Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic Group: antineoplastic agent, protein kinase inhibitor, ATC Code: L01EX04 Mechanism of action and pharmacodynamic effects
Vandetanib is a potent inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2 also known as kinase insert domain containing receptor [KDR]), epidermal growth factor receptor (EGFR) and RET tyrosine kinases. Vandetanib is also a sub-micromolar inhibitor of vascular endothelial receptor-3 tyrosine kinase.

Vandetanib inhibits VEGF-stimulated endothelial cell migration, proliferation, survival and new blood vessel formation in in vitro models of angiogenesis. In addition, vandetanib inhibits epidermal growth factor (EGF)-stimulated EGF receptor tyrosine kinase in tumour cells and endothelial cells. Vandetanib inhibits EGFR-dependent cell proliferation and cell survival in vitro. Vandetanib also inhibits both wild type and the majority of mutated, activated forms of RET, and significantly inhibits the proliferation of MTC cell lines in vitro.

In vivo vandetanib administration reduced tumour cell-induced angiogenesis, tumour vessel permeability, tumour microvessel density, and inhibited tumour growth of a range of human xenograft tumour models in athymic mice. Vandetanib also inhibited the growth of MTC xenograft tumours in vivo.

The precise mechanism of action of vandetanib in locally advanced or metastatic MTC is unknown.


Clinical data from MTC
A randomised, double-blind, placebo-controlled study (Study 58) was conducted to demonstrate safety and efficacy of vandetanib 300 mg versus placebo. This study included 331 patients with unresectable locally advanced or metastatic MTC. Only patients with CTN ≥ 500 pg/mL (conventional units) or ≥ 146.3 pmol/L (international standard units) were enrolled. Of the patients enrolled in the study 10 patients on vandetanib and 4 on placebo (4% of all patients) had a World Health Organization performance status (WHO PS) score of ≥ 2 and 28 (12.1%) patients on vandetanib and 10 (10.1%) on placebo had cardiac impairment. Cardiac impairment was defined as patients with previous cardiovascular abnormality.

The primary objective of this study was to demonstrate an improvement in progression-free survival (PFS) with vandetanib compared to placebo. The secondary endpoints were evaluation of overall objective response rate (ORR), disease control rate (DCR) defined as, partial response (PR) or complete response (CR) or stable disease (SD) lasting at least 24 weeks, duration of response (DOR), time to worsening of pain based on Brief Pain Inventory (BPI) worst pain scale, and overall survival (OS). The PFS primary endpoint, ORR and DCR were based on centralized, independent blinded review of the imaging data. Biochemical response with vandetanib as compared to placebo as measured by CTN and CEA was also assessed as secondary endpoints.

Patients were treated with vandetanib or placebo until they reached objective disease progression. Upon objective disease progression based on the investigator's assessment, patients were discontinued from blinded study treatment and given the option to receive open-label vandetanib. Twenty-eight of the 231 patients (12.1%) on vandetanib and 3 of the 99 (3.0%) on placebo discontinued treatment because of an adverse event. Fourteen of the 28 patients (50%) who stopped vandetanib for an adverse event discontinued without a dose reduction. Five out of 6 patients (83%) with moderate renal failure who were treated with vandetanib had a dose reduction to 200 mg for adverse reaction; 1 patient required a further reduction to 100 mg.

The result of the primary analysis of PFS showed a statistically significant improvement in PFS for patients randomised to vandetanib compared to placebo (Hazard Ratio (HR) = 0.46; 95% Confidence Interval (CI) = 0.31-0.69; p=0.0001).

The median PFS for patients randomised to vandetanib has not been reached; however, based on statistical modelling of data observed up to the 43rd percentile, the median PFS is predicted to be 30.5 months with 95% confidence interval 25.5 to 36.5 months. The median PFS for patients randomised to placebo was 19.3 months. At 12 months, the proportion of patients alive and progression-free was 192 (83%) for patients randomised to vandetanib and 63 (63%) for patients randomised to placebo. In the vandetanib arm, a total of 73 (32%) patients progressed: 64 (28%) by response evaluation criteria in solid tumours (RECIST) progression and 9 (4%) by death in the absence of progression. The remaining 158 patients (68%) were censored in the analysis of PFS. In the placebo arm, a total of 51 (51%) of patients had progressed: 46 (46%) by RECIST progression and 5 (5%) by death in the absence of progression. The remaining 49 patients (49%) were censored in the analysis of PFS.

Figure 1: Kaplan Meier plot of PFS
months            0         6            12         18          24          30          36  n-vandetanib      231       196          169        140         40          1           0  n-placebo         100       71           57         45          13          0           0 

____ vandetanib 300 mg, ------ placebo, y-axis=PFS, x-axis=time in months, n- vandetanib=number of patients at risk-vandetanib, n-placebo=number of patients at risk-placebo 
HR = 0.46, 95%CI (0.31-0.69), p = 0.0001
PFS                N               Median PFS                     HR       95% CI       p-value 
Vandetanib 300     73/231 (32%) Not reached (predicted 30.5 0.46           0.31, 0.69   0.0001 mg                              months)

Placebo            51/100 (51%) 19.3 months

Survival status and the median final overall survival (81.6 months in the vandetanib arm and 80.4 months in the placebo arm) were similar across both treatment arms. There was no statistically significant difference in final OS (HR 0.99, 95.002% CI 0.72, 1.38, p=0.9750).
Results should be interpreted with caution due to the high percentage of patients in the placebo arm switching to open-label vandetanib (79.0% [79/100] of patients).

Most (95% of the patients) had metastatic disease. Fourteen patients treated with vandetanib, and 3 with placebo had unresectable locally advanced disease only. There is limited clinical experience with vandetanib in patients with unresectable locally advanced disease and without metastasis.

Statistically significant advantages were seen for vandetanib for the secondary endpoints of response rate, disease control rate, and biochemical response.

Table 2 Summary of other efficacy findings in study 58
ORRa                  N            Response rate ORb                 95% CI         p-value 
Vandetanib 300 mg 104/231          45%
5.48             2.99, 10.79    < 0.0001
Placebo               13/100       13%

DCRa                  N            Response rate ORb                 95% CI         p-value 
Vandetanib 300 mg 200/231          87%
2.64             1.48, 4.69     0.001
Placebo               71/100       71%
CTN Response             N               Response rate ORb                      95% CI            p-value 
Vandetanib 300 mg 160/231                69%
72.9               26.2, 303.2       < 0.0001
Placebo                  3/100           3%

CEA Response             N               Response rate ORb                      95% CI            p-value 
Vandetanib 300 mg 119/231                52%
52.0               16.0, 320.3       < 0.0001
Placebo                  2/100           2%

OVERALL                  N               Median OS           HRc                                  p-value SURVIVAL                                                                        95% CI 
Vandetanib 116/231                 81.6 months         0.99
300 mg                                                                          0.72, 1.38        0.9750 
Placebo          52/100          80.4 months a
Overall response rate = complete + partial responses. Disease control rate = response rate + stable disease at 24 weeks. Intent-to-treat (ITT) analysis includes patients who received open-label vandetanib before progression according to the central read.
b
OR=Odds Ratio. A value > 1 favors vandetanib. The analysis was performed using a logistic regression model with treatment as the only factor.
c
HR= Hazard Ratio. A value <1 favors vandetanib. The analysis was performed using a log rank test with treatment as the only factor.
N=Number of events/number of randomised patients

A statistically significant advantage was seen for vandetanib for the secondary endpoint of time to worsening of pain (derived as a composite endpoint using the worst pain score from BPI and patient reported opioid analgesic use) (vandetanib 49%, placebo 57%, HR 0.61, 97.5%CI 0.43- 0.87, p< 0.006: 8 vs. 3 months). There were no statistically significant differences observed for the exploratory endpoint of diarrhoea (reported as stool frequency).
RET mutation status in Study 58
In Study 58, RET mutation testing was performed by using the polymerase chain reaction (PCR) based Amplification Refractory Mutation System (ARMS) assay for the M918T mutation, and direct sequencing of DNA for mutations in exons 10, 11, 13, 14, 15 and 16 (site of M918T mutation) on all sporadic patients where DNA was available (297/298).

However, RET status could not be tested in a large proportion of patients (mainly because of unavailable results for direct sequencing of DNA) and response rate was somewhat lower in the patients with unknown RET status compared with RET mutation positive status: 51.8% vs. 35.9 % respectively. In the blinded comparison of vandetanib vs. placebo, only 2 patients known to be RET negative at all 6 exons received vandetanib and none demonstrated responses.

A post-hoc subgroup analysis of RET negative status based on absence of M918T mutation of the pivotal study 58 was performed. A patient was considered to have a RET mutation if either an M918T mutation by the ARMS assay, or a RET mutation in any exons sequenced was present in the tumour. Actually 79 patients were identified by absence of an M918T mutation and no RET mutation identified at any of the other 6 exons tested but in 71 of such patients sequencing of the 6 exons was incomplete. M918T mutation is the most frequent mutation observed in patients with sporadic MTC; however it cannot be ruled out that some patients tested RET negative for M918T mutation might be positive for mutation on other exons.

Results according to RET status (positive, unknown and RET M918T mutation negative definition) are presented in Table 3.

Table 3: Summary of efficacy findings in a segment of patients according to RET mutation status
Patients with documented                Patients with no M918T
RET mutation (n=187)                    mutation and other mutations not tested or negative (n=79)*

Objective response rate                   52%                                     35% (vandetanib arm)
Efficacy endpoint                         0.45 (0.26, 0.78)                       0.57 (0.29, 1.13) PFS HR (95%) confidence interval
*
RET mutation status was obtained at the time of diagnosis in a majority of patients and could have changed since.

Pharmacokinetic Properties

5.2        Pharmacokinetic properties
Absorption
Following oral administration of vandetanib absorption is slow with peak plasma concentrations typically achieved at a median of 6 hours, range 4-10 hours, after dosing. Vandetanib accumulates approximately 8-fold on multiple dosing with steady state achieved from approximately 2 months.


Distribution
Vandetanib binds to human serum albumin and alpha-1-acid-glycoprotein with in vitro protein binding being approximately 90%. In ex vivo plasma samples from colorectal cancer patients at steady state exposure after 300 mg once daily, the mean percentage protein binding was 93.7% (range 92.2 to 95.7%). The pharmacokinetics of vandetanib at the 300 mg dose in MTC patients are characterised by a volume of distribution of approximately 7450 l.

Biotransformation
Following oral dosing of 14C- vandetanib, unchanged vandetanib and metabolites vandetanib N- oxide and N-desmethyl vandetanib were detected in plasma, urine and feces. A glucuronide conjugate was seen as a minor metabolite in excreta only. N-desmethyl-vandetanib is primarily produced by CYP3A4, and vandetanib-N-oxide by flavin-containing monooxygenase enzymes (FM01 and FMO3). N-desmethyl-vandetanib and vandetanib-N-oxide circulate at concentrations of approximately 11% and 1.4% of those of vandetanib.

Elimination
The pharmacokinetics of vandetanib at the 300 mg dose in MTC patients are characterised by a clearance of approximately 13.2 l/h. and plasma half-life of approximately 19 days. Within a 21 day collection period after a single dose of 14C-vandetanib, approximately 69% was recovered with 44% in faeces and 25% in urine. Excretion of the dose was slow and further excretion beyond 21 days would be expected based on the plasma half-life.

Special populations
Renal impairment
A single dose pharmacokinetic study in volunteers indicated that exposure to vandetanib is enhanced (up to 1.5, 1.6 and 2-fold) in mild, moderate and severe renal impaired subjects respectively compared to subjects with normal renal function (see sections 4.2, 4.4 and 4.5).

Hepatic impairment
A single dose pharmacokinetic study in volunteers indicated that hepatic impairment did not affect exposure to vandetanib. There is limited data in patients with hepatic impairment (serum bilirubin greater than 1.5 times upper limit of normal (see sections 4.2 and 4.4).

Food effect
Exposure to vandetanib is not affected by food.