- Data supported FDA accelerated approval of Marqibo (http://jco.ascopubs.org/)
- Data published online ahead of print as a Rapid Communication
- Data represents the per protocol, planned analysis based on established endpoints
SOUTH SAN FRANCISCO, Calif., Nov. 27, 2012 (GLOBE NEWSWIRE) -- Talon Therapeutics, Inc. (OTCBB:TLON), a biopharmaceutical company dedicated to developing leading oncology products, today announced the publication of the complete data from its Phase 2 RALLY Study of Marqibo in the Journal of Clinical Oncology, the official journal of the American Society of Clinical Oncology (ASCO). The study results were published as a rapid communication and online ahead of in print. Marqibo received FDA accelerated approval in August of this year for treatment of adult patients with Philadelphia chromosome negative (Ph-) ALL in second or greater relapse or whose disease has progressed following two or more anti-leukemia therapies.
"This publication highlights the heavily pre-treated nature of this relapsed and refractory adult ALL population," said Steven R. Deitcher, MD, President and CEO of Talon. "The results of this study, in their totality, show that Marqibo facilitates vincristine dose-intensification and achievement of complete responses. Despite universal prior vincristine treatment and residual neurotoxicity in most patients, Marqibo's adverse event profile was comparable to that historically observed with non-liposomal vincristine."
About RALLY
The pivotal Phase 2 RALLY clinical trial enrolled a total of 65 evaluable patients at 22 sites in the U.S., Canada, Germany, and Israel. The primary objective of the RALLY clinical trial was to assess the efficacy of single-agent, once per week Marqibo 2.25 mg/m2 of actual patient body surface area as assessed by achievement of complete response (CR) or CR with incomplete blood count recovery (CRi). Secondary objectives included assessments of duration of CR/CRi, overall survival (OS), ability to undergo subsequent hematopoietic cell transplantation (HCT), safety, and pharmacokinetics. Marqibo was dosed weekly based on actual body surface area without any dose capping. The study population was defined as Philadelphia chromosome-negative adult patients in second or greater relapse, or those patients who relapsed following two lines of anti-leukemia chemotherapy, including those who have previously undergone HCT.
About Marqibo®
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 tumor 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.
Important safety information and full prescribing information for Marqibo can be found at www.marqibo.com.
CONTRAINDICATIONS
- 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
WARNING
See full prescribing information for complete boxed warning.
- For Intravenous Use Only — Fatal if Given by Other Routes
- Death has occurred with intrathecal use
- 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.
Warnings and Precautions
For Intravenous Use Only
For Intravenous use only. Fatal if given by other routes.
Extravasation Tissue Injury
Only administer through a secure and free‑flowing venous access line. If extravasation is suspected, discontinue infusion immediately and consider local treatment measures.
Neurologic Toxicity
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% of patients. Worsening neuropathy requires dose delay, reduction, or discontinuation of Marqibo.
Myelosuppression
Monitor complete blood counts prior to each dose of Marqibo. If Grade 3 or 4 neutropenia, thrombocytopenia, or anemia develops, consider Marqibo dose modification or reduction as well as supportive care measures.
Tumor Lysis Syndrome
Tumor lysis syndrome (TLS) may occur in patients with ALL receiving Marqibo. Anticipate, monitor for, and manage.
Constipation and Bowel Obstruction
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.
Fatigue
Marqibo can cause severe fatigue. Marqibo dose delay, reduction, or discontinuation may be necessary.
Hepatic Toxicity
Fatal liver toxicity and elevated levels of aspartate aminotransferase have occurred. Elevated levels of aspartate aminotransferase of Grade ≥3 occurred in 6‑11% of patients in clinical trials. Monitor hepatic function tests. Reduce or interrupt Marqibo for hepatic toxicity.
Embryofetal 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 [see Use in Specific Populations].
Adverse Reactions
The most common adverse reactions ( > 30%) were constipation (57%), nausea (52%), pyrexia (43%), fatigue (41%), peripheral neuropathy (39%), febrile neutropenia (38%), diarrhea (37%), anemia (34%), decreased appetite (33%), and insomnia (32%).
The most commonly reported SAEs included febrile neutropenia (20.5%), pyrexia (13.3%), hypotension (7.2%), respiratory distress (6.0%), and cardiac arrest (6.0%).
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%), leukemia‑related (7%), and tumor lysis syndrome (2%).
Deaths occurred in 23% of patients in study 1. The non-leukemia related causes of deaths were brain infarct (1), intracerebral hemorrhage (2), liver failure (1), multi-system organ failure (2), pneumonia and septic shock (3), respiratory failure (4), pulmonary hemorrhage (1), and sudden cardiac death (1).
Drug Interactions
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.
CYP3A Interactions
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).
P‑glycoprotein Interactions
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.
Use in Specific Populations
Pregnancy
Pregnancy Category D [see Warnings and Precautions]
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% of those reported in patients at the recommended dose.
Nursing Mothers
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.
Pediatric Use
The safety and effectiveness of Marqibo in pediatric patients have not been established.
Geriatric Use
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.
Renal Impairment
The influence of renal impairment on the safety, efficacy, and pharmacokinetics of Marqibo has not been evaluated.
Hepatic Impairment
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.
About Talon Therapeutics
Talon Therapeutics, Inc. is a biopharmaceutical company dedicated to seizing upon medical opportunities, efficiently and expertly leading product candidates through clinical development, and transferring value to patients, patient care providers, shareholders, corporate partners, and employees.
In addition to Marqibo, the Company has additional pipeline opportunities some of which, like Marqibo, have the potential to improve delivery and enhance the therapeutic benefits of well characterized, proven chemotherapies and enable high-potency dosing without increased toxicity.
Additional information on Talon Therapeutics can be found at www.talontx.com.
The Talon Therapeutics, Inc. logo is available at http://www.globenewswire.com/newsroom/prs/?pkgid=3290