英文药名：HALAVEN(eribulin mesylate) injection

中文药名：甲磺酸艾日布林注射剂–以前名E7389

生产厂家：卫材公司
药品介绍
新型抗癌药Halaven（eribulin mesylate）获美国FDA批准首个扩展治疗脂肪肉瘤且能够延长患者生存期的药物
美国FDA于2016年1月28日批准一种化疗药Halaven (eribulin mesylate，甲磺酸艾瑞布林)，治疗脂肪肉瘤(STS,软组织肉瘤特定类型)，无法通过手术(切除)或者晚期(转移性)瘤。这种治疗被批准在先前接受过蒽环类药物的化疗患者。
FDA药物评价和研究中心血液学和肿瘤学产品办公室主任Richard Pazdur, M.D.说，Halaven 是首个治疗脂肪肉瘤批准的药物，并证明对生存时间有改善。FDA 审查的临床试验数据表明 Halaven 增加整体生存期大约七个月，向病人提供一种具有临床意义的药物。

HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use HALAVEN safely and effectively. See full prescribing information for HALAVEN.
HALAVEN®(eribulin mesylate) injection, for intravenous use
Initial U.S. Approval: 2010
RECENT MAJOR CHANGES
Indications and Usage (1.2)                    01/2016
Warnings and Precautions (5.1, 5.2, 5.3)       01/2016
INDICATIONS AND USAGE
HALAVEN is a microtubule inhibitor indicated for the treatment of patients with:
Metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting. (1.1)
Unresectable or metastatic liposarcoma who have received a prior anthracycline-containing regimen. (1.2)
DOSAGE AND ADMINISTRATION
Administer 1.4 mg/m2 intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle. (2.1)
Reduce dose in patients with hepatic impairment or with moderate or severe renal impairment. (2.1)
Do not mix with other drugs or administer with dextrose-containing solutions. (2.3)
DOSAGE FORMS AND STRENGTHS
Injection: 1mg per 2mL(0.5mg per mL) (3)
CONTRAINDICATIONS
None (4)
WARNINGS AND PRECAUTIONS
Neutropenia:  Monitor peripheral blood cell counts and adjust dose as appropriate. (5.1)
Peripheral Neuropathy:  Monitor for signs of neuropathy. Manage with dose delay and adjustment. (5.2)
Embryo-Fetal Toxicity:  Can cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception. (5.3, 8.1, 8.3)
QT Prolongation:  Monitor for prolonged QT intervals in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, and electrolyte abnormalities. Avoid in patients with congenital long QT syndrome. (5.4)
ADVERSE REACTIONS
The most common adverse reactions (≥25%) in metastatic breast cancer were neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea, and constipation. (6.1)
The most common adverse reactions (≥25%) in liposarcoma and leiomyosarcoma were fatigue, nausea, alopecia, constipation, peripheral neuropathy, abdominal pain, and pyrexia.  The most common (≥5%) Grade 3-4 laboratory abnormalities in liposarcoma and leiomyosarcoma were neutropenia, hypokalemia, and hypocalcemia. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Eisai Inc. at (1-877-873-4724) or contact FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
USE IN SPECIFIC POPULATIONS
Lactation:  Do not breastfeed. (8.2)
Hepatic Impairment:  A lower starting dose is recommended for patients with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment. Patients with severe hepatic impairment (Child-Pugh C) were not studied. (8.6)
Renal Impairment: A lower starting dose is recommended for patients with moderate (CLcr 30-49 mL/min) or severe (CLcr 15-29 mL/min) renal impairment. (8.7)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 1/2016
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
1.1 Metastatic Breast Cancer
HALAVEN is indicated for the treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease.  Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting [see Clinical Studies (14.1)].
1.2 Liposarcoma
HALAVEN is indicated for the treatment of patients with unresectable or metastatic liposarcoma who have received a prior anthracycline-containing regimen [see Clinical Studies (14.2)].
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dose
The recommended dose of HALAVEN is 1.4 mg/m2 administered intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle.
The recommended dose of HALAVEN in patients with mild hepatic impairment (Child-Pugh A) is 1.1 mg/m2 administered intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle [see Use in Specific Populations (8.6)].
The recommended dose of HALAVEN in patients with moderate hepatic impairment (Child-Pugh B) is 0.7 mg/m2 administered intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle [see Use in Specific Populations (8.6)].
The recommended dose of HALAVEN in patients with moderate to severe renal impairment (creatinine clearance (CLcr) 15-49 mL/min) is 1.1 mg/m2 administered intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle [see Use in Specific Populations (8.7)].
2.2 Dose Modification
Assess for peripheral neuropathy and obtain complete blood cell counts prior to each dose.
Recommended dose delays
Do not administer HALAVEN on Day 1 or Day 8 for any of the following:
- ANC < 1,000/mm3
- Platelets < 75,000/mm3
- Grade 3 or 4 non-hematological toxicities.
The Day 8 dose may be delayed for a maximum of 1 week.
- If toxicities do not resolve or improve to ≤ Grade 2 severity by Day 15, omit the dose.
- If toxicities resolve or improve to ≤ Grade 2 severity by Day 15, administer HALAVEN at a reduced dose and initiate the next cycle no sooner than 2 weeks later.
Recommended dose reductions
If a dose has been delayed for toxicity and toxicities have recovered to Grade 2 severity or less, resume HALAVEN at a reduced dose as set out in Table 1.
Do not re-escalate HALAVEN dose after it has been reduced.
Table 1: Recommended Dose Reductions

Event Description	Recommended HALAVEN Dose
Permanently reduce the 1.4 mg/m2 HALAVEN dose for any of the following:	1.1 mg/m2
ANC <500/mm3 for >7 days
ANC <1,000 /mm3 with fever or infection
Platelets <25,000/mm3
Platelets <50,000/mm3 requiring transfusion
Non-hematologic Grade 3 or 4 toxicities
Omission or delay of Day 8 HALAVEN dose in previous cycle for toxicity
Occurrence of any event requiring permanent dose reduction while receiving 1.1 mg/m2	0.7 mg/m2
Occurrence of any event requiring permanent dose reduction while receiving 0.7 mg/m2	Discontinue HALAVEN
ANC = absolute neutrophil count. Toxicities graded in accordance with National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.

2.3 Instructions for Preparation and Administration
Aseptically withdraw the required amount of HALAVEN from the single-use vial and administer undiluted or diluted in 100 mL of 0.9% Sodium Chloride Injection, USP.
Do not dilute in or administer through an intravenous line containing solutions with dextrose. Do not administer in the same intravenous line concurrent with the other medicinal products.
Store undiluted HALAVEN in the syringe for up to 4 hours at room temperature or for up to 24 hours under refrigeration (40°F or/ 4°C). Store diluted solutions of HALAVEN for up to 4 hours at room temperature or up to 24 hours under refrigeration.
Discard unused portions of the vial.
3 DOSAGE FORMS AND STRENGTHS
Injection:  1 mg/2 mL (0.5 mg/mL).
4 CONTRAINDICATIONS
None.
5 WARNINGS AND PRECAUTIONS
5.1 Neutropenia
In Study 1, severe neutropenia (ANC < 500/mm3) lasting more than one week occurred in 12% (62/503) of patients with metastatic breast cancer, leading to discontinuation in <1% of patients.  Febrile neutropenia (fever ≥38.5°C with Grade 3 or 4 neutropenia) occurred in 5% (23/503) of patients; two patients (0.4%) died from complications of febrile neutropenia [see Adverse Reactions (6.1)].
In Study 1, patients with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 × ULN (upper limit of normal) experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia than patients with normal aminotransferase levels. Patients with bilirubin > 1.5 × ULN also had a higher incidence of Grade 4 neutropenia and febrile neutropenia.
In Study 2, severe neutropenia (ANC < 500/mm3) lasting more than one week occurred in 12% (26/222) of patients with liposarcoma or leiomyosarcoma. Febrile neutropenia occurred in 0.9% of patients treated with HALAVEN and fatal neutropenic sepsis in 0.9% [see Adverse Reactions (6.1)].
Monitor complete blood counts prior to each dose; increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. Delay administration of HALAVEN and reduce subsequent doses in patients who experience febrile neutropenia or Grade 4 neutropenia lasting longer than 7 days [see Dosage and Administration (2.2)]. Clinical studies of HALAVEN did not include patients with baseline neutrophil counts below 1,500/mm3.
5.2 Peripheral Neuropathy
In Study 1, Grade 3 peripheral neuropathy occurred in 8% (40/503) of patients, and Grade 4 in 0.4% (2/503) of patients with metastatic breast cancer (MBC). Peripheral neuropathy was the most common toxicity leading to discontinuation of HALAVEN (5% of patients; 24/503) in Study 1.  Neuropathy lasting more than one year occurred in 5% (26/503) of patients. Twenty-two percent (109/503) of patients developed a new or worsening neuropathy that had not recovered within a median follow-up duration of 269 days (range 25-662 days).
In Study 2, Grade 3 peripheral neuropathy occurred in 3.1% (7/223) of HALAVEN-treated patients. Peripheral neuropathy led to discontinuation of HALAVEN in 0.9% of patients. The median time to first occurrence of peripheral neuropathy of any severity was 5 months (range: 3.5 months to 9 months).  Neuropathy lasting more than 60 days occurred in 58% (38/65) of patients.  Sixty three percent (41/65) had not recovered within a median follow-up duration of 6.4 months (range: 27 days to 29 months).
Monitor patients closely for signs of peripheral motor and sensory neuropathy. Withhold HALAVEN in patients who experience Grade 3 or 4 peripheral neuropathy, until resolution to Grade 2 or less [see Dosage and Administration (2.2)].
5.3 Embryo-Fetal Toxicity
Based on findings from an animal reproduction study and its mechanism of action, HALAVEN can cause fetal harm when administered to a pregnant woman.  There are no adequate and well-controlled studies of HALAVEN in pregnant women. In animal reproduction studies, eribulin mesylate caused embryo-fetal toxicity when administered to pregnant rats during organogenesis at doses below the recommended human dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with HALAVEN and for at least 2 weeks following the final dose.  Advise males with female partners of reproductive potential to use effective contraception during treatment with HALAVEN and for 3.5 months following the final dose [see Use in Specific Populations (8.1)].
5.4 QT Prolongation
In an uncontrolled open-label ECG study in 26 patients, QT prolongation was observed on Day 8, independent of eribulin concentration, with no QT prolongation observed on Day 1. ECG monitoring is recommended if therapy is initiated in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics, and electrolyte abnormalities. Correct hypokalemia or hypomagnesemia prior to initiating HALAVEN and monitor these electrolytes periodically during therapy. Avoid HALAVEN in patients with congenital long QT syndrome.
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.
The following adverse reactions are discussed in detail in other sections of the labeling:
Neutropenia [see Warnings and Precautions (5.1)]
Peripheral neuropathy [see Warnings and Precautions (5.2)]
QT prolongation [see Warnings and Precautions (5.4)]
In clinical trials, HALAVEN has been administered to 1963 patients including 467 patients exposed to HALAVEN for 6 months or longer. The majority of the 1963 patients were women (92%) with a median age of 55 years (range: 17 to 85 years). The racial and ethnic distribution was White (72%), Black (4%), Asian (9%), and other (3%).
Metastatic Breast Cancer
The most common adverse reactions (≥25%) reported in patients receiving HALAVEN were neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea, and constipation. The most common serious adverse reactions reported in patients receiving HALAVEN were febrile neutropenia (4%) and neutropenia (2%). The most common adverse reaction resulting in discontinuation of HALAVEN was peripheral neuropathy (5%).
The adverse reactions described in Table 2 were identified in 750 patients treated in Study 1 [see Clinical Studies (14.1)]. In Study 1, patients were randomized (2:1) to receive either HALAVEN (1.4 mg/m2 on Days 1 and 8 of a 21-day cycle) or single agent treatment chosen by their physician (control group). A total of 503 patients received HALAVEN and 247 patients in the control group received therapy consisting of chemotherapy [total 97% (anthracyclines 10%, capecitabine 18%, gemcitabine 19%, taxanes 15%, vinorelbine 25%, other chemotherapies 10%)] or hormonal therapy (3%). The median duration of exposure was 118 days for patients receiving HALAVEN and 63 days for patients receiving control therapy. Table 2 reports the most common adverse reactions occurring in at least 10% of patients in either group.
Table 2: Adverse Reactionsa with a Per-Patient Incidence of at Least 10% in Study 1 

Adverse Reactions	HALAVEN n=503		Control Group n=247
	All Grades	≥ Grade 3	All Grades	≥ Grade 3
Blood and lymphatic system disordersb
Neutropenia	82%	57%	53%	23%
Anemia	58%	2%	55%	4%
Nervous system disorders
Peripheral neuropathyc	35%	8%	16%	2%
Headache	19%	<1%	12%	<1%
General disorders
Asthenia/Fatigue	54%	10%	40%	11%
Pyrexia	21%	<1%	13%	<1%
Mucosal inflammation	9%	1%	10%	2%
Gastrointestinal disorders
Nausea	35%	1%	28%	3%
Constipation	25%	1%	21%	1%
Vomiting	18%	1%	18%	1%
Diarrhea	18%	0	18%	0
Musculoskeletal and connective tissue disorders
Arthralgia/Myalgia	22%	<1%	12%	1%
Back pain	16%	1%	7%	2%
Bone pain	12%	2%	9%	2%
Pain in extremity	11%	1%	10%	1%
Metabolism and nutrition disorders
Decreased weight	21%	1%	14%	<1%
Anorexia	20%	1%	13%	1%
Respiratory, thoracic, and mediastinal disorders
Dyspnea	16%	4%	13%	4%
Cough	14%	0	9%	0
Skin and subcutaneous tissue disorders
Alopecia	45%	NAd	10%	NAd
Infections
Urinary Tract Infection	10%	1%	5%	0
a. adverse reactions were graded per National Cancer Institute Criteria for Adverse Events version 4.0.  b based upon laboratory data c includes peripheral neuropathy, peripheral sensorimotor neuropathy, peripheral motor neuropathy, polyneuropathy, peripheral sensory neuropathy, and paraesthesia. d  not applicable; (grading system does not specify > Grade 2 for alopecia).

Cytopenias: Grade 3 neutropenia occurred in 28% (143/503) of patients who received HALAVEN in Study 1, and 29% (144/503) of patients experienced Grade 4 neutropenia. Febrile neutropenia occurred in 5% (23/503) of patients; two patients (0.4%) died from complications of febrile neutropenia. Dose reduction due to neutropenia was required in 12% (62/503) of patients and discontinuation was required in <1% of patients.  The mean time to nadir was 13 days and the mean time to recovery from severe neutropenia (<500/mm3) was 8 days.  Grade 3 or greater thrombocytopenia occurred in 1% (7/503) of patients.  G-CSF (granulocyte colony-stimulating factor) or GM-CSF (granulocyte–macrophage colony-stimulating factor) was used in 19% of patients who received HALAVEN.
Peripheral Neuropathy:  In Study 1, 17 % of enrolled patients had Grade 1 peripheral neuropathy and 3% of patients had Grade 2 peripheral neuropathy at baseline. Dose reduction due to peripheral neuropathy was required by 3% (14/503) of patients who received HALAVEN. Four percent (20/503) of patients experienced peripheral motor neuropathy of any grade and 2% (8/503) of patients developed Grade 3 peripheral motor neuropathy.
Liver Function Test Abnormalities:  Among patients with Grade 0 or 1 ALT levels at baseline, 18% of HALAVEN-treated patients experienced Grade 2 or greater ALT elevation. One HALAVEN-treated patient without documented liver metastases had concomitant Grade 2 elevations in bilirubin and ALT; these abnormalities resolved and did not recur with re-exposure to HALAVEN.
Less Common Adverse Reactions:  The following additional adverse reactions were reported in ≥5% to <10% of the HALAVEN-treated group:
Eye Disorders:  increased lacrimation
Gastrointestinal Disorders:  dyspepsia, abdominal pain, stomatitis, dry mouth
General Disorders and Administration Site Conditions:  peripheral edema
Infections and Infestations:  upper respiratory tract infection
Metabolism and Nutrition Disorders:  hypokalemia
Musculoskeletal and Connective Tissue Disorders:  muscle spasms, muscular weakness
Nervous System Disorders:  dysgeusia, dizziness
Psychiatric Disorders:  insomnia, depression
Skin and Subcutaneous Tissue Disorders:  rash
Liposarcoma
The safety of HALAVEN was evaluated in Study 2, an open-label, randomized, multicenter, active-controlled trial, in which patients were randomized (1:1) to receive either HALAVEN 1.4 mg/m2 on Days 1 and 8 of a 21-day cycle or dacarbazine at doses of 850 mg/m2 (20%), 1000 mg/m2 (64%), or 1200 mg/m2 (16%) every 3 weeks.  A total of  223 patients received HALAVEN and 221 patients received dacarbazine. Patients were required to have received at least two prior systemic chemotherapy regimens.  The trial excluded patients with pre-existing ≥ Grade 3 peripheral neuropathy, known central nervous system metastasis, elevated serum bilirubin or significant chronic liver disease, history of myocardial infarction within 6 months, history of New York Heart Association Class II or IV heart failure, or cardiac arrhythmia requiring treatment. The median age of the safety population in Study 2 was 56 years (range: 24 to 83 years); 67% female; 73% White, 3% Black or African American, 8% Asian/Pacific Islander, and 15% unknown; 99% received prior anthracycline-containing regimen; and 99% received ≥ 2 prior regimens. The median duration of exposure was 2.3 months (range: 21 days to 26 months) for patients receiving HALAVEN [see Clinical Studies (14.2)].
The most common adverse reactions (≥25%) reported in patients receiving HALAVEN were fatigue, nausea, alopecia, constipation, peripheral neuropathy, abdominal pain, and pyrexia.  The most common (≥5%) Grade 3-4 laboratory abnormalities reported in patients receiving HALAVEN were neutropenia, hypokalemia, and hypocalcemia. The most common serious adverse reactions reported in patients receiving HALAVEN were neutropenia (4.9 %) and pyrexia (4.5%). Permanent discontinuation of HALAVEN for adverse reactions occurred in 8% of patients. The most common adverse reactions resulting in discontinuation of HALAVEN were fatigue and thrombocytopenia (0.9% each).  Twenty-six percent of patients required at least one dose reduction. The most frequent adverse reactions that led to dose reduction were neutropenia (18%) and peripheral neuropathy (4.0%).
Table 3 summarizes the incidence of adverse reactions occurring in at least 10% of patients in the HALAVEN-treated arm in Study 2.
Table 3: Adverse Reactionsa Occurring in ≥10% (all Grades) of Patients Treated on the HALAVEN arm and at a Higher Incidence than in the Dacarbazine Arm (Between Arm Difference of ≥5% for All Grades or ≥2% for Grades 3 and 4) (Study 2)b 

Adverse Reaction	HALAVEN n=223		Dacarbazine n=221
	All Grades	Grades 3-4	All Grades	Grades 3-4
Nervous system disorders
Peripheral Neuropathyc	29%	3.1%	8%	0.5%
Headache	18%	0%	10%	0%
General disorders
Pyrexia	28%	0.9%	14%	0.5%
Gastrointestinal disorders
Constipation	32%	0.9%	26%	0.5%
Abdominal paind	29%	1.8%	23%	4.1%
Stomatitis	14%	0.9%	5%	0.5%
Skin and subcutaneous tissue disorders
Alopecia	35%	NAe	2.7%	NAe
Infections
Urinary tract infection	11%	2.2%	5%	0.5%
a Adverse reactions were graded per National Cancer Institute Criteria for Adverse Events version 4.03 (NCI CTCAE v4.03). b Safety data from one study site enrolling six patients were excluded. cIncludes peripheral neuropathy, peripheral sensorimotor neuropathy, peripheral motor neuropathy, polyneuropathy, peripheral sensory neuropathy, and paraesthesia d Includes abdominal pain, upper abdominal pain, lower abdominal pain, abdominal discomfort e Not applicable; (grading system does not specify > Grade 2 for alopecia)

Other clinically important adverse reactions occurring in ≥10% of the HALAVEN-treated patients were:
Gastrointestinal Disorders: nausea (41%); vomiting (19%), diarrhea (17%)
General Disorders:  asthenia/fatigue (62%); peripheral edema (12%)
Metabolism and Nutrition Disorders: decreased appetite (19%)
Musculoskeletal and Connective Tissue Disorders:  arthralgia/myalgia (16%); back pain (16%)
Respiratory Disorders: cough (18%)
Less Common Adverse Reactions: The following additional clinically important adverse reactions were reported in ≥5% to <10% of the HALAVEN-treated group:
Blood and Lymphatic System Disorders: thrombocytopenia
Eye Disorders: increased lacrimation
Gastrointestinal Disorders: dyspepsia
Metabolism and Nutrition Disorders: hyperglycemia
Musculoskeletal and Connective Tissue Disorders: muscle spasms, musculoskeletal pain
Nervous System Disorders: dizziness, dysgeusia
Psychiatric Disorders: insomnia, anxiety
Respiratory, Thoracic, and Mediastinal Disorders: oropharyngeal pain
Vascular Disorders: hypotension
Table 4: Laboratory Abnormalities Occurring in ≥10% (all Grades) of Patients Treated on the HALAVEN arm and at a Higher Incidence than in the Dacarbazine Arm (Between Arm Difference of ≥5% forAll Grades or ≥2% for Grades 3 and 4)a (Study 2)† 

Laboratory Abnormality	Halaven		Dacarbazine
	All Grades	Grades 3 - 4	All Grades	Grades 3 – 4
Hematology
Anemia	70%	4.1%	52%	6%
Neutropenia	63%	32%	30%	8.9%
Chemistry
Increased alanine aminotransferase (ALT)	43%	2.3%	28%	2.3%
Increased aspartate aminotransferase (AST)	36%	0.9%	16%	0.5%
Hypokalemia	30%	5.4%	14%	2.8%
Hypocalcemia	28%	5%	18%	1.4%
Hypophosphatemia	20%	3.2%	11%	1.4%
aEach test incidence is based on the number of patients who had both baseline and at least one on-study measurement and at least 1 grade increase from baseline.Halaven group (range 221-222) and dacarbazine group (range 214-215) Laboratory results were graded per NCI CTCAE v4.03.

6.2 Postmarketing Experience
The following adverse drug reactions have been identified during post-approval of HALAVEN.  Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Blood and Lymphatic System Disorders:  lymphopenia
Gastrointestinal Disorders:  pancreatitis
Hepatobiliary Disorders:  hepatotoxicity
Immune System Disorders:  drug hypersensitivity
Infections and Infestations:  pneumonia, sepsis/neutropenic sepsis
Metabolism and Nutrition Disorders:  hypomagnesemia, dehydration
Respiratory, thoracic and mediastinal disorders:  interstitial lung disease
Skin and Subcutaneous Tissue Disorders:  pruritus, Stevens-Johnson syndrome, toxic epidermal necrolysis
7 DRUG INTERACTIONS
7.1 Effects of Other Drugs on HALAVEN
No drug-drug interactions are expected with CYP3A4 inhibitors, CYP3A4 inducers or P-glycoprotein (P-gp) inhibitors. Clinically meaningful differences in exposure (AUC) were not observed in patients with advanced solid tumors when HALAVEN was administered with or without ketoconazole (a strong inhibitor of CYP3A4 and a P-gp inhibitor) and when HALAVEN was administered with or without rifampin (a CYP3A4 inducer) [see Clinical Pharmacology (12.3)].  
7.2 Effect of HALAVEN on Other Drugs
Eribulin does not inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4 enzymes or induce CYP1A2, CYP2C9, CYP2C19 or CYP3A4 enzymes at relevant clinical concentrations. Eribulin is not expected to alter the plasma concentrations of drugs that are substrates of these enzymes [see Clinical Pharmacology (12.3)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Based on findings from an animal reproduction study and its mechanism of action, HALAVEN can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on the use of HALAVEN during pregnancy. In an animal reproduction study, eribulin mesylate caused embryo-fetal toxicity when administered to pregnant rats during organogenesis at doses below the recommended human dose [see Data].  Advise pregnant women of the potential risk to a fetus.
The estimated background risks of major birth defects and miscarriage for the indicated populations are unknown. 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 toxicity study, pregnant rats received intravenous infusion of eribulin mesylate during organogenesis (Gestation Days 8, 10, and 12) at doses approximately 0.04, 0.13, 0.43 and 0.64 times the recommended human dose, based on body surface area. Increased abortion and severe fetal external or soft tissue malformations, including the absence of a lower jaw and tongue, or stomach and spleen, were observed at doses 0.64 times the recommended human dose of 1.4 mg/m2 based on body surface area. Increased embryo-fetal death/resorption, reduced fetal weights, and minor skeletal anomalies consistent with developmental delay were also reported at doses at or above a maternally toxic dose of approximately 0.43 times the recommended human dose.
8.2 Lactation
Risk Summary
There is no information regarding the presence of eribulin mesylate or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. No lactation studies in animals were conducted.  Because of the potential for serious adverse reactions in breastfed infants from eribulin mesylate, advise women not to breastfeed during treatment with HALAVEN and for 2 weeks after the final dose.
8.3 Females and Males of Reproductive Potential
Contraception
Females
Based on findings from an animal reproduction study and its mechanism of action, HALAVEN can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].  Advise females of reproductive potential to use effective contraception during treatment with HALAVEN and for at least 2 weeks following the final dose.
Males
Based on its mechanism of action, advise males with female partners of reproductive potential to use effective contraception during treatment with HALAVEN and for 3.5 months following the final dose.
Infertility 
Males
Based on animal data, HALAVEN may result in damage to male reproductive tissues leading to impaired fertility of unknown duration [see Nonclinical Toxicology (13.1)].
8.4 Pediatric Use
The safety and effectiveness of HALAVEN in pediatric patients below the age of 18 years have not been established.
8.5 Geriatric Use
Study 1 did not include sufficient numbers of subjects with metastatic breast cancer aged 65 years and older to determine whether they respond differently from younger subjects. Of the 827 subjects who received the recommended dose and schedule of HALAVEN in clinical studies with advanced breast cancer, 15% (121/827) were 65 and older and 2% (17/827) patients were 75 and older. No overall differences in safety were observed between these subjects and younger subjects.
Clinical studies of HALAVEN did not include a sufficient number of subjects in Study 2 aged 65 years and older to determine whether they respond differently from younger subjects.
8.6 Hepatic Impairment
Administration of HALAVEN at a dose of 1.1 mg/m2 to patients with mild hepatic impairment and 0.7 mg/m2 to patients with moderate hepatic impairment resulted in similar exposure to eribulin as a dose of 1.4 mg/m2 to patients with normal hepatic function. Therefore, a lower starting dose of 1.1 mg/m2 is recommended for patients with mild hepatic impairment (Child-Pugh A) and of 0.7 mg/m2 is recommended for patients with moderate hepatic impairment (Child-Pugh B). HALAVEN was not studied in patients with severe hepatic impairment (Child-Pugh C) [see Dosage and Administration (2.1), Clinical Pharmacology (12.3)]. 
8.7 Renal Impairment
For patients with moderate or severe renal impairment (CLcr 15-49 mL/min), reduce the starting dose to 1.1 mg/m2 [see Dosage and Administration (2.1), Clinical Pharmacology (12.3)].
10 OVERDOSAGE 
Overdosage of HALAVEN has been reported at approximately 4 times the recommended dose, which resulted in Grade 3 neutropenia lasting seven days and a Grade 3 hypersensitivity reaction lasting one day.
There is no known antidote for HALAVEN overdose.
11 DESCRIPTION
HALAVEN contains eribulin mesylate, a microtubule dynamics inhibitor. Eribulin mesylate is a synthetic analogue of halichondrin B, a product isolated from the marine sponge Halichondria okadai. The chemical name for eribulin mesylate is 11,15:18,21:24,28-Triepoxy-7,9-ethano-12,15-methano-9H,15H-furo[3,2-i]furo[2',3':5,6]pyrano[4,3-b][1,4]dioxacyclopentacosin-5(4H)-one, 2-[(2S)-3-amino-2-hydroxypropyl]hexacosahydro-3-methoxy-26-methyl-20,27-bis(methylene)-, (2R,3R,3aS,7R,8aS,9S,10aR,11S,12R,13aR,13bS,15S,18S,21S,24S,26R,28R,29aS)-, methanesulfonate (salt). It has a molecular weight of 826.0 (729.9 for free base). The empirical formula is C40H59NO11•CH4O3S. Eribulin mesylate has the following structural formula:

HALAVEN is a clear, colorless, sterile solution for intravenous administration. Each vial contains 1 mg of eribulin mesylate as a 0.5 mg/mL solution in ethanol: water (5:95). 
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Eribulin inhibits the growth phase of microtubules without affecting the shortening phase and sequesters tubulin into nonproductive aggregates. Eribulin exerts its effects via a tubulin-based antimitotic mechanism leading to G2/M cell-cycle block, disruption of mitotic spindles, and, ultimately, apoptotic cell death after prolonged mitotic blockage.
In addition, eribulin treatment of human breast cancer cells caused changes in morphology and gene expression as well as decreased migration and invasiveness in vitro. In mouse xenograft models of human breast cancer, eribulin treatment was associated with increased vascular perfusion and permeability in the tumor cores, resulting in reduced tumor hypoxia, and changes in the expression of genes in tumor specimens associated with a change in phenotype.
12.2 Pharmacodynamics
Cardiac Electrophysiology
The effect of HALAVEN on the QTc interval was assessed in an open-label, uncontrolled, multicenter, single-arm dedicated QT trial. A total of 26 patients with solid tumors received 1.4 mg/m2 of HALAVEN on Days 1 and 8 of a 21-day cycle. A delayed QTc prolongation was observed on Day 8, with no prolongation observed on Day 1.  The maximum mean QTcF change from baseline (95% upper confidence interval) was 11.4 (19.5) ms.
12.3 Pharmacokinetics
The pharmacokinetics (PK) of eribulin is linear with a mean elimination half-life of approximately 40 hours, a mean volume of distribution of 43 L/m2 to 114 L/m2 and mean clearance of 1.16 L/hr/m2 to 2.42 L/hr/m2 over the dose range of 0.25 mg/m2 to 4.0 mg/m2.  The human plasma protein binding of eribulin at concentrations of 100 ng/mL to 1,000 ng/mL ranges from 49% to 65%. Eribulin exposure after multiple dosing is comparable to that following a single dose. No accumulation of eribulin is observed with weekly administration.
Elimination
Metabolism
Unchanged eribulin was the major circulating species in plasma following administration of 14C-eribulin to patients. Metabolite concentrations represented <0.6% of parent compound, confirming that there are no major human metabolites of eribulin.  Cytochrome P450 3A4 (CYP3A4) negligibly metabolizes eribulin in vitro.
Excretion
Eribulin is eliminated primarily in feces unchanged. After administration of 14C-eribulin to patients, approximately 82% of the dose was eliminated in feces and 9% in urine.  Unchanged eribulin accounted for approximately 88% and 91% of total eribulin in feces and urine, respectively.
Specific Populations
Age, Sex, and Race/Ethnicity:  Based on a population pharmacokinetic analysis with data collected from 340 patients, sex, race, and age do not have a clinically meaningful effect on the exposure of eribulin.
Hepatic Impairment
In a study evaluating the effect of hepatic impairment on the PK of eribulin, eribulin exposures increased by 1.8-fold in patients with mild hepatic impairment (Child-Pugh A; n=7) and by 2.5-fold in patients with moderate (Child-Pugh B; n=5) hepatic impairment as compared to patients with normal hepatic function (n=6).  Administration of HALAVEN at a dose of 1.1 mg/m2 to patients with mild hepatic impairment and 0.7 mg/m2 to patients with moderate hepatic impairment resulted in similar exposure to eribulin at a dose of 1.4 mg/m2 to patients with normal hepatic function [see Dosage and Administration (2.1), Use in Specific Populations (8.6)].
Renal Impairment
In a study evaluating the effect of renal impairment on the PK of eribulin, patients with moderate (CLcr 30-49 mL/min; n=7) and severe renal impairment (CLcr 15-29 mL/min; n=6) had 1.5-fold higher eribulin dose-normalized exposures compared to that in patients with normal renal function (CLcr ≥ 80 mL/min; n=6).  There were no clinically meaningful changes in patients with mild renal impairment (CLcr 50-79 mL/min; n=27) [see Dosage and Administration (2.1), Use in Specific Populations (8.7)].
Drug Interaction Studies
Effect of Strong Inhibitors or Inducers of CYP3A4 on Eribulin:  The effect of a strong CYP3A4 inhibitor and a P-gp inhibitor, ketoconazole, on the PK of eribulin was studied in a crossover trial of 12 patients with advanced solid tumors. No clinically relevant PK interaction was observed when HALAVEN was administered with or without ketoconazole (the geometric mean ratio of the AUC: 0.97; 90% CI: 0.83, 1.12).
The effect of a CYP3A4 inducer, rifampin, on the PK of eribulin was studied in a crossover trial of 14 patients with advanced solid tumors. No clinically relevant PK interaction was observed when HALAVEN was administered with or without rifampin (the geometric mean ratio of the AUC: 1.10; 90 CI%: 0.91, 1.34).
Effect of Eribulin on CYP Substrates:  Eribulin shows no induction potential for CYP1A, CYP2B6, CYP2C9, CYP2C19, and CYP3A in primary human hepatocytes. Eribulin inhibits CYP3A4 activity in human liver microsomes, but it is unlikely that eribulin will substantially increase the plasma levels of CYP3A4 substrates. No significant inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP2E1 was detected with eribulin concentrations up to 5 μM in pooled human liver microsomes. In vitro drug interaction studies indicate that eribulin does not inhibit drugs that are substrates of these enzymes and it is unlikely that eribulin will affect plasma levels of drugs that are substrates of CYP enzymes.
Effect of Transporters on Eribulin: In vitro data suggest that eribulin at clinically relevant concentrations is a substrate of P-gp, but is not a substrate of breast cancer resistance protein (BCRP), multidrug resistance proteins (MRP2, MRP4), bile salt extrusion pump (BSEP), organic anion transporting polypeptides (OATP1B1, OATP1B3), organic anion transporters (OAT1, OAT3), organic cation transporters (OCT1, OCT2), or multidrug and toxin extrusion 1 (MATE1).
Effect of Eribulin on Transporters: In vitro data suggest that eribulin at clinically relevant concentrations may inhibit P-gp, but does not inhibit BCRP, OATP1B1, OCT1, OAT1, OAT3, or MATE1.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have not been conducted with eribulin mesylate.  Eribulin mesylate was not mutagenic in in vitro bacterial reverse mutation assays (Ames test). Eribulin mesylate was positive in mouse lymphoma mutagenesis assays, and was clastogenic in an in vivo rat bone marrow micronucleus assay.
Fertility studies have not been conducted with eribulin mesylate in humans or animals; however, nonclinical findings in repeat-dose dog and rat toxicology studies suggest that male fertility may be compromised by treatment with eribulin mesylate.  Rats exhibited testicular toxicity (hypocellularity of seminiferous epithelium with hypospermia/aspermia) following dosing with eribulin mesylate at or above 0.43 times the recommended human dose (based on body surface area) given once weekly for 3 weeks, or at or above 0.21 times the recommended human dose (based on body surface area) given once weekly for 3 out of 5 weeks, repeated for 6 cycles. Testicular toxicity was also observed in dogs given 0.64 times the recommended human dose (based on body surface area) weekly for 3 out of 5 weeks, repeated for 6 cycles.
14 CLINICAL STUDIES
14.1 Metastatic Breast Cancer
Study 1 was an open-label, randomized, multicenter trial of 762 patients with metastatic breast cancer who received at least two chemotherapeutic regimens for the treatment of metastatic disease and experienced disease progression within 6 months of their last chemotherapeutic regimen. Patients were required to receive prior anthracycline- and taxane- based chemotherapy for adjuvant or metastatic disease. Patients were randomized (2:1) to receive HALAVEN (n=508) or a single agent therapy selected prior to randomization (control arm, n=254). Randomization was stratified by geographic region, HER2/neu status, and prior capecitabine exposure. HALAVEN was administered at a dose of 1.4 mg/m2 on Days 1 and 8 of a 21-day cycle. HALAVEN-treated patients received a median of 5 cycles (range: 1 to 23 cycles) of therapy.  Control arm therapy consisted of 97% chemotherapy (26% vinorelbine, 18% gemcitabine, 18% capecitabine, 16% taxane, 9% anthracycline, 10% other chemotherapy), and 3% hormonal therapy. The main efficacy outcome was overall survival.
Patient demographic and baseline characteristics were comparable between the treatment arms. The median age was 55 (range: 27 to 85 years) and 92% were White. Sixty-four percent of patients were enrolled in North America/Western Europe/Australia, 25% in Eastern Europe/Russia, and 11% in Latin America/South Africa.  Ninety-one percent of patients had a baseline ECOG performance status of 0 or 1. Tumor prognostic characteristics, including estrogen receptor status (positive: 67%, negative: 28%), progesterone receptor status (positive: 49%, negative: 39%), HER2/neu receptor status (positive: 16%, negative: 74%), triple negative status (ER-, PR-, HER2/neu-: 19%), presence of visceral disease (82%, including 60% liver and 38% lung) and bone disease (61%), and number of sites of metastases (greater than two: 50%), were also similar in the HALAVEN and control arms. Patients received a median of four prior chemotherapy regimens in both arms.
In Study 1, a statistically significant improvement in overall survival was observed in patients randomized to the HALAVEN arm compared to the control arm (see Table 5). An updated, unplanned survival analysis, conducted when 77% of events had been observed (see Figure 1), was consistent with the primary analysis. In patients randomized to HALAVEN, the objective response rate by the RECIST criteria was 11% (95% CI: 8.6%, 14.3%) and the median response duration was 4.2 months (95% CI: 3.8, 5.0 months).
Table 5: Comparison of Overall Survival in HALAVEN and Control Arm - Study 1 

Overall Survival	HALAVEN (n=508)	Control Arm (n=254)
Primary survival analysis
Number of deaths	274	148
Median, months (95% CI)	13.1 (11.8, 14.3)	10.6 (9.3, 12.5)
Hazard Ratio (95% CI)a	0.81 (0.66, 0.99)
P valueb	0.041
Updated survival analysis
Number of deaths	386	203
Median, months (95% CI)	13.2 (12.1, 14.4)	10.6 (9.2, 12.0)
CI = confidence interval a Based on Cox proportional hazards model stratified by geographic region, HER2 status, and prior capecitabine therapy. b Based on a log-rank test stratified by geographic region, HER2 status, and prior capecitabine therapy.

Figure 1: Updated Overall Survival Analysis for Study 1
14.2 Liposarcoma
The efficacy and safety of HALAVEN were evaluated in Study 2, an open-label, randomized (1:1), multicenter, active-controlled trial.  Eligible patients were required to have unresectable, locally advanced or metastatic liposarcoma or leiomyosarcoma, at least two prior systemic chemotherapies (one of which must have included an anthracycline), and disease progression within 6 months of the most recent chemotherapy regimen.  Patients were randomized to HALAVEN 1.4 mg/m2 administered intravenously on Days 1 and 8 of a 21-day cycle or to dacarbazine at a dose of 850 mg/m2, 1000 mg/m2, or 1200 mg/m2 administered intravenously every 21 days (dacarbazine dose was selected by the investigator prior to randomization).  Treatment continued until disease progression or unacceptable toxicity.  Randomization was stratified by histology (liposarcoma or leiomyosarcoma), number of prior therapies (2 vs. > 2), and geographic region (U.S. and Canada vs. Western Europe, Australia, and Israel vs. Eastern Europe, Latin America, and Asia).  The major efficacy outcome measure was overall survival (OS). Additional efficacy outcome measures were progression-free survival (PFS) and confirmed objective response rate (ORR) as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1).  Patients in the dacarbazine arm were not offered HALAVEN at the time of disease progression.
A total of 446 patients were randomized, 225 to the HALAVEN arm and 221 to the dacarbazine arm. The median age was 56 years (range: 24 to 83); 33% were male; 73% were White; 44% had ECOG performance status (PS) 0 and 53% had ECOG PS 1; 68% had leiomyosarcoma and 32% had liposarcoma; 39% were enrolled in U.S. and Canada (Region 1) and 46% were enrolled in Western Europe, Australia, and Israel (Region 2); and 47% received more than two prior systemic chemotherapies.  The most common (>40%) prior systemic chemotherapies were doxorubicin (90%), ifosfamide (62%), gemcitabine (59%), trabectedin (50%), and docetaxel (48%).
Of the 143 patients with liposarcoma, the median age was 55 years (range: 32 to 83); 62% were male, 72% were White; 41% had ECOG PS of 0 and 53% had ECOG PS of 1; 35% were enrolled in Region 1 and 51% were enrolled in Region 2; and 44% received more than two prior systemic chemotherapies.  The distribution of subtypes of liposarcoma, based on local histologic assessment, were 45% dedifferentiated, 37% myxoid/round cell, and 18% pleomorphic.
Study 2 demonstrated a statistically significant improvement in OS in patients randomized to HALAVEN compared with dacarbazine (see Table 6).  There was no significant difference in progression-free survival in the overall population. Treatment effects of HALAVEN were limited to patients with liposarcoma based on pre-planned, exploratory subgroup analyses of OS and PFS (see Tables 6 and 7 and Figure 2). There was no evidence of efficacy of HALAVEN in patients with advanced or metastatic leiomyosarcoma in Study 2 (see Table 7).
Table 6: Efficacy Results for the Liposarcoma Stratum and All Patients* in Study 2a

Liposarcoma Stratum			All Patients*
	Halaven (n=71)		Dacarbazine (n=72)	Halaven (n=225)	Dacarbazine (n=221)
Overall survival
Deaths, n (%)	52 (73)		63 (88)	173 (77)	179 (81)
Median, months    (95% CI)	15.6 (10.2, 18.6)		8.4 (5.2, 10.1)	13.5 (11.1, 16.5)	11.3 (9.5, 12.6)
Hazard ratio (HR)    (95% CI)	0.51 (0.35, 0.75)			0.75 (0.61, 0.94)
Stratified log-rank p value	N/A†			0.011
Progression-free survival
Events, n (%)	57 (80)		59 (82)	194 (86)	185 (84)
Disease progression	53		52	180	170
Death	4		7	14	15
Median, months    (95% CI)	2.9 (2.6, 4.8)		1.7 (1.4, 2.6)	2.6 (2.0, 2.8)	2.6 (1.7, 2.7)
HR    (95% CI)	0.52  (0.35, 0.78)			0.86  (0.69, 1.06)
Objective response rate
Objective response rate (%)    (95% CI)	1.4  (0, 7.6)	0  (0, 4.2)		4.0  (1.8, 7.5)	5.0 (2.5, 8.7)

a Efficacy data from one study site enrolling six patients were excluded.
*All patients = liposarcoma and leiomyosarcoma.
N/A = not applicable

Figure 2: Kaplan-Meier Curves of Overall Survival in the Liposarcoma Stratum in Study 2
Table 7: Efficacy Results for the Leiomyosarcoma Stratum in Study 2a 

Leiomyosarcoma Stratum
	Halaven (n=154)	Dacarbazine (n=149)
Overall survival
Deaths, n (%)	121 (79)	116 (78)
Median, months       (95% CI)	12.8 (10.3, 14.8)	12.3 (11.0, 15.1)
HR (95% CI)	0.90 (0.69, 1.18)
Progression-free survival
Events, n (%)	137 (89)	126 (85)
Disease progression	127	118
Death	10	8
Median, months    (95% CI)	2.2 (1.5, 2.7)	2.6 (2.2, 2.9)
HR (95% CI)	1.05 (0.81, 1.35)
Objective response rate (%)    (95% CI)	5.2 (2.3, 10)	7.4 (3.7, 12.8)

a Efficacy data from one study site enrolling six patients were excluded.
16 HOW SUPPLIED/STORAGE AND HANDLING
NDC 62856-389-01      
Injection: 1 mg/2 mL, in a single-use vial. One vial per carton.
Store at 25°C (77°F); excursions permitted to 15° – 30° C (59° -86° F). Do not freeze. Store the vials in their original cartons.
http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=31ce4750-ded5-4a0b-95e9-f229fa6bc822

卫材HALAVEN(ERIBULIN MESYLATE)SOLUTION INTRAVENOUS -获美国FDA批准全球首个可显著延长晚期脂肪肉瘤患者生存的新型抗癌药
2016年2月1日，新型抗癌药Halaven（甲磺酸艾日布林 eribulinmesylate）获美国FDA已批准Halaven用于之前已接受过含蒽环类药物方案治疗的晚期或转移性脂肪肉瘤（liposarcoma）患者。
迄今为止，Halaven是首个也是唯一一个在III期临床中治疗晚期或复发性和转移性软组织肉瘤（STS，平滑肌肉瘤、脂肪肉瘤）表现出总生存期（OS）受益的单一制剂系统疗法。继之前获得FDA批准用于转移性乳腺癌之后，此次批准也标志着FDA基于统计学显著改善的总生存期（OS）数据所批准的Halaven的第二个适应症。
卫材于2015年7月向美国、日本、欧盟提交了Halaven治疗软组织肉瘤的新适应症申请。
在美国和日本，Halaven均被授予治疗软组织肉瘤的孤儿药地位。
Halaven是一种软海绵素类（halichondrin）微管动力学抑制剂，具有新颖的作用机制，该药是唯一的一种单药化疗药物，由卫材内部发现和开发，于2010年首次获FDA批准用于转移性乳腺癌的治疗。
目前，Halaven已获全球约60个国家批准，包括日本、欧洲、美国、亚洲。
此次批准是基于一项多中心、开放标签、随机III期研究（Study 309）的积极顶线数据。该研究在452例（年龄18岁及以上）经标准疗法（包括蒽环类及至少一种其他化疗方案）治疗后病情进展的局部晚期或复发性和转移性软组织肉瘤（STS，2种亚型：平滑肌肉瘤或脂肪肉瘤）患者中开展，评估了Halaven相对于化疗药物达卡巴嗪（dacarbazine）的疗效和安全性。
数据显示，与达卡巴嗪治疗组相比，Halaven治疗组总生存期（OS）得到统计学意义的显著延长（中位OS：13.5个月 vs 11.5个月，HR=0.768，95%CI:0.618-0.954，p=0.017），达到了研究的主要终点。治疗脂肪肉瘤方面，与达卡巴嗪治疗组（n=72）相比，Halaven治疗组（n=71）总生存期（OS）也得到统计学意义的显著延长（中位OS：15.6个月 vs 8.4个月，HR=0.51，95%CI:0.35-075）。此外，在研究的次要终点方面（无进展生存期，PFS），与达卡巴嗪治疗组相比，Halaven治疗组也得到改善（中位PFS：2.9个月 vs 1.7个月，HR=0.52，95%CI:0.35-0.78）。
该研究中，脂肪肉瘤患者和平滑肌肉瘤患者接受Halaven治疗时最常见的不良反应（发生率≥25%）包括疲劳、恶心、脱发、便秘、周围神经病变、腹痛及发热，这与Halaven已知的副作用一致。Halaven治疗组最常见的3-4级实验室异常（发生率≥5%）包括中性粒细胞减少症、低钾血症、低钙血症。Halaven治疗组最常见的严重不良反应包括中性粒细胞减少症（4.9%）和发热（4.5%）。
软组织肉瘤（STS）是对发生于全身软组织（脂肪、肌肉、神经、纤维组织、血管）的一大类恶性肿瘤的统称。据估计，在美国每年确诊病例约1.2万例，欧洲约2.9万例。据日本MHLW开展的一项调查显示，日本约有4000例患者。