Versavo Mechanism of Action

Therapeutic/Pharmacologic Class: Anti-neoplastic agent. ATC code: L01XC07.
Pharmacology: Pharmacodynamics: Mechanism of Action: Versavo (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 is produced by recombinant DNA technology in a Chinese Hamster ovary mammalian cell expression system and is purified by a process that includes specific viral inactivation and removal steps consists of 214 amino acids and has a molecular weight of approximately 149,000 daltons.
Bevacizumab inhibits the binding of VEGF to its receptors, Flt-1 and KDR, on the surface of endothelial cells. Neutralizing the biologic activity of VEGF reduces the vascularization of tumors, thereby inhibiting tumor growth. Administration of bevacizumab or its parental murine antibody to xerotransplant models of cancer in nude mice resulted in extensive antitumor activity in human cancers, including colon, breast cancer, pancreas, and prostate. Metastatic disease progression was inhibited and microvascular permeability was reduced.
Clinical/Efficacy Studies: Metastatic colon and rectal cancer (rectum or anus): Data on the safety and effectiveness of bevacizumab at the recommended dose (5 mg/kg of body weight given every two weeks) were obtained from three studies in metastatic colon and rectal cancer (rectum or anus). A randomized clinical study in which the group received a therapeutic drug in a joint control group with the first parallel chemotherapy group containing fluoropyrimidine compounds. Bevacizumab was administered in combination with two chemotherapy treatment schemes: AVF2107g: Administer weekly with irinotecan and bolus 5-Fluorouracil/Leucovorin (IFL regimen) for a total of 4 weeks each of the 6-week treatment cycles.
AVF0780g: Administered jointly with bolus 5-Fluorouracil/Leucovorin (5-FU/LV) for a total of 6 weeks, each 8-week treatment cycle (Roswell Park regimen).
AVF2192g: Administer bolus 5-Fluorouracil/Leucovorin (5-FU/LV) for a total of 6 weeks of each 8-week treatment cycle (Roswell Park regimen) to patients unfit to receive the first parallel treatment with Irinotecan.
There are three additional bevacizumab studies conducted in patients with metastatic colon and rectal cancer (rectum or anus), using it as the first group of drugs (first line) (NO16966) or use it as a second group of drugs (second line) in patients who have never previously been treated with bevacizumab (E3200). It also was used as a second line drug in patients who have previously been treated with bevacizumab as the first group of drugs (ML18147). All those studies, the doses of bevacizumab were in combination with FOLFOX-4 (5FU/LV/oxaliplatin), XELOX (capecitabine/oxaliplatin), and fluoropyrimidine/irinotecan and fluoropyrimidine/oxaliplatin: NO16966: Parenteral administration of a dosage of bevacizumab 7.5 mg/kg of body weight in combinations with capecitabine orally and with oxaliplatin (XELOX) or 5 mg/kg of bevacizumab every two weeks in combination with leucovorin with bolus 5-fluorouracil, then 5-fluorouracil, in combination with intravascular Oxaliplatin (FOLFOX-4).
E3200: Administer bevacizumab 10 mg/kg of bodyweight every two weeks in combination with leucovorin and bolus 5-fluorouracil, then 5-fluorouracil discontinued intravascularly in combination with Oxaliplatin intravascular injection (FOLFOX-4) in patients who have not previously received bevacizumab.
ML18147: Administer bevacizumab at a dose of 5 mg/kg of body weight every two weeks or 7.5 mg/kg of bevacizumab every three weeks in combination with fluoropyrimidine/irinotecan or fluoropyrimidine/oxaliplatin in patients who have previously been treated with bevacizumab as the first group of drugs. Treatment regimens of irinotecan or oxaliplatin are alternated depending on the first dose, whether irinotecan or oxaliplatin has been used before.
AVF2107g: A randomized Phase III trial had a controlled group that received a treatment drug where both patients and clinicians were unaware of the type of medication. To understand the effects of bevacizumab plus IFL, the first parallel drug formulation is used in the treatment of Metastatic colon and rectal cancer (rectum or anus). A total of 813 metastatic stage patients were randomly assigned to IFL plus placebo (Group one) or IFL with bevacizumab (5 mg/kg given every 2 weeks, group two). A third group of 110 patients received bolus 5-FU/LV in combination with bevacizumab (third group). It later stopped bringing patients into the third group, as outlined in protocol, when it was found that bevacizumab and IFL drug treatment was acceptably safe.
The first measurement value indicating the effectiveness of the study was overall survival. Surviving with remission and the overall tumor response rate was statistically significantly higher (see Table 1 for details). The clinical benefits of bevacizumab, when evaluated using livelihoods, can be found in patients of all subgroups divided according to several criteria: age, gender, level of physical condition, location of the initial cancer, the number of organs involved, and the duration of the disease in the metastatic stage. (See Table 1.)

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AVF2192g: A randomized phase II trial with a controlled group that received a therapeutic drug, with both patients and treatment unknown, evaluated the effects of Bevacizumab in combination with 5-FU/Leucovorin as the first parallel drug formulation in the treatment of metastatic colon and rectal cancer (rectum or anus). Metastatic stage in patients unsuitable to be treated with Irinotecan is the first parallel drug. A total of 105 patients were randomly selected for 5-FU/LV treatment with placebo, and another 104 were treated with 5-FU/LV in combination with Bevacizumab (5 mg/kg given every two weeks) until the disease progressed.
Administering 5 mg/kg of bevacizumab every two weeks in addition to 5-FU/LV leads to a higher rate of nodule response. The duration of survival is significantly longer and tends to live longer compared to chemotherapy 5-FU/LV alone.
NO16966: It is a randomized Phase III clinical trial with no known type of treatment for both the doctor and the patient (for bevacizumab). To study the administration of 7.5 mg/kg of bevacizumab in combination with capecitabine by taking orally and oxaliplatin injected intravenously (XELOX) or 5 mg/kg bevacizumab in combination with leucovorin and bolus 5-fluorouracil, then 5-fluorouracil in combination with Oxaliplatin injected intravascularly (FOLFOX-4) every two weeks. This trial consisted in two phases: patients are randomly recruited (phase 1) for treatment in two different treatment groups (XELOX and FOLFOX-4) and in the second phase, patients are randomly recruited for treatment in four treatment groups (XELOX + Placebo; FOLFOX-4 + Placebo, XELOX + Bevacizumab, FOLFOX-4 + Bevacizumab). For the second phase, the admission will be an unknown type of treatment with bevacizumab therapy for both the doctor and the patient.
Approximately 350 patients were randomly recruited for treatment in four treatment groups during the second phase of the trial. (See Table 2.)

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The study's main effectiveness scorecard was the duration of survival by disease. In this study, there were two main objectives: to show that XELOX was not inferior to FOLFOX-4, and to show that the administration of bevacizumab in combination with XELOX or FOLFOX-4 chemotherapy was superior to chemotherapy alone, as follows: 1. Based on the overall comparison, the group that received XELOX was not inferior compared to the group receiving FOLFOX-4. As demonstrated by the duration of survival by disease and the overall survival of patients who met the research outlines.
2. Based on the overall comparison, the group receiving Bevacizumab had superior results compared to the group that received chemotherapy alone. This is demonstrated by the duration of survival among ITT patients (Table 3).
From the evaluation of the survival period for subsequent disease, based on the assessment by an independent review committee of the response to treatment (Independent Review Committee, IRC), patients treated with bevacizumab had clearly superior clinical benefits (The subgroup analysis is shown in Table 3). This is in line with the overall results of the analysis, which also clearly show statistical benefits. (See Table 3.)

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ECOG E3200: It is a randomized phase III study that knows the type of treatment and has a control group that received a therapeutic dose to study the administration of bevacizumab at a dose of 10 mg/kg in combination with Leucovorin and bolus 5-fluorouracil followed by 5-fluorouracil with Oxaliplatin injected intravenously (FOLFOX-4) every two weeks in patients with advanced colon and rectal cancer who have received prior treatment (second line). For the chemotherapy group, the same dose and schedule of FOLFOX-4 was obtained according to Table 2 for the NO16966 study.
The main indicator of this study was overall survival, which was based on the length of time from random selection to death by any cause. A total of 829 patients were randomly selected for the study (292 FOLFOX-4, 293 Bevacizumab + FOLFOX-4, and 244 received Bevacizumab alone). Administering bevacizumab in combination with FOLFOX-4 has a marked effect on longer viability. It was found that survival by peaceful disease and objective response rates improved markedly significantly (Table 4). (See Table 4.)

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There were no clear differences in terms of overall survival duration between the group of patients who received bevacizumab compared to the FOLFOX-4-treated group for pacific disease survival. And the objective response rates in the groups receiving bevacizumab alone were lower than those receiving FOLFOX-4.
ML18147: It is a randomized, controlled phase III study in which both doctors and patients know the type of medication. In the study, the patients received bevacizumab 5.0 mg/kg of body weight every two weeks or received bevacizumab 7.5 mg/kg of body weight every three weeks in combination with chemotherapy with fluoropyrimidine as the primary body, compared with chemotherapy with fluoropyrimidine as the only primary body. In patients with metastatic colon and rectal cancer (anus or rectum) who have previously been treated with bevacizumab as the first group of medications, the progression of the disease has already occurred.
Patients who have been tested for Metastatic colon and rectal cancer (anus or rectum) (mCRC) and with disease progression were randomized to 1:1 within 3 months after discontinuation of treatment with bevacizumab, which was used as the first group of drugs, to start giving fluoropyrimidine/oxaliplatin chemotherapy or fluoropyrimidine/irinotecan instead (The choice of chemotherapy depends on which chemotherapy drug was used in the first group (first line)). By giving or not giving in conjunction with bevacizumab the treatment continues until progression of the disease or unacceptable poisoning occurs. The first indicator of this study was overall survival, which was based on the length of time from random admission to death from any cause.
A total of 820 patients received bevacizumab in combination with chemotherapy containing fluoropyrimidine. There was a significant increase in overall survival period in patients with metastatic colon and rectal cancer, previously treated with Bevacizumab as the first drug group, leading to statistically significant disease progression. (ITT = 819) (Table 5). (See Table 5.)

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A statistically significant increase by progression-free survival was observed. For both objective response rates, treatment is considered minimal and statistically insignificant.
Complementary treatments in colon cancer: BO17920: In this trial there are three randomized phase III studies. Studies have been conducted on the effectiveness and safety of bevacizumab at a dose of 2.5 mg/kg per week, either with FOLFOX-4 every two weeks or with XELOX every three weeks, versus FOLFOX-4 alone as an adjuvant treatment (adjuvant chemotherapy) in 3,451 patients at high risk of developing stage II and stage III colorectal cancer. Recurrence and mortality due to disease progression were observed in the treatment group comprising both groups of bevacizumab compared to the control group. This study failed to achieve the primary purpose of prolonging survival without disease (DFS) by adding bevacizumab to the chemotherapy treatment regimen. It was observed from the study that with chemotherapy in patients with stage III colorectal cancer (n=2867), the DFS hazard ratio was 1.17 (95% CI 0.98-1.39) for the group that was given FOLFOX-4 plus bevacizumab, and 1.07 (95% Cl 090-1.28) for the group that was given XELOX in plus bevacizumab.
Locally recurrent or metastatic Breast Cancer: ECOG E2100: The E2100 study was a randomized clinical study with a controlled group that received a multi-institutional treatment revealing to evaluate the effects of bevacizumab administered in combination with paclitaxel in patients with metastatic or recurrent breast cancer who had never previously received chemotherapy treatment. Previous treatment with hormones is allowed for the treatment of metastatic cancer. On the other hand, supplementary treatment with taxane is allowed only if the treatment is completed at least 12 months prior to participation in the study.
Patients were randomly assigned to paclitaxel drug alone (90 mg/m² with intravenous therapy within 1 hour, 3 times a week or 4 weeks) or paclitaxel plus bevacizumab (10 mg/kg with intravenous therapy every 2 weeks). All patients will continue to be treated according to the study until the progression of the disease is made. If the patient needs to first discontinue chemotherapy, treatment with bevacizumab can be maintained alone until the progression of the disease is observed. The primary endpoint is survival by peaceful disease (PFS) by evaluating the researcher's physician. Primary endpoints are also assessed by an independent committee.
Of the 722 patients in the study, the majority (90%) had HER2-negative, with an unknown HER-2 receptor state (8%), and HER2-positive (2%). Patients who are HER2-positive were previously treated with trastuzumab. In addition, most patients (65%) were treated with chemotherapy, including 19% of patients who had previously received taxanes and 49% who had previously received anthracyclines. The patient attributes are similar in all treatment groups. The results of this study are shown in Table 6. (See Table 6.)

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BO17708: The BO17708 study was a randomized study in which both physician and patients did not know the type of medication. There was a control group that received a placebo. There were studies in many institutions (Phase 3) to evaluate the effectiveness and safety of bevacizumab in combination with docetaxel versus docetaxel with placebo. This is the first line of treatment for patients with metastatic breast cancer who are HER2-negative and who have never received metastatic chemotherapy before.
Patients are randomized in a ratio of 1:1:1 to undergo one of the treatments: Placebo with docetaxel 100 mg/m² every 3 weeks; Bevacizumab 7.5 mg/kg plus docetaxel 100 m g/m² every 3 weeks; Bevacizumab 15 mg/kg plus docetaxel 100 mg/m² every 3 weeks.
Docetaxel treatment is limited to a maximum of 9 treatment cycles. Meanwhile, the administration of bevacizumab or placebo will continue.
Until there is an advancing disease/death or poisoning of unacceptable levels the characteristics of the patient and disease are similar in all 3 treatment groups.
If there is evidence of progression of the disease. Patients from all three treatment groups were able to enter the post-study treatment phase, where patients were given bevacizumab in combination with other drugs used for second-order treatment (second line).
Primary endpoints are the duration of survival by progression-free survival (PFS), according to the physician's assessment, and the endpoints were evaluated in terms of effectiveness by comparing two different models: Bevacizumab 7.5 mg/kg plus docetaxel 100 mg/m² every 3 weeks vs. placebo plus docetaxel 100 mg/m² every 3 weeks.
Bevacizumab 15 mg/kg plus docetaxel 100 mg/m² every 3 weeks vs. placebo plus docetaxel 100 mg/m² every 3 weeks.
The results of this study are shown in Table 7 for the duration of progression-free survival, for the response rates that have counted towards the predetermined final analysis (pre-specified final analysis) and for improved exploratory analysis results (updated exploratory analysis). This was done at the same time because the final overall survival (OS) analysis included an additional 18 months of follow-up period, with the results of overall survival (OS) shown from the final analysis predetermined for overall survival, at which point approximately 45% of patients from all treatment groups had died.
Additional analysis is shown as follows: Bevacizumab 15 mg/kg every 3 weeks in combination with docetaxel provides better primary and secondary endpoint treatment effectiveness. Meanwhile, safety was similar compared to the group that received bevacizumab 7.5 mg/kg every 3 weeks in combination with docetaxel.
Bevacizumab 7.5 mg/kg every 3 weeks in combination with docetaxel provides a therapeutic effect in terms of duration of survival by peaceful disease, and the response rate is no higher than control group.
However, a dose of 15 mg/kg is recommended every 3 weeks for the treatment of patients with advanced breast cancer (see Dosage & Administration). (See Table 7.)

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AVF3694g Trial: The AVF3694g study is a phase III, multi-institutional clinical study. A randomized and placebo-controlled group was used to evaluate the efficacy and safety of bevacizumab in combination with chemotherapy versus chemotherapy with placebo as the first parallel drug for patients with recurred or metastatic breast cancer and a negative HER-2 gene test result.
The researchers selected chemotherapy drugs before the 2:1 random sampling. The patient to receive chemotherapy in combination with Bevacizumab or chemotherapy in combination with placebo, selective chemotherapy including taxane (protein-bound paclitaxel, docetaxel), anthracycline-based agents (doxorubicin/cyclophosphamide, epirubicin/cyclophosphamide, 5-fluorouracil/doxorubicin/cyclophosphamide, 5-fluorouracil/epirubicin/cyclophosphamide) or capecitabine is given every 3 weeks, while bevacizumab or placebo is given at a dose of 15 mg/kg every 3 weeks.
This study included a concealed treatment phase and an open-label treatment phase (optional) after post-advanced disease and survival follow-up stage. During the concealed treatment period, patients receive chemotherapy in combination with research drugs (bevacizumab or placebo) every 3 weeks until the progression of the disease, limited poisoning, or death.
According to evidence of the progression of the disease, the patients entering the open-label (optional) treatment phase may receive Bevacizumab in combination with a variety of second-line medications.
The percentage of patients in each group who received Taxane/Anth + Placebo: 43.0%; Taxane/Anth + Bevacizumab: 29.6%; Cap + Placebo: 51.9%; Cap + Bevacizumab: 34.7%.
Patients were analyzed in two separate groups (cohorts) depending on the treatment received as follows: Patients were given Taxane/Anthracycline + Bevacizumab/Placebo (Taxane/Anth + Bevacizumab/Placebo) as Cohort 1.
Patients were given Capecitabine + Bevacizumab/Placebo (Cap + Bevacizumab/Placebo) as Cohort 2.
Primary endpoints are the periods of progression-free survival according to the assessment of the investigators as follows: 1) Patients treated with taxane or anthracycline-based (Cohort 1); and 2) Patients treated with capecitabine (Cohort 2) Each of which is cohort independent of each other, as well as primary endpoint assessments, were conducted separately.
The results of the study analyses presented in the final research project on disease survival and response rates are included in Table 8 (Cohort 1) and Table 9 (Cohort 2). The surveyed analysis on overall survival included an additional 7 months of follow-up periods in the two Cohorts, and at this point found that approximately 45% of patients from all treatment groups had died. (See Tables 8 and 9.)

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There was an unstratified disease survival analysis (the researchers assessed) for both cohorts, excluding treatments not specified in the pre-progression research outline. The results of this analysis are very close to the survival outcomes by primary survival.
AVF3693g Trial: The AVF3693g random study is a phase III, multi-institutional clinical study. There was a placebo control group and both sides were covered. To evaluate the efficacy and safety of bevacizumab plus chemotherapy versus chemotherapy plus placebo in patients with metastatic breast cancer failed by chemotherapy. The first drug options for chemotherapy were taxane (paclitaxel, protein-bound paclitaxel, docetaxel), gemcitabine, capecitabine or vinorelbine, which is decided by the researcher's physician before being randomized 2:1 to receive chemotherapy in combination with bevacizumab or chemotherapy in combination with placebo. The dose of bevacizumab/placebo administered in this study was 15 mg/kg every three weeks (q3w) or 10 mg/kg every two weeks (q2w) with the chosen chemotherapy schedule: Taxane: Paclitaxel: 90 mg/m² to be administered intravenously weekly for a period of three weeks, then take a week off from treatment; Paclitaxel: 175 mg/m² to be administered intravenously every three weeks; Paclitaxel in particle form 260 mg/m² to be administered intravenously every three weeks; Docetaxel: 75 - 100 mg/m² to be administered intravenously every three weeks.
Gemcitabine: 1250 mg/m² to be administered intravenously on the first and eighth day of each treatment cycle every three weeks.
Capecitabine: 1000 mg/m² to be taken twice a day on the first to fourteenth day of each treatment cycle every three weeks.
Vinorelbine: 30 mg/m² to be administered intravenously every week.
The studies included a concealed treatment phase. The open treatment phase (optional) and survival follow-up phase during the hidden treatment, patients received chemotherapy and investigational drugs (bevacizumab or placebo) until disease progression, poisoning restricting treatment, termination at the investigator's discretion, or by cause of death.
The primary endpoint of this study was the duration of progression-free survival (PFS), which was evaluated by the investigating physician and was the sum of all chemotherapy groups. The results of the key endpoints from this study, summarized in Table 10, were analyzed for survival by unstratified progression-free survival, and the results of this analysis were like the survival outcomes by primary peaceful disease. The interim analysis (57% of events) summarized livelihoods in Table 10, which was done in conjunction with a primary survival analysis. (See Table 10.)

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This study did not have sufficient strength in each chemotherapy group analyzed. However, survival by peaceful disease in all chemotherapy groups is already considered a predetermined secondary endpoint, where the results of all chemotherapy groups are consistent with the results of primary studies except for the smallest group of vinorelbine chemotherapy (n = 76).
Advanced, metastatic, or recurrent Non-Small Cell Lung Cancer; NSCLC: Data on the safety and efficacy of bevacizumab used as the first drug to treat patients with non-small cell lung cancer without a history of predominant squamous cell. The following studies E4599 and BO17704 were conducted.
E4599 Trial: Study E4599 was an open, randomized, selective, and therapeutic control group to evaluate the use of Bevacizumab as the first drug to treat patients with advanced non-small cell lung cancer and without spread or recurrence of a prior history of predominant squamous cells.
Patients were randomly selected for platinum-based chemotherapy (paclitaxel 200 mg/m² and carboplatin AUC = 6.0 with both intravenous administration) (PC). Patients received the drug on day one of every three-week treatment for a maximum of 6 treatment cycles or were administered with PC plus bevacizumab at a dose of 15 mg/kg by intravenous infusion on day one of all three-week treatment cycles. After completing 6 cycles of chemotherapy with carboplatin-paclitaxel or discontinuing chemotherapy earlier, the patients will continue to receive bevacizumab alone every three weeks until the progression of the disease. A total of 878 patients were randomly selected for both treatment groups.
During the study 32.2% (136/422) patients received 7-12 bevacizumab doses, and 21.1% (89/422) of patients received 13 or more doses of Bevacizumab.
The primary endpoint of this study, the duration of viability, is shown in Table 11. (See Table 11.)

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BO17704 Trial: In this phase III randomized study, BO17704, there was no known treatment of any kind for either the treater or the patient. Patients had increased administration of cisplatin and gemcitabine plus bevacizumab compared to cisplatin and gemcitabine plus placebo in patients with advanced, metastatic, or recurrent non-squamous cell lung cancer who never received chemotherapy treatment.
The primary endpoint is the period when the patient lives with the disease but without getting worse (Progression free survival). There is also a secondary endpoint of the study included overall survival periods. Patients were randomly assigned to receive platinum-based chemotherapy, 80 mg/m² of cisplatin infusion on day 1 and 1,250 mg/m² of gemcitabine are administered intravenously on day 1 and 8 of every three-week treatment cycle, for a maximum of 6 treatment cycles (CG) in combination with placebo or CG with bevacizumab at a dose of 7.5 mg/kg or 15 mg/kg on day 1 of every three-week treatment cycle. In this treatment, patients could receive bevacizumab alone every three weeks until the progression of the disease or unacceptable levels of poisoning occur. The results of the study showed that 94% (277/296) of patients who met the study criteria received bevacizumab alone at the 7th treatment cycle with a large proportion of patients (approximately 62%) treated with a variety of cancer treatments not defined in the research outline, which could affect the overall analysis of survival time.
The results of this study were shown in Table 12. (See Table 12.)

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JO25567 Trial: The JO25567 study is a phase II, randomized, multicenter, open clinical study. This study was conducted in Japan to assess the effectiveness and safety of bevacizumab administered in combination with erlotinib in patients with non-squamous cell lung cancer with epidermal growth factor receptor (EGFR) gene mutations that have never been treated in stage IIB/IV or had a recurrence.
The primary endpoint is the period when the patient lives with the disease but without getting worse (Progression free survival). According to an assessment of the independent committee, the secondary endpoints included overall survival duration, response rate, disease control rate, response duration, safety, and health-related quality of life (Health Related Quality of Life; HRQoL) using the FACT-L questionnaire (Functional Assessment of Cancer Therapy for Patients with Lung Cancer).
Each patient will undergo an EGFR test prior to patient screening. 154 patients were randomly assigned to erlotinib in combination with Bevacizumab [erlotinib 150 mg oral once a day with 15 mg/kg of bevacizumab injected intravenously every 3 weeks] or erlotinib alone [erlotinib 150 mg oral once a day] until the spread of the disease or unacceptable toxicity occurs. In the absence of disease progression, discontinuation of any drug was studied among patients receiving erlotinib plus bevacizumab. However, the discontinuation of the other drug was not induced in this study.
The results of this study may be seen in Table 13. (See Table 13.)

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In the open JO25587 study, health-related quality of life (HRQoL) outcomes was evaluated by all scores of FACT-L and Trial outcome index (TOI) and symptoms of lung cancer assessed using FACT-L lung cancer symptom subscale (LCS). It was found that both groups of patients were able to maintain their average FACT-L scores without finding clinically significant differences. However, among patients receiving erlotinib plus bevacizumab there was a longer period of treatment, and it was found that intravenous injections of bevacizumab were different from those of patients who had taken erlotinib alone.
Advanced and/or metastatic Renal Cell Cancer: mRCC: BO17705 Trial: The BO17705 study is a phase III randomized study with no known type of treatment for both the treater and the multicenter patient category. The main goal of the study was to assess the effectiveness and safety of bevacizumab when administered in combination with interferon (IFN) alfa-2a (Roferon) compared to interferon (IFN) alfa-2a alone as treatment, being the firstorder treatment in patients with metastatic renal cell cancer. A total of 649 patients were randomly selected for the study (641 were treated).
mRCC malignat cells were evident, Karnovsky's performance scale (KPS) ≥ 70%. There was no spread of the cancer to the central nervous system, and organ function remained healthy, treated with IFN alfa-2a (Recommended dose 9 MIU three times a week) in combination with bevacizumab (10 mg/kg every two weeks) or placebo, which is given to patients until the progression of the disease. Patients were graded by country and by Motzer score by conducting a balanced segmentation of treatments based on predictive factors.
The results of this study are shown in Table 14. (See Table 14.)

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Exploratory analysis with the multiple-variance Cox regression model, which uses reverse selection, suggests that the underlying factors of disease progression are highly dependent on survival independent of treatment, factors like gender, number of white blood cells, platelets, decreased body weight during the 6 months prior to participating in the study, the number of areas where cancer is spreading, the total value of the longest diameter of the target lesion. Motzer values and improvements in these fundamentals resulted in a treatment hazard ratio value of 0.78 (confidence interval 95% [0.63; 0.96], p-value = 0.0219), showing a decrease in the risk of death of patients receiving bevacizumab + IFN alfa 2a compared to the group receiving IFN alfa-2a plus placebo.
There were 97 patients in the group who received IFN alfa-2a and 131 in the group who received bevacizumab. The IFN alfa-2a dose was reduced from 9 MIU to 6 or 3 MIU three times a week, as outlined in the research outline. The reduction of IFN alfa-2a dose had no effect on the effectiveness of bevacizumab in combination with IFN alfa-2a based on survival rates without progression of disease over time, as shown by the subgroup analysis.
131 patients in the group who received bevacizumab in combination with IFN alfa-2a, which reduced the dose and stabilized it at doses 6 or 3 MIU, showed no progression survival rates at stages 6, 12 and 18 months, namely 73, 52 and 21%, respectively. In comparison to 61, 43 and 17% of the total population who received bevacizumab in combination with IFN alfa-2a.
AVF2938 Trial: It is a phase II randomized study in which the type of treatment is unknown to both the treater and the patient. The main goal is to study whether bevacizumab should be given at a dose of 10 mg/kg every two weeks in combination with erlotinib 150 mg once a day in patients with metastatic renal cell carcinoma, clear cell type (clean cell). A total of 104 patients were randomly selected for treatment in this study, 53 of whom received 10 mg/kg of Bevacizumab every two weeks with a placebo, and 51 patients received 10 mg/kg of bevacizumab every two weeks in combination with erlotinib 150 mg. Primary endpoint analysis showed no difference between the group that received bevacizumab with placebo and the group that received bevacizumab with Erlotinib (Median PFS 8.5 vs. 9.9 months). However, 7 patients in each group responded to the objectives.
Severe brain tumors (Level 4 severity according to the World Health Organization WHO): AVF3708g Study: It is a study based on multicenter clinical studies with random selection and known treatment types without a comparison group. To assess the effectiveness and safety of bevacizumab in the treatment of patients with brain tumors, (AVF3708g trial), recurrent after receiving radiotherapy and temozolomide before (at least 8 weeks of radiotherapy have been completed before receiving bevacizumab). The patients were randomly selected (model 1:1) for treatment with bevacizumab (10 mg/kg intravenous administration every 2 weeks) or treatment with bevacizumab plus irinotecan (125 mg/m² or 340 mg/m² for patients who received enzyme-induced antiepileptic drugs with intravenous injections every 2 weeks). These treatments were performed until disease progression or poisoning occurs at unacceptable levels. The primary endpoints of the study were progression-free survival (PFS) and objective response rate (ORR) over a six-month period based on independent investigators' (IRF) assessments, among other assessments, including duration of survival by peaceful disease, response duration, and overall survival duration.
The results of the study are summarized in Table 15. (See Table 15.)

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According to the AVF3708g study, survival without progression of the disease at 6 months, as assessed by independent investigators, was significantly higher (p < 0.0001) compared to the two control groups: 42.6% in the bevacizumab group and 50.3% in the group receiving bevacizumab in combination with irinotecan (doctor's estimates were 43.6% in the group that received bevacizumab and 57.9% in the group who received bevacizumab in combination with irinotecan). Similarly, the measured response rate was significantly higher (p < 0.0001) compared to the two treatment groups: 28.2% in the group that received bevacizumab and 37.8% in the group who received bevacizumab in combination with irinotecan (doctor's estimates were 41.2% in the group that received bevacizumab and 51.2% in the group who received bevacizumab in combination with irinotecan).
Most patients who received early steroids, including those who responded and those who did not respond, were able to reduce the use of steroids during treatment with bevacizumab. Also, most patients when treated according to research studies, had a response or a progression-free survival phase (from week 24) and were able to maintain or improve the brain's memory system compared to the beginning. In addition, the most patients who remained in the study and had survived without progression of the disease as of week 24 were assessed for their physical condition according to the Karnovsky Model (KPS).
BO21990: Safety information and effectiveness of the use of bevacizumab with Temozolomide and Radiotherapy in patients with brain tumors who had recently been diagnosed, studied in two randomized phase III studies. The control group received a placebo. Patients who have just been diagnosed with a brain tumor in the above the tentorium (supranational glioblastoma) will be randomly assigned to receive the bevacizumab (10 mg/kg of body weight by intravenous administration every two weeks) or received a placebo in combination with radiotherapy (Total size 60 Gy divided into 2 Gy each time, 5 days a week) and temozolomide (75 mg/m² per day) for 6 weeks.
Then discontinue the treatment for 4 weeks and start temozolomide administration (dose 150 to 200 mg/m² a day on day 1-5 of each week, every 4 weeks) for a total of 6 cycles, together with bevacizumab (10 mg/kg of body weight by intravenous administration every two weeks) or in combination with a placebo.
After treatment with bevacizumab in combination with temozolomide, continue treatment with bevacizumab (15 mg/kg of body weight every three weeks) or placebo alone until the progression of the disease or unacceptable toxicity occurs.
The primary endpoint for treatment is survival without progression of the disease (Progression-free survival, PFS - Evaluated by the investigating doctor (Inv) and overall survival, OS). This study would achieve its objectives if one of these co-primary endpoints had significant statistical results. Secondary endpoints are survival without progression disease (PFS-Assessed by Independent Committee (IRF)) at 1 year and 2 years, and quality of life (Health-related quality of life, HRQoL).
The summary results of survival without progression of disease (PFS) and overall survival (OS) are shown in Table 16. (See Table 16.)

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The BO21990 study found that the group receiving bevacizumab reduced the risk of progression or death by up to 36% (p-value <0.0001) compared to the placebo group, according to the researcher's assessment. While survival to the end did not show statistical significance (HR = 0.88, p = 0.0987).
The main cause of death was disease progression. Deaths from causes other than progression were found to be of the same proportion in both patient groups. The group with placebo + radiotherapy + Temozolomide PI + RT/T) had 32 cases (7.1%) and the group with bevacizumab + radiotherapy + Temozolomide (Bv + RT/T) had 30 cases (6.5%). Most deaths from causes other than progression of these diseases was reported as deaths from adverse reactions. There were 20 cases (4.3%) in the group receiving Versavo, compared to 12 (2.7%) in the placebo group.
The group of patients who received bevacizumab was found to have better health quality (HRQoL) and overall clinical benefits.
Patients who have been treated with bevacizumab were able to maintain a healthy quality of life while living without progression (PFS) (the median PFS is 10.6 months). This was done with the help of the EORTC QLQ-C30 questionnaire to assess general health conditions and the EORTC QLQ-BN20 questionnaire to assess deterioration of communication and movement disorders compared (motor dysfunction) to the control group.
While living without the progression of the disease, patients can take care of themselves. Kanovsky's performance status is ≥ 70.
In addition, patients can reduce the use of steroids during the treatment with bevacizumab.
Epithelial Ovarian, Fallopian Tube and Primary Peritoneal Cancer: The first treatment of ovarian cancer: With these studies we try to analyze the safety and effectiveness of bevacizumab as a front-line treatment in patients with epithelial ovarian cancer, fallopian mucosal cancer, and primary peritoneal cancer. We take into consideration two Phase III studies (GOG-0218 and BO17707) compared the effects of bevacizumab plus carboplatin and paclitaxel compared with chemotherapy alone.
GOG-0218 Trial: The GOG-0218 study is a phase III, multicenter study and randomly selected without knowing the type of treatment for both the treater and the patient. In this study we have a controlled versus placebo divided in three groups of patients to evaluate the effects of bevacizumab administration in combination with approved chemotherapy (carboplatin and paclitaxel) for the treatment of patients with epithelial ovarian cancer, fallopian mucosal cancer, or stage III or IV primary peritoneal cancer that optimally or similarly reduced the nodule size.
A total of 1,873 patients were randomly selected in equal proportions in all 3 groups as follows: CPP group: placebo in combination with carboplatin (AUC6) and paclitaxel (175 mg/m²) for six treatment cycles followed by placebo alone, including a maximum treatment period of 15 months.
CPB 15 group: 5 treatment cycles of bevacizumab (15 mg/kg every 3 weeks) in combination with carboplatin (AUC6) and paclitaxel (175 mg/m²) for 6 treatment cycles (bevacizumab is started in the second treatment cycle of chemotherapy). This is followed by placebo alone, including a maximum treatment period of 15 months.
CPB 15+ group: 5 treatment cycles of bevacizumab (15 mg/kg every 3 weeks) in combination with carboplatin (AUC6) and paclitaxel (175 mg/m²) for 6 treatment cycles (bevacizumab is started in the second treatment cycle of chemotherapy). Then maintain the dose of bevacizumab 15 mg/kg every 3 weeks), including a maximum treatment period of 15 months.
The primary endpoint is disease-free survival (PFS), according to the researcher's assessment based on radiological exams. Primary endpoints are also assessed by an independent committee.
The results of the study were summarized as shown in Table 17. (See Table 17.)

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This study has achieved primary objectives, by the duration of disease-free survival (PFS), there is an improvement in values when comparing patients treated with chemotherapy alone (carboplatin and paclitaxel). Patients treated with 15 mg/kg bevacizumab every 3 weeks plus chemotherapy were first administered (frontline) followed by bevacizumab alone, showed that patients with clinical symptoms, including disease-free survival, statistically significantly improved. Although survival from disease-free improved in patients treated with bevacizumab in combination with chemotherapy as the first dose, taking bevacizumab later showed no significant result. Being that the improvements showed no significant differences in clinical and statistical symptoms compared to patients receiving chemotherapy alone.
BO17707 (ICON7) Study: BO17707 is a phase III study in two groups of patients. It is multicenter randomized, controlled, open selection compared the effects of carboplatin and paclitaxel-based with bevacizumab administration in patients with epithelial ovarian cancer, fallopian mucosal cancer, or primary peritoneal cancer after surgery and patients without a pre-invasive surgical plan. There are stages of the disease, according to FIGO (International Federation of Gynecology and Obstetrics), stage I and IIA (level 3 severity or tissue examination only), or stage IIB - IV (all levels of severity and tissue examination can find all types of cells).
A total of 1,528 patients were randomly selected in equal proportions in both groups as follows: CP group: treatment with carboplatin (AUC 6) and paclitaxel (175 mg/m²) for 6 cycles.
CPB7.5+ group: treatment with carboplatin (AUC 6) and paclitaxel (175 mg/m²) for 6 cycles plus bevacizumab (75 mg/kg every 3 weeks) for a maximum of 18 treatment cycles. The primary endpoint is progression-free survival (PFS), according to the investigator's physician.
The study results are summarized in Table 18. (See Table 18.)

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The study achieved its primary objective once the progression-free survival improved compared to patients in a treatment with chemotherapy (carboplatin and paclitaxel) alone. Patients receiving bevacizumab 75 mg/kg plus chemotherapy, followed by bevacizumab alone, over a maximum period of 18 treatment cycles, were found to have statistically significant improvements in progression-free survival.
Recurring bone marrow cancer: GOG-0213: GOG-0213 is a phase III study, randomized, controlled, to study the safety and effectiveness of Bevacizumab in patients with epithelial ovarian cancer, fallopian mucosal cancer, and recurrent primary peritoneal cancer who are sensitive to platinum chemotherapy and has not been treated with chemotherapy when recurrence occurs. There are no exclusion criteria for patients who have previously received anti-angiogenic drugs. This study was an evaluation of the administration of bevacizumab in combination with carboplatin and paclitaxel, followed by bevacizumab as a continuous monotherapy, compared to carboplatin in combination with paclitaxel alone.
A total of 673 patients were selected in equal proportions in both groups: CP group: treatment with carboplatin (AUC5) and paclitaxel (175 mg/m² with intravenous administration for 3 hours) every 3 weeks for 6 to 8 cycles.
CPB group: treatment with carboplatin (AUC5), paclitaxel (175 mg/m² with intravenous administration for 3 hours) and bevacizumab (15 mg/kg) every 3 weeks for 6 to 8 cycles. Followed by bevacizumab (15 mg/kg every 3 weeks) alone until the progression of the disease occurs or unacceptable toxicity occurs.
The primary endpoint is overall survival (OS), while the secondary endpoint is progression-free survival (PFS) and objective response rate (ORR). The results of the study are summarized in Table 19. (See Table 19.)

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Treatment with Bevacizumab (15 mg/kg every 3 weeks) in combination with chemotherapy (carboplatin and paclitaxel) for 6 to 8 treatment cycles. Followed by the administration of bevacizumab (15 mg/kg every 3 weeks) alone. Improved clinical symptoms and statistically significant duration of overall survival were observed with this treatment compared with therapy with carboplatin and paclitaxel alone.
AVF4095g: A randomized, codified, placebo-controlled phase III clinical study (AVF4095g) studied the safety and effectiveness of bevacizumab in treating patients with epithelial ovarian cancer, fallopian mucosal cancer, and recurrent primary peritoneal cancer that is sensitive to platinum chemotherapy, which has not been treated with chemotherapy at the time of recurrence, or has not previously been treated with bevacizumab. This study compared the effects of additional bevacizumab administration with carboplatin and gemcitabine and continued treatment of bevacizumab until the progression of the disease, versus the use of only carboplatin in combination with gemcitabine.
484 people who were able to measure lesions were randomized in equal proportions as follows: Carboplatin (AUC4 day 1), gemcitabine (1000 mg/m² day 1 and day 8) and placebo are administered every 3 weeks for 6 to 10 cycles. This is followed by placebo alone until the disease progresses or unacceptable toxicity occurs.
Carboplatin (AUC4 day 1), gemcitabine (1000 mg/m² day 1 and day 8) and bevacizumab (15 mg/kg day 1) are administered every 3 weeks for 6 to 10 cycles. This is followed by bevacizumab (15 mg/kg day 1) alone until the disease progresses or unacceptable toxicity occurs.
The primary endpoint of the study was progression-free survival based on the intervention physician's assessment, using RECIST criteria. Primary endpoints were also reviewed by an independent committee.
The results of the studies are summarized in Table 20. (See Table 20.)

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M022224 (AURELIA): The study M022224 evaluated the effectiveness and safety of bevacizumab administered in combination with chemotherapy for patients with recurrent ovarian cancer resistant to platinum chemotherapy. This study is a phase III, randomized, open-type, treatment-type study to evaluate the effects of bevacizumab administered in combination with chemotherapy (CTBV) compared with chemotherapy alone (CT).
A total of 361 patients were recruited into this study, either with chemotherapy alone (paclitaxel, topotecan or PLD) or in combination with bevacizumab: For patients receiving chemotherapy alone: Paclitaxel 80 mg/m² intravenous administration for 1 hour on days 1, 8, 15 and 22 every 4 weeks; Topotecan 4 mg/m² intravenous administration for 30 min on days 1, 8 and 15 every 4 weeks or it can be administrated 1.25mg/m² for more than 30 min on days 1-5 every 3 weeks; PLD 40 mg/m² intravenous administration in a rate of 1mg/min only on day 1 every 4 weeks after the first dose. After this the dose can be administered with intravenous drops for 1 hour.
For patients who received chemotherapy in combination with bevacizumab: Select one of the chemotherapy drugs in combination with bevacizumab 10 mg/kg of body weight with intravenous administration every 2 weeks (or bevacizumab 15 mg/m² of body weight every 3 weeks in combination with topotecan 1.25 mg/m² on day 1-5 every 3 weeks).
Patients in the study were patients with ovarian cancer who had progressed from platinum chemotherapy within 6 months.
The primary endpoint was progression-free survival, while the secondary endpoints were objective response rates and overall survival.
The results of the study are summarized in Table 21. (See Table 21.)

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Cervical Cancer: GOG-0240: It was evaluated in GOG-0240, a phase III, multicenter study in which patients were randomly selected into four groups, the efficacy and safety of Bevacizumab given in combination with chemotherapy (paclitaxel and cisplatin or paclitaxel and topotecan) in the treatment of patients with chronic cervical cancer.
A total of 452 patients were randomly selected for the following medications: Paclitaxel 135 mg/m² with intravenous infusion for more than 24 hours on day 1 plus 50 mg/m² of Cisplatin with intravenous infusion on day 2 every three weeks (q3w); or Paclitaxel 175 mg/m² with intravenous infusion for 3 hours on day 1 plus 50 mg/m² of Cisplatin with intravenous infusion on day 2 every three weeks; or Paclitaxel 175 mg/m² with intravenous infusion over 3 hours plus 50 mg/m² of Cisplatin with intravenous infusion on day 1 every three weeks.
Paclitaxel 135 mg/m² with intravenous infusion for more than 24 hours on day 1 plus 50 mg/m² of Cisplatin with intravenous infusion in combination with Bevacizumab 15mg/kg of body weight on day 2 every three weeks; or Paclitaxel 175 mg/m² with intravenous infusion for over 3 hours on day 1 plus 50 mg/m² of Cisplatin with intravenous infusion in combination with Bevacizumab 15mg/kg of body weight on day 2 every three weeks; or Paclitaxel 175 mg/m² with intravenous infusion over 3 hours plus 50 mg/m² of Cisplatin and Bevacizumab 15mg/kg with intravenous infusion on day 1 every three weeks.
Paclitaxel 175 mg/m² with intravenous infusion over 3 hours on day 1 and topotecan 0.75 mg/m² over 30 minutes on days 1-3 every three weeks.
Paclitaxel 175 mg/m² with intravenous infusion for more than 3 hours on day 1 and topotecan 0.75 mg/m² over than 30 minutes on day 1-3 in combination with bevacizumab 15 mg/kg of body weight with intravenous infusion on day 1 every three weeks.
Patients participating in the study were patients with squamous cell carcinoma, adenosquamous carcinoma or cervical adenocarcinoma, where the cancer was in a chronic condition, recurrent, or metastatic, and unresponsive to surgery and/or radiation therapy.
The primary endpoints were overall survival (OS), while secondary endpoints are progression-free survival (PFS) and objective response rate (ORR).
The results of the study summarized in Table 22. (See Table 22.)

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Immunogenicity: No robust assessment of anti-drug antibodies has been done in bevacizumab clinical trials.
Pharmacokinetics: The pharmacokinetics of bevacizumab were characterized in patients with various types of solid tumors. 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; studies; 5 mg/kg (q2w) or 15 mg/kg (q3w) in phase III. In all clinical trial, bevacizumab was administered as an IV infusion.
An observed with other antibodies, the pharmacokinetics of bevacizumab are well described by a two-compartment model. Overall, in all clinical studies, bevacizumab disposition was characterized by a low clearance, a limited volume of the central compartment (V_c), and a long elimination half-life. This enables target therapeutic bevacizumab 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 pharmacokinetics of bevacizumab in relation to race when body weight is taken into account, or in relation to age (no correlation between bevacizumab clearance and patient age [the median age was 59 years with 5^th and 95^th percentiles of 37 and 76 years]). Low albumin and high tumor burden when compared with a typical patient with median values of albumin and tumor burden.
Distribution: The typical value for central volume (V_c) 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 (V_p) was 1.69 L and 2.35 L for female and male patients respectively, when bevacizumab is coadministered with anti-neoplastic agents. After correcting for body weight, male subjects had a larger V_c (20%) than females.
Metabolism: Assessment of bevacizumab metabolism in rabbits following a single IV injection dose of ¹²⁵I-bevacizumab indicated that its metabolic profile was similar to that expected for a native IgG molecule which does not bind to VEGF. The metabolism and elimination of bevacizumab 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 are linear at doses ranging from 1.5 to 10 mg/kg per wk.
The values 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 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 were analyzed to evaluate the effects of demographic characteristics. In adults, the results showed no significant difference in the pharmacokinetics of bevacizumab in relation to age.
Pediatric Population: The pharmacokinetics of bevacizumab 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 were comparable between pediatric and adult patients when normalized by body-weight. Age was not associated with the pharmacokinetics of bevacizumab when bodyweight was taken into account.
Renal impairment: No studies have been conducted to investigate the pharmacokinetics of bevacizumab in renally impaired patients since the kidneys are not a major organ for bevacizumab metabolism or excretion.
Hepatic impairment: No studies have been conducted to investigate the pharmacokinetics of bevacizumab in patients with hepatic impairment since the liver is not a major organ for bevacizumab metabolism or excretion.
Toxicology: Non-clinical Safety: Carcinogenicity: Studies have not been performed to evaluate the carcinogenic potential of bevacizumab.
Genotoxicity: 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 effects 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 characterized by decreases in ovarian and/or uterine weight and the number of corpora lutea, a reduction in endometrial proliferation and an inhibition of the follicular maturation in Cynomolgus monkeys treated with bevacizumb for 13 or 26 weeks. The doses associated with this effects were ≥ 4 times the humans 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 of bevacizumab resulted in a 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 fetal body weight, an increase number of fetal resorptions and an increased incidence of specific gross and skeleton fetal alterations. Adverse Fetal outcomes were observed at all tested doses of 10-100 mg/kg. Information on fetal malformations observed in the post marketing experience are provided in Female and Male of Reproductive Potential under Use in Pregnancy & Lactation and Post marketing experience 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 characterized primarily by thickened growth plate cartilage, subchondral bony plate formation and inhibition of vascular invasion of the growth plate. These effects occur at doses ≥ 0.8 times the human therapeutic dose and exposure levels slightly below the expected human clinical exposure, based on average serum concentration. 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-epithelialization 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 does, the capacity for bevacizumab to adversely impact wound healing in human should be considered. In Cynomolgus monkeys, the effect of bevacizumab on 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.
Hemostasis: Non-clinical toxicology studies of up to 26 weeks duration in Cynomolgus monkeys did not find change in hematology or coagulation parameters including platelet counts, prothrombin and activated partial thromboplastin time. A model of hemostasis in rabbits, used to investigate the effect of bevacizumab on thrombus formation, did not show alteration in rate of clot formation or any other hematological parameters compared to treatment with bevacizumab vehicle.