VEGF Trap and Docetaxel in Treating Patients With Persistent or Recurrent Ovarian Epithelial Cancer, Primary Peritoneal Cancer, or Fallopian Tube Cancer

Study Overview
=================
Brief Summary
-----------------
This phase I/II trial is studying the side effects and best dose of VEGF Trap when given together with docetaxel and to see how well they work in treating patients with persistent or recurrent ovarian epithelial cancer, primary peritoneal cancer, or fallopian tube cancer. VEGF Trap may stop the growth of tumor cells by blocking blood flow to the tumor. Drugs used in chemotherapy, such as docetaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving VEGF Trap together with docetaxel may kill more tumor cells

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. Determine the safety and tolerability of VEGF Trap and docetaxel in patients with persistent or recurrent ovarian epithelial, primary peritoneal, or fallopian tube cancer. (Phase I [closed to accrual as of 3/14/2008]) II. Determine the maximum tolerated dose of VEGF Trap in these patients. (Phase I [closed to accrual as of 3/14/2008]) III. Determine the pharmacokinetics of VEGF Trap when administered alone and in combination with docetaxel in these patients. (Phase I [closed to accrual as of 3/14/2008]) IV. Determine the effects of VEGF Trap on tumor perfusion and metabolism in these patients. (Phase I [closed to accrual as of 3/14/2008]) V. Determine the effect of VEGF Trap and docetaxel on circulating endothelial precursors and circulating endothelial cells in these patients. (Phase I [closed to accrual as of 3/14/2008]) VI. Determine the frequency of clinical response (partial response and complete response) in patients treated with this regimen. (Phase II [open to accrual as of 5/9/2008]) VII. Determine the progression-free survival (PFS) and overall survival (OS) of patients treated with this regimen. (Phase II [open to accrual as of 5/9/2008]) SECONDARY OBJECTIVES: I. Determine the duration of PFS and OS of patients treated with this regimen. (Phase II) II. Determine the frequency and severity of adverse effects of this regimen in these patients. (Phase II) III. Determine the proportion of patients with PFS at 6 months. (Phase II) OUTLINE: This is a multicenter, phase I, dose-escalation study of VEGF Trap followed by a phase II study. PHASE I (closed to accrual as of 3/14/2008): Patients receive VEGF Trap IV over 1 hour on day 1 of course 1. Patients then receive VEGF Trap IV over 1 hour and docetaxel IV over 1 hour on day 1 in all subsequent courses. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of VEGF Trap until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 or 6 patients experience dose-limiting toxicity. PHASE II (opened to accrual as of 5/9/2008): Patients receive VEGF Trap at the MTD determined in phase I and docetaxel as in phase I. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients enrolled in phase I (closed to accrual as of 3/14/2008) undergo blood sample collection periodically for pharmacokinetic studies and surrogate marker studies. These patients also undergo dynamic contrast-enhanced MRI, fludeoxyglucose F 18 positron emission tomography, and CT scan at baseline and on day 1 of courses 1 and 2 to evaluate blood flow parameters and metabolic activity of tumors. Patients enrolled in phase I (closed to accrual as of 3/14/2008) and phase II will also undergo blood collection for Anti-VEGF trap antibody. After the completion of study treatment, patients are followed at 1 and 2 months and then periodically thereafter.

Official Title
-----------------
Phase I/II and Pharmacokinetic Study of Docetaxel Plus VEGF Trap (AVE0005, NSC# 724770) in Patients With Recurrent Ovarian, Primary Peritoneal, and Fallopian Tube Cancer

Conditions
-----------------
Fallopian Tube Cancer, Malignant Tumor of Peritoneum, Recurrent Ovarian Epithelial Cancer

Intervention / Treatment
-----------------
* Drug: docetaxel
* Biological: ziv-aflibercept
* Other: laboratory biomarker analysis
* Other: pharmacological study


Participation Criteria
=================
Eligibility Criteria
-----------------
Criteria: Histologically confirmed ovarian epithelial, primary peritoneal, or fallopian tube cancer: Persistent or recurrent disease Measurable disease, defined as >= 1 unidimensionally measurable lesion >= 20 mm by conventional techniques: Must have >= 1 target lesion to assess response; Tumors within a previously irradiated field are considered nontarget lesions Must have received 1 prior platinum-based chemotherapy regimen (for primary disease) containing carboplatin, cisplatin, or other organoplatinum compound: Initial treatment may have included any of the following: High-dose therapy; Consolidation therapy; Extended therapy administered after surgical or nonsurgical assessment AND Must have received 1 prior platinum-based chemotherapy regimen (for primary disease) containing carboplatin, cisplatin, or other organoplatinum compound: One additional cytotoxic regimen for recurrent or persistent disease allowed No history or evidence of CNS disease, including primary brain tumor or brain metastases Zubrod performance status 0-2 (0-1 for patients who received 2 prior regimens [taxane and/or platinum regimens are counted separately]) Absolute neutrophil count >= 1,500/mm^3 Platelet count >= 100,000/mm^3 Hemoglobin >= 9 g/dL Bilirubin normal aspartate aminotransferase / alanine aminotransferase (AST/ALT) < 2.5 times upper limit of normal (ULN) Creatinine < 1.5 times ULN OR creatinine clearance > 60 mL/min Prothrombin Time (PT)/international normalized ratio (INR) < 1.5 OR in-range INR 2-3 (if patient is on a stable dose of therapeutic warfarin or low molecular weight heparin) PTT < 1.2 times control Urine protein:creatinine ratio < 1 Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for at least 6 months after completion of study treatment No active infection requiring antibiotics No sensory and motor neuropathy >= grade 2 No history of allergic reactions attributed to compounds of similar chemical or biologic composition to VEGF Trap, Magnevist, or fludeoxyglucose F 18 No history of allergic reaction to paclitaxel or docetaxel or to products mixed in Cremophor EL or Tween 80 No active bleeding or pathologic condition that would carry a high risk of bleeding, including any of the following: Known bleeding disorder; Coagulopathy; Peptic ulcer disease; Diverticulitis; Tumor involving major vessels No active and/or untreated pulmonary embolism, deep vein thrombosis, or other thromboembolic event (i.e., any condition associated with aberrant clotting or migration of an induced clot) No history or evidence of other CNS disease, including any of the following: Seizures not controlled with standard medical therapy; Cerebrovascular accident; Transient ischemic attack; Subarachnoid hemorrhage within the past 6 months No clinically significant cardiovascular disease, including any of the following: Uncontrolled hypertension (i.e., systolic blood pressure [BP] > 150 mm Hg or diastolic BP > 100 mm Hg; systolic BP > 180 mm Hg and diastolic BP < 90 mm Hg OR diastolic BP > 90 mm Hg on >= 2 measurements within the past 3 months); Myocardial infarction; Coronary or peripheral artery bypass graft No clinically significant cardiovascular disease, including any of the following: New York Heart association class III or IV congestive heart failure; Serious cardiac arrhythmia requiring medication; Peripheral vascular disease >= grade 2; Unstable angina within the past 6 months; Clinically significant peripheral artery disease (e.g., claudication) within the past 6 months No known hypersensitivity to Chinese hamster ovary cell products or other recombinant human or humanized antibodies Able to undergo an MRI scan: No claustrophobia; No implanted devices or metallic foreign bodies not compatible with MRI (e.g., ferromagnetic implants or pacemakers); No known history of allergic reaction to gadolinium contrast agents No other invasive malignancy within the past 5 years except nonmelanoma skin cancer No significant traumatic injury within the past 28 days Recovered from prior therapy to NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 grade =< 1: Alopecia allowed No prior VEGF Trap No prior cancer treatment that would preclude study treatment Prior paclitaxel allowed Prior docetaxel for primary or recurrent disease allowed provided the following criteria are met: No disease progression during therapy; No disease relapse within 3 months of completing therapy; No persistent disease at the completion of primary therapy More than 7 days since prior placement of a vascular access device or core biopsy At least 1 week since prior hormonal therapy for the malignant tumor At least 4 weeks since other prior therapy, including immunologic agents (6 weeks for nitrosoureas or mitomycin C) More than 28 days since prior major surgery, open biopsy, dental extraction, or other dental surgery/procedure resulting in an open wound No concurrent major surgery No concurrent combination antiretroviral therapy for HIV-positive patients No other concurrent anticancer therapy No other concurrent investigational agents No concurrent hematopoietic growth factors during course 1 of phase I Concurrent hormone replacement therapy allowed White blood count (WBC) >= 3,000/mm^3

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (VEGF Trap, Docetaxel)<br>Phase I (closed to accrual as of 3/14/2008): Patients receive VEGF Trap IV over 1 hour on day 1 of course 1. Patients then receive VEGF Trap IV over 1 hour and docetaxel IV over 1 hour on day 1 in all subsequent courses. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of VEGF Trap until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 or 6 patients experience dose-limiting toxicity. | Drug: docetaxel<br>* 25 mg/m^2 given intravenously (IV) over 1 hour (+/- 10 minutes) following VEGF Trap every 3 weeks starting cycle 1 (21 day cycles)<br>* Other names: TXT;Biological: ziv-aflibercept<br>* Starting dose 2 mg/kg given IV Cycle 0. Phase I Group: Every 3 weeks beginning with Cycle 0 (Completed 03/14/2008); Phase II Group: Every 3 weeks starting cycle 1 (Opened 05/09/2008).<br>* Other names: Zaltrap;Other: laboratory biomarker analysis<br>* Correlative studies<br>Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;|
| Experimental: Phase II Treatment (VEGF Trap, Docetaxel)<br>Phase II (opened to accrual as of 5/9/2008): Patients receive VEGF Trap at the MTD determined in phase I and docetaxel as in phase I. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Drug: docetaxel<br>* 25 mg/m^2 given intravenously (IV) over 1 hour (+/- 10 minutes) following VEGF Trap every 3 weeks starting cycle 1 (21 day cycles)<br>* Other names: TXT;Biological: ziv-aflibercept<br>* Starting dose 2 mg/kg given IV Cycle 0. Phase I Group: Every 3 weeks beginning with Cycle 0 (Completed 03/14/2008); Phase II Group: Every 3 weeks starting cycle 1 (Opened 05/09/2008).<br>* Other names: Zaltrap;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose of VEGF Trap (Phase I) | Escalating dose levels of VEGF Trap were administered intravenously over three dose levels (2, 4, or 6 mg/kg; one dose every 21 days) to identify the maximum tolerated dose (MTD). The MTD is defined as the highest dose level below which 2 or more patients encounter a dose limiting toxicity (DLT), graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. MTD established on absence of observed DLT(s) in either cycle 0 (single agent) or cycle 1 (combination therapy) of any given dose level. | 21 day cycle, up to 3 cycles | 
| Number of Participants With Clinical Response (Partial Response or Complete Response) According to the Response Evaluation Criteria in Solid Tumors (RECIST) | Frequency of clinical response (partial response or complete response) according to the Response Evaluation Criteria in Solid Tumors (RECIST). Complete Response (CR): Disappearance all target lesions; Partial Response (PR): >/= 30% decrease in sum of longest diameter (LD) of target lesions, reference baseline sum LD; Progressive Disease (PD): >/= 20% increase in sum of LD of target lesions, reference smallest sum LD recorded since treatment started or appearance of 1+ new lesions; Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, reference smallest sum LD since treatment started. | Up to 6 months | 
| Median Overall Survival (OS) (Phase II) | Overall survival was defined from the date of study entry until death or date of last contact. Median survival time points calculated in the method of Kaplan-Meier. Standard RECIST criteria followed to evaluate response and progression, and all documented responses required confirmation by imaging, examination, or both, no sooner than 4 weeks after the initial documentation of response. In the absence of new symptoms, response assessment consistently done after two additional cycles of therapy. | Time from start of treatment to time of progression, assessed up to 6 years. | 
| Overall Objective Response Rate According to RECIST (Phase II) | The percentage of participants in the Phase II arm with an objective response defined as a measurable response according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0. Standard RECIST criteria were followed to evaluate response and progression. All documented responses were required to undergo confirmation by imaging, examination, or both, no sooner than 4 weeks after the initial documentation of response. In the absence of new symptoms, this response assessment was consistently done after two additional cycles of therapy. | Up to 6 months | 
| Median Progression-Free Survival (PFS) (Phase II) | Progression-Free Survival was calculated from study entry until documented disease, death or date of last contact. | Time from start of treatment to time of progression, assessed up to 6 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Median Duration of Response (Phase II) | Duration of the response from time response is achieved until disease progression is detected. Response assessed following treatment (every 3 weeks) for disease progression. Study duration January 2007 to May 2013, approximately six and half years. | Response assessed following treatment (every 3 weeks), up to 6 years. Study duration January 2007 to May 2013. | 
| Number of Participants With Treatment-related Adverse Effects as Assessed by NCI CTCAE v3.0 (Phase II) | Number of participants with adverse effects of treatment. Frequency and severity of adverse effects of treatment as assessed by NCI CTCAE v3.0 (Phase II) | Up to 6 years | 
| Number of Participants With PFS (Phase II) | Progression-free survival (PFS) defined as number of participants out of total in arm that had no disease progression as measured at 6 months. Standard RECIST criteria used to evaluate response and progression. All documented responses required confirmation by imaging, examination, or both, no sooner than 4 weeks after initial documentation of response. In the absence of new symptoms, response assessment was consistently done after two additional cycles of therapy. | 6 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
primary peritoneal cavity cancer, Ovarian Epithelial Cancer, Peritoneal Cancer, Fallopian Tube Cancer, VEGF Trap, aflibercept, vascular endothelial growth factor trap, Zaltrap, docetaxel, RP 56976, Taxotere, TXT