February 25, 2017
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Halaven

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Halaven Injection




CLINICAL PHARMACOLOGY

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 G 2/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.

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.

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, Use in Specific Populations].

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, Use in Specific Populations].

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.

Clinical Studies

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

Updated Overall Survival Analysis for Study 1 -  Illustration

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 15.6 8.4 13.5 11.3
  (95% CI) (10.2, 18.6) (5.2, 10.1) (11.1, 16.5) (9.5, 12.6)
  Hazard ratio (HR) 0.51 0.75
  (95% CI) (0.35, 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 2.9 1.7 2.6 2.6
  (95% CI) (2.6, 4.8) (1.4, 2.6) (2.0, 2.8) (1.7, 2.7)
  HR 0.52 0.86
  (95% CI) (0.35, 0.78) (0.69, 1.06)
Objective response rate
  Objective response rate (%)  1.4 0 4.0 5.0
  (95% CI) (0, 7.6) (0, 4.2) (1.8, 7.5) (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

Kaplan-Meier Curves of Overall Survival in the Liposarcoma Stratum in Study 2 -  Illustration

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 12.8 12.3
  (95% CI) (10.3, 14.8) (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 2.2 2.6
  (95% CI) (1.5, 2.7) (2.2, 2.9)
  HR (95% CI) 1.05 (0.81, 1.35)
  Objective response rate (%) 5.2 7.4
  (95% CI) (2.3, 10) (3.7, 12.8)
a Efficacy data from one study site enrolling six patients were excluded.

Last reviewed on RxList: 11/8/2016
This monograph has been modified to include the generic and brand name in many instances.

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