1.1 Acute Lymphoblastic Leukemia

Marqibo® is indicated 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 anti leukemia therapies.

This indication is approved under accelerated approval based on overall response rate [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

2.1 Important Safety Information

For Intravenous Use only. Fatal if given by other routes [see Warnings and Precautions (5.1)].

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 [see Warnings and Precautions (5.1)].

2.2 Recommended Dosage

The recommended dosage of Marqibo is 2.25 mg/m2 intravenously over 1 hour once every 7 days.

2.3 Dose modifications: Peripheral Neuropathy

Marqibo is contraindicated in patients with demyelinating conditions, including Charcot-Marie-Tooth syndrome [see Contraindications (4)]. Patients with preexisting severe neuropathy should be treated with Marqibo only after careful risk-benefit assessment [see Warnings and Precautions (5.3)]. For dose or schedule modifications guidelines for patients who experience peripheral neuropathy, see Table 1


  Table 1  Recommended Dosage Modifications for Marqibo-related Peripheral Neuropathy 

a Grading based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v3.0.
b Self care ADL: refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden.
c Instrumental ADL: refers to preparing meals, shopping for groceries and clothes, using telephone, and managing money.

2.4 Preparation

5.1 For Intravenous Use Only: Fatal if Given by Other Routes

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 [see Dosage and Administration (2.1)].

5.2 Extravasation Tissue Injury

Extravasation can occur with Marqibo and extravasation causes 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

5.3 Neurologic Toxicity

Sensory and motor neuropathies are common and are cumulative. Monitor patients for symptoms of peripheral motor and sensory, central and autonomic 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.

Patients with preexisting severe neuropathy should be treated with Marqibo only after careful risk-benefit assessment. Interrupt, reduce the dose, or discontinue Marqibo based on severity [see Dosage and Administration (2.3)].

5.4 Myelosuppression

Neutropenia, thrombocytopenia, or anemia may occur with Marqibo. Monitor complete blood counts prior to each dose of Marqibo. For Grade 3 or 4 neutropenia, thrombocytopenia, or anemia, consider Marqibo dose delay or reduction, as well as supportive care measures.

5.5 Tumor Lysis Syndrome

Tumor lysis syndrome (TLS) may occur in patients with ALL receiving Marqibo. Anticipate, monitor for, and manage as appropriate.

5.6 Constipation and Bowel Obstruction

Ileus, bowel obstruction, and colonic pseudo obstruction have occurred. Marqibo can cause constipation [see Adverse Reactions (6)].
Institute a prophylactic bowel regimen to mitigate potential constipation, bowel obstruction, and paralytic ileus. Consider adequate dietary fiber intake, hydration, and stool softeners. Use additional laxative products as needed.

5.7 Fatigue

Marqibo can cause severe fatigue. Consider dose delay, reduction, or discontinuation of Marqibo as appropriate.

5.8 Hepatic Toxicity

Fatal hepatic toxicity and increased aspartate aminotransferase (AST) occurred. Grade ≥3 increased AST occurred in 6% to 11% of patients in clinical trials. Monitor hepatic function tests. Interrupt or reduce the dose of Marqibo as appropriate.

5.9 Embryo-fetal Toxicity

Based on findings from nonclinical studies and the mechanism of action, Marqibo can cause fetal harm when administered to a pregnant woman. In toxicology studies in rats, vincristine sulfate liposome injection was teratogenic and caused embryo fetal mortality at exposures less than those reported in patients at the recommended dose.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Marqibo and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Marqibo and for 3 months after the last dose [see Use in Specific Populations (8.1,8.3)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Acute Lymphoblastic Leukemia

Relapsed or Refractory Philadelphia Chromosome Negative ALL

The safety of Marqibo was evaluated in a total of 83 adults in two trials: study 1 and study 2. Patients received Marqibo 2.25 mg/m2 once every seven days. Adverse reactions were observed in 100% of patients. 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%).

Adverse reactions of Grade 3 or greater were reported in 96% of patients. Adverse reactions of Grade 3 or greater and occurring in ≥ 5% of patients are summarized in Table 2.

Table 2 Most Commonly Reported (> 5%) Grade 3a or Greater Adverse Reactions among 83 Patients Receiving the Clinical Dosing Regimen

a National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v3.0.
b Including neuropathy-associated adverse reactions.

A total of 76% of patients experienced serious adverse reactions during the studies. The most frequent serious adverse reactions included febrile neutropenia (20%), pyrexia (13%), hypotension (7%), respiratory distress (6%), and cardiac arrest (6%).

Twenty-eight percent of patients experienced adverse reactions leading to treatment discontinuation. The most frequent adverse reactions that caused treatment discontinuation were peripheral neuropathy (10%), leukemia related (7%), and tumor lysis syndrome (2%).

Dose reduction, delay, or omission occurred in 53% of patients.

Adverse reactions related to neuropathy and leading to treatment discontinuation were decreased vibratory sense, facial palsy, hyporeflexia, constipation, asthenia, fatigue, and musculoskeletal pain, each reported in at least 1 patient.

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).

7.1 Effects of Other Drugs on Marqibo

Strong CYP3A Inhibitors

Concomitant use of strong CYP3A4 inhibitors may increase the concentrations of vincristine, which may increase the risk of adverse reactions. Avoid concomitant use of strong CYP3A inhibitors.

Strong CYP3A Inducers
Concomitant use of strong CYP3A4 inducers may decrease the concentrations of vincristine, which may decrease antitumor activity. Avoid concomitant use of strong CYP3A inducers.

P-glycoprotein Inhibitors and Inducers
Concomitant use of Marqibo with P-glycoprotein inhibitors or inducers may alter the pharmacokinetics or pharmacodynamics of vincristine. Avoid the concomitant use of P-gp inhibitors or inducers.

7.2 Effects of Marqibo on Other Drugs

Phenytoin
Simultaneous oral or intravenous administration of phenytoin and chemotherapy combinations that included non liposomal vincristine sulfate have been reported to reduce blood levels of phenytoin and to increase seizure activity. Monitor phenytoin blood levels and seizure activity as appropriate.

8.1 Pregnancy

Risk Summary

Based on findings from nonclinical studies and its mechanism of action, Marqibo can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1), Nonclinical Toxicology (13.1)]. There are insufficient data on use of vincristine sulfate in pregnant women to evaluate for a drug-associated risk. In animal reproduction studies, intravenous administration of vincristine sulfate liposome injection to pregnant rats during organogenesis caused adverse developmental outcomes including increased embryo-fetal mortality, alterations to growth, and structural abnormalities (see Data). Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

In an embryo-fetal 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.

8.2 Lactation

Risk Summary

There are no data on the presence of vincristine sulfate or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with Marqibo and for at least 1 week after the last dose.

8.3 Females and Males of Reproductive Potential

Marqibo can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify the pregnancy status in females of reproductive potential prior to initiating Marqibo.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with Marqibo and for 6 months after the last dose.

Males

Based on genotoxicity findings with non-liposomal vincristine, advise males with female partners of reproductive potential to use effective contraception during treatment with Marqibo and for 3 months after the last dose [see Nonclinical Toxicology (13.1)].

Infertility

Based on findings in humans with non-liposomal vincristine sulfate and in animals administered vincristine sulfate liposome injection, Marqibo may impair fertility.

Gonadal dysfunction has been reported in both male and female post pubertal patients who received multi agent chemotherapy, including non liposomal vincristine sulfate. The degree to which testicular or ovarian functions are affected is age , dose , and agent dependent. Recovery may occur in some, but not all patients.

In animals, adverse effects on male reproductive organs were not reversible after a recovery period [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

The safety and effectiveness of Marqibo in pediatric patients have not been established.

8.5 Geriatric Use

Of the total number of patients in clinical studies of Marqibo, 11% were aged 65 years or older. Clinical studies of Marqibo did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger patients. 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.

8.6 Hepatic Impairment

Monitor patients closely for adverse reactions, including hepatic toxicity. No dose adjustment is recommended for patients with mild or moderate hepatic impairment. The influence of severe hepatic impairment on the exposure, safety and efficacy of Marqibo has not been evaluated.

12.1 Mechanism of Action

Marqibo is a sphingomyelin/cholesterol liposome encapsulated formulation of vincristine sulfate. Non liposomal vincristine sulfate binds to tubulin, altering the tubulin polymerization equilibrium, resulting in altered microtubule structure and function. Non liposomal vincristine sulfate stabilizes the spindle apparatus, preventing chromosome segregation, triggering metaphase arrest and inhibition of mitosis.

12.3 Pharmacokinetics

The pharmacokinetics of total plasma vincristine sulfate in patients who received Marqibo 2.25 mg/m2 administered as a 1-hour intravenous infusion are summarized in Table 3. The vincristine sulfate levels reported in Table 3 reflect liposome-encapsulated drug that may not be immediately bioavailable and are not directly comparable to plasma levels of vincristine sulfate after administration of non-liposomal vincristine sulfate, which is immediately bioavailable.

Table 3. Pharmacokinetic Parameters from Patients with Acute Lymphoblastic Leukemia who Received Marqibo 2.25 mg/m2a

a Dose was administered as a 1-hour infusion.

Elimination

Metabolism

Vincristine is metabolized by CYP3A4.

Excretion

Following intravenous administration of Marqibo, less than 8% of the administered dose was eliminated in urine over 96 hours, which is similar to the urinary excretion of non-liposomal vincristine sulfate. Following non-liposomal vincristine sulfate infusion, fecal route accounted for 69% of the administered dose over 72 hours.

Specific Populations

Patients with Hepatic Impairment

Following the administration of Marqibo 1 mg/m2 (0.44 times the recommended dose) every 14 days in patients with cancer and moderate hepatic impairment (Child-Pugh scores 7-8), the median (min-max) dose adjusted Cmax was 399 ng/mL (217 – 531) and AUC0-inf was 4926 ng*hr/mL (4650 – 9640). The change in pharmacokinetics in patients with moderate hepatic impairment are not considered clinically meaningful. The impact of severe hepatic impairment on the pharmacokinetics of vincristine is unknown.

Drug Interaction Studies

In Vitro Studies

Transporters: Vincristine is a substrate of P-glycoprotein in vitro.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity studies have been conducted with Marqibo or non liposomal vincristine sulfate. Based on the mechanism of action and genotoxicity findings in nonclinical studies conducted with non liposomal vincristine sulfate, Marqibo may be carcinogenic.

No genotoxicity studies have been conducted with Marqibo. Non liposomal vincristine was genotoxic in in vitro and in vivo studies.

The single-and-repeat dose animal toxicology study results indicate that Marqibo can impair male fertility, consistent with the literature on non liposomal vincristine sulfate. Administration of vincristine liposome injection to rats at dose levels comparable to the recommended clinical dose caused testicular degeneration and atrophy, and epididymal aspermia. Adverse effects in male reproductive organs were not reversible following a 14 day recovery period.

13.2 Animal Toxicology and/or Pharmacology

In a repeat dose comparative toxicology study in rats, vincristine sulfate liposome injection or non liposomal vincristine sulfate was administered to animals intravenously once per week for 6 weeks. Clinical signs of toxicity consistent with neurotoxicity were greater with vincristine sulfate liposome injection than with non liposomal vincristine sulfate at equal vincristine sulfate doses of 2 mg/m2/week and included uncoordinated movements, weakness, reduced muscle tone, and limited usage of the limbs.  Vincristine sulfate liposome injection induced greater peripheral neurotoxicity (nerve fiber degeneration) and secondary skeletal muscle atrophy than the equal dose of non liposomal vincristine sulfate.

14.1 Acute Lymphoblastic Leukemia

Marqibo was studied in an international, open-label, multi-center, single-arm trial (Study 1). Eligible patients were 18 years of age or older with Philadelphia chromosome negative ALL in second or greater relapse or whose disease progressed after two or greater treatment lines of anti-leukemia therapy. Patients had to have achieved a complete remission (CR) to at least one prior anti-leukemia chemotherapy, defined by a leukemia-free interval of equal or more than 90 days. Patients were not eligible for immediate hematopoietic stem cell transplantation (HSCT) at the time of screening and enrollment.

Patients received intravenous Marqibo monotherapy at 2.25 mg/m2 over 60 minutes every 7 days. Concomitant corticosteroids were not permitted beyond Day 5.

The treated population included 65 patients who received at least 1 dose of Marqibo. All of the treated patients had received prior vincristine sulfate and 80% had evidence of residual neuropathy at study baseline. Among treated patients, 51% were male, 86% were white, 45% were under 30 years of age, 11% were age 65 or older, 48% had undergone prior HSCT, 51% had received 3 or more prior therapies, and 45% were refractory to their immediate prior therapy. Disease characteristics were 85% precursor B-cell ALL and 15% precursor T-cell ALL. In addition, 22 of 65 (34%) treated patients did not receive asparaginase products prior to enrollment. Efficacy results are shown in Table 4.


                                                                                             Table 4. Study 1 Results

a CI = Confidence interval (Clopper-Pearson).