Study of Bevacizumab/Doxil in Treatment of Platinum-Resistant/Refractory Ovarian Cancer (CA)

• Sponsor: New Mexico Cancer Care Alliance (Other)
• Overall Status: Completed
• CT.gov ID: NCT00945139
• Collaborator: Genentech, Inc. (Industry), NYU Langone Health (Other)
• Enrollment: 46
• Locations: 3
• Arm: 1
• Duration (Months): 53
• Patients Per Site: 15.3
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The purpose of this research study is to test the safety, tolerability, and effectiveness of two chemotherapy drugs, pegylated liposomal doxorubicin (Doxil) and bevacizumab (Avastin). How Doxil is metabolized and excreted from the body will also be studied.

Condition or Disease	Intervention/Treatment	Phase
Ovarian Cancer	Drug: Doxil; Drug: Avastin	Phase 2

Detailed Description

Avastin:

Avastin is a humanized monoclonal antibody (a type of protein that is normally made by the immune system to help defend the body from infection and cancer). Avastin has been approved for the treatment of colorectal cancer and lung cancer. Avastin is investigational for the treatment of ovarian cancer and has not been approved by the United States Food and Drug Administration (FDA) for this use.

Avastin is thought to work by attaching to a protein called vascular endothelial growth factor (VEGF) to block its action. VEGF plays a role in the formation of both normal and abnormal blood vessels. It is present in normal tissues, but is produced in excess by most solid cancers (tumors). In cancer, VEGF helps blood vessels bring nutrients to tumor cells, allowing the tumor cells to grow. In laboratory studies with human cancer cells grown in animals, Avastin has been shown to prevent or slow the growth of different types of cancer cells by blocking the effects of VEGF.

Doxorubicin:

Doxorubicin is a type of antibiotic that is only used in cancer chemotherapy. It slows or stops the growth of cancer. Doxorubicin has been approved by the FDA to treat cancers of the head, neck, cervix, vagina, testes, prostate, uterus and Ewing's tumor.

Study Design

• Study Type: Interventional
• Actual Enrollment: 46 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of Bevacizumab and Doxil in the Treatment of Platinum-Resistant or Refractory Ovarian Cancer
• Study Start Date: Mar 1, 2007
• Actual Primary Completion Date: Dec 1, 2010
• Actual Study Completion Date: Aug 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Single Arm: Doxil and Avastin Patients receive both agents, doxil and Avastin.	Drug: Doxil; Open label study of Doxil given as 30 mg/m2 every three weeks by itself in cycle 1; Other Names: Doxorubicin ; Drug: Avastin; First agent (Doxil) will be following by Avastin 15 mg/kg on cycle 2 and every cycle thereafter until disease progression; Other Names: Bevacizumab

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival (PFS) by RECIST Criteria [Up to 25 months]

   Tumor response is evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.0). Target lesions are assessed by hysical exam and/or computerized tomography (CT): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient decrease in the sum of the longest diameter of target lesions to qualify for PR nor sufficient increase in the sum of the longest diameter of target lesions to qualify for Progressive Disease; Progressive Disease (PD), 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions

2. Progression Free Survival (PFS) by GCIC Criteria [Up to 25 months]

   Using GCIC criteria, progression is defined as CA-125 levels greater than, or equal to, 2 times the upper limit of a reference range on 2 occasions and at least 1 week apart.

Secondary Outcome Measures

1. Overall Survival [4 years]

   The time from treatment initiation to death by any cause

2. Overall Response Rate (ORR) by RECIST [3 years]

   ORR is the sum of the percentages of patients achieving complete and partial responses. Tumor response is evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.0)

3. Clinical Benefit Rate (by RECIST) [3 years]

   Clinical Benefit Rate (CBR) is the sum of the percentages of patients achieving complete response, partial response, and stable disease. Tumor response is evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.0). Target lesions are assessed by physical exam and/or computerized tomography (CT): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient decrease in the sum of the longest diameter of target lesions to qualify for PR nor sufficient increase in the sum of the longest diameter of target lesions to qualify for Progressive Disease; Progressive Disease (PD), 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions

4. Overall Response Rate (ORR) by GCIC Criteria [3 years]

   A response according to GCIC criteria has occurred if there is at least a 50% reduction in CA 125 levels from a pretreatment sample. The response must be confirmed and maintained for at least 28 days. Patients can be evaluated according to CA-125 only if they have a pretreatment sample that is at least twice the upper limit of normal and within 2 weeks prior to starting treatment.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients must be platinum resistant

• Patients will be included in the study based on the following criteria:

• No prior anthracycline use

• PS less or equal 2

• Lab values within certain limits (ANC greater 1000, platelets greater 100,000; ALT, AST 2 time ULN, creatinine less 2.0)

• No more than 3 prior chemotherapy regimens, only 2 of which can have included platinum-containing regimens

• Use of effective means of contraception in subjects of child-bearing potential

Exclusion Criteria:

1. Disease-Specific Exclusions:

• Evidence of complete or partial bowel obstruction

• Need for IV hydration or TPN

• Greater 2 prior abdominal surgeries

• History of gastrointestinal perforation

• Gastrointestinal perforation due to any other cause within the last 6 months

1. General Medical Exclusions:

• Inability to comply with study and/or follow-up procedures

• Life expectancy of less than 12 weeks

• Current, recent (within 4 weeks of the first infusion of this study), or planned participation in an experimental drug study other than a Genentech-sponsored Avastin cancer study

1. Avastin-Specific Exclusions

• Inadequately controlled hypertension (defined as systolic blood pressure 150 and/or diastolic blood pressure greater 100 mmHg on antihypertensive medications)

• Any prior history of hypertensive crisis or hypertensive encephalopathy

• New York Heart Association (NYHA) Grade II or greater congestive heart failure (see Appendix E)

• History of myocardial infarction or unstable angina within 6 months prior to study enrollment

• History of stroke or transient ischemic attack within 6 months prior to study enrollment

• Known CNS disease

• Significant vascular disease (e.g., aortic aneurysm, aortic dissection)

• Symptomatic peripheral vascular disease

• Evidence of bleeding diathesis or coagulopathy

• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study enrollment or anticipation of need for major surgical procedure during the course of the study

• Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to study enrollment

• History of abdominal fistula, or intra-abdominal abscess within 6 months prior to study enrollment

• Serious, non-healing wound, ulcer, or bone fracture

• Proteinuria at screening as demonstrated by either:

• Urine protein:creatinine (UPC) ratio 1.0 at screening OR

• Urine dipstick for proteinuria greater or equal 2plus (patients discovered to have greater or equal 2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate less or equal 1g of protein in 24 hours to be eligible)

• Known hypersensitivity to any component of Avastin

• Pregnant (positive pregnancy test) or lactating. No effective means of contraception (men and women) in subjects of child-bearing potential

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of New Mexico	Albuquerque	New Mexico	United States	87106
2	New Mexico Cancer Care Associates	Santa Fe	New Mexico	United States	87505
3	New York University Cancer Institute	New York City	New York	United States	10016

Sponsors and Collaborators

• New Mexico Cancer Care Alliance
• Genentech, Inc.
• NYU Langone Health

Investigators

• Principal Investigator: Claire F. Verschraegen, M.D., University of New Mexico
• Study Director: Franco Muggia, MD, New York University Cancer Institute

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• University of New Mexico Cancer Center
• New Mexico Cancer Care Alliance

Publications

None provided.

• Responsible Party: New Mexico Cancer Care Alliance
• ClinicalTrials.gov Identifier: NCT00945139
• Other Study ID Numbers: INST AVF3911s; NCI-2011-02890
• First Posted: Jul 23, 2009
• Last Update Posted: Jul 31, 2015
• Last Verified: Jul 1, 2015

• Additional relevant MeSH terms: Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Bevacizumab; Doxorubicin

Study Results

Participant Flow

Recruitment Details	A total of 60 patients were screened for this study at all sites beginning March 2007. 46 patients were enrolled at the UNM Cancer Center, NYU Medical Center and NM Cancer Care Associates/Santa Fe.

Arm/Group Title	Doxil (PLD) + Avastin (Bevacizumab)
Arm/Group Description	Open label study of Doxil given as 30 mg/m2 every three weeks by itself in cycle 1, and then followed by Avastin 15 mg/kg on cycle 2 and every cycle thereafter until disease progression (Progression-Free Survival determination) or withdrawal for other causes (unacceptable toxicity, patient preference). Patients undergoing PK determinations will have the dose of Avastin on cycle 2 given 24 hours after Doxil.
Period Title: Overall Study
STARTED	46
COMPLETED	46
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Doxil (PLD) + Avastin (Bevacizumab)
Arm/Group Description	Open label study of Doxil given as 30 mg/m2 every three weeks by itself in cycle 1, and then followed by Avastin 15 mg/kg on cycle 2 and every cycle thereafter until disease progression (Progression-Free Survival determination) or withdrawal for other causes (unacceptable toxicity, patient preference). Patients undergoing PK determinations will have the dose of Avastin on cycle 2 given 24 hours after Doxil.
Overall Participants	46
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	10 21.7%
>=65 years	36 78.3%
Sex: Female, Male (Count of Participants)
Female	46 100%
Male	0 0%

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival (PFS) by RECIST Criteria
Description	Tumor response is evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.0). Target lesions are assessed by hysical exam and/or computerized tomography (CT): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient decrease in the sum of the longest diameter of target lesions to qualify for PR nor sufficient increase in the sum of the longest diameter of target lesions to qualify for Progressive Disease; Progressive Disease (PD), 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
Time Frame	Up to 25 months

Outcome Measure Data

Analysis Population Description

43 out of 46 enrolled patients were assessable for PFS by RECIST criteria. The remaining patients could not be evaluated for this endpoint because of missed imaging scans that prevented analysis according to the defined criteria.

Arm/Group Title	Doxil (PLD) + Avastin (Bevacizumab)
Arm/Group Description	Treatment was administered every 3 weeks (bevacizumab 15 mg/kg beginning on cycle 2 and PLD 30 mg/m2).
Measure Participants	43
Median (Full Range) [Months]	7.8

2. Secondary Outcome

Title	Overall Survival
Description	The time from treatment initiation to death by any cause
Time Frame	4 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Doxil (PLD) + Avastin (Bevacizumab)
Arm/Group Description	Treatment was administered every 3 weeks (bevacizumab 15 mg/kg beginning on cycle 2 and PLD 30 mg/m2).
Measure Participants	46
Median (Full Range) [Months]	33.2

3. Secondary Outcome

Title	Overall Response Rate (ORR) by RECIST
Description	ORR is the sum of the percentages of patients achieving complete and partial responses. Tumor response is evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.0)
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

43 out of 46 enrolled patients were assessable for PFS by RECIST criteria. The remaining patients could not be evaluated for this endpoint because of missed imaging scans that prevented analysis according to the defined criteria.

Arm/Group Title	Doxil (PLD) + Avastin (Bevacizumab)
Arm/Group Description	Treatment was administered every 3 weeks (bevacizumab 15 mg/kg beginning on cycle 2 and PLD 30 mg/m2).
Measure Participants	43
Complete Response (CR)	9 19.6%
Partial Response (PR)	21 45.7%
Overall Response Rate (ORR)	30 65.2%

4. Secondary Outcome

Title	Clinical Benefit Rate (by RECIST)
Description	Clinical Benefit Rate (CBR) is the sum of the percentages of patients achieving complete response, partial response, and stable disease. Tumor response is evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.0). Target lesions are assessed by physical exam and/or computerized tomography (CT): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient decrease in the sum of the longest diameter of target lesions to qualify for PR nor sufficient increase in the sum of the longest diameter of target lesions to qualify for Progressive Disease; Progressive Disease (PD), 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

43 out of 46 enrolled patients were assessable for PFS by RECIST criteria. The remaining patients could not be evaluated for this endpoint because of missed imaging scans that prevented analysis according to the defined criteria.

Arm/Group Title	Doxil (PLD) + Avastin (Bevacizumab)
Arm/Group Description	Treatment was administered every 3 weeks (bevacizumab 15 mg/kg beginning on cycle 2 and PLD 30 mg/m2).
Measure Participants	43
Complete Response (CR)	9 19.6%
Partial Response (PR)	21 45.7%
Stable Disease (SD)	56 121.7%
Clinical Benefit Rate (CBR)	86 187%

5. Secondary Outcome

Title	Overall Response Rate (ORR) by GCIC Criteria
Description	A response according to GCIC criteria has occurred if there is at least a 50% reduction in CA 125 levels from a pretreatment sample. The response must be confirmed and maintained for at least 28 days. Patients can be evaluated according to CA-125 only if they have a pretreatment sample that is at least twice the upper limit of normal and within 2 weeks prior to starting treatment.
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

43 out of 46 enrolled patients were assessable for PFS by RECIST criteria. The remaining patients could not be evaluated for this endpoint because of missed imaging scans that prevented analysis according to the defined criteria.

Arm/Group Title	Doxil (PLD) + Avastin (Bevacizumab)
Arm/Group Description	Open label study of Doxil given as 30 mg/m2 every three weeks by itself in cycle 1, and then followed by Avastin 15 mg/kg on cycle 2 and every cycle thereafter until disease progression (Progression-Free Survival determination) or withdrawal for other causes (unacceptable toxicity, patient preference). Patients undergoing PK determinations will have the dose of Avastin on cycle 2 given 24 hours after Doxil.
Measure Participants	28
Number (95% Confidence Interval) [percentage of participants]	50 108.7%

6. Primary Outcome

Title	Progression Free Survival (PFS) by GCIC Criteria
Description	Using GCIC criteria, progression is defined as CA-125 levels greater than, or equal to, 2 times the upper limit of a reference range on 2 occasions and at least 1 week apart.
Time Frame	Up to 25 months

Outcome Measure Data

Analysis Population Description

28 out of 46 enrolled patients were assessable for PFS per GCIC criteria. The remaining patients could not be evaluated for this endpoint because the timing of their CA-125 measurements did not meet the defined criteria.

Arm/Group Title	Doxil (PLD) + Avastin (Bevacizumab)
Arm/Group Description	Open label study of Doxil given as 30 mg/m2 every three weeks by itself in cycle 1, and then followed by Avastin 15 mg/kg on cycle 2 and every cycle thereafter until disease progression (Progression-Free Survival determination) or withdrawal for other causes (unacceptable toxicity, patient preference). Patients undergoing PK determinations will have the dose of Avastin on cycle 2 given 24 hours after Doxil.
Measure Participants	28
Median (95% Confidence Interval) [Months]	6.6

Adverse Events

Time Frame	3 years
Arm/Group Title	Doxil (PLD) + Avastin (Bevacizumab)
Arm/Group Description	Treatment was administered every 3 weeks (bevacizumab 15 mg/kg beginning on cycle 2 and PLD 30 mg/m2).
All Cause Mortality
	Doxil (PLD) + Avastin (Bevacizumab)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Doxil (PLD) + Avastin (Bevacizumab)
	Affected / at Risk (%)	# Events
Total	3/46 (6.5%)
Gastrointestinal disorders
Nausea	1/46 (2.2%)	1
Vomiting	1/46 (2.2%)	1
Dehydration	1/46 (2.2%)	1
Esophagoscopy abnormal: ulceration	1/46 (2.2%)	1
Infections and infestations
Bladder Infection	1/46 (2.2%)	1
Musculoskeletal and connective tissue disorders
Muscle weakness	1/46 (2.2%)	1
Nervous system disorders
Cognitive disturbance	1/46 (2.2%)	1
Headache	1/46 (2.2%)	1
Speech impairment: global aphasia	1/46 (2.2%)	1
Respiratory, thoracic and mediastinal disorders
Pleural effusion	1/46 (2.2%)	1
Other (Not Including Serious) Adverse Events
	Doxil (PLD) + Avastin (Bevacizumab)
	Affected / at Risk (%)	# Events
Total	45/46 (97.8%)
Blood and lymphatic system disorders
Hemoglobin decreased	6/46 (13%)	9
Leukocyte count decreased	5/46 (10.9%)	11
Neutrophil count decreased	6/46 (13%)	8
Platelet count decreased	4/46 (8.7%)	7
Cardiac disorders
Hypertension (High blood pressure)	18/46 (39.1%)	34
Eye disorders
Blurred vision	3/46 (6.5%)	5
Gastrointestinal disorders
Abdominal distension	4/46 (8.7%)	5
Abdominal pain	14/46 (30.4%)	20
Constipation	15/46 (32.6%)	22
Diarrhea	8/46 (17.4%)	13
Dyspepsia (Indigestion)	3/46 (6.5%)	4
Mucositis - oral (Mouth inflammation)	9/46 (19.6%)	16
Nausea	17/46 (37%)	32
Vomiting	6/46 (13%)	12
Anorexia (Loss of appetite)	8/46 (17.4%)	11
Dehydration	3/46 (6.5%)	3
General disorders
Allergic reaction	4/46 (8.7%)	4
Fatigue	23/46 (50%)	40
Fever	3/46 (6.5%)	3
Edema: limbs	4/46 (8.7%)	5
Ear, nose and throat examination abnormal	14/46 (30.4%)	18
Infections and infestations
Urinary tract infection	6/46 (13%)	8
Investigations
Hyperglycemia (High blood glucose)	9/46 (19.6%)	17
Hypocalcemia (Low calcium levels)	4/46 (8.7%)	4
Hypokalemia (Low potassium levels)	5/46 (10.9%)	8
Hypomagnesemia (Low magnesium levels)	3/46 (6.5%)	5
Hyponatremia (Low sodium levels)	8/46 (17.4%)	13
Creatinine increased	5/46 (10.9%)	8
Proteinuria	4/46 (8.7%)	6
Metabolism and nutrition disorders
Weight Loss	5/46 (10.9%)	7
Musculoskeletal and connective tissue disorders
Back pain	4/46 (8.7%)	6
Joint pain	3/46 (6.5%)	3
Myalgia (Muscle pain)	3/46 (6.5%)	4
Pain in extremity	5/46 (10.9%)	8
Pain - Other	8/46 (17.4%)	9
Nervous system disorders
Dizziness	4/46 (8.7%)	4
Headache	20/46 (43.5%)	31
Peripheral sensory neuropathy	11/46 (23.9%)	15
Anxiety	5/46 (10.9%)	6
Depression	3/46 (6.5%)	3
Renal and urinary disorders
Urinary frequency	5/46 (10.9%)	5
Respiratory, thoracic and mediastinal disorders
Cough	7/46 (15.2%)	9
Dyspnea (Shortness of breath)	6/46 (13%)	6
Epistaxis (Nosebleed)	10/46 (21.7%)	14
Voice alteration	3/46 (6.5%)	6
Skin and subcutaneous tissue disorders
Skin disorders - Other	7/46 (15.2%)	9
Dry skin	12/46 (26.1%)	13
Hand-and-foot syndrome	21/46 (45.7%)	76
Hyperpigmentation	7/46 (15.2%)	8
Rash	15/46 (32.6%)	22
Desquamating rash	5/46 (10.9%)	9

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT 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.