First-line Treatment of Weekly Paclitaxel With Carboplatin and Bevacizumab in Ovarian Cancer

The goal of this clinical research study is to learn if therapy with bevacizumab, carboplatin, and weekly doses of paclitaxel is safe and can be tolerated in patients with newly diagnosed epithelial ovarian, primary peritoneal, or fallopian tube cancer. Researchers will also study if and how well this study therapy may help to control the disease.

Standard chemotherapy for newly diagnosed epithelial ovarian, primary peritoneal, or fallopian tube cancer is usually a combination of 2 chemotherapy drugs called carboplatin and paclitaxel. This treatment has been found to be effective, but the cancer often comes back, requiring additional treatment. For this study, researchers will give carboplatin, bevacizumab, and weekly paclitaxel to see if the treatment is effective and safe in treating the disease.

The Study Drugs:

Bevacizumab is designed to block the growth of blood vessels that supply nutrients necessary for tumor growth. This may prevent or slow down the growth of cancer cells.

Carboplatin is designed to interfere with the growth of cancer cells by stopping cell division.

Paclitaxel is designed to block the mechanisms of cell division in cancer cells, causing them to die.

Study Drug Administration:

If you choose to take part in this study, you will receive up to 6 "cycles" of treatment with the study drugs. Each cycle is 21 days (3 weeks) long.

On Day 1 of Cycle 1, you will receive paclitaxel and carboplatin by vein. Paclitaxel is given first over about 3 hours, followed by carboplatin over about 1 hour.

On Days 8 and 15 of Cycle 1, you will only receive paclitaxel by vein over about 3 hours.

On Day 1 of Cycles 2-6, you will receive paclitaxel, carboplatin, and bevacizumab by vein. Paclitaxel is given first over about 3 hours, followed by carboplatin over about 1 hour, and then bevacizumab over about 1 ½ hours.

If you tolerate your first dose of bevacizumab well, the dose of bevacizumab during Cycle 3 may be given over 60 minutes. If you tolerate the 60 minute dose well, the bevacizumab doses during Cycles 4, 5, and 6 may be given over 30 minutes.

On Days 8 and 15 of Cycles 2-6, you will only receive paclitaxel by vein over about 3 hours.

Before you begin each treatment, you will receive the drug dexamethasone by vein to help decrease the risk of study drug side effects. If the study doctor thinks it is needed, you may also receive other drugs (such as cimetidine and diphenhydramine) by vein to help prevent side effects such as nausea and allergic reaction.

Study Visits:

Before starting each cycle:

• Your medical history will be recorded, including a list of any drugs you may be taking.
• Your performance status will be recorded.
• You will have a physical exam, including measurement of weight and vital signs.
• A pelvic exam will be performed if the study doctor thinks it is necessary.
• You will be asked about any side effects you may be experiencing.
• Blood (about 3 teaspoons) will be drawn for routine tests.
• Blood (about 1 teaspoon) will be drawn to measure levels of CA125.
• If the study doctor thinks it is necessary, you will have a CT or MRI scan of the abdomen and pelvis.

Before Cycles 2, 4, and 6 only, urine will be collected for routine tests.

Length of Study:

You may remain on study for up to 6 cycles. You will be taken off study early if the disease gets worse or you experience any intolerable side effects.

End-of-Study Visit:

Within 4 weeks after your last dose of study drugs, you will have an end-of-study visit, at which the following tests and procedures will be performed:

• Your medical history will be recorded, including a list of any drugs you may be taking.
• You will have a physical exam, including measurement of weight, vital signs, and a pelvic exam.
• Your performance status will be recorded.
• Blood (about 4 teaspoons) will be drawn for routine tests and to measure levels of CA125.
• Urine will be collected for routine tests.
• You will have a CT scan or MRI scan of the abdomen and pelvis.
• If the study doctor thinks it is necessary, you will have a chest x-ray and/or an ECG.

Long-Term Follow-Up:

After your end-of-study visit, you will have long-term follow-up visits every 3 months for 2 years, at which the following tests and procedures will be performed:

• Your medical history will be recorded, including a list of any drugs you may be taking.
• You will have a physical exam, including measurement of weight, vital signs, and a pelvic exam.
• Your performance status will be recorded.
• Blood (about 4 teaspoons) will be drawn for routine tests and to measure levels of CA125.
• Urine will be collected for routine tests.
• You will have a CT scan or MRI scan of the abdomen and pelvis.
• If the study doctor thinks it is necessary, you will have a chest x-ray and/or an ECG.

If you are unable to come to M. D. Anderson for your long-term follow-up visits, researchers will call you on the phone every 3 months for 2 years to ask you questions about how you are doing. Your doctor will tell you if any standard tests and procedures need to be performed. The phone calls should last about 10 minutes each time.

This is an investigational study. Bevacizumab, carboplatin, and paclitaxel are each FDA approved and commercially available for the treatment of many types of cancer. The combination of carboplatin and paclitaxel is FDA approved and commercially available for the treatment of epithelial ovarian, primary peritoneal, or fallopian tube cancer. At this time, the addition of bevacizumab to the combination of carboplatin and paclitaxel is not FDA approved and is being used in research only.

Up to 30 patients will take part in this study. All will be enrolled at MD Anderson.

• Epithelial Ovarian Cancer
• Primary Peritoneal Cancer
• Fallopian Tube Cancer

• Drug: Carboplatin
  AUC 5 by vein Day 1 of Cycles 1-6.
  Other Name: Paraplatin
• Drug: Paclitaxel
  60 mg/m2 by vein (IV) over about 3 hours on Day 1 followed by Carboplatin, then on Days 8 and 15 of Cycle 1 Paclitaxel alone. On Day 1 of Cycles 2-6 Paclitaxel is followed by Carboplatin and Bevacizumab, then on Days 8 and 15 only Paclitaxel.
  Other Name: Taxol
• Drug: Bevacizumab
  15 mg/kg IV over about 1 ½ hours on Day 1 of Cycles 2-6.
  Other Name: Avastin

Inclusion Criteria:

1. Patients with a histologic diagnosis of epithelial ovarian cancer, peritoneal primary carcinoma or fallopian tube cancer; FIGO stage III and IV defined surgically at the completion of initial abdominal surgery and with appropriate tissue available for histologic evaluation. The minimum surgery required is an abdominal surgery providing tissue for histologic evaluation and establishing and documenting the primary site and stage, as well as a maximal effort at tumor debulking.
2. (continued from no. 1) Those patients with stage III cancer in which the largest maximal diameter of any residual tumor implant at the completion of this initial surgery is no greater than 1 cm will be defined as optimal; all others will be defined as suboptimal.
3. The histologic features of the tumor must be compatible with a primary Müllerian epithelial adenocarcinoma. Patients with the following histologic epithelial cell types are eligible: Serous adenocarcinoma, Endometrioid adenocarcinoma, Mucinous adenocarcinoma, Undifferentiated carcinoma, Clear cell adenocarcinoma, Mixed epithelial carcinoma, Transitional cell, Malignant Brenner's Tumor, Adenocarcinoma N.O.S. Patients may have co-existing fallopian tube carcinoma in-situ so long as the primary origin of invasive tumor is ovarian, peritoneal or fallopian tube.
4. Patients must be entered no later than 12 weeks after initial surgery performed for the combined purpose of diagnosis, staging and cytoreduction.
5. Patients with measurable and non-measurable disease are eligible. Patients may or may not have cancer-related symptoms.
6. Patients in this trial may receive ovarian estrogen +/- progestin replacement therapy as indicated at the lowest effective dose(s) for control of menopausal symptoms at any time, but not progestins for management of anorexia while on protocol directed therapy.
7. Patients with an ECOG Performance Status of 0, 1, or 2.
8. Patients must have normal organ and marrow function as defined below: leukocytes >3,000/mcL; absolute neutrophil count >1,500/mcL; platelets >100,000/mcL; total bilirubin <1.5 X institutional upper limits of normal; AST(SGOT)/ALT(SGPT) <2.5 X institutional upper limit of normal; Alkaline phosphatase (AP) <2.5 X institutional upper limit of normal; creatinine <1.5X institutional upper limit of normal OR creatinine clearance >50 mL/min/1.73 m2 for patients with creatinine levels above institutional normal
9. Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

1. Patients with borderline epithelial ovarian tumor (formerly "tumors of low malignant potential") or recurrent invasive epithelial ovarian, primary peritoneal or fallopian tube cancer treated with surgery only are not eligible. Patients with a prior diagnosis of a borderline tumor that was surgically resected and who subsequently develop an unrelated, new invasive epithelial ovarian, peritoneal primary or fallopian tube cancer are eligible, provided that they have not received prior chemotherapy for any ovarian tumor.
2. Patients who have received prior radiotherapy to any portion of the abdominal cavity or pelvis are excluded. Prior radiation for localized cancer of the breast, head and neck, or skin is permitted, provided that it was completed more than three years prior to registration, and the patient remains free of recurrent or metastatic disease.
3. Patients who have received prior chemotherapy for any abdominal or pelvic tumor including neo-adjuvant chemotherapy for their ovarian, primary peritoneal or fallopian tube cancer are excluded. Patients may have received prior adjuvant chemotherapy for localized breast cancer, provided that it was completed more than three years prior to registration, and that the patient remains free of recurrent or metastatic disease.
4. Patients who have received any targeted therapy (including but not limited to vaccines, antibodies, tyrosine kinase inhibitors) or hormonal therapy for management of their epithelial ovarian or peritoneal primary cancer.
5. Patients who are currently participating or planning to participate in an experimental drug study other than a Genentech-sponsored bevacizumab cancer study or who are receiving other investigational agents.
6. Patients with synchronous primary endometrial cancer, or a past history of primary endometrial cancer, are excluded, unless all of the following conditions are met: Stage not greater than IB; no more than superficial myometrial invasion, without vascular or lymphatic invasion; no poorly differentiated subtypes, including papillary serous, clear cell or other FIGO Grade 3 lesions.
7. With the exception of superficial basal cell and superficial squamous (skin) cell, carcinoma in situ of the cervix and other specific malignancies as noted above, patients with other invasive malignancies who had (or have) any evidence of the other cancer present within the last five years or whose previous cancer treatment contraindicates this protocol therapy are excluded.
8. Patients with acute hepatitis or active infection that requires parenteral antibiotics.
9. Patients with serious non-healing wound, ulcer, or untreated bone fracture. This includes a history of abdominal fistula or gastrointestinal perforation within 6 months prior to Day 1. Patients with granulating incisions healing by secondary intention with no evidence of fascial dehiscence or infection are eligible but require weekly wound examinations until closure.
10. Patients with active bleeding or pathologic conditions that carry high risk of bleeding, such as known bleeding disorder, coagulopathy (in the absence of therapeutic anticoagulation), or tumor involving major vessels.
11. History of hemoptysis (>/=1/2 teaspoon of bright red blood per episode) within 1 month prior to Day 1.
12. Patients with history or evidence upon physical examination of CNS disease, including primary brain tumor, seizures not controlled with standard medical therapy, any brain metastases, or history of cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA) or subarachnoid hemorrhage within six months of the first date of treatment on this study.
13. Patients with clinically significant cardiovascular disease. This includes: 1) Uncontrolled hypertension, defined as systolic > 140 mm Hg or diastolic > 90 mm Hg; 2) Myocardial infarction or unstable angina < 6 months prior to registration; 3) New York Heart Association (NYHA) Grade II or greater congestive heart failure; 4) Serious cardiac arrhythmia requiring medication. This does not include asymptomatic, atrial fibrillation with controlled ventricular rate
14. (continued from no. 13) CTCAE Grade 2 or greater peripheral vascular disease (at least brief (<24 hrs) episodes of ischemia managed non-surgically and without permanent deficit); Prior history of hypertensive crisis or hypertensive encephalopathy; Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Day 1
15. Patients with known hypersensitivity to Chinese hamster ovary cell products or other recombinant human or humanized antibodies
16. Patients with known hypersensitivity to any component of bevacizumab
17. Patients with clinically significant proteinuria at screening as demonstrated by urine protein:creatinine (UPCR) ratio >/= 1.0 at screening. The UPCR has been found to correlate directly with the amount of protein excreted in a 24 hour urine collection. Specifically, a UPCR of 1.0 is equivalent to 1.0 gram of protein in a 24 hour urine collection. Obtain at least 4 ml of a random urine sample in a sterile container (does not have to be a 24 hour urine). Send sample to lab with request for urine protein and creatinine levels [separate requests].
18. (continued from no. 17) The lab will measure protein concentration (mg/dL) and creatinine concentration (mg/dL). The UPCR is derived as follows: protein concentration (mg/dL)/creatinine (mg/dL).
19. Patients with or with anticipation of invasive procedures as defined below: Major surgical procedure within 28 days of initiating bevacizumab or major procedures anticipated during the course of the study. This includes, but is not limited to abdominal surgery (laparotomy or laparoscopy) prior to disease progression, such as colostomy or enterostomy reversal, interval or secondary cytoreductive surgery, or second look surgery.
20. (continued from no. 19) Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to the first date of bevacizumab therapy
21. Patients with ECOG Performance Grade of 3 or 4
22. Patients who are pregnant (positive pregnancy test) or nursing. Use of effective means of contraception (men and women) in subjects of child-bearing potential. To date, no fetal studies in animals or humans have been performed. The possibility of harm to a fetus is likely. Bevacizumab specifically inhibits VEGF, which is responsible for formation of new blood vessels during development, and antibodies can cross the placenta. Therefore, bevacizumab should not be administered to pregnant women.
23. (continued from no. 22) Subjects will be apprised of the large potential risk to a developing fetus. It is not known whether bevacizumab is excreted in human milk. Because many drugs are excreted in human milk, bevacizumab should not be administered to nursing women. Patients of childbearing potential must agree to use contraceptive measures during study therapy and for at least six months after completion of bevacizumab therapy.
24. Patients under the age of 18.
25. Patients who have received prior therapy with any anti-VEGF drug, including bevacizumab.
26. Patients with clinical symptoms or signs of gastrointestinal obstruction and who require parenteral hydration and/or nutrition.
27. Patients with medical history or conditions not otherwise previously specified which in the opinion of the investigator should exclude participation in this study.
28. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
29. Known HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with bevacizumab. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.
30. Inability to comply with study and/or follow-up procedures.