Halaven - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology.
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Halaven - Scientific Information

Manufacture: Eisai Inc.
Country: Canada
Condition: Breast Cancer, Breast Cancer, Metastatic, Liposarcoma, Metastatic Breast Cancer (Breast Cancer, Metastatic)
Class: Antineoplastics, Mitotic inhibitors
Form: Liquid solution, Intravenous (IV)
Ingredients: eribulin mesylate,ethanol, water

Pharmaceutical Information

Drug Substance
Common name: eribulin mesylate
Chemical name: 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)
Molecular formula and molecular mass:
Molecular formula: C40H59NO11 • CH4SO3
Molecular weight: 826.0 (729.9 for free base)
Structural formula:

Physicochemical properties: White powder and freely soluble in water, methanol, ethanol, 1-octanol, benzyl alcohol, dimethylsulfoxide, N-methylpyrrolidone, dichloromethane and ethylacetate, soluble in acetone, sparingly soluble in acetonitrile, practically insoluble in tert-butylmethyl ether, n-heptane and n-pentane. In Britton-Robinson buffer, eribulin mesylate was freely soluble at pH 3-7, soluble at pH 9 and slightly soluble at pH 11.

Clinical Trials

In an open-label, randomized, multicenter, multinational study of 762 patients with metastatic breast cancer (EMBRACE Study - Table 5), the efficacy and safety of HALAVEN were assessed in patients previously treated with a minimum of 2 and a maximum of 5 prior chemotherapy regimens (at least 2 for locally recurrent or metastatic disease), including an anthracycline and a taxane (unless contraindicated). Patients received a median of 4 prior chemotherapy regimens. Patients must have progressed within 6 months of their last chemotherapeutic regimen. Patients with pre-existing peripheral neuropathy Grade ≤2 were enrolled. Patients were randomized 2:1 to receive HALAVEN (1.4 mg/m2 on Days 1 and 8 in a 21-day cycle administered IV over 2 to 5 minutes) or Treatment of Physician’s Choice, defined as any single- agent chemotherapy, hormonal treatment, or biologic therapy approved for the treatment of cancer; or palliative treatment or radiotherapy, administered according to local practice, if applicable. The Treatment of Physician’s Choice arm consisted of chemotherapy for 97% of patients or hormonal therapy for 3% of patients. Patients were treated with a median of 5 cycles (range, 1 to 23 cycles) of HALAVEN therapy. The median relative dose intensity for HALAVEN was 91%.

Patient characteristics were well balanced across treatment arms. Select baseline patient and disease characteristics are summarized in Table 5.

Sixty-four percent of patients were enrolled from North America/Western Europe/Australia, 25% from Eastern Europe/Russia, and 11% from Latin America/South Africa.

Table 1: Patient and Baseline Disease Characteristics (ITT Population)
Patient Characteristic HALAVEN(n=508) Treatment of Physician’s Choice (n=254)
Age (years)
Median (range) 55 (28-85) 56 (27-81)
Age (years) distribution, n (%)
<40 34 (7) 17 (7)
≥40 to <65 380 (75) 180 (71)
≥65 to ≤75 86 (17) 51 (20)
>75 8 (2) 6 (2)
Race, n(%)
Black 20 (4) 14 (6)
White 470 (93) 233 (92)
Asian/Pacific Islander 3 (1) 2 (1)
Other 15 (3) 5 (2)
ECOG performance status, n (%)
0 217 (43) 103 (41)
1 244 (48) 126 (50)
2 39 (8) 22 (9)
Not reported 8 (2) 3 (1)
Estrogen receptor status, n (%)
Positive 336 (66) 171 (67)
Negative 143 (28) 72 (28)
Unknown 29 (6) 11 (4)
Progesterone receptor status, n (%)
Positive 254 (50) 123 (48)
Negative 197 (39) 102 (40)
Unknown 57 (11) 29 (11)
HER2 receptor status, n (%)
Positive 83 (16) 40 (16)
Negative 373 (73) 192 (76)
Unknown 52 (10) 22 (9)
ER, PR, HER2, n (%) 93 (18) 51 (20)
Number of prior chemotherapy regimens, n (%)
1 Regimen 1 (<1) 0 (0)
2 Regimen 65 (13) 31 (12)
3 Regimen 176 (35) 83 (33)
">4 Regimen 166 (33) 79 (31)
5 Regimen 85 (28) 51 (20)
>6 Regimen 13 (3) 9 (4)
Sites of involvement
Liver 296 (59) 159 (63)
Lung 197 (39) 95 (37)
Bone 306 (60) 158 (62)
Number of sites of metastases
≤2 sites of metastases 257 (51) 117 (46)
≥2 sites of metastases 249 (49) 137 (54)

Abbreviations: ECOG, Eastern Cooperative Oncology Group, ER, estrogen receptor, HER2, human epidermal growth factor receptor 2, PR, progesterone receptor.

The primary endpoint of the study was overall survival. A statistically significant improvement in overall survival was observed in patients randomized to HALAVEN compared to Treatment of Physician’s Choice (Table 6). An improvement of 2.5 months median survival (HR 0.809, 95% CI: 0.660, 0.991, p=0.041) was demonstrated. The 1-year survival rates were 54% (95% CI: 0.492, 0.586) in patients randomized to HALAVEN and 44% (95% CI: 0.371, 0.502) in the Treatment of Physician’s Choice group. An updated survival analysis, conducted when 77% of events had been observed (Figure 1), was consistent with the primary analysis with an improvement in median overall survival of 2.6 months (HR 0.805, 95% CI: 0.677, 0.958, nominal p=0.014) observed in patients randomized to HALAVEN compared to Treatment of Physician’s Choice. 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 2: Comparison of Overall Survival: HALAVEN vs Treatment of Physician’s Choice—ITT Analysis
Efficacy Parameter HALAVEN
(n=508)
Treatment of Physician’s Choice
(n=254)
Overall Survival
Number of deaths 274 148
Median, months (95% CI) 13.1 months (11.8, 14.3) 10.6 months (9.3, 12.5)
Hazard Ratio (95% CI)a 0.809b (0.660, 0.991)
P valuec 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)
Hazard Ratio (95% CI)a 0.805 (0.677, 0.958)
P valuec 0.014

Abbreviations: CI, confidence interval; HER2, human epidermal growth factor receptor 2; ITT, intent to treat.
a Based on a Cox proportional hazards model stratified by geographic region, HER2 status, and prior capecitabine therapy.
b For the hazard ratio, a value less than 1.00 favors treatment with HALAVEN.
c Based on a log-rank test stratified by geographic region, HER2 status, and prior capecitabine therapy.

Figure 1: Updated Overall Survival Analysis—ITT Analysis

Detailed Pharmacology

Animal

Pharmacodynamics

Results of in vitro studies demonstrate that addition of eribulin mesylate inhibits cell growth with sub- to low-nmol/L half-maximal inhibitory concentration (IC50) values in a wide range of established human cancer cell lines, including breast, colon, prostate, ovarian, small cell lung, and non-small cell lung cancers, as well as histiocytic lymphoma, promyelocytic leukemia, pharyngeal squamous cell (head and neck cancer) carcinoma, melanoma and uterine sarcoma. Eribulin mesylate exerts its anticancer effects via a tubulin-based antimitotic mechanism, leading to G2/M (Gap 2/mitosis stages of cell cycle) cell cycle blocks, disruption of mitotic spindles, and ultimately apoptotic cell death after prolonged mitotic blockage. Eribulin mesylate leads to inhibition of microtubule growth and formation of non-productive tubulin aggregates, but without effects on microtubule shortening.

Eribulin mesylate retained undiminished in vitro activity against a cancer cell line that was taxane-resistant due to β-tubulin mutations. Eribulin mesylate is a substrate for the P-gp drug efflux pump, and showed reduced in vitro potency against a human cancer cell line expressing P-gp.

Electrophysiological Systems

Intravenous infusion over 1 hour of eribulin mesylate at 0.04 mg/kg (0.8 mg/m >2) in dogs resulted in transiently decreased systolic, diastolic and mean arterial pressure and heart rate, and increased RR interval but no effects on other ECG parameters were observed for up to 8 hours post-dose. The estimated maximal plasma concentrations achieved in the cardiovascular safety pharmacology studies were approximately 6% of the clinical Cmax.

Evaluation of potential cardiac effects in vitro were conducted at concentrations far exceeding (>300 times) the clinical Cmax concentrations. In vitro, eribulin at concentrations up to 30 μmol/L did not inhibit hERG activity in stably transfected HEK293 cells and had no effects on the cardiac action potential parameters in isolated dog Purkinje fibers.

Central Nervous System and Respiratory Systems

Administration of eribulin mesylate by a slow bolus intravenous injection at 0.1 or 0.25 mg/kg produced no notable effects on the central nervous or respiratory systems in male rats.

Pharmacokinetics

Eribulin is eliminated primarily by biliary excretion. The transport protein involved in the excretion is presently unknown. Preclinical studies indicate that eribulin is transported by P-gp. However, it is unknown whether P-gp is contributing to the biliary excretion of eribulin.

Toxicology

Repeated-dose Toxicity

Intravenous repeated-dose toxicity studies were conducted in F344 rats and beagle dogs. In these studies, eribulin mesylate was administered three times with 4-day (Q4D×3) or 7-day (Q7D×3) intervals. In the 6-month chronic toxicity studies in rats and dogs, the dosing schedule of Q7D×3 followed by a 14-day recovery period was repeated in six cycles. In these studies, eribulin mesylate was administered to rats by slow bolus injection and to dogs as a 1-hour intravenous infusion. The dose-limiting toxicity precluded administration on a repeated basis of doses exceeding the clinical recommended dose (1.4 mg/m2 of eribulin mesylate administered IV over 2 to 5 minutes). At the doses that could be administered, plasma concentrations in animals were lower than the clinical exposure.

The antiproliferative activity of eribulin mesylate was associated with bone marrow, lymphoid and testicular toxicity in all of the Q4D×3 and Q7D×3 repeated-dose toxicity studies in both rats and dogs. In dogs, emesis, diarrhea as well as necrosis and hyperplasia in the crypts/glands of the small and large intestine occurred at lethal doses (0.075 mg/kg [1.5 mg/m2] Q4Dx2). Bone marrow toxicity and/or gastro-intestinal toxicity appeared to be the dose-limiting toxicity of eribulin mesylate. Bone marrow toxicity included a decreased number of hematopoietic cells, resulting in reduced peripheral blood cell counts and histologically visible bone marrow hypocellularity. These bone marrow alterations were often accompanied by compensatory extramedullary hematopoiesis in the spleen. The lowest doses at which bone marrow toxicity appeared in the repeated-dose toxicity studies were 0.05 mg/kg (0.30 mg/m2) in rats and 0.03 mg/kg (0.60 mg/m2) in dogs. Lymphoid toxicity, represented by a decreased circulating lymphocyte count and/or atrophy of the lymphoid organs was noted at doses of ≥0.60 mg/m2(≥0.10 mg/kg in rats and ≥0.03 mg/kg in dogs) in the Q7D×3 and Q4D×3 studies. Bone marrow and lymphoid toxicity were reversible, with recovery underway or completed within 26 days post-dosing during the post-dosing observation period in the Q4D×3 and Q7D×3 toxicity studies, in both rats and dogs. Testicular toxicity included the macroscopic findings of soft and/or small testes and decreased testicular weight. Histological observations in the testes included hypocellularity or degeneration of the seminiferous tubules. These changes were associated with secondary epididymal hypospermia/aspermia. Testicular toxicity occurred at ≥0.05 mg/kg (0.30 mg/m2) in rats and 0.045 mg/kg (0.90 mg/m2 ) in dogs. In the rat, testicular degeneration noted at necropsy was generally more severe 14 to 26 days after the last dose than 3 days post dose. This may be related to the failure of the damaged cells to divide and suggests that the testicular damage may be irreversible. It may also be a reflection of insufficient recovery time since the duration of the spermatogenic cycle in rats is 48-52 days.

Degeneration of myocytes and neurofiber degeneration of the sciatic nerve were also observed in rats at doses of ≥0.20 mg/kg (1.20 mg/m 2) in the Q4D×3 and Q7D×3 studies, respectively. These effects may appear as neuropathy and/or myalgia in humans. Although degeneration of myocytes disappeared by Day 35 (26 days post dose), fiber degeneration of sciatic nerve was still present on Day 29 (14 days post dose). There was one male rat at the high dose (0.15 mg/kg [0.90 mg/m 2]) in the chronic toxicity study with neurofiber degeneration. Six month studies (Q7Dx3 IV administration followed by 14 non-dosing days for 6 cycles) did not identify any unexpected toxicity at the dose administered (up to 0.90 mg/m2 in rats and dogs). Focal and multifocal necrosis in the liver of male rats in the chronic rat study were attributed to bacterial infections and considered secondary to the effects of eribulin on bone marrow.

Genotoxicity

Eribulin mesylate was non-mutagenic in the Ames test, both with and without exogenous metabolizing system (S9). Eribulin mesylate was weakly positive in the mouse lymphoma tk assay in both activated and non-activated cultures. In the in vivo rat micronucleus assay, eribulin mesylate showed some evidence of genotoxic activity, forming substantially larger micronuclei than those seen with cyclophosphamide. The generally large-sized micronuclei induced by eribulin mesylate were consistent with interference or disruption of chromosome segregation rather than to a clastogenic action resulting in chromosome breakage.

Reproductive and Developmental Toxicity

The effects of eribulin mesylate on pregnancy and embryo-fetal development were evaluated by intermittent administration during the mid-organogenesis period in rats. The dose of 0.10 mg/kg (0.60 mg/m2 ) and higher exhibited embryo-fetal lethality with reduced fetal body weight. The dose of 0.15 mg/kg (0.90 mg/m2) induced external and/or soft tissue anomalies (absence of lower jaw, tongue, stomach and spleen) and early delivery.

Other Toxicity Studies

In vitro myelotoxicity studies were performed in bone marrow cells (CFU-GM) of mouse, dog and human using Hipple’s soft agar assay. Bone marrow cells were incubated with eribulin mesylate at concentrations of 0, 0.01, 0.1, 1, 10 and 100 nmol/L. The inhibition of CFU-GM colony formation was measured, and the concentrations that caused inhibition of colony formation were calculated by a regression analysis where possible. The mean IC90 were 63.1, 19.8, and 21.85 nmol/L in mice, dogs, and human, respectively.

Similar in vitro HALO (hemotoxicity assays via luminescence output) studies were performed with bone marrow multipotential stem cells (CFC-GEMM) of mouse, dog and human. Bone marrow cells were incubated with eribulin mesylate and comparators (paclitaxel and vinblastine) at concentrations of 0.1 to 1000 nmol/L. The murine CFC-GEMM cells appeared to be less sensitive to the antiproliferative effects of eribulin mesylate, whereas human and canine cells appeared to be equally sensitive. The IC50 values of eribulin mesylate were 148, 11.4 and 15.9 nmol/L in mice, dogs and human, respectively. Species sensitivity to eribulin mesylate-caused toxicity can be ranked as follows: dog ≥ human > mouse.