Journal of Clinical Oncology. The trial was conducted by Susan O'Brien, MD, from the M.D. Anderson Cancer Center in Houston, Texas, and colleagues.

The small RALLY trial showed that the liposomal delivery of vincristine allows larger doses to be administered without extra toxicity. Further studies in the many other malignancies for which vincristine is used are now needed, the editorialists note.

Reduce Adverse Effects to Allow Larger Dose

The liposomal delivery system was developed specifically to reduce the adverse effects associated with standard vincristine, particularly dose-limiting neurotoxicity, to allow higher doses of the drug to be used.

Neurotoxicity limits the dose of standard vincristine that can be administered, Drs. Liesveld and Asselin explain in their editorial. The approved dose in adults is 1.4 mg/m² weekly, but most regimens cap the dose at 2.0 mg per infusion to avoid severe neurotoxicity, they explain. In almost all adults and in some children, this capped dose is no doubt suboptimal, they add.

VSLI was designed to deliver a larger dose of vincristine, they continue.

In the pivotal RALLY trial, VSLI was administered at a higher dose than standard vincristine, which led to improved efficacy and neuropathy that was no greater than that seen with the standard drug, they note.

VSLI was administered at a dose of 2.25 mg/m² weekly for a median of 4 doses. This is nearly double the usual dose for standard vincristine, the editorialists note. Some patients in the trial received up to 70 mg of vincristine. All of the patients had previous vincristine exposure, and 77% had some evidence of previous neuropathy at study entry.

"Despite that, toxicity was comparable to that with standard vincristine," Drs. Liesveld and Asselin note. In the study, 86% of patients had some neuropathy, but it was grade 3 in only 23% of patients, they report. "Importantly, responses were seen in those who did not have significant neuropathy," they explain. Other significant adverse events were neutropenic fever and tumor lysis.

The editorialists reviewed the efficacy results from the trial, and found them to be "impressive on several fronts." These patients had advanced disease and were heavily pretreated (some had undergone stem cell transplantation), yet the product was able to induce complete responses (in 20% of patients) without an undue increase in neurotoxicity, they note.

The median duration of complete response was 23 weeks, and 12 patients bridged to a stem cell transplant. In those who responded, median survival was 7.7 months, and 5 patients achieved long-term survival (>1 year).

Survival in RALLY was "better than anticipated," note Dr. O'Brien and colleagues. They point out that it is consistent with what would be expected in a second-line setting, and not in such a heavily pretreated patient population. They conclude that their trial showed "meaningful clinical outcomes including durable responses and ability to bridge to HCT in a near end-stage adult ALL population desperately in need of new therapies."

The toxicity profile of high-dose VSLI was "predictable, manageable, and comparable" to that of standard vincristine, they add, "despite the delivery of large, normally unachievable individual and cumulative doses."

An imperative next step is to expedite trials of VSLI in pediatric patients and to explore its use the multiple other malignancies for which standard vincristine is regularly used, Drs. Liesveld and Asselin write in their editorial.

Further Studies Underway

There are currently several studies underway, according to the Talon Therapeutics, the manufacturer of VSLI.

As part of the accelerated approval, the company is conducting a confirmatory phase 3 trial (known as HALLMARQ, NCTO1439347) comparing VSLI and standard vincristine in the front-line treatment of ALL in adults 60 years and older.

The company is also supporting an active phase 3 study known as OPTIMAL>60 (NCT01478542), which is currently enrolling patients with front-line, aggressive non-Hodgkin's lymphoma. The study is being carried out in collaboration with the German High-Grade Non-Hodgkin's Lymphoma Study Group and will directly compare the activity of VSLI and standard vincristine administered as part of the R-CHOP regimen (rituximab plus cyclophosphamide, hydroxydaunorubicin, vincristine [Oncovin], and prednisone).

In the United States, the company is collaborating with the National Cancer Institute on a phase 1 study (NCT01222780) of children and adolescents with refractory cancers. Interim data from that study were presented at the annual meeting of the American Society of Hematology in December 2012 (abstract 1497). The phase 1 study includes both solid and hematologic cancers, and has a provision for an expanded cohort with ALL.

"We plan to conduct a phase 2 study in pediatric ALL at the conclusion of this phase 1 study," said Jeffrey Silverman, PhD, vice president of clinical pharmacology and translational research at Talon Therapeutics, and coauthor of the RALLY trial. "To date, VSLI appears to be safe and tolerable, and demonstrates preliminary activity in pediatric patients with refractory ALL and solid tumors," he said.

Dr. Silverman noted that there are several investigator-initiated and institution-sponsored studies under consideration, and a trial is already underway at the M.D. Anderson Cancer Center. That study (NCT01319981) is substituting VSLI for standard vincristine in the Hyper-CVAD regimen (cyclophosphamide, vincristine, doxorubicin [Adriamycin], and dexamethasone) in patients with newly diagnosed ALL or lymphoblastic lymphoma.

"We are also actively seeking collaborators who may be interested in further investigating VSLI in new indications," Dr. Silverman said.

Dr. Liesveld reports receiving honoraria from Bristol-Myers Squibb. Dr. Asselin has disclosed no relevant financial relationships. Dr. O'Brien and several coauthors report receiving research grants and honoraria from Talon Therapeutics, and several of the coauthors, including Dr. Silverman, are company employees.

J Clinical Oncol. Published online January 14, 2013 and November 19, 2012. Editorial, Abstract