Spectrum Pharmaceuticals Highlights Encouraging FOLOTYN® and MARQIBO® Clinical Data Presented at the 55th Annual Meeting of the American Society of Hematology (ASH)
"At the ASH meeting there were several presentations on our drugs and we
are especially excited about two," said
Select ASH Presentation Summaries
Following are summaries of key presentations at ASH:
Abstract # 3033 - Long Term Results Of a Phase 2 Study Of Vincristine Sulfate Liposome Injection (Marqibo®) Substituted For Non-Liposomal Vincristine In CHOP With Or Without Rituximab For Patients With Untreated Aggressive Non-Hodgkin's Lymphomas
This study evaluated 60 patients with untreated DLBCL in which Marqibo was substituted for Vincristine (VCR) in R-CHOP creating R-CHMP. The primary endpoint was overall response rate (ORR), and secondary endpoints were Progression free survival (PFS) and overall survival (OS). The overall response rate was 95% (57/60) and the complete response rate (CR) was 90% (54/60). Ten year PFS and OS were 64% and 87%, respectively. In patients greater than 60 years of age, overall response rate was 91%, 10 year PFS= 48%, and 10 year OS was 65%. The safety profile of R-CHMP was comparable to what has been reported in the literature for R-CHOP. Grade 3 peripheral neuropathy was 3%. The authors concluded that the R-CHMP "resulted in a high ORR and encouraging PFS and OS without apparent increased toxicity compared to historical experience with R-CHOP. In particular, elderly DLBCL patients with an unfavorable prognosis, based on age-adjusted International Prognostic Index (aaIPI) experienced remarkable PFS and OS."
Abstract # 4284 - Analysis of Peripheral T-Cell Lymphoma (PTCL) Subtype By Race and Geography Using The Comprehensive Oncology Measures For Peripheral T-Cell Lymphoma Treatment (COMPLETE) Dataset
This study evaluated 34 patients treated with cyclophosphamide, etoposide, vincristine and prednisone (CEOP) alternating with pralatrexate as front line therapy for patients with Peripheral T-Cell Lymphoma (PTCL). Patients who achieved remission were eligible for consolidative Autologous Stem Cell Transplant (ASCT) after Cycle 4. Of 34 patients, 27 received at least 2 cycles of therapy. At the end of stage 1, 50% achieved a complete response rate (CR). At the time of this initial analysis, the ORR was 70%, and the CR was 45%. Six patients (18%) had received consolidation with ASCT and all are in CR post transplant. The authors concluded that CEOP-Pralatrexate met the pre-defined stage 1 response criteria. While these results are encouraging, longer term follow-up is warranted to assess impact on final CR, EFS and OS outcome measures.
About Non-Hodgkin's Lymphoma
According to the
FOLOTYN, (pralatrexate injection), a folate analogue metabolic
inhibitor, was discovered by
Important FOLOTYN® Safety Information
Warnings and Precautions
FOLOTYN may suppress bone marrow function, manifested by thrombocytopenia, neutropenia, and anemia. Monitor blood counts and omit or modify dose for hematologic toxicities.
Mucositis may occur. If greater-than or equal to Grade 2 mucositis is observed, omit or modify dose. Patients should be instructed to take folic acid and receive vitamin B12 to potentially reduce treatment-related hematological toxicity and mucositis.
Fatal dermatologic reactions may occur. Dermatologic reactions may be progressive and increase in severity with further treatment. Patients with dermatologic reactions should be monitored closely, and if severe, FOLOTYN should be withheld or discontinued. Tumor lysis syndrome may occur. Monitor patients and treat if needed.
FOLOTYN can cause fetal harm. Women should avoid becoming pregnant while being treated with FOLOTYN and pregnant women should be informed of the potential harm to the fetus.
Use caution and monitor patients when administering FOLOTYN to patients with moderate to severe renal function impairment.
Elevated liver function test abnormalities may occur and require monitoring. If liver function test abnormalities are greater-than or equal to Grade 3, omit or modify dose.
The most common adverse reactions were mucositis (70%), thrombocytopenia (41%), nausea (40%), and fatigue (36%). The most common serious adverse events are pyrexia, mucositis, sepsis, febrile neutropenia, dehydration, dyspnea, and thrombocytopenia.
Use in Specific Patient Population
Nursing mothers should be advised to discontinue nursing or the drug, taking into consideration the importance of the drug to the mother.
Co-administration of drugs subject to renal clearance (e.g., probenecid, NSAIDs, and trimethoprim/sulfamethoxazole) may result in delayed renal clearance.
Please see FOLOTYN Full Prescribing Information at www.FOLOTYN.com.
About ZEVALIN® and the ZEVALIN Therapeutic Regimen
ZEVALIN (ibritumomab tiuxetan) injection for intravenous use, is indicated for the treatment of patients with relapsed or refractory, low-grade or follicular B-cell non-Hodgkin's lymphoma (NHL). ZEVALIN is also indicated for the treatment of patients with previously untreated follicular non-Hodgkin's Lymphoma who achieve a partial or complete response to first-line chemotherapy.
ZEVALIN is a CD20-directed radiotherapeutic antibody. The ZEVALIN
therapeutic regimen consists of two components: rituximab, and
Important ZEVALIN® Safety Information
Deaths have occurred within 24 hours of rituximab infusion, an essential component of the ZEVALIN therapeutic regimen. These fatalities were associated with hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, or cardiogenic shock. Most (80%) fatalities occurred with the first rituximab infusion. ZEVALIN administration can result in severe and prolonged cytopenias in most patients. Severe cutaneous and mucocutaneous reactions, some fatal, can occur with the ZEVALIN therapeutic regimen.
Please see full Prescribing Information, including BOXED WARNINGS, for ZEVALIN and rituximab. Full prescribing information for ZEVALIN can be found at www.ZEVALIN.com.
Marqibo is a novel, sphingomyelin/cholesterol liposome-encapsulated,
formulation of vincristine sulfate. Vincristine, a microtubule
Please see important safety information below and the full prescribing information for Marqibo at www.marqibo.com.
Indication and usage
Marqibo is a liposomal vinca alkaloid indicated for the treatment of
adult patients with
Important safety information
- 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
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.
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.
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.
Marqibo can cause severe fatigue. Marqibo dose delay, reduction, or discontinuation may be necessary.
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.
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].
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).
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.
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).
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 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.
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.
The safety and effectiveness of Marqibo in pediatric patients have not been established.
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.
The influence of renal impairment on the safety, efficacy, and pharmacokinetics of Marqibo has not been evaluated.
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.
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forward-looking statements regarding future events and the future
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