Ziv-Aflibercept in Treating Patients With Metastatic or Unresectable Kidney Cancer

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ClinicalTrials.gov Identifier: NCT00357760

Recruitment Status : Completed

First Posted : July 27, 2006

Results First Posted : April 4, 2017

Last Update Posted : June 23, 2017

Sponsor:

Information provided by (Responsible Party):

National Cancer Institute (NCI)

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition	Metastatic Renal Cell Carcinoma
Intervention	Biological: VEGF Trap
Enrollment	94

Participant Flow

Recruitment Details	The study was activated on 12/21/2007 and closed to accrual on 12/6/2013 with a total accrual of 94 patients.
Pre-assignment Details


Arm/Group Title	Arm A (Higher Dose of VEGF Trap)	Arm B (Lower Dose of VEGF Trap)
Arm/Group Description	Patients receive a higher dose of z...	Patients receive a lower dose of zi...
Arm/Group Description	Patients receive a higher dose of ziv-aflibercept (VEGF Trap) IV over 1 hour on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.	Patients receive a lower dose of ziv-aflibercept (VEGF Trap) IV over 1 hour on day 1. In both arms, courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. At the time of disease progression, the dose of ziv-aflibercept (VEGF Trap) may be escalated to the higher dose in Arm A.
Period Title: Overall Study
Started	59	35
Patients Who Started Treatment	57	34
Eligible and Treated Patients	57	32
Patients Who Undergo Dose Escalation	0 ^[1]	16
Completed	0 ^[2]	0 ^[2]
Not Completed	59	35
Reason Not Completed
Disease progression	44	17
Adverse Event	10	7
Death	0	3
Alternative therapy	1	0
Withdrawal by Subject	0	2
Never started treatment	2	1
Ineligible	0	2
Physician Decision	2	1
Protocol Violation	0	1
To receive hospice care	0	1
[1] Only patients who progressed on the low dose (Arm B) had the opportunity to undergo dose escalation. [2] Patients continued receiving protocol treatment until progressive disease or unacceptable toxicity.

Baseline Characteristics

Arm/Group Title		Arm A (Higher Dose of VEGF Trap)	Arm B (Lower Dose of VEGF Trap)	Total
Arm/Group Description		Patients receive a higher dose of z...	Patients receive a lower dose of zi...	Total of all reporting groups
Arm/Group Description		Patients receive a higher dose of ziv-aflibercept (VEGF Trap) IV over 1 hour on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.	Patients receive a lower dose of ziv-aflibercept (VEGF Trap) IV over 1 hour on day 1. In both arms, courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. At the time of disease progression, the dose of ziv-aflibercept (VEGF Trap) may be escalated to the higher dose in Arm A.	Total of all reporting groups
Overall Number of Baseline Participants		57	32	89
Baseline Analysis Population Description		...
Baseline Analysis Population Description		Eligible and treated patients are included in this analysis.
Age, Continuous Median (Full Range) Unit of measure: Years
	Number Analyzed	57 participants	32 participants	89 participants
		60 (35 to 80)	62 (33 to 73)	61 (33 to 80)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	57 participants	32 participants	89 participants
	Female	14 24.6%	10 31.3%	24 27.0%
	Male	43 75.4%	22 68.8%	65 73.0%

Outcome Measures

1.Primary Outcome


Title	Proportion of Patients Alive and Progression-free at 8 Weeks
Description	Progression-free surviva...
Description	Progression-free survival (PFS) was defined as time from randomization to the earlier of documentation of progression or death. The proportion of patients who are progression-free and alive at 8 weeks was estimated using the Kaplan-Meier method and the confidence interval was estimated using log transformation method. Progression is defined using Response Evaluation Criteria In Solid Tumors (RECIST), as a 20% increase in the sum of the longest diameters of target lesions, or the appearance of new lesions, or unequivocal progression of existing nontarget lesions.
Time Frame	Assessed at 8 weeks

Outcome Measure Data

Analysis Population Description

Eligible and treated patients are included in this analysis.


Arm/Group Title	Arm A (Higher Dose of VEGF Trap)	Arm B (Lower Dose of VEGF Trap)
Arm/Group Description:	Patients receive a higher dose of z...	Patients receive a lower dose of zi...
Arm/Group Description:	Patients receive a higher dose of ziv-aflibercept (VEGF Trap) IV over 1 hour on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.	Patients receive a lower dose of ziv-aflibercept (VEGF Trap) IV over 1 hour on day 1. In both arms, courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. At the time of disease progression, the dose of ziv-aflibercept (VEGF Trap) may be escalated to the higher dose in Arm A.
Overall Number of Participants Analyzed	57	32
Measure Type: Number Number (90% Confidence Interval) Unit of Measure: proportion of participants
	0.70 (0.59 to 0.79)	0.52 (0.37 to 0.66)

2.Secondary Outcome


Title	Proportion of Patients With Objective Response
Description	Objective response is de...
Description	Objective response is defined as complete response (CR) or partial response (PR) determined by Solid Tumor Response Criteria (RECIST). CR: The disappearance of all target lesions without the appearance of new lesion(s) and/or unequivocal progression of existing non-target lesions. PR: At least a 30% decrease in the sum of the longest diameters of target lesions, taking as reference the baseline sum longest diameter without the appearance of new lesion(s) and/or unequivocal progression of existing non-target lesions. To be assigned a status of CR or PR, changes in tumor measurements must be confirmed by repeat assessments performed no less than four weeks after the criteria for response are first met.
Time Frame	Assessed every 8 weeks while on treatment and then every 3 months until patient is 2 years from enrollment, and then every 6 months until patient is 3 years from enrollment

Outcome Measure Data

Analysis Population Description

Eligible and treated patients are included in this analysis.


Arm/Group Title	Arm A (Higher Dose of VEGF Trap)	Arm B (Lower Dose of VEGF Trap)
Arm/Group Description:	Patients receive a higher dose of z...	Patients receive a lower dose of zi...
Arm/Group Description:	Patients receive a higher dose of ziv-aflibercept (VEGF Trap) IV over 1 hour on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.	Patients receive a lower dose of ziv-aflibercept (VEGF Trap) IV over 1 hour on day 1. In both arms, courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. At the time of disease progression, the dose of ziv-aflibercept (VEGF Trap) may be escalated to the higher dose in Arm A.
Overall Number of Participants Analyzed	57	32
Measure Type: Number Number (90% Confidence Interval) Unit of Measure: proportion of participants
	0.053 (0.014 to 0.13)	0.031 (0.002 to 0.14)

3.Secondary Outcome


Title	Progression-free Survival (PFS) Among Patients Who Undergo Dose Escalation Following Progression on Lower-dose VEGF Trap
Description	Patients who progressed ...
Description	Patients who progressed on the 1 mg/kg dose (Arm B) at 8 weeks would have the opportunity to receive the 4 mg/kg dose. PFS is defined as the time from dose escalation to disease progression or death, whichever occurs first. Disease progression is defined using Response Evaluation Criteria In Solid Tumors (RECIST), as a 20% increase in the sum of the longest diameters of target lesions, or the appearance of new lesions, or unequivocal progression of existing nontarget lesions.
Time Frame	Assessed every 8 weeks while on treatment and then every 3 months until patient is 2 years from enrollment, and then every 6 months until patient is 3 years from enrollment

Outcome Measure Data

Analysis Population Description

Only patients who progressed on the low dose (Arm B) and underwent dose escalation were included in this analysis.


Arm/Group Title	Arm A (Higher Dose of VEGF Trap)	Arm B (Lower Dose of VEGF Trap)
Arm/Group Description:	Patients receive a higher dose of z...	Patients receive a lower dose of zi...
Arm/Group Description:	Patients receive a higher dose of ziv-aflibercept (VEGF Trap) IV over 1 hour on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.	Patients receive a lower dose of ziv-aflibercept (VEGF Trap) IV over 1 hour on day 1. In both arms, courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. At the time of disease progression, the dose of ziv-aflibercept (VEGF Trap) may be escalated to the higher dose in Arm A.
Overall Number of Participants Analyzed	0	16
Median (90% Confidence Interval) Unit of Measure: weeks
		14.57 (7.57 to 33.00)

4.Other Pre-specified Outcome


Title	Circulating Levels of VEGF-Trap Complex
Description	[Not Specified]
Description	[Not Specified]
Time Frame	Assessed at baseline, 4 weeks, 6 weeks, 8 weeks and end of treatment

Outcome Measure Data Not Reported

5.Other Pre-specified Outcome


Title	Angiogenesis-related Protein Expression
Description	[Not Specified]
Description	[Not Specified]
Time Frame	Assessed every 8 weeks during treatment and end of treatment

Outcome Measure Data Not Reported

Adverse Events

Time Frame	Assessed every 2 weeks while on treatment and for 30 days after the end of treatment, assessed up to 3 years
Adverse Event Reporting Description	[Not Specified]

Arm/Group Title	Arm A (Higher Dose of VEGF Trap)	Arm B (Lower Dose of VEGF Trap)
Arm/Group Description	Patients receive a higher dose of z...	Patients receive a lower dose of zi...
Arm/Group Description	Patients receive a higher dose of ziv-aflibercept (VEGF Trap) IV over 1 hour on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.	Patients receive a lower dose of ziv-aflibercept (VEGF Trap) IV over 1 hour on day 1. In both arms, courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. At the time of disease progression, the dose of ziv-aflibercept (VEGF Trap) may be escalated to the higher dose in Arm A.
All-Cause Mortality
	Arm A (Higher Dose of VEGF Trap)	Arm B (Lower Dose of VEGF Trap)
	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--
Serious Adverse Events Serious Adverse Events
	Arm A (Higher Dose of VEGF Trap)	Arm B (Lower Dose of VEGF Trap)
	Affected / at Risk (%)	Affected / at Risk (%)
Total	35/57 (61.40%)	18/34 (52.94%)
Blood and lymphatic system disorders
Anemia ^† 1	2/57 (3.51%)	3/34 (8.82%)
Cardiac disorders
Supraventricular tachycardia ^† 1	0/57 (0.00%)	1/34 (2.94%)
Cardiac-ischemia ^† 1	1/57 (1.75%)	0/34 (0.00%)
Pericardial effusion (non-malignant) ^† 1	1/57 (1.75%)	0/34 (0.00%)
Gastrointestinal disorders
Esophagitis ^† 1	0/57 (0.00%)	1/34 (2.94%)
Abdomen, pain ^† 1	2/57 (3.51%)	0/34 (0.00%)
General disorders
Fatigue ^† 1	2/57 (3.51%)	7/34 (20.59%)
Immune system disorders
Cytokine release syndrome ^† 1	1/57 (1.75%)	0/34 (0.00%)
Infections and infestations
Infection Gr0-2 neut, urinary tract ^† 1	1/57 (1.75%)	0/34 (0.00%)
Investigations
Cardiac troponin I (cTnI) increased ^† 1	0/57 (0.00%)	1/34 (2.94%)
Metabolism and nutrition disorders
Anorexia ^† 1	1/57 (1.75%)	0/34 (0.00%)
Hypoalbuminemia ^† 1	0/57 (0.00%)	1/34 (2.94%)
Hypophosphatemia ^† 1	0/57 (0.00%)	1/34 (2.94%)
Hypokalemia ^† 1	1/57 (1.75%)	0/34 (0.00%)
Hyponatremia ^† 1	2/57 (3.51%)	0/34 (0.00%)
Musculoskeletal and connective tissue disorders
Back, pain ^† 1	0/57 (0.00%)	1/34 (2.94%)
Bone, pain ^† 1	0/57 (0.00%)	1/34 (2.94%)
Muscle, pain ^† 1	0/57 (0.00%)	1/34 (2.94%)
Nervous system disorders
CNS, hemorrhage ^† 1	0/57 (0.00%)	1/34 (2.94%)
Cognitive disturbance ^† 1	1/57 (1.75%)	0/34 (0.00%)
Encephalopathy ^† 1	1/57 (1.75%)	0/34 (0.00%)
Head/headache ^† 1	2/57 (3.51%)	0/34 (0.00%)
Renal and urinary disorders
Urinary hemorrhage NOS ^† 1	0/57 (0.00%)	1/34 (2.94%)
Glomerular filtration rate decreased ^† 1	0/57 (0.00%)	1/34 (2.94%)
Proteinuria ^† 1	9/57 (15.79%)	2/34 (5.88%)
Renal/GU-other ^† 1	0/57 (0.00%)	1/34 (2.94%)
Respiratory, thoracic and mediastinal disorders
Dyspnea ^† 1	3/57 (5.26%)	1/34 (2.94%)
Vascular disorders
Hypertension ^† 1	20/57 (35.09%)	5/34 (14.71%)
Hypotension ^† 1	1/57 (1.75%)	0/34 (0.00%)
Thrombosis/thrombus/embolism ^† 1	3/57 (5.26%)	0/34 (0.00%)
† Indicates events were collected by systematic assessment 1 Term from vocabulary, CTCAE 3.0
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Arm A (Higher Dose of VEGF Trap)	Arm B (Lower Dose of VEGF Trap)
	Affected / at Risk (%)	Affected / at Risk (%)
Total	52/57 (91.23%)	33/34 (97.06%)
Blood and lymphatic system disorders
Anemia ^† 1	11/57 (19.30%)	11/34 (32.35%)
Hemolysis ^† 1	5/57 (8.77%)	0/34 (0.00%)
Gastrointestinal disorders
Constipation ^† 1	11/57 (19.30%)	10/34 (29.41%)
Diarrhea w/o prior colostomy ^† 1	11/57 (19.30%)	8/34 (23.53%)
Dry mouth ^† 1	4/57 (7.02%)	1/34 (2.94%)
Dyspepsia ^† 1	1/57 (1.75%)	2/34 (5.88%)
Muco/stomatitis by exam, oral cavity ^† 1	0/57 (0.00%)	4/34 (11.76%)
Muco/stomatitis (symptom) oral cavity ^† 1	5/57 (8.77%)	6/34 (17.65%)
Nausea ^† 1	11/57 (19.30%)	17/34 (50.00%)
Vomiting ^† 1	1/57 (1.75%)	6/34 (17.65%)
Abdomen, pain ^† 1	0/57 (0.00%)	2/34 (5.88%)
General disorders
Fatigue ^† 1	36/57 (63.16%)	24/34 (70.59%)
Fever w/o neutropenia ^† 1	1/57 (1.75%)	2/34 (5.88%)
Rigors/chills ^† 1	0/57 (0.00%)	3/34 (8.82%)
Edema limb ^† 1	4/57 (7.02%)	5/34 (14.71%)
Chest/thoracic pain NOS ^† 1	2/57 (3.51%)	3/34 (8.82%)
Pain-other ^† 1	5/57 (8.77%)	0/34 (0.00%)
Investigations
Leukocytes decreased ^† 1	5/57 (8.77%)	1/34 (2.94%)
Neutrophils decreased ^† 1	2/57 (3.51%)	2/34 (5.88%)
Platelets decreased ^† 1	5/57 (8.77%)	3/34 (8.82%)
Weight loss ^† 1	7/57 (12.28%)	4/34 (11.76%)
Alkaline phosphatase increased ^† 1	4/57 (7.02%)	5/34 (14.71%)
Alanine aminotransferase increased ^† 1	6/57 (10.53%)	1/34 (2.94%)
Aspartate aminotransferase increased ^† 1	4/57 (7.02%)	3/34 (8.82%)
Creatinine increased ^† 1	8/57 (14.04%)	6/34 (17.65%)
Metabolism and nutrition disorders
Anorexia ^† 1	22/57 (38.60%)	16/34 (47.06%)
Hypoalbuminemia ^† 1	6/57 (10.53%)	2/34 (5.88%)
Hypercalcemia ^† 1	0/57 (0.00%)	3/34 (8.82%)
Hypocalcemia ^† 1	2/57 (3.51%)	2/34 (5.88%)
Hyperglycemia ^† 1	3/57 (5.26%)	5/34 (14.71%)
Hypophosphatemia ^† 1	4/57 (7.02%)	1/34 (2.94%)
Hyperkalemia ^† 1	2/57 (3.51%)	4/34 (11.76%)
Hyponatremia ^† 1	7/57 (12.28%)	7/34 (20.59%)
Musculoskeletal and connective tissue disorders
Back, pain ^† 1	0/57 (0.00%)	3/34 (8.82%)
Extremity-limb, pain ^† 1	0/57 (0.00%)	2/34 (5.88%)
Joint, pain ^† 1	11/57 (19.30%)	8/34 (23.53%)
Muscle, pain ^† 1	4/57 (7.02%)	3/34 (8.82%)
Nervous system disorders
Taste disturbance ^† 1	4/57 (7.02%)	3/34 (8.82%)
Dizziness ^† 1	5/57 (8.77%)	1/34 (2.94%)
Neuropathy-sensory ^† 1	2/57 (3.51%)	4/34 (11.76%)
Head/headache ^† 1	17/57 (29.82%)	8/34 (23.53%)
Psychiatric disorders
Anxiety ^† 1	0/57 (0.00%)	2/34 (5.88%)
Renal and urinary disorders
Proteinuria ^† 1	25/57 (43.86%)	20/34 (58.82%)
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis ^† 1	3/57 (5.26%)	1/34 (2.94%)
Nose, hemorrhage ^† 1	3/57 (5.26%)	6/34 (17.65%)
Pleura, hemorrhage ^† 1	4/57 (7.02%)	2/34 (5.88%)
Cough ^† 1	8/57 (14.04%)	6/34 (17.65%)
Dyspnea ^† 1	8/57 (14.04%)	12/34 (35.29%)
Nasal cavity/paranasal sinus reaction ^† 1	4/57 (7.02%)	0/34 (0.00%)
Voice changes/dysarthria ^† 1	12/57 (21.05%)	10/34 (29.41%)
Skin and subcutaneous tissue disorders
Sweating ^† 1	2/57 (3.51%)	2/34 (5.88%)
Alopecia ^† 1	3/57 (5.26%)	1/34 (2.94%)
Rash: acne/acneiform ^† 1	4/57 (7.02%)	2/34 (5.88%)
Hand-foot reaction ^† 1	3/57 (5.26%)	1/34 (2.94%)
Vascular disorders
Hypertension ^† 1	22/57 (38.60%)	10/34 (29.41%)
† Indicates events were collected by systematic assessment 1 Term from vocabulary, CTCAE 3.0

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Study Statistician
Organization:	ECOG-ACRIN Statistical Office
Phone:	617-632-3012

Layout table for additonal information

Responsible Party:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00357760
Other Study ID Numbers:	NCI-2009-00559 NCI-2009-00559 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) E4805 ( Other Identifier: ECOG-ACRIN Cancer Research Group ) U10CA180820 ( U.S. NIH Grant/Contract ) U10CA021115 ( U.S. NIH Grant/Contract )
First Submitted:	July 26, 2006
First Posted:	July 27, 2006
Results First Submitted:	February 8, 2017
Results First Posted:	April 4, 2017
Last Update Posted:	June 23, 2017

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