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Pharmacology: Mechanism of action: Bevacizumab is a recombinant humanized monoclonal antibody that selectively binds to and neutralizes the biologic activity of human vascular endothelial growth factor (VEGF). Bevacizumab contains human framework regions with antigen binding regions of a humanized murine antibody that binds to VEGF.
Bevacizumab inhibits the binding of VEGF to its receptors, Flt-1 and KDR, on the surface of endothelial cells. Neutralising the biological activity of VEGF reduces the vascularisation of tumour, thereby inhibiting tumour growth.
Pharmacodynamics: Clinical/Efficacy Studies of Bevaas: A prospective, randomized, multiple-dose, multi-center, comparative, parallel clinical study was conducted to evaluate the efficacy, safety, immunogenicity and pharmacokinetics of an intravenous infusion of Test Product-Bevacizumab and Reference Product-Bevacizumab administered in combination with standard chemotherapy in patients of metastatic colorectal cancer.
Patients were screened for study eligibility up to 21 days followed by 24 weeks of treatment period [8 cycles with XELOX regimen (each cycle 3 weeks) or 12 cycles with FOLFOX-4 regimen (each cycle 2 weeks)].
All eligible patients were randomly assigned to receive either Hetero-Bevacizumab or Reference-Bevacizumab in 2:1 ratio either with XELOX or FOLFOX-4 chemotherapy regimen. The choice of the concomitant chemotherapy regimen was based on investigator's discretion. No dose adjustments were allowed for Bevacizumab.
Dose adjustments for other concomitant chemotherapeutic agents were permitted as per the prescribing information of the respective drugs/as per the institutional standards/PIs discretion.
First fifteen patients randomly assigned to Hetero-Bevacizumab (ten patients) and Reference Bevacizumab (five patients) treatment arms were evaluated for infusion related reactions (IRRs) after first dose. Data and Safety Monitoring Board (DSMB) reviewed the safety data of 1st 15 patients before further recruitment.
Computerized Tomography (CT) or Magnetic Resonance Imaging (MRI) scan was performed at baseline (screening), at the end of cycle 2, cycle 4, cycle 6, and End of Treatment (EOT) visit for XELOX regimen and baseline (screening), at the end of cycle 3, cycle 6, cycle 9 and EOT visit for FOLFOX-4 regimen.
Immunogenicity assessed by testing serum for the presence of anti-bevacizumab antibodies in Hetero-Bevacizumab or Reference-Bevacizumab groups at screening, end of cycle 4 and EOT visit in XELOX regimen and at screening, end of cycle 6, and EOT visit in FOLFOX-4 regimen. Blood samples for Vascular Endothelial Growth Factor (VEGF) levels were collected at screening, end of cycle 1, cycle 6 and EOT visit. VEGF levels were considered as pharmacodynamic marker of Bevacizumab.
Pharmacokinetic, pharmacodynamic and immunogenicity parameters were tested at Syngene Bioanalytical Laboratory as per the applicable regulatory guidelines and standard operating procedures.
Safety was evaluated by monitoring of adverse events (AE), significant clinical signs symptoms and laboratory abnormalities throughout the study.
Efficacy analysis included patients who have completed at least three cycles of FOLFOX-4 regimen or two cycles of XELOX regimen and have at least one post baseline radiological assessment.
Statistical analysis was performed on the efficacy, safety, pharmacokinetic and pharmacodynamic data by Cliantha Research Limited.
Overall Response Rate (CR+PR) according to RECIST 1.1 guidelines: ITT Population: Overall Response Rate (ORR) was 35.53%, 46.97%, 49.02% and 46.94% in Hetero Bevacizumab at week 6, week 12, week 18 and week 24 respectively compared to 16.22%, 32.35%, 37.04% and 33.33% in Roche-Bevacizumab. Hetero-Bevacizumab was comparable to Roche-Bevacizumab at week 6, week 12, week 18 and week 24 with significantly higher response at week 6. (See Table 1.)
Click on icon to see table/diagram/imagePP Population: Overall Response Rate (ORR) was 42.31%, 50%, 50% and 47.73% in Hetero-Bevacizumab at week 6, week 12, week 18 and week 24 respectively compared to 19.23%, 32%, 33.33% and 33.33% in Roche-Bevacizumab. Hetero-Bevacizumab was comparable to Roche Bevacizumab at week 6, week 12, week 18 and week 24 with significantly higher response at week 6. (See Table 2.)
Click on icon to see table/diagram/imagePharmacokinetic study: This study was a double blind, randomized, balanced, pararell group Phase I study comparing the pharmacokinetics and safety of Bevacizumab.
The primary objective of this study was to evaluate the pharmacokinetic and safety profiles of Bevacizumab after administering the following products under investigation: A single IV dose containing 1 mg/kg of Local reference product; A single IV dose containing 1 mg/kg of Test Product 2.
The Test 2 Formulation, solution for intravenous infusion containing Bevacizumab 100 mg/4 ml showed a similar pharmacokinetic profile of Bevacizumab, in terms of the amount and speed of absorption with respect to the reference formulation. (See Tables 3, 4 and 5.)
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Click on icon to see table/diagram/imagePharmacodynamics Results - Vascular Endothelial Growth Factor (VEGF) Assessments: The VEGF levels were decreased from screening to week 2 (-393.32 pg/ml in Hetero Bevacizumab group and -214.01 pg/ml in Roche- Bevacizumab), week 12 (-330.19 pg/ml in Hetero-Bevacizumab and -179.99 pg/ml in Roche- Bevacizumab) and week 24 (-369.08 pg/ml in Hetero-Bevacizumab and -161.97 pg/ml in Roche- Bevacizumab). The reduction in VEGF levels from baseline to week 2, week 12 and week 24 were comparable between Hetero-Bevacizumab and Roche-Bevacizumab. (See Tables 6 and 7.)
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Click on icon to see table/diagram/imageConclusion: Overall Response Rate (ORR) was 35.53%, 46.97%, 49.02% and 46.94% in Hetero Bevacizumab at week 6, week 12, week 18 and week 24 respectively compared to 16.22%, 32.35%, 37.04% and 33.33% in Roche-Bevacizumab. Hetero-Bevacizumab was comparable to Roche-Bevacizumab at week 6, week 12, week 18 and week 24 with significantly higher response at week 6.
This data of ORR demonstrate that efficacy of Hetero-Bevacizumab is comparable with that of Roche-Bevacizumab in patients with Metastatic Colorectal cancer.
Both the treatment arms showed comparable safety profile in this study. No significant safety concerns were reported with the Hetero-Bevacizumab or Roche-Bevacizumab.
The decrease in VEGF levels were also comparable between the two groups. Improvement in quality of life data based on FACT-C questionnaire was also comparable between the two groups.
Pharmacokinetic results: The analysis of Bevacizumab bioavailable fraction of Test Product 2, solution for IV infusion containing Bevacizumab 100 mg/4 mL, in comparison with the Reference Product, solution for intravenous infusion containing Bevacizumab 100 mg/4 ml, shows that for: Ln Cmax: The point estimate μTest 2/μReference= 100.95% and the 90% CI (89.75 - 113.55) are within the 80 - 125% region.
Ln AUC0-t: The point estimate μTest 2/μReference= 94.87% and the 90% CI (84.91 - 105.99) are within the 80 - 125% region.
Ln AUC0-inf: The point estimate μTest 2/μReference= 95.02% and the 90% CI (84.80 - 106.49) are within the 80 - 125% region.
The Test 2 Formulation - Solution for intravenous containing Bevacizumab 100 mg/4 mL, showed a similar pharmacokinetic profile of Bevacizumab, in terms of the amount and speed of absorption with respect to the reference formulation.
Clinical/Efficacy Studies of Bevacizumab Innovator: Metastatic Colorectal Cancer (mCRC): The safety and efficacy of the recommended dose of Bevacizumab innovator (5 mg/kg of body weight every two weeks) in metastatic carcinoma of the colon or rectum were studied in three randomized, active controlled clinical trials in combination with fluoropyrimidine-based first-line chemotherapy.
Bevacizumab innovator was combined with two chemotherapy regimens: AVF2107g: A weekly schedule of irinotecan/bolus 5 fluorouracil/leucovorin (IFL regimen) for total of 4 weeks of each 6 week-cycle.
AVF0780g: In combination with bolus 5-fluorouracil/leucovorin (5-FU/LV) for a total of 6 weeks of each 8 week-cycle (Roswell Park regimen).
AVF2192g: In combination with bolus 5-fluoroacil/leucovorin (5-FU/LV) for a total of 6 weeks of each 8 week-cycle (Roswell Park regimen) in patients who were not optimal candidates for first-line irinotecan treatment.
Bevacizumab innovator in Combination with IFL Chemotherapy for First-Line Treatment of Metastatic Carcinoma of the Colon or Rectum (AVF2107g): This was a phase III randomized, double-blind, active-controlled clinical trial evaluating Bevacizumab innovator in combination with IFL as first-line treatment for metastatic carcinoma of the colon or rectum.
Eight hundred and thirteen patients were randomized to receive IFL + placebo (Arm 1) or IFL + Bevacizumab (5 mg/kg every 2 weeks, Arm 2). A third group of 110 patients received bolus 5-FU/LV+Bevacizumab innovator (Arm 3). Enrollment in Arm 3 was discontinued, as pre-specified, once safety of Bevacizumab innovator with the IFL regimen was established and considered acceptable. All treatments were continued until disease progression. The overall mean age was 59.4 years; 56.6% of patients had an ECOG performance status of 0.43% had a value of 1 and 0.4% had a value of 2. 15.5% had received prior radiotherapy and 28.4% prior chemotherapy. (See Table 8.)
Click on icon to see table/diagram/imageThe primary efficacy parameter of the trial was overall survival. The addition of Bevacizumab innovator to IFL resulted in statistically significant increases in overall survival, progression-free survival and overall response rate (see Table 9). The clinical benefit of Bevacizumab innovator, as measured by survival, was seen in all pre-specified patient subgroups, including those defined by age, sex, performance status, location of primary tumour, number of organs involved, and duration of metastatic disease.
The efficacy results of Bevacizumab innovator in combination with IFL-chemotherapy are displayed in Table 9. (See Table 9.)
Click on icon to see table/diagram/imageAmong the 110 patients randomized to Arm 3 (5-FU/FA+Bevacizumab innovator) prior to discontinuation of this arm, the median overall survival was 18.3 months, and the median progression free survival was 8.8 months.
Bevacizumab innovator in Combination with 5-FU/FA Chemotherapy for the First-Line Treatment of Metastatic Carcinoma of the Colon or Rectum in Patients Who Were Not Optimal Candidates for First-Line Irinotecan Treatment (AVF2192g): This was a phase II randomized, double-blind, active-controlled clinical trial evaluating the efficacy and safety of Bevacizumab innovator in combination with 5-FU/FA as first-line treatment for metastatic colorectal cancer in patients who were not optimal candidates for first-line irinotecan treatment.
Patients had to be either more susceptible to irinotecan toxicity (≥ 65 years, prior radiotherapy to pelvis or abdomen) or less likely to benefit from irinotecan treatment (PS ≥ 1, baseline albumin < 3.5 g/dL) in order to be eligible for enrollment. One hundred and five patients were randomized to 5-FU/FA + placebo arm and 104 patients to 5-FU/FA + Bevacizumab innovator (5 mg/kg every 2 weeks) arm.
All treatments were continued until disease progression. The overall mean age was 71 years; 28.2% of patients had a ECOG performance status of 0, 65.1% had a value of 1, and 6.7% had a value of 2.
The addition of Bevacizumab innovator 5 mg/kg every two weeks to 5-FU/FA resulted in higher objective response rates, significantly longer progression-free survival, and a trend in longer survival, compared to 5-FU/FA chemotherapy alone (see Table 9). These efficacy data were consistent with the results observed in studies AVF2107g and AVF0780g.
Bevacizumab innovator in Combination with 5-FU/FA Chemotherapy for the First-Line Treatment of Metastatic Carcinoma of the Colon or Rectum (AVF0780g): This was a phase II randomized, active-controlled, open-labelled clinical trial investigating Bevacizumab innovator in combination with 5-FU/FA as first-line treatment of metastatic colorectal cancer. The median age was 64 years. 19% of the patients had received prior chemotherapy and 14% prior radiotherapy. Seventy-one patients were randomized to receive bolus 5-FU/FA or 5-FU/FA + Bevacizumab innovator (5 mg/kg every 2 weeks). A third group of 33 patients received bolus 5-FU/FA + Bevacizumab innovator (10 mg/kg every 2 weeks). Patients were treated until disease progression. The primary endpoints of the trial were objective response rate and progression-free survival. The addition of Bevacizumab innovator 5 mg/kg every two weeks to 5-FU/FA resulted in higher objective response rates, longer progression-free survival, and a trend in longer survival, compared with 5-FU/FA chemotherapy alone (see Table 10). These efficacy data are consistent with the results from study AVF2107g.
The efficacy data from studies AVF0780g and AVF2192g investigating Bevacizumab innovator in combination with 5-FU/FA-chemotherapy are summarized in Table 10. (See Table 10.)
Click on icon to see table/diagram/imagePharmacokinetics: The pharmacokinetics of Bevacizumab innovator were characterised in patients with various types of solid tumours. The doses tested were 0.1-10 mg/kg weekly in phase I; 3-20 mg/kg every two weeks (q2w) or every three weeks (q3w) in phase II; 5 mg/kg (q2w) or 15 mg/kg q3w in phase III. In all clinical trials, Bevacizumab innovator was administered as an IV infusion.
As observed with other antibodies, the pharmacokinetics of Bevacizumab innovator are well described by a two-compartment model. Overall, in all clinical trials, Bevacizumab innovator disposition was characterized by a low clearance, a limited volume of the central compartment (Vc), and a long elimination half-life. This enables target therapeutic Bevacizumab innovator serum levels to be maintained with a range of administration schedules (such as one administration every 2 or 3 weeks).
In a population pharmacokinetic meta-analysis there was no significant difference in the pharmacokinetics of Bevacizumab innovator in relation to race when body weight is taken into account, or in relation to age (no correlation between Bevacizumab innovator clearance and patient age [the median age was 59 year with 5th and 95th percentiles of 37 and 76 year]).
Low albumin and high tumour burden are generally indicative of disease severity. Bevacizumab innovator clearance was approximately 30% faster in patients with low levels of serum albumin and 7% faster in subjects with higher tumour burden when compared with a typical patient with median values of albumin and tumour burden.
Absorption: No text.
Distribution: The typical value for central volume (Vc) was 2.73 L and 3.28 L for female and male subjects respectively, which is in the range that has been described for IgGs and other monoclonal antibodies. The typical value for peripheral volume (Vp) was 1.69 L and 2.35 L for female and male patients respectively, when Bevacizumab innovator is coadministered with anti-neoplastic agents.
After correcting for body weight, male subjects had a larger Vc (+ 20%) than females.
Metabolism: Assessment of Bevacizumab innovator metabolism in rabbits following a single IV dose of 125I-Bevacizumab innovator indicated that its metabolic profile was similar to that expected for a native IgG molecule which does not bind VEGF. The metabolism and elimination of Bevacizumab innovator is similar to endogenous IgG i.e. primarily via proteolytic catabolism throughout the body, including endothelial cells, and does not rely primarily on elimination through the kidneys and liver. Binding of the IgG to the FcRn receptor result in protection from cellular metabolism and the long terminal half-life.
Elimination: The pharmacokinetics of Bevacizumab innovator are linear at doses ranging from 1.5 to 10 mg/kg/wk. The value for clearance is, on average, equal to 0.188 and 0.220 L/day for female and male patients, respectively. After correcting for body weight, male patients had a higher Bevacizumab innovator clearance (+ 17%) than females. According to the two-compartmental model, the elimination half-life is 18 days for a typical female patient and 20 days for a typical male patient.
Pharmacokinetics in Special Populations: The population pharmacokinetics of Bevacizumab innovator were analysed to evaluate the effects of demographic characteristics. In adults, the results showed no significant difference in the pharmacokinetics of Bevacizumab innovator in relation to age.
Pediatric Population: The pharmacokinetics of Bevacizumab innovator were evaluated in 152 patients (7 months to 21 years; 5.9 to 125 kg) across 4 clinical studies using a population pharmacokinetic model. The pharmacokinetic results show that the clearance and the volume of distribution of Bevacizumab innovator were comparable between pediatric and adult patients when normalized by bodyweight. Age was not associated with the pharmacokinetics of Bevacizumab innovator when body weight was taken into account.
Renal impairment: No studies have been conducted to investigate the pharmacokinetics of Bevacizumab innovator in renally impaired patients since the kidneys are not a major organ for Bevacizumab innovator metabolism or excretion.
Hepatic impairment: No studies have been conducted to investigate the pharmacokinetics of Bevacizumab innovator in patients with hepatic impairment since the liver is not a major organ for Bevacizumab innovator metabolism or excretion.
Toxicology: Non clinical safety: Carcinogenicity: Studies have not been performed to evaluate the carcinogenic potential of Bevacizumab.
Mutagenicity: Studies have not been performed to evaluate the mutagenic potential of Bevacizumab.
Impairment of Fertility: No specific studies in animals have been performed to evaluate the effect of Bevacizumab on fertility. No adverse effect on male reproductive organs was observed in repeat dose toxicity studies in cynomolgus monkeys.
Inhibition of ovarian function was characterised by decreases in ovarian and/or uterine weight and the number of corpora lutea, a reduction in endometrial proliferation and an inhibition of follicular maturation in cynomolgus monkeys treated with Bevacizumab for 13 or 26 weeks. The doses associated with this effect were ≥ 4 times the human therapeutic dose or ≥ 2-fold above the expected human exposure based on average serum concentrations in female monkeys. In rabbits, administration of 50 mg/kg resulted in a Bevacizumab significant decrease in ovarian weight and number of corpora lutea. The results in both monkeys and rabbits were reversible upon cessation of treatment. The inhibition of angiogenesis following administration of Bevacizumab is likely to result in an adverse effect on female fertility.
Reproductive Toxicity: Bevacizumab has been shown to be embryotoxic and teratogenic when administered to rabbits. Observed effects included decreases in maternal and foetal body weights, an increased number of foetal resorptions and an increased incidence of specific gross and skeletal foetal alterations. Adverse foetal outcomes were observed at all tested doses of 10 - 100 mg/kg. Information on foetal malformations observed in the post marketing setting are provided in Use in Pregnancy & Lactation and Post Marketing under Adverse Reactions.
Other: Physeal Development: In studies of up to 26 weeks duration in cynomolgus monkeys, Bevacizumab was associated with physeal dysplasia. Physeal dysplasia was characterised primarily by thickened growth plate cartilage, subchondral bony plate formation and inhibition of vascular invasion of the growth plate. This effect occurred at doses ≥ 0.8 times the human therapeutic dose and exposure levels slightly below the expected human clinical exposure, based on average serum concentrations. It should be noted, however, that physeal dysplasia occurred only in actively growing animals with open growth plates.
Wound Healing: In rabbits, the effects of Bevacizumab on circular wound healing were studied. Wound re-epithelialisation was delayed in rabbits following five doses of Bevacizumab, ranging from 2 - 50 mg/kg, over a 2-week period. A trend toward a dose-dependent relationship was observed. The magnitude of effect on wound healing was similar to that observed with corticosteroid administration. Upon treatment cessation with either 2 or 10 mg/kg Bevacizumab, the wounds closed completely. The lower dose of 2 mg/kg was approximately equivalent to the proposed clinical dose. A more sensitive linear wound healing model was also studied in rabbits. Three doses of Bevacizumab ranging from 0.5 - 2 mg/kg dose-dependently and significantly decreased the tensile strength of the wounds, consistently with delayed wound healing. The low dose of 0.5 mg/kg was 5-fold below the proposed clinical dose.
As effects on wound healing were observed in rabbits at doses below the proposed clinical dose, the capacity for Bevacizumab to adversely impact wound healing in human should be considered. In cynomolgus monkeys, the effects of Bevacizumab on the healing of a linear incision were highly variable and no dose-response relationship was evident.
Renal Function: In normal cynomolgus monkeys, Bevacizumab had no measurable effect on renal function treated once or twice weekly for up to 26 weeks, and did not accumulate in the kidney of rabbits following two doses up to 100 mg/kg (approximately 80-folds the proposed clinical dose).
Investigative toxicity studies in rabbits, using models of renal dysfunction, showed that Bevacizumab did not exacerbate renal glomerular injury induced by bovine serum albumin or renal tubular damage induced by Cisplatin.
Albumin: In male cynomolgus monkeys, Bevacizumab administered at doses of 10 mg/kg twice weekly or 50 mg/kg once weekly for 26 weeks was associated with a statistically significant decrease in albumin and albumin to globulin ratio and increase in globulin. These effects were reversible upon cessation of exposure. As the parameters remained within the normal reference range of values for these endpoints, these changes were not considered as clinically significant.
Hypertension: At doses up to 50 mg/kg twice weekly in cynomolgus monkeys, Bevacizumab showed no effects on blood pressure.
Haemostasis: Non-clinical toxicology studies of up to 26 weeks duration in cynomolgus monkeys did not find changes in haematology or coagulation parameters including platelet counts, prothrombin and activated partial thromboplastin time. A model of haemostasis in rabbits, used to investigate the effect of Bevacizumab on thrombus formation, did not show alteration in the rate of clot formation or any other haematological parameters compared to treatment with Bevacizumab vehicle.
