Bevacizumab With or Without MEDI-522 in Treating Patients With Unresectable or Metastatic Kidney Cancer

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Terminated
• CT.gov ID: NCT00684996
• Collaborator: (none)
• Enrollment: 5
• Locations: 5
• Arms: 2
• Duration (Months): 28
• Patient Per Site: 1
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This phase I/randomized phase II trial is studying the side effects and best dose of bevacizumab and to see how well it works when given together with or without MEDI-522 in treating patients with unresectable or metastatic kidney cancer. Monoclonal antibodies, such as bevacizumab and MEDI-522, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab and MEDI-522 may also stop the growth of tumor cells by blocking blood flow to the tumor. It is not yet known whether bevacizumab is more effective when given together with or without MEDI-522 in treating kidney cancer.

Condition or Disease	Intervention/Treatment	Phase
Recurrent Renal Cell Cancer; Renal Cell Carcinoma; Stage III Renal Cell Cancer; Stage IV Renal Cell Cancer	Drug: etaracizumab; Biological: bevacizumab	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To assess the appropriate dose of bevacizumab when administered with humanized monoclonal antibody MEDI-522 in patients with unresectable or metastatic renal cell carcinoma previously treated with sunitinib malate or sorafenib tosylate. (Phase I) II. To compare the progression-free survival of these patients treated with bevacizumab with versus without humanized monoclonal antibody MEDI-522. (Phase II) III. To evaluate the qualitative and quantitative toxicities of bevacizumab and humanized monoclonal antibody MEDI-522 in these patients. (Phase II) IV. To estimate overall survival and RECIST response rate (i.e., confirmed and unconfirmed, complete and partial responses) in both treatment arms. (Phase II)

OUTLINE: This is a multicenter, phase I, dose-escalation study of bevacizumab followed by a randomized phase II study.

PHASE I: Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and humanized monoclonal antibody MEDI-522 IV on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity until the recommended phase II dose (RPTD) of bevacizumab is determined.

PHASE II: Patients are stratified according to the number of prior treatment regimens for renal cell carcinoma (1 vs 2) and whether there is a clear cell component (yes vs no).

Patients are randomized to 1 of 2 treatment arms:

ARM I: Patients receive bevacizumab (10 mg/kg) IV over 30-90 minutes on days 1 and 15.

ARM II: Patients receive bevacizumab IV as in arm I at the RPTD determined in phase I, and humanized monoclonal antibody MEDI-522 (8 mg/kg) IV over 30 minutes on days 1, 8, 15, and 22.

In both arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed periodically for up to 3 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 5 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I and a Randomized Phase II Study of Maximal Angiogenic Blockade in Advanced Renal Carcinoma: Bevacizumab (NSC-704865) With or Without MEDI-522 (NSC-719850)
• Study Start Date: Jun 1, 2008
• Actual Primary Completion Date: Oct 1, 2010
• Actual Study Completion Date: Oct 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Phase II Arm I Patients receive bevacizumab (10mg/kg) IV over 30-90 minutes on days 1 and 15.	Biological: bevacizumab; Given IV; Other Names: anti-VEGF humanized monoclonal antibody anti-VEGF monoclonal antibody Avastin rhuMAb VEGF
Active Comparator: Phase II Arm II Patients receive bevacizumab IV as in arm I at the RPTD determined in phase I, and humanized monoclonal antibody MEDI-522 (8mg/kg) IV over 30 minutes on days 1, 8, 15, and 22.	Drug: etaracizumab; Given IV; Other Names: Abegrin humanized monoclonal antibody MEDI-522 MEDI-522 monoclonal antibody anti-alpha V beta 3 integrin MEDI-522 ; Biological: bevacizumab; Given IV; Other Names: anti-VEGF humanized monoclonal antibody anti-VEGF monoclonal antibody Avastin rhuMAb VEGF

Outcome Measures

Primary Outcome Measures

1. Maximum Tolerated Dose of Bevacizumab , Based on Incidence of Dose-limiting Toxicity (DLT) Graded According to the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 (Phase I) [Up to 8 weeks]

2. Progression-free Survival (Phase II) [From date of registration to date of first observation of progressive disease, systemic deterioration, or death due to any cause, assessed up to 3 years]

   Measured from date of registration to date of first observation of progressive disease, symptomatic deterioration or death due to any cause. Patients last known to be alive and progression-free are censored at date of last contact.

3. Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug, Graded According to NCI CTCAE Version 3.0 (Phase II) [Up to 3 years]

   Adverse Events (AEs) are reported by the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. For each patient, worst grade of each event type is reported. Grade 3 = Severe, Grade 4 = Life-threatening, Grade 5 = Fatal.

4. Overall Survival (Phase II) [From date of registration to date of death due to any cause, assessed up to 3 years]

   Measure from date of registration to date of death due to any cause. Patients last known to be alive are censored at date of last contact.

5. Response Rate According to Response Evaluation Criteria in Solid Tumors (RECIST), Including Confirmed and Unconfirmed Complete and Partial Responses (Phase II) [Up to 3 years]

   Complete Response (CR) is a complete disappearance of all measurable and non-measurable disease. No new lesions. No disease related symptoms. Partial Response (PR) applies only to patients with at least one measurable lesion. Greater than or equal to 30% decrease under baseline of the sum of longest diameters of all target measurable lesions. No unequivocal progression of nonmeasurable disease. No new lesions.

Secondary Outcome Measures

1. Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug [Patients were assessed for the first 8 weeks for dose-limiting toxicities, then assessed for adverse events after every cycle (1 cycle = 28 days) of protocol treatment, up to 3 years]

   Adverse Events (AEs) are reported by the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. For each patient, worst grade of each event type is reported. Grade 3 = Severe, Grade 4 = Life-threatening, Grade 5 = Fatal.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria:

• Histologically or cytologically confirmed renal cell carcinoma

• Metastatic or unresectable disease

• Must have received prior sunitinib malate or sorafenib tosylate for metastatic or unresectable disease

• Measurable disease

• No soft tissue disease that has been irradiated within the past 2 months

• More than 6 months since prior and no concurrent treated or untreated brain metastases

• Stable, treated brain metastases allowed provided they remained stable for more than 6 months

• Patients with clinical evidence of brain metastases must have a negative brain CT or MRI scan for metastatic disease

• Zubrod performance status 0-1

• Urine protein:creatinine ratio =< 0.5 OR urine protein < 1,000 mg by 24-hour collection

• Not be pregnant or nursing

• Fertile patients must use effective contraception during and for at least 6 months after completion of study therapy

• No serious or non-healing wound, ulcer, or bone fracture

• No clinically relevant bleeding diathesis or coagulopathy

• No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 28 days

• No significant traumatic injury within the past 28 days

• No known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies

• No other prior malignancy, except adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease-free for 5 years

• No New York Heart Association class II-IV congestive heart failure

• No unstable symptomatic arrhythmia requiring medication

• Chronic, controlled arrhythmias (e.g., atrial fibrillation or paroxysmal supraventricular tachycardia) allowed

• None of the following cardiovascular conditions within the past 6 months: Arterial thrombosis, Unstable angina, Myocardial infarction, Cerebrovascular accident

• Must have controlled blood pressure, defined as systolic blood pressure (BP) =< 160 mm Hg and/or diastolic BP =< 90 mm Hg

• More than 7 days since prior core biopsy

• At least 14 days since completion of prior therapy and recovered

• At least 28 days since prior radiotherapy and recovered

• No prior radiotherapy to >= 25% of bone marrow

• No more than two prior systemic regimens for renal cell carcinoma (including adjuvant treatment)

• No prior bevacizumab or humanized monoclonal antibody MEDI-522

• No major surgical procedure or open biopsy within the past 28 days

• No concurrent need for a major surgical procedure

• Concurrent full-dose anticoagulation with warfarin allowed provided INR is between 2-3

• Concurrent low molecular weight heparin allowed

• No clinically significant vascular disease (e.g., aortic aneurysm or history of aortic dissection)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Fremont - Rideout Cancer Center	Marysville	California	United States	95901
2	University of California at Davis Cancer Center	Sacramento	California	United States	95817
3	University of Michigan	Ann Arbor	Michigan	United States	48109
4	Novant Health Presbyterian Medical Center	Charlotte	North Carolina	United States	28204
5	SWOG	Portland	Oregon	United States	97239

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Christopher Ryan, Southwest Oncology Group

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00684996
• Other Study ID Numbers: NCI-2009-01099; NCI-2009-01099; CDR0000596555; S0717; S0717; U10CA032102
• First Posted: May 28, 2008
• Last Update Posted: May 15, 2014
• Last Verified: Apr 1, 2013

• Additional relevant MeSH terms: Carcinoma; Carcinoma, Renal Cell; Bevacizumab; Antineoplastic Agents, Immunological; Antibodies; Immunoglobulins; Antibodies, Monoclonal

Study Results

Participant Flow

Arm/Group Title	Phase I Bevacizumab (10 mg/kg) + MEDI-522
Arm/Group Description	Patients receive bevacizumab (10/mg/kg or 5 mg/kg) IV over 30-90 minutes on days 1 and 15 and humanized monoclonal antibody MEDI-522 IV on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity until the recommended phase II dose (RPTD) of bevacizumab is determined.
Period Title: Overall Study
STARTED	5
Eligible	5
COMPLETED	0
NOT COMPLETED	5

Baseline Characteristics

Arm/Group Title	Phase I Bevacizumab (10 mg/kg) + MEDI-522
Arm/Group Description	Patients receive bevacizumab (10 mg/kg or 5mg/kg) IV over 30-90 minutes on days 1 and 15 and humanized monoclonal antibody MEDI-522 IV on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity until the recommended phase II dose (RPTD) of bevacizumab is determined.
Overall Participants	5
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	61.5
Sex: Female, Male (Count of Participants)
Female	3 60%
Male	2 40%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	3 60%
Unknown or Not Reported	2 40%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	5 100%
More than one race	0 0%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	Maximum Tolerated Dose of Bevacizumab , Based on Incidence of Dose-limiting Toxicity (DLT) Graded According to the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 (Phase I)
Time Frame	Up to 8 weeks

Outcome Measure Data

Analysis Population Description

The study was permanently closed to accrual on April 1, 2009, due to drug supply issues.

Arm/Group Title	Phase I Bevacizumab (10 mg/kg) + MEDI-522
Arm/Group Description	Patients receive bevacizumab (10 mg/kg or 5 mg/kg) IV over 30-90 minutes on days 1 and 15 and humanized monoclonal antibody MEDI-522 IV on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity until the recommended phase II dose (RPTD) of bevacizumab is determined.
Measure Participants	0

2. Primary Outcome

Title	Progression-free Survival (Phase II)
Description	Measured from date of registration to date of first observation of progressive disease, symptomatic deterioration or death due to any cause. Patients last known to be alive and progression-free are censored at date of last contact.
Time Frame	From date of registration to date of first observation of progressive disease, systemic deterioration, or death due to any cause, assessed up to 3 years

Outcome Measure Data

Analysis Population Description

The study was permanently closed to accrual on April 1, 2009, due to drug supply issues.

Arm/Group Title	Phase II Arm I	Phase II Arm II
Arm/Group Description	Patients receive bevacizumab (10mg/kg) IV over 30-90 minutes on days 1 and 15.	Patients receive bevacizumab IV as in arm I at the RPTD determined in phase I, and humanized monoclonal antibody MEDI-522 (8mg/kg) IV over 30 minutes on days 1, 8, 15, and 22.
Measure Participants	0	0

3. Primary Outcome

Title	Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug, Graded According to NCI CTCAE Version 3.0 (Phase II)
Description	Adverse Events (AEs) are reported by the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. For each patient, worst grade of each event type is reported. Grade 3 = Severe, Grade 4 = Life-threatening, Grade 5 = Fatal.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

The study was permanently closed to accrual on April 1, 2009, due to drug supply issues.

Arm/Group Title	Phase II Arm I	Phase II Arm II
Arm/Group Description	Patients receive bevacizumab (10mg/kg) IV over 30-90 minutes on days 1 and 15.	Patients receive bevacizumab IV as in arm I at the RPTD determined in phase I, and humanized monoclonal antibody MEDI-522 (8mg/kg) IV over 30 minutes on days 1, 8, 15, and 22.
Measure Participants	0	0

4. Primary Outcome

Title	Overall Survival (Phase II)
Description	Measure from date of registration to date of death due to any cause. Patients last known to be alive are censored at date of last contact.
Time Frame	From date of registration to date of death due to any cause, assessed up to 3 years

Outcome Measure Data

Analysis Population Description

The study was permanently closed to accrual on April 1, 2009, due to drug supply issues.

Arm/Group Title	Phase II Arm I	Phase II Arm II
Arm/Group Description	Patients receive bevacizumab (10mg/kg) IV over 30-90 minutes on days 1 and 15.	Patients receive bevacizumab IV as in arm I at the RPTD determined in phase I, and humanized monoclonal antibody MEDI-522 (8mg/kg) IV over 30 minutes on days 1, 8, 15, and 22.
Measure Participants	0	0

5. Primary Outcome

Title	Response Rate According to Response Evaluation Criteria in Solid Tumors (RECIST), Including Confirmed and Unconfirmed Complete and Partial Responses (Phase II)
Description	Complete Response (CR) is a complete disappearance of all measurable and non-measurable disease. No new lesions. No disease related symptoms. Partial Response (PR) applies only to patients with at least one measurable lesion. Greater than or equal to 30% decrease under baseline of the sum of longest diameters of all target measurable lesions. No unequivocal progression of nonmeasurable disease. No new lesions.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

The study was permanently closed to accrual on April 1, 2009, due to drug supply issues.

Arm/Group Title	Phase II Arm I	Phase II Arm II
Arm/Group Description	Patients receive bevacizumab (10mg/kg) IV over 30-90 minutes on days 1 and 15.	Patients receive bevacizumab IV as in arm I at the RPTD determined in phase I, and humanized monoclonal antibody MEDI-522 (8mg/kg) IV over 30 minutes on days 1, 8, 15, and 22.
Measure Participants	0	0

6. Secondary Outcome

Title	Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug
Description	Adverse Events (AEs) are reported by the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. For each patient, worst grade of each event type is reported. Grade 3 = Severe, Grade 4 = Life-threatening, Grade 5 = Fatal.
Time Frame	Patients were assessed for the first 8 weeks for dose-limiting toxicities, then assessed for adverse events after every cycle (1 cycle = 28 days) of protocol treatment, up to 3 years

Outcome Measure Data

Analysis Population Description

Eligible patients who had received any treatment were included in the adverse event summaries. Any CTCAE 3.0 event of Grade 3 (severe), Grade 4 (life threatening), or Grade 5 (fatal) which deemed to be related to protocol treatment are included.

Arm/Group Title	Phase I Bevacizumab (10 mg/kg) + MEDI-522
Arm/Group Description	Patients receive bevacizumab (10/mg/kg or 5 mg/kg) IV over 30-90 minutes on days 1 and 15 and humanized monoclonal antibody MEDI-522 IV on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity un til the recommended phase II dose (RPTD) of bevacizumab is determined.
Measure Participants	3
Allergic reaction/hypersensitivity	1 20%
Dyspnea (shortness of breath)	1 20%

Adverse Events

Time Frame	Patients were assessed for the first 8 weeks for dose-limiting toxicities, then assessed for adverse events after every cycle (1 cycle = 28 days) of protocol treatment, up to 3 years
Arm/Group Title	Phase I Bevacizumab (10 mg/kg) + MEDI-522
Arm/Group Description	Patients receive bevacizumab (10/mg/kg or 5 mg/kg) IV over 30-90 minutes on days 1 and 15 and humanized monoclonal antibody MEDI-522 IV on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity until the recommended phase II dose (RPTD) of bevacizumab is determined.
All Cause Mortality
	Phase I Bevacizumab (10 mg/kg) + MEDI-522
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Phase I Bevacizumab (10 mg/kg) + MEDI-522
	Affected / at Risk (%)	# Events
Total	2/3 (66.7%)
General disorders
Rigors/chills	1/3 (33.3%)
Immune system disorders
Allergic reaction/hypersensitivity	2/3 (66.7%)
Other (Not Including Serious) Adverse Events
	Phase I Bevacizumab (10 mg/kg) + MEDI-522
	Affected / at Risk (%)	# Events
Total	3/3 (100%)
Blood and lymphatic system disorders
Hemoglobin	1/3 (33.3%)
Gastrointestinal disorders
Diarrhea	1/3 (33.3%)
Nausea	1/3 (33.3%)
Pain - Esophagus	1/3 (33.3%)
General disorders
Fatigue (asthenia, lethargy, malaise)	3/3 (100%)
Fever in absence of neutropenia, ANC lt1.0x10e9/L	2/3 (66.7%)
Flu-like syndrome	1/3 (33.3%)
Rigors/chills	2/3 (66.7%)
Infections and infestations
Infection with unknown ANC - Upper airway NOS	1/3 (33.3%)
Investigations
ALT, SGPT (serum glutamic pyruvic transaminase)	1/3 (33.3%)
AST, SGOT	1/3 (33.3%)
Alkaline phosphatase	1/3 (33.3%)
Creatinine	1/3 (33.3%)
Metabolism and nutrition disorders
Calcium, serum-low (hypocalcemia)	1/3 (33.3%)
Glucose, serum-high (hyperglycemia)	2/3 (66.7%)
Musculoskeletal and connective tissue disorders
Pain - Joint	1/3 (33.3%)
Renal and urinary disorders
Glomerular filtration rate	1/3 (33.3%)
Respiratory, thoracic and mediastinal disorders
Cough	1/3 (33.3%)
Dyspnea (shortness of breath)	1/3 (33.3%)
Hemorrhage, pulmonary/upper respiratory - Nose	1/3 (33.3%)
Vascular disorders
Hypertension	2/3 (66.7%)
Hypotension	1/3 (33.3%)
Thrombosis/thrombus/embolism	1/3 (33.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.