Avastin

Name: Avastin

Warnings

Included as part of the PRECAUTIONS section.

Inform MD

Tell your doctor if you are allergic to any ingredient in Avastin.

Tell your doctor about all of your medical conditions, including if you:

  • have high blood pressure (hypertension)
  • have heart disease (history of heart attack, stroke, blood clot, congestive heart failure)
  • have kidney disease
  • have any infection or fever
  • are planning to have surgery
  • are pregnant or breastfeeding

Tell your doctor about all of the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

 

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

What should I avoid while receiving bevacizumab?

Avoid activities that may increase your risk of bleeding or injury. Use extra care to prevent bleeding while shaving or brushing your teeth.

Advice to Patients

  • Importance of understanding potential risks associated with therapy, including severe hypertension, wound healing complications, arterial thromboembolic events, and ovarian failure.1

  • Importance of routine monitoring of BP; advise patients to inform clinician if BP is elevated.1

  • Importance of immediately informing clinician if unusual bleeding, high fever, rigors, sudden worsening of neurologic function, persistent or severe abdominal pain, severe constipation, or vomiting occurs.1

  • Risk of fetal toxicity.1 Necessity of advising women to use an effective method of contraception during and for ≥6 months after last dose of bevacizumab.1 3

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Before Using Avastin

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of bevacizumab injection in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of bevacizumab injection in the elderly. However, elderly patients are more likely to have age-related heart or blood vessel problems, which may require caution in patients receiving bevacizumab injection.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

  • Angina (severe chest pain) or
  • Bleeding problems or
  • Blood clots or
  • Diabetes or
  • Esophagus problems or
  • Heart attack, history of or
  • Heart failure or
  • Hypertension (high blood pressure) or
  • Kidney problems or
  • Liver problems or
  • Protein in the urine or
  • Stomach or intestinal problems (eg, fistula, perforation) or
  • Stroke, history of or
  • Wound healing problems—Use with caution. May make these conditions worse.
  • Hemoptysis (coughing up blood), recent history of—Should not be used in patients with this condition.

Proper Use of Avastin

You will receive this medicine while you are in a hospital or cancer treatment center. A nurse or other trained health professional will give you this medicine. This medicine is given through a needle placed in one of your veins.

Bevacizumab is often given together with other cancer medicines. If you are using a combination of medicines, make sure that you take each one at the proper time and do not mix them. Ask your doctor to help you plan a way to remember to take your medicines at the right times.

What do I need to tell my doctor BEFORE I take Avastin?

  • If you have an allergy to bevacizumab or any other part of this medicine.
  • If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
  • If Avastin is being used to treat ovarian cancer and the cancer is also in certain parts of your bowels or you have bowel blockage.
  • If you are breast-feeding. Do not breast-feed while you take this medicine.

This is not a list of all drugs or health problems that interact with Avastin.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

How is this medicine (Avastin) best taken?

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

  • It is given as an infusion into a vein over a period of time.
  • Have blood work checked as you have been told by the doctor. Talk with the doctor.
  • Have your urine checked as you have been told by your doctor.
  • If you have upset stomach, throwing up, loose stools (diarrhea), or are not hungry, talk with your doctor. There may be ways to lower these side effects.

What do I do if I miss a dose?

  • Call your doctor to find out what to do.

What are some side effects that I need to call my doctor about right away?

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Signs of high blood pressure like very bad headache or dizziness, passing out, or change in eyesight.
  • Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight.
  • Signs of high blood sugar like confusion, feeling sleepy, more thirst, more hungry, passing urine more often, flushing, fast breathing, or breath that smells like fruit.
  • Signs of electrolyte problems like mood changes, confusion, muscle pain or weakness, a heartbeat that does not feel normal, seizures, not hungry, or very bad upset stomach or throwing up.
  • A fast heartbeat.
  • Shortness of breath, a big weight gain, or swelling in the arms or legs.
  • Very upset stomach or throwing up.
  • Very hard stools (constipation).
  • Very bad belly pain.
  • Skin wound that will not heal.
  • Mouth irritation.
  • Sweating a lot.
  • Redness or irritation of the palms of hands or soles of feet.
  • A very bad skin problem (necrotizing fasciitis) has happened in people taking Avastin. Sometimes, this has been deadly. Call your doctor right away if your skin is warm with red or purple areas of swelling that spread quickly. Call your doctor right away if you have ulcers, blisters, black spots on the skin, or any other skin changes that concern you.

What are some other side effects of Avastin?

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

  • Dizziness.
  • Headache.
  • Belly pain.
  • Back pain.
  • Muscle or joint pain.
  • Hard stools (constipation).
  • Loose stools (diarrhea).
  • Upset stomach or throwing up.
  • Feeling tired or weak.
  • Not hungry.
  • Hair loss.
  • Dry skin.
  • Change in nails.
  • Change in taste.
  • Weight loss.
  • Dry mouth.
  • Change in voice.
  • Runny nose.
  • Not able to sleep.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

Avastin Dosage and Administration

Administration

Do not administer as an intravenous push or bolus. Administer only as an intravenous (IV) infusion.

  • Do not initiate Avastin until at least 28 days following major surgery. Administer Avastin after the surgical incision has fully healed.
  • First infusion: Administer infusion over 90 minutes.
  • Subsequent infusions: Administer second infusion over 60 minutes if first infusion is tolerated; administer all subsequent infusions over 30 minutes if infusion over 60 minutes is tolerated.

Recommended Doses and Schedules

Patients should continue treatment until disease progression or unacceptable toxicity.

Metastatic Colorectal Cancer (mCRC)

The recommended doses are 5 mg/kg or 10 mg/kg every 2 weeks when used in combination with intravenous 5-FU-based chemotherapy.

  • Administer 5 mg/kg when used in combination with bolus-IFL.
  • Administer 10 mg/kg when used in combination with FOLFOX4.
  • Administer 5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks when used in combination with a fluoropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin based chemotherapy regimen in patients who have progressed on a first-line Avastin-containing regimen.

Non-Squamous Non-Small Cell Lung Cancer (NSCLC)

The recommended dose is 15 mg/kg every 3 weeks in combination with carboplatin and paclitaxel.

Glioblastoma

The recommended dose is 10 mg/kg every 2 weeks.

Metastatic Renal Cell Carcinoma (mRCC)

The recommended dose is 10 mg/kg every 2 weeks in combination with interferon alfa.

Cervical Cancer

The recommended dose of Avastin is 15 mg/kg every 3 weeks as an intravenous infusion administered in combination with one of the following chemotherapy regimens: paclitaxel and cisplatin, or paclitaxel and topotecan.

Platinum-Resistant Recurrent Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer

The recommended dose is 10mg/kg every 2 weeks in combination with one of the following intravenous chemotherapy regimens: paclitaxel, pegylated liposomal doxorubicin, or topotecan (weekly); or 15 mg/kg every 3 weeks in combination with topotecan (every 3 weeks).

Platinum-Sensitive Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

The recommended dose is 15 mg/kg every 3 weeks when administered in combination with carboplatin and paclitaxel for 6 cycles and up to 8 cycles, followed by continued use of Avastin 15 mg/kg every 3 weeks as a single agent until disease progression. Alternatively, 15 mg/kg every 3 weeks when administrated in combination with carboplatin and gemcitabine for 6 cycles and up to 10 cycles, followed by continued use of Avastin 15 mg/kg every 3 weeks as a single agent until disease progression.

Preparation for Administration

Use appropriate aseptic technique. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Withdraw necessary amount of Avastin and dilute in a total volume of 100 mL of 0.9% Sodium Chloride Injection, USP. Discard any unused portion left in a vial, as the product contains no preservatives.

DO NOT ADMINISTER OR MIX WITH DEXTROSE SOLUTION.

Dose Modifications

There are no recommended dose reductions.

Discontinue Avastin for:

  • Gastrointestinal perforations (gastrointestinal perforations, fistula formation in the gastrointestinal tract, intra-abdominal abscess), fistula formation involving an internal organ [See Boxed Warning, Warnings and Precautions (5.1, 5.2).]
  • Wound dehiscence and wound healing complications requiring medical intervention [See Warnings and Precautions (5.3).]
  • Serious hemorrhage (i.e., requiring medical intervention) [See Boxed Warning, Warnings and Precautions (5.4).]
  • Severe arterial thromboembolic events [See Warnings and Precautions (5.5).]
  • Life-threatening (Grade 4) venous thromboembolic events, including pulmonary embolism [See Warnings and Precautions (5.6).]
  • Hypertensive crisis or hypertensive encephalopathy [See Warnings and Precautions (5.7).]
  • Posterior Reversible Encephalopathy Syndrome (PRES) [See Warnings and Precautions (5.8).]
  • Nephrotic syndrome [See Warnings and Precautions (5.9).]

Temporarily suspend Avastin for:

  • At least 4 weeks prior to elective surgery [See Warnings and Precautions (5.3).]
  • Severe hypertension not controlled with medical management [See Warnings and Precautions (5.7).]
  • Moderate to severe proteinuria [See Warnings and Precautions (5.9).]
  • Severe infusion reactions [See Warnings and Precautions (5.10).]

Contraindications

None.

Drug Interactions

A drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38.

In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin. However, 3 of the 8 patients receiving Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0.

In Study 8, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone.

Clinical Studies

   Metastatic Colorectal Cancer (mCRC)

Study 1

In this double-blind, active-controlled study, patients were randomized (1:1:1) to IV bolus-IFL (irinotecan 125 mg/m2, 5-FU 500 mg/m2, and leucovorin (LV) 20 mg/m2 given once weekly for 4 weeks every 6 weeks) plus placebo (Arm 1), bolus-IFL plus Avastin (5 mg/kg every 2 weeks) (Arm 2), or 5-FU/LV plus Avastin (5 mg/kg every 2 weeks) (Arm 3). Enrollment in Arm 3 was discontinued, as pre-specified, when the toxicity of Avastin in combination with the bolus-IFL regimen was deemed acceptable. The main outcome measure was overall survival (OS).

Of the 813 patients randomized to Arms 1 and 2, the median age was 60, 40% were female, 79% were Caucasian, 57% had an ECOG performance status of 0, 21% had a rectal primary and 28% received prior adjuvant chemotherapy. In 56% of the patients, the dominant site of disease was extra-abdominal, while the liver was the dominant site in 38% of patients.

The addition of Avastin resulted in an improvement in survival across subgroups defined by age ( < 65 yrs, ≥ 65 yrs) and gender. Results are presented in Table 8 and Figure 1.

Table 8 Study 1 Efficacy Results
IFL + Placebo IFL + Avastin
5 mg/kg q 2 wks
* p < 0.001 by stratified log rank test. † p < 0.01 by χ2 test.
Number of Patients 411 402
Overall Survival*
  Median (months) 15.6 20.3
  Hazard ratio 0.66
Progression-free Survival*
  Median (months) 6.2 10.6
  Hazard ratio 0.54
Overall Response Rate†
  Rate (percent) 35% 45%
Duration of Response
  Median (months) 7.1 10.4
Figure 1
Duration of Survival in Study 1

Among the 110 patients enrolled in Arm 3, median OS was 18.3 months, median progression-free survival (PFS) was 8.8 months, objective response rate (ORR) was 39%, and median duration of response was 8.5 months.

Study 2

Study 2 was a randomized, open-label, active-controlled trial in patients who were previously treated with irinotecan ± 5-FU for initial therapy for metastatic disease or as adjuvant therapy. Patients were randomized (1:1:1) to IV FOLFOX4 (Day 1: oxaliplatin 85 mg/m2 and LV 200 mg/m2 concurrently, then 5-FU 400 mg/m2 bolus followed by 600 mg/m2 continuously; Day 2: LV 200 mg/m2, then 5-FU 400 mg/m2 bolus followed by 600 mg/m2 continuously; repeated every 2 weeks), FOLFOX4 plus Avastin (10 mg/kg every 2 weeks prior to FOLFOX4 on Day 1), or Avastin monotherapy(10 mg/kg every 2 weeks). The main outcome measure was OS.

The Avastin monotherapy arm was closed to accrual after enrollment of 244 of the planned 290 patients following a planned interim analysis by the data monitoring committee based on evidence of decreased survival compared to FOLFOX4 alone.

Of the 829 patients randomized to the three arms, the median age was 61 years, 40% were female, 87% were Caucasian, 49% had an ECOG performance status of 0, 26% received prior radiation therapy, and 80% received prior adjuvant chemotherapy, 99% received prior irinotecan, with or without 5-FU as therapy for metastatic disease, and 1% received prior irinotecan and 5-FU as adjuvant therapy.

The addition of Avastin to FOLFOX4 resulted in significantly longer survival as compared to FOLFOX4 alone (median OS 13.0 months vs. 10.8 months; hazard ratio 0.75 [95% CI 0.63, 0.89], p = 0.001 stratified log rank test) with clinical benefit seen in subgroups defined by age (< 65 yrs, ≥ 65 yrs) and gender. PFS and ORR based on investigator assessment were higher in the Avastin plus FOLFOX4 arm.

Study 3

The activity of Avastin in combination with bolus or infusional 5-FU/LV was evaluated in a single arm study enrolling 339 patients with mCRC with disease progression following both irinotecan- and oxaliplatin-containing chemotherapy regimens. Seventy-three percent of patients received concurrent bolus 5-FU/LV. One objective partial response was verified in the first 100 evaluable patients for an overall response rate of 1% (95% CI 0–5.5%).

Study 4

Study 4 was a prospective, randomized, open-label, multinational, controlled trial in patients with histologically confirmed metastatic colorectal cancer who had progressed on a first-line Avastin containing regimen. Patients were excluded if they progressed within 3 months of initiating first-line chemotherapy and if they received Avastin for less than 3 consecutive months in the first-line setting.

Patients were randomized (1:1) within 3 months after discontinuation of Avastin as first-line therapy to receive fluoropyrimidine/oxaliplatin- or fluoropyrimidine/irinotecan-based chemotherapy with or without Avastin administered at 5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks. The choice of second line therapy was contingent upon first-line chemotherapy treatment. Second-line treatment was administered until progressive disease or unacceptable toxicity. The main outcome measure was OS defined as the time from randomization until death from any cause.

Of the 820 patients randomized, the majority of patients were male (64%) and the median age was 63.0 years (range 21 to 84 years). At baseline, 52% of patients were ECOG performance status (PS) 1, 44% were ECOG PS 0, 58% received irinotecan-based therapy as first-line treatment, 55% progressed on first-line treatment within 9 months, and 77% received their last dose of Avastin as first-line treatment within 42 days of being randomized. Second-line chemotherapy regimens were generally balanced between each treatment arm.

The addition of Avastin to fluoropyrimidine-based chemotherapy resulted in a statistically significant prolongation of survival and PFS; there was no significant difference in overall response rate, a key secondary outcome measure. Results are presented in Table 9 and Figure 2.

Table 9 Study 4 Efficacy Results
Chemotherapy Avastin + Chemotherapy
* p = 0.0057 by unstratified log rank test. † p-value < 0.0001 by unstratified log rank test.
Number of Patients 411 409
Overall Survival*
  Median (months) 9.8 11.2
  Hazard ratio (95% CI) 0.81 (0.69, 0.94)
Progression-Free Survival†
  Median (months) 4.0 5.7
  Hazard ratio (95% CI) 0.68 (0.59, 0.78)
Figure 2
Duration of Survival in Study 4

Lack of Efficacy in Adjuvant Treatment of Colon Cancer

Lack of efficacy of Avastin as an adjunct to standard chemotherapy for the adjuvant treatment of colon cancer was determined in two randomized, open-label, multicenter clinical trials.

The first study conducted in 3451 patients with high risk stage II and III colon cancer, who had undergone surgery for colon cancer with curative intent, was a 3-arm study of Avastin administered at a dose equivalent to 2.5 mg/kg/week on either a 2-weekly schedule in combination with FOLFOX4, or on a 3-weekly schedule in combination with XELOX and FOLFOX4 alone. Patients were randomized as follows: 1151 patients to FOLFOX4 arm, 1155 to FOLFOX4 plus Avastin arm, and 1145 to XELOX plus Avastin arm. The median age was 58 years, 54% were male, 84% were Caucasian and 29% were ≥ age 65. Eighty-three percent had stage III disease.

The main efficacy outcome of the study was disease free survival (DFS) in patients with stage III colon cancer. Addition of Avastin to chemotherapy did not improve DFS. As compared to the control arm, the proportion of stage III patients with disease recurrence or with death due to disease progression were numerically higher in the FOLFOX4 plus Avastin and in the XELOX plus Avastin arms. The hazard ratios for DFS were 1.17 (95% CI: 0.98–1.39) for the FOLFOX4 plus Avastin versus FOLFOX4 and 1.07 (95% CI: 0.90–1.28) for the XELOX plus Avastin versus FOLFOX4. The hazard ratios for overall survival were 1.31 (95% CI=1.03, 1.67) and 1.27 (95% CI=1.00, 1.62) for the comparison of Avastin plus FOLFOX4 versus FOLFOX4 and Avastin plus XELOX versus FOLFOX4, respectively. Similar lack of efficacy for DFS were observed in the Avastin-containing arms compared to control in the high-risk stage II cohort.

In a second study, 2710 patients with stage II and III colon cancer who had undergone surgery with curative intent, were randomized to receive either Avastin administered at a dose equivalent to 2.5 mg/kg/week in combination with mFOLFOX6 (N=1354) or mFOLFOX6 alone (N=1356). The median age was 57 years, 50% were male and 87% Caucasian. Seventy-five percent had stage III disease. The main efficacy outcome was DFS among stage III patients. The hazard ratio for DFS was 0.92 (95% CI: 0.77, 1.10). Overall survival, an additional efficacy outcome, was not significantly improved with the addition of Avastin to mFOLFOX6 (HR=0.96, 95% CI=[0.75,1.22].

   Unresectable Non–Squamous Non–Small Cell Lung Cancer (NSCLC)

Study 5

The safety and efficacy of Avastin as first-line treatment of patients with locally advanced, metastatic, or recurrent non–squamous NSCLC was studied in a single, large, randomized, active-controlled, open-label, multicenter study.

Chemotherapy-naïve patients with locally advanced, metastatic or recurrent non–squamous NSCLC were randomized (1:1) to receive six 21-day cycles of paclitaxel 200 mg/m2 and carboplatin AUC = 6.0, by IV on day 1 (PC) or PC in combination with Avastin 15 mg/kg by IV on day 1 (PC plus Avastin). After completion or upon discontinuation of chemotherapy, patients in the PC plus Avastin arm continued to receive Avastin alone until disease progression or until unacceptable toxicity. Patients with predominant squamous histology (mixed cell type tumors only), central nervous system (CNS) metastasis, gross hemoptysis ( ≥ 1/2 tsp of red blood), unstable angina, or receiving therapeutic anticoagulation were excluded. The main outcome measure was duration of survival.

Of the 878 patients randomized, the median age was 63, 46% were female, 43% were ≥ age 65, and 28% had ≥ 5% weight loss at study entry. Eleven percent had recurrent disease and of the 89% with newly diagnosed NSCLC, 12% had Stage IIIB with malignant pleural effusion and 76% had Stage IV disease.

The results are presented in Figure 3. OS was statistically significantly higher among patients receiving PC plus Avastin compared with those receiving PC alone; median OS was 12.3 months vs. 10.3 months [hazard ratio 0.80 (repeated 95% CI 0.68, 0.94), final p- value 0.013, stratified log-rank test]. Based on investigator assessment which was not independently verified, patients were reported to have longer PFS with Avastin in combination with PC compared to PC alone.

Figure 3
Duration of Survival in Study 5

In an exploratory analyses across patient subgroups, the impact of Avastin on OS was less robust in the following: women [HR = 0.99 (95% CI: 0.79, 1.25)], age ≥ 65 years [HR = 0.91 (95% CI: 0.72, 1.14)] and patients with ≥ 5% weight loss at study entry [HR = 0.96 (95% CI: 0.73, 1.26)].

The safety and efficacy of Avastin in patients with locally advanced, metastatic or recurrent non-squamous NSCLC, who had not received prior chemotherapy was studied in another randomized, double-blind, placebo controlled, three-arm study of Avastin in combination with cisplatin and gemcitabine (CG) versus placebo and CG. A total of 1043 patients were randomized 1:1:1 to receive placebo plus CG, Avastin 7.5 mg/kg plus CG or Avastin 15.0 mg/kg plus CG. The median age was 58 years, 36% were female, and 29% were ≥ age 65. Eight percent had recurrent disease and 77% had Stage IV disease. Progression-free survival, the main efficacy outcome measure, was significantly higher in both Avastin containing arms compared to the placebo arm [HR 0.75 (95% CI 0.62, 0.91), p = 0.0026 for the Avastin 7.5 mg/kg plus CG arm and HR 0.82 (95% CI 0.68; 0.98), p = 0.0301 for the Avastin 15.0 mg/kg plus CG arm]. The addition of Avastin to CG chemotherapy failed to demonstrate an improvement in the duration of overall survival, an additional efficacy outcome measure, [HR 0.93 (95% CI 0.78; 1.11), p = 0.4203 for the Avastin 7.5 mg/kg plus CG arm and HR 1.03 (95% CI 0.86; 1.23), p = 0.7613 for the Avastin 15.0 mg/kg plus CG arm].

   Glioblastoma

Study 6

The efficacy and safety of Avastin was evaluated in Study 6, an open-label, multicenter, randomized, non-comparative study of patients with previously treated glioblastoma. Patients received Avastin (10 mg/kg IV) alone or Avastin plus irinotecan every 2 weeks until disease progression or until unacceptable toxicity. All patients received prior radiotherapy (completed at least 8 weeks prior to receiving Avastin) and temozolomide. Patients with active brain hemorrhage were excluded.

Of the 85 patients randomized to the Avastin arm, the median age was 54 years, 32% were female, 81% were in first relapse, Karnofsky performance status was 90–100 for 45% and 70–80 for 55%.

The efficacy of Avastin was demonstrated using response assessment based on both WHO radiographic criteria and by stable or decreasing corticosteroid use, which occurred in 25.9% (95% CI 17.0%, 36.1%) of the patients. Median duration of response was 4.2 months (95% CI 3.0, 5.7). Radiologic assessment was based on MRI imaging (using T1 and T2/FLAIR). MRI does not necessarily distinguish between tumor, edema, and radiation necrosis.

Study 7

Study 7, was a single-arm, single institution trial with 56 patients with glioblastoma. All patients had documented disease progression after receiving temozolomide and radiation therapy. Patients received Avastin 10 mg/kg IV every 2 weeks until disease progression or unacceptable toxicity.

The median age was 54, 54% were male, 98% Caucasian, and 68% had a Karnofsky Performance Status of 90–100.

The efficacy of Avastin was supported by an objective response rate of 19.6% (95% CI 10.9%, 31.3%) using the same response criteria as in Study 6. Median duration of response was 3.9 months (95% CI 2.4, 17.4).

   Metastatic Renal Cell Carcinoma (mRCC)

Study 8

Patients with treatment-naïve mRCC were evaluated in a multicenter, randomized, double-blind, international study comparing Avastin plus interferon alfa 2a (IFN-α2a) versus placebo plus IFN-α2a. A total of 649 patients who had undergone a nephrectomy were randomized (1:1) to receive either Avastin (10 mg/kg IV infusion every 2 weeks; n = 327) or placebo (IV every 2 weeks; n = 322) in combination with IFN-α2a (9 MIU subcutaneously three times weekly, for a maximum of 52 weeks). Patients were treated until disease progression or unacceptable toxicity. The main outcome measure of the study was investigator-assessed PFS. Secondary outcome measures were ORR and OS.

The median age was 60 years (range 18–82), 96% were white, and 70% were male. The study population was characterized by Motzer scores as follows: 28% favorable (0), 56% intermediate (1-2), 8% poor (3–5), and 7% missing.

The results are presented in Figure 4. PFS was statistically significantly prolonged among patients receiving Avastin plus IFN-α2a compared to those receiving IFN-α2a alone; median PFS was 10.2 months vs. 5.4 months [HR 0.60 (95% CI 0.49, 0.72), p-value < 0.0001, stratified log-rank test]. Among the 595 patients with measurable disease, ORR was also significantly higher (30% vs. 12%, p < 0.0001, stratified CMH test). There was no improvement in OS based on the final analysis conducted after 444 deaths, with a median OS of 23 months in the Avastin plus IFN-α2a arm and 21 months in the IFN-α2a plus placebo arm [HR 0.86, (95% CI 0.72, 1.04)].

Figure 4
Progression-Free Survival in Study 8

Persistent, Recurrent, or Metastatic Carcinoma of the Cervix

Study 9

Patients with persistent, recurrent, or metastatic carcinoma of the cervix were evaluated in a randomized, four-arm, multi-center trial comparing Avastin plus chemotherapy versus chemotherapy alone (Study 9; GOG-0240). A total of 452 patients were randomized (1:1:1:1) to receive paclitaxel and Cisplatin with or without Avastin, or paclitaxel and topotecan with or without Avastin.

The dosing regimens for Avastin, Paclitaxel, Cisplatin and Topotecan were as follows:

  • Day 1: Paclitaxel 135 mg/m2 IV over 24 hours, Day 2: cisplatin 50 mg/m2 IV plus Avastin; or Day 1: paclitaxel 175 mg/m2 IV over 3 hours, Day 2: cisplatin 50 mg/m2 IV plus Avastin ; or Day 1: paclitaxel 175 mg/m2 IV over 3 hours plus cisplatin 50 mg/m2 IV plus Avastin
  • Day 1: Paclitaxel 175 mg/m2 over 3 hours plus Avastin, Days 1-3: topotecan 0.75 mg/m2 over 30 minutes

Patients were treated until disease progression or unacceptable adverse events precluded further therapy. The main outcome measure of the study was overall survival (OS). Response rate (ORR) was a secondary outcome measure.

The median age was 48 years (range: 20–85). Of the 452 patients randomized at baseline, 78% of patients were Caucasian, 80% had received prior radiation, 74% had received prior chemotherapy concurrent with radiation, and 32% had a platinum-free interval of less than 6 months. Patients had a GOG Performance Status (PS) of 0 (58%) or 1 (42%). Demographic and disease characteristics were balanced across arms.

The study results for OS in patients who received chemotherapy plus Avastin as compared to chemotherapy alone are presented in Table 10 and Figure 5.

Figure 5
Study 9: Overall Survival for Chemotherapy vs. Chemotherapy plus Avastin
Table 10 Study 9 Efficacy Results: Chemotherapy versus Chemotherapy + Avastin
Chemotherapy
(n=225)
Chemotherapy + Avastin
(n=227)
Overall Survival
* Kaplan-Meier estimates. † log-rank test (stratified).
Median (months)* 12.9 16.8
Hazard ratio [95% CI] 0.74 [0.58;0.94]
(p-value† = 0.0132)

The overall response rate was also higher in patients who received chemotherapy plus Avastin [45% (95% CI: 39, 52)] than in patients who received chemotherapy alone [34% (95% CI: 28,40)].

Table 11 Study 9 Efficacy Results: Platinum Doublet versus Nonplatinum Doublet
Topotecan + Paclitaxel +/- Avastin
(n=223)
Cisplatin + Paclitaxel +/- Avastin
(n=229)
Overall Survival
* Kaplan-Meier estimates.
Median (months)* 13.3 15.5
Hazard ratio [95% CI] 1.15 [0.91, 1.46]
p-value=0.23

The hazard ratio for OS with Cisplatin +Paclitaxel + Avastin as compared to Cisplatin +Paclitaxel alone was 0.72 (95% CI: 0.51,1.02). The hazard ratio for OS with Topotecan +Paclitaxel +Avastin as compared to Topotecan +Paclitaxel alone was 0.76 (95% CI: 0.55, 1.06).

Platinum-Resistant Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Study 10

Avastin was evaluated in a multicenter, open-label, randomized, two-arm study (Study 10; AURELIA) comparing Avastin plus chemotherapy versus chemotherapy alone in patients with platinum-resistant, recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer that recurred within < 6 months from the most recent platinum-based therapy (N=361). Patients had received no more than 2 prior chemotherapy regimens. Patients received one of the following intravenous chemotherapies at the discretion of the investigator: paclitaxel (80mg/m2 on days 1, 8, 15 and 22 every 4 weeks; pegylated liposomal doxorubicin (PLD) 40mg/m2 on day 1 every 4 weeks; or topotecan 4mg/m2 on days 1, 8 and 15 every 4 weeks or 1.25mg/m2 on days 1-5 every 3 weeks). Patients were treated until disease progression, unacceptable toxicity, or withdrawal. Forty percent of patients on the chemotherapy alone arm received Avastin monotherapy upon progression.. The main outcome measure was investigator-assessed Progression-Free Survival (PFS). Secondary outcome measures were Objective Response Rate (ORR) and Overall Survival (OS).

The median age was 61 years (range 25–84 years) and 37% of patients were ≥ age 65. Seventy-nine percent had measurable disease at baseline, 87% had baseline CA-125 levels ≥ 2 × ULN and 31% had ascites at baseline. Seventy-three percent had a platinum-free interval (PFI) of 3–6 months and 27% had PFI of < 3 months. ECOG Performance Status was 0 for 59%, 1 for 34% and 2 for 7% of the patients.

The addition of Avastin to chemotherapy demonstrated a statistically significant improvement in investigator-assessed PFS, which was supported by a retrospective independent review analysis. Study results for the intent to treat (ITT) population are presented in Table 12 and Figure 6. Results for the separate chemotherapy cohorts are presented in Table 13.

Table 12 Efficacy Results in Study 10 ITT Population
Efficacy Parameter CT*
(N=182)
CT*+Avastin
(N=179)
* chemotherapy † per stratified Cox proportional hazards model ‡ per stratified logrank test
PFS per Investigator
  Median (95% CI), in months 3.4 (2.1, 3.8) 6.8 (5.6, 7.8)
  HR (95% CI)† 0.38 (0.30, 0.49)
  p-value ‡ <0.0001
Overall Survival
  Median (95% CI), in months 13.3 (11.9, 16.4) 16.6 (13.7, 19.0)
  HR (95% CI)† 0.89 (0.69, 1.14)
Objective Response Rate
Number of Patients with Measurable 144 142
Disease at Baseline Rate, % (95% CI) 13% (7%, 18%) 28% (21%, 36%)
Median of Response Duration
  in months 5.4 9.4
Figure 6
Investigator-Assessed Progression-Free Survival in Study 10 ITT Population

 

Table 13 Study 10 Efficacy Results in Chemotherapy Cohorts
Efficacy Parameter Paclitaxel Topotecan PLD
  CT*
(N=55)
CT*+Avastin
(N=60)
CT*
(N=63)
CT*+Avastin
(N=57)
CT*
(N=64)
CT*+Avastin
(N=62)
NE= Not Estimable
* chemotherapy † per stratified Cox proportional hazards model
PFS per Investigator      
  Median (months) 3.9 9.6 2.1 6.2 3.5 5.1
  (95% CI) (3.5, 5.5) (7.8, 11.5) (1.9, 2.3) (5.3, 7.6) (1.9, 3.9) (3.9, 6.3)
  HR (95% CI)† 0.47 (0.31, 0.72) 0.24 (0.15, 0.38) 0.47 (0.32, 0.71)
Overall Survival      
  Median (months) 13.2 22.4 13.3 13.8 14.1 13.7
  (95% CI) (8.2, 19.7) (16.7, 26.7) (10.4, 18.3) (11.0, 18.3) (9.9, 17.8) (11.0, 18.3)
  HR (95% CI)† 0.64 (0.41, 1.01) 1.12 (0.73, 1.73) 0.94 (0.63, 1.42)
Objective Response Rate      
Number of Patients with Measurable Disease at Baseline 43 45 50 46 51 51
  Rate, % (95% CI) 30
(17, 44)
53
(39, 68)
2
(0, 6)
17
(6, 28)
8
(0, 15)
16
(6, 26)
Median of Response Duration (months) 6.8 11.6 NE 5.2 4.6 8.0

Platinum-Sensitive Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Study 11

Study 11 was a randomized, double-blind, placebo-controlled trial (AVF4095g; OCEANS) studying Avastin plus chemotherapy versus chemotherapy alone in the treatment of patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who have not received prior chemotherapy in the recurrent setting or prior bevacizumab treatment (n=484). Patients were randomized (1:1) to receive carboplatin (AUC4, Day 1) and gemcitabine (1000 mg/m2 on Days 1 and 8) and concurrent placebo every 3 weeks for 6 to 10 cycles followed by placebo alone until disease progression or unacceptable toxicity (n=242) or carboplatin (AUC4, Day 1) and gemcitabine (1000 mg/m2 on Days 1 and 8) and concurrent Avastin (15 mg/kg Day 1) every 3 weeks for 6 to 10 cycles followed by Avastin (15 mg/kg every 3 weeks) as a single agent until disease progression or unacceptable toxicity (n=242).

The main efficacy outcome measures was investigator-assessed PFS. Secondary outcome measures were ORR and OS.

The median age was 61 years (range 28–87 years) and 37% of patients were ≥ age 65. All patients had measurable disease at baseline, 74% had baseline CA-125 levels greater than the ULN (35 U/mL). The platinum-free interval (PFI) was 6–12 months in 42 % of patients and > 12 months in 58% of patients. The ECOG performance status was 0 or 1 for 99.8% of patients.

A statistically signficant prolongation in PFS was demonstrated among Avastin plus chemotherapy-treated patients compared to those receiving placebo plus chemotherapy (Table 14 and Figure 7). Independent radiology review of PFS was consistent with investigator assessment (HR=0.45, 95% CI=[0.35, 0.58]). Overall survival was not significantly improved with the addition of Avastin to chemotherapy [HR=0.95, 95% CI (0.77, 1.17)].

Table 14 Investigator Assessed Efficacy Results from Study 11
Crb + Gem + Placebo
(n=242)
Crb + Gem + Bev
(n=242)
Progression Free Survival
Median PFS (months) 8.4 12.4
Hazard ratio
(95% CI)
0.46
(0.37, 0.58)
p –value < 0.0001
Objective Response Rate
% patients with objective response 57% 78%
p –value < 0.0001
Figure 7
Progression-Free Survival Based on Investigator Assessment for Study 11

Study 12

Study 12 was a randomized, controlled, open-label trial (GOG-0213) studying Avastin plus chemotherapy versus chemotherapy alone in the treatment of patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have not received more than one previous regimen of chemotherapy (n=673). Patients were randomized (1:1) to receive carboplatin (AUC5) and paclitaxel (175 mg/m2 IV over 3 hours) every 3 weeks for 6 to 8 cycles (n=336) or carboplatin (AUC5) and paclitaxel (175 mg/m2 IV over 3 hours) and concurrent Avastin (15 mg/kg) every 3 weeks for 6 to 8 cycles followed by Avastin (15 mg/kg every 3 weeks) as a single agent until disease progression or unacceptable toxicity (n=337).

The main efficacy outcome measure was OS. Other additional efficacy outcomes were investigator-assessed PFS, and ORR.

The median age was 60 years (range 23–85 years) and 33% of patients were ≥ age 65. Eighty-three percent had measurable disease at baseline, 74% had abnormal CA-125 levels at baseline. There were 69 (10.3%) patients who had received prior bevacizumab. Twenty-six percent had a platinum-free interval (PFI) of 6–12 months and 74% had a PFI of >12 months. GOG Performance Status was 0 or 1 for 99% of the patients.

Study results are presented in Table 15 and Figure 8.

Table 15 Efficacy Results from Study 12
Carboplatin + Paclitaxel
(n=336)
Carboplatin + Paclitaxel + Bevacizumab
(n=337)
* Hazard ratio was estimated from Cox proportional hazards models stratified by the duration of treatment free-interval prior to enrolling onto this study per IVRS (interactive voice response system) and secondary surgical debulking status. † Hazard ratio was estimated from Cox proportional hazards models stratified by the duration of platinum free-interval prior to enrolling onto this study per eCRF (electronic case report form) and secondary surgical debulking status.
Overall Survival (OS)
Median OS (months) 37.3 42.6
Hazard ratio (95% CI) (IVRS)* 0.84 (0.69, 1.01)
Hazard ratio (95% CI) (eCRF)† 0.82 (0.68, 0.996)
Progression-free Survival (PFS)
Median PFS (months) 10.4 13.8
Hazard ratio (95% CI) (IVRS)* 0.61 (0.51, 0.72)
Objective Response Rate
Number of patients with measurable disease at baseline 286 274
Rate, % 159 (56%) 213 (78%)
Figure 8
Overall Survival ITT Population of Study 12

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of bevacizumab injection in the pediatric population. Safety and efficacy have not been established.

What is Avastin?

Avastin (bevacizumab) is a cancer medicine that interferes with the growth and spread of cancer cells in the body.

Avastin is used to treat a certain type of brain tumor, and certain types of cancers of the kidney, lung, colon, rectum, cervix, ovary, or fallopian tube.

Avastin is also used to treat cancer of the membrane lining the internal organs in your abdomen. It is usually given as part of a combination of cancer medicines.

Important information

Avastin can make it easier for you to bleed. Contact your doctor or seek emergency medical attention if you have any bleeding that will not stop. You may also have bleeding on the inside of your body, such as in your stomach or intestines, or in your brain.

Call your doctor at once if you have: signs of bleeding in your digestive tract - feeling very weak or dizzy, severe stomach pain, black or bloody stools, or if you cough up blood or vomit that looks like coffee grounds; or signs of bleeding in the brain - sudden numbness or weakness (especially on one side of the body), sudden severe headache, or problems with vision or balance.

Avastin can also cause problems with wound healing, which could result in bleeding or infection. Do not use this medicine within 28 days before or after a planned surgery.

Avastin can cause a rare but serious neurologic disorder affecting the brain. Symptoms include headache, confusion, vision problems, feeling very weak or tired, fainting, and seizure (blackout or convulsions). These rare symptoms may occur within hours of your first dose of Avastin, or they may not appear for up to a year after your treatment started. Call your doctor at once if you have any of these side effects.

Some people receiving a Avastin injection have had a reaction to the infusion (when the medicine is injected into the vein). Tell your caregiver right away if you feel dizzy, nauseated, light-headed, sweaty, itchy, or have a fast heartbeat, chills, wheezing, or chest pain during the injection.

Avastin may cause a woman's ovaries to stop working correctly. Symptoms of ovarian failure include 3 or more missed menstrual periods in a row. This may affect your fertility (ability to have children). Talk to your doctor about your specific risks.

Before taking this medicine

You should not use Avastin if you are allergic to bevacizumab, or:

  • if you have slow healing of a skin wound or surgical incision;

  • if you have had surgery within the past 4 weeks (28 days);

  • if you have recently been coughing up blood; or

  • if you plan to have surgery within the next 4 weeks (28 days).

To make sure Avastin is safe for you, tell your doctor if you have:

  • heart disease, high blood pressure;

  • a history of heart attack, stroke, or blood clots;

  • a bleeding or blood-clotting disorder; or

  • a history of stomach or intestinal bleeding, or perforation (a hole or tear) in your esophagus, stomach, or intestines.

It is not known whether Avastin will harm an unborn baby. In animal studies, Bevacizumab caused birth defects. However, it is not known whether these effects would occur in humans. Use effective birth control to prevent pregnancy while you are using this medicine and for at least 6 months after your treatment ends.

Avastin may cause a woman's ovaries to stop working correctly. Symptoms of ovarian failure include 3 or more missed menstrual periods in a row. This may affect your fertility (ability to have children). Talk to your doctor about your specific risks.

It is not known whether bevacizumab passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are being treated with Avastin.

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