A Study of Avastin (Bevacizumab) in Combination With Chemotherapy in Patients With Breast Cancer Progressing After First-Line Therapy With Avastin and Chemotherapy (TANIA)

Study Overview
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Brief Summary
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This randomized, open-label, parallel-group study will assess the efficacy and s afety of Avastin (bevacizumab) in combination with chemotherapy versus chemother apy alone as second- and third-line therapy in patients with locally recurrent o r metastatic breast cancer progressing after first-line therapy with Avastin and chemotherapy. Patients will be randomized to receive either Avastin (15 mg/kg e very 3 weeks or 10 mg/kg every 2 weeks intravenously) plus standard chemotherapy or chemotherapy alone. Anticipated time on study treatment is until third-line disease progression or unacceptable toxicity occurs.

Official Title
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A Phase III Randomized Study Evaluating the Efficacy and Safety of Continued and Re-induced Bevacizumab in Combination With Chemotherapy for Patients With Locally Recurrent or Metastatic Breast Cancer After First-line Chemotherapy and Bevacizumab Treatment

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: bevacizumab [Avastin]
* Drug: Chemotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female patients, >/= 18 years of age Histologically confirmed HER2-negative breast cancer Disease progression during or following first-line treatment with Avastin and chemotherapy for locally recurrent or metastatic breast cancer Avastin treatment in first-line setting must have been a minimum of 4 cycles (15 mg/kg) or 6 cycles (10 mg/kg) in combination with chemotherapy ECOG performance status 0-2 At least 28 days since prior radiation therapy or surgery and recovery from treatment Exclusion Criteria: Anti-angiogenic therapy or anti-vascular endothelial growth factors other than Avastin for first-line treatment Active malignancy other than superficial basal cell and superficial squamous cell carcinoma of the skin, or in situ carcinoma of the cervix or breast within the last 5 years Inadequate renal function Clinically relevant cardio-vascular disease Known CNS disease except for treated brain metastases Chronic daily treatment with high-dose aspirin (>325 mg/day) or clopidogrel (>75 mg/day) Pregnant or lactating women

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1<br> | Drug: Chemotherapy<br>* Standard chemotherapy (doublets not allowed)<br>|
| Experimental: 2<br> | Drug: bevacizumab [Avastin]<br>* 10 mg/ kg iv every 2 weeks or 15 mg/kg iv every 3 weeks<br>Drug: Chemotherapy<br>* Standard chemotherapy (doublets not allowed)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Second-Line Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (v1.1) | Second-line PFS was defined as the time from randomization to progressive disease (PD) or death due to any cause during their second-line of treatment with bevacizumab and/or chemotherapy, whichever occurred first. For target lesions (TLs), PD was defined at least a 20 percent (%) increase in the sum of the largest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of one or more new lesions. For non-target lesions (NTLs), PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing NTLs. Participants without second-line PD or death were censored at the date of last tumor assessment where non-progression was documented. | Baseline (less than or equal to [≤] 28 days after randomization), every 8-9 weeks thereafter according to the standard of care of the treatment site until approximately 3 years | 
| Second-Line PFS | The median time, in months, from randomization to second-line PFS event. For TLs, PD was defined at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of one or more new lesions. For NTLs, PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing NTLs. Participants without second-line PD or death were censored at the date of last tumor assessment where non-progression was documented. | Baseline (≤28 days after randomization), every 8-9 weeks thereafter according to the standard of care of the treatment site until approximately 3 years | 
| Percentage of Participants Estimated to be Alive and Free of Second-Line Disease Progression at Month 6 | Second-line PFS was defined as the time from randomization to PD or death due to any cause during their second-line of treatment with bevacizumab and/or chemotherapy, whichever occurred first. For TLs, PD was defined at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of one or more new lesions. For NTLs, PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing NTLs. Participants without second-line PD or death were censored at the date of last tumor assessment where non-progression was documented. | Month 6 | 
| Percentage of Participants Estimated to be Alive and Free of Second-Line Disease Progression at Month 12 | Second-line PFS was defined as the time from randomization to PD or death due to any cause during their second-line of treatment with bevacizumab and/or chemotherapy, whichever occurred first. For TLs, PD was defined at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of one or more new lesions. For NTLs, PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing NTLs. Participants without secondline PD or death were censored at the date of last tumor assessment where non-progression was documented. | Month 12 | 
| Percentage of Participants Estimated to be Alive and Free of Second-Line Disease Progression at Month 18 | Second-line PFS was defined as the time from randomization to PD or death due to any cause during their secondline of treatment with bevacizumab and/or chemotherapy, whichever occurred first. For TLs, PD was defined at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of one or more new lesions. For NTLs, PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing NTLs. Participants without second-line PD or death were censored at the date of last tumor assessment where non-progression was documented. | Month 18 | 
| Percentage of Participants Estimated to be Alive and Free of Second-Line Disease Progression at Month 24 | Second-line PFS was defined as the time from randomization to PD or death due to any cause during their second-line of treatment with bevacizumab and/or chemotherapy, whichever occurred first. For TLs, PD was defined at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of one or more new lesions. For NTLs, PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing NTLs. Participants without second-line PD or death were censored at the date of last tumor assessment where non-progression was documented. | Month 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Second-Line PFS by Baseline Risk Factor (Data Cutoff 20 December 2013) | The median time, in months, from randomization to second-line PFS event according to the following baseline risk factors: hormone receptor negative, HER2 negative (triple negative), hormone receptor positive/HER-2 negative (HR-pos/HER-neg), first-line PFS less than (<) 6 months, first-line PFS greater than or equal to (≥) 6 months, taxane chemotherapy (chemo), non-taxane chemo, vinorelbine chemo, LDH ≤ 1.5 upper limit of normal (ULN), LDH greater than (>) 1.5 ULN, < 65 years of age, ≥ 65 years of age, < 70 years of age, ≥ 70 years of age, < 3 metastatic organ sites, ≥ 3 metastatic organ sites, bevacizumab-free (B-free) interval ≤ 6 weeks, B-free > 6 weeks, disease-free (D-free) interval ≤ 24 months, D-free > 24 months, D-free ≤ 12 months, and D-free > 12 months. Participants without second-line PD or death were censored at the date of last tumor assessment where non-progression was documented. PD: defined in Outcome measure 1. The 95% CI was estimated using Kaplan-Meier methodology. | Baseline (≤28 days after randomization), every 8-9 weeks thereafter according to the standard of care of the treatment site until approximately 3 years | 
| Percentage of Participants With a Second-Line Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) According to RECIST v1.1 (Data Cutoff 20 December 2013) | BOR was defined as a confirmed CR or PR during second-line treatment. For TLs, CR was defined as the disappearance of all TLs, and PR was defined as at least a 30% decrease in the SLD of the TLs, taking as a reference the baseline SLD. For NTLs, CR was defined as the disappearance of all NTLs and normalization of tumor marker levels. The 95% Cl was determined using the Pearson-Clopper method. | Baseline (≤28 days after randomization), every 8-9 weeks thereafter according to the standard of care of the treatment site until approximately 3 years | 
| Percentage of Participants With a Second-Line CR, PR, Stable Disease, and PD According to RECIST v1.1 (Data Cutoff 20 December 2013) | For TLs, CR was defined as the disappearance of all TLs; PR was defined as at least a 30% decrease in the SLD of the TLs, taking as a reference the baseline SLD; SD was defined as neither sufficient decrease in SLD to qualify for PR nor sufficient increase in SLD to qualify for PD; and PD was defined as at least a 20% increase in the SLD of TLs, taking as reference the smallest SLD recorded since the treatment started. For NTLs, CR was defined as the disappearance of all NTLs and normalization of tumor marker levels; stable disease was defined as the persistence of 1 or more NTLs and/or maintenance of tumor marker levels above normal limits; and PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing NTLs. The 95% CI was determined using the Pearson-Clopper method. | Baseline (≤28 days after randomization), every 8-9 weeks thereafter according to the standard of care of the treatment site until approximately 3 years | 
| Duration of Second-Line Objective Response (Data Cutoff 20 December 2013) | The median time, in months, from the date of the first second-line documentation of CR or PR according to RECIST v1.1 to the date of the first second-line documentation of PD or death due to any cause. For TLs, CR was defined as the disappearance of all TLs; PR was defined as at least a 30% decrease in the SLD of the TLs, taking as a reference the baseline SLD; and PD was defined as at least a 20% increase in the SLD of TLs, taking as reference the smallest SLD recorded since the treatment started. For NTLs, CR was defined as the disappearance of all NTLs and normalization of tumor marker levels, and PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing NTLs. Participants with CR or PR who had experienced neither disease progression nor died were censored at the date of the last available tumor assessment when the participant was known to be progression free. | Baseline (≤28 days after randomization), every 8-9 weeks thereafter according to the standard of care of the treatment site until approximately 3 years | 
| Percentage of Participants With a Second-Line Documented CR or PR According to RECIST v1.1 Estimated to be Alive and Free of Disease Progression at Months 3, 6, and 9 (Data Cutoff 20 December 2013) | Duration of objective response was defined as the median time, in months, from the date of the first second-line documentation of CR or PR to the date of the first second-line documentation of PD or death due to any cause. For TLs, CR was defined as the disappearance of all TLs; PR was defined as at least a 30% decrease in the SLD of the TLs, taking as a reference the baseline SLD; and PD was defined as at least a 20% increase in the SLD of TLs, taking as reference the smallest SLD recorded since the treatment started. For NTLs, CR was defined as the disappearance of all NTLs and normalization of tumor marker levels, and PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing NTLs. Participants with CR or PR who had experienced neither disease progression nor died were censored at the date of the last available tumor assessment when the participant was known to be progression free. | Months 3, 6, and 9 | 
| Percentage of Participants With Third-Line PFS According to RECIST v1.1 | Third-line PFS was defined as the time from the date of first dose of third-line bevacizumab and/or chemotherapy to the date of third-line PD or death due to any cause. For TLs, PD was defined at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of one or more new lesions. For NTLs, PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing NTLs. Participants without second-line PD or death were censored at the date of last tumor assessment where non-progression was documented. Participants without third-line PD or death were censored at the date of last tumor assessment where non-progression was documented. | First dose of third-line treatment until PD or death due to any cause (assessed every 8-9 weeks, over a period of approximately 14 months) | 
| Third-Line PFS | The median time, in months, from the first dose of third-line bevacizumab and/or chemotherapy to third-line PD or death due to any cause. For TLs, PD was defined at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of one or more new lesions. For NTLs, PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing NTLs. Participants without third-line PD or death were censored at the date of last tumor assessment where non-progression was documented. | First dose of third-line treatment until PD or death due to any cause (over a period of approximately 14 months) | 
| Percentage of Participants With Second- and Third-Line PFS According to RECIST v1.1 | Second- and third-line PFS was defined as the time from the date randomization to the date of third-line PD or death due to any cause. For TLs, PD was defined at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of one or more new lesions. For NTLs, PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing NTLs. Participants without third-line PD or death were censored at the date of last tumor assessment where non-progression was documented. | Baseline (≤28 days after randomization), every 8-9 weeks thereafter according to the standard of care of the treatment site until approximately 4 years | 
| Second- and Third-Line PFS | The median time, in months, from randomization to second-line and third-line PFS event. For TLs, PD was defined at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of one or more new lesions. For NTLs, PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing NTLs. Participants without third-line PD or death were censored at the date of last tumor assessment where non-progression was documented. | Baseline (≤28 days after randomization), every 8-9 weeks thereafter according to the standard of care of the treatment site until approximately 4 years | 
| Percentage of Participants With Second- and Third-Line Tumor Progression | Second- and third-line tumor progression was defined as occurrence of third-line PD according to RECIST v1.1 or death due to progression of disease. For TLs, PD was defined at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of one or more new lesions. For NTLs, PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing NTLs. Participants without third-line PD or death due to progression of disease were censored at the date of last tumor assessment where non-progression was documented. | Baseline (≤28 days after randomization), every 8-9 weeks thereafter according to the standard of care of the treatment site until approximately 4 years | 
| Time to Second- and Third-Line Tumor Progression | The median time, in months, from randomization to second- and third-line tumor progression. Second- and third-line tumor progression was defined as third-line PD according to RECIST v1.1 or death due to progression of disease. For TLs, PD was defined at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of one or more new lesions. For NTLs, PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing NTLs. Participants without third-line PD or death were censored at the date of last tumor assessment where non-progression was documented. | Baseline (≤28 days after randomization), every 8-9 weeks thereafter according to the standard of care of the treatment site until approximately 4 years | 
| Percentage of Participants Who Died | Percentage of participants who died due to any reason were reported. | Baseline until death (up to approximately 4 years) | 
| Overall Survival (OS) | OS was defined as the median time, in months, from the date of randomization to the date of death, due to any cause. Participants who had not died were censored at the date the patient was last known to be alive. | Baseline until death (up to approximately 4 years) | 
| Percentage of Participants Estimated to be Surviving at Months 6, 12, 18, and 24 | OS was defined as the median time, in months, from the date of randomization to the date of death, due to any cause. | Months 6, 12, 18, and 24 | 
| Percentage of Participants Experiencing Problems by European Quality of Life Instrument (EQ-5D) Category (Data Cutoff 20 December 2013) | The EQ-5D is composed of 5 single-item measures where participants responded to questions assessing health status by responding with either no problems, some problems, or extreme problems in the following categories: mobility (M) (no problems=I have no problems in walking about to extreme problems=I am confined to bed), self-care (SC) (no problems=I have no problems with self-care to extreme problems=I am unable to wash or dress myself), usual activities (UA) (no problems=I have no problems performing my usual activities to extreme problems=I am unable to perform my usual activities), pain/discomfort (P/D) (no problems=I have no pain or discomfort to extreme problems=I have extreme pain or discomfort), and anxiety/depression (A/D) (no problems=I am not anxious or depressed to extreme problems='I am extremely anxious or depressed). | Baseline, during second-line treatment at Weeks 8 and 16 (4-week cycles) or Weeks 9 and 18 (3-week cycles) and at second-line PD (up to approximately 3 years) | 
| Quality of Life Assessed As an Index Score Using the EQ-5D (Data Cutoff 20 December 2013) | The EQ-5D is composed of 5 single-item measures where participants responded to questions assessing health status by responding with either no problems, some problems, or extreme problems in the following categories: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Based on large population surveys, an algorithm was used to combine the responses to each of these 5 measures into 1 single EQ-5D index score ranging from -0.59 (extreme problems) to +1 (no problems). | Baseline, during second-line treatment at Weeks 8 and 16 (4-week cycles) or Weeks 9 and 18 (3-week cycles) and at second-line PD (up to approximately 3 years) | 
| Change From Baseline in EQ-5D Index Scores (Data Cutoff 20 December 2013) | The EQ-5D is composed of 5 single-item measures where participants responded to questions assessing health status by responding with either no problems, some problems, or extreme problems in the following categories: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Based on large population surveys, an algorithm was used to combine the responses to each of these 5 measures into 1 single EQ-5D index score ranging from -0.59 (extreme problems) to +1 (no problems) where a negative value indicated a worsening of perceived quality of life and a positive value indicated an improvement of perceived quality of life. | Baseline, during second-line treatment at Weeks 8 and 16 (4-week cycles) or Weeks 9 and 18 (3-week cycles) and at second-line PD (up to approximately 3 years) | 
| Quality of Life Assessed Using the EQ-5D Visual Analogue Scale (VAS) Scores (Data Cutoff 20 December 2013) | The participant was asked to rate their overall health on a 0-100 millimeter (mm) vertical scale, where the lowest endpoint=0 (labeled as worst imaginable health state) and the highest endpoint =100 (labeled as the best imaginable health state). The participant marked the line corresponding to their assessment and the distance from the bottom was measured in millimeters. A higher value indicated a better health state. | Baseline, during second-line treatment at Weeks 8 and 16 (4-week cycles) or Weeks 9 and 18 (3-week cycles) and at second-line PD (up to approximately 3 years) | 
| Change From Baseline in VAS Scores (Data Cutoff 20 December 2013) | The participant was asked to rate their overall health on a 0-100 mm vertical scale, where the lowest endpoint = 0 (labeled as worst imaginable health state) and the highest endpoint =100 (labeled as the best imaginable health state). The participant marked the line corresponding to their assessment and the distance from the bottom was measured in millimeters. A negative value indicated a worsening of perceived quality of life and a positive value indicated an improvement of perceived quality of life. | Baseline, during second-line treatment at Weeks 8 and 16 (4-week cycles) or Weeks 9 and 18 (3-week cycles) and at second-line PD (up to approximately 3 years) | 
| Functional Assessment of Cancer Therapy-Breast (FACT-B) Scores (Data Cutoff 20 December 2013) | The Functional Assessment of Cancer Therapy-Breast (FACT-B) is composed of 5 multi-item sections where participants responded to questions assessing symptoms (scale: 0-4; 0=not at all and 4=very much), as follows: physical well-being (PWB) (7 items, total score 0-28), social/family well-being (SWB) (7 items, total score 0-28), emotional well-being (EWB) (6 items, total score 0-24), functional well-being (FWB) (7 items, total score 0-28); and breast cancer score based on the additional concerns section of FACT-B (10 items, total score 0-40). The FACT-B Trial Outcomes Index (TOI) score=sum of PWB, FWB, and breast cancer score subscale scores (total score 0-96). The Functional Assessment of Cancer Therapy-General (FACT-G) total score=sum of PWB, SWB, EWB, and FWB subscales scores (total score 0-108). The FACT-B total score=sum of PWB, SWB, EWB, FWB, and breast cancer score subscales scores (total score 0-148). In all cases a higher value indicated a better perceived quality of life. | Baseline (≤28 days after randomization), every 8-9 weeks thereafter until second-line PD (up to approximately 3 years) | 
| Change From Baseline in FACT-B Scores (Data Cutoff 20 December 2013) | The FACT-B is composed of 5 multi-item sections where participants responded to questions assessing symptoms (scale: 0-4; 0=not at all and 4=very much), as follows: PWB (7 items, total score 0-28), SWB (7 items, total score 0-28), EWB (6 items, total score 0-24), FWB (7 items, total score 0-28); and breast cancer score based on the additional concerns section of FACT-B (10 items, total score 0-40). The FACT-B TOI score=sum of PWB, FWB, and breast cancer score subscale scores (total score 0-96). The FACT-G total score=sum of PWB, SWB, EWB, and FWB subscales scores (total score 0-108). The FACT-B total score=sum of PWB, SWB, EWB, FWB, and breast cancer score subscale scores (total score 0-148). In all cases a higher value indicated a better perceived quality of life. | Baseline (≤28 days after randomization), every 8-9 weeks thereafter until second-line PD (up to approximately 3 years) |