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Trial registered on ANZCTR


Registration number
ACTRN12614001079639
Ethics application status
Approved
Date submitted
22/08/2014
Date registered
9/10/2014
Date last updated
28/02/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
BL12: A Multicentre Randomized Phase II Trial Comparing Nab-Paclitaxel to Paclitaxel in Patients With Advanced Urothelial Cancer Progressing on or After a Platinum Containing Regimen
Scientific title
A Multicentre Randomized Phase II Trial in Patients With Advanced Urothelial Cancer Progressing on or After a Platinum Containing Regimen with two parallel arms Comparing the effectiveness of Nab-Paclitaxel to Paclitaxel to treat this disease.
Secondary ID [1] 285202 0
ClinicalTrials.gov registry number: NCT Number:
NCT02033993
Universal Trial Number (UTN)
Nil
Trial acronym
BL12
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Advanced Urothelial Cancer 292818 0
Condition category
Condition code
Cancer 293110 293110 0 0
Bladder

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Nab-Paclitaxel
Nab-Paclitaxel - 260mg/m2:
Given every 21 days (3 weeks) via intravenous infusion until disease progression or unacceptable toxicity.



Intervention code [1] 290075 0
Treatment: Drugs
Comparator / control treatment
Paclitaxel
Paclitaxel - 175mg/m2:
Given every 21 days (3 weeks) via intravenous infusion until disease progression or unacceptable toxicity.
Control group
Active

Outcomes
Primary outcome [1] 292977 0
To compare progression free survival (PFS) between the two arms

PFS is defined as the time from randomization to the first observation of disease progression or death due to any cause.

Timepoint [1] 292977 0
Time Frame: up to 42 months
Secondary outcome [1] 310064 0
To compare overall survival (OS) between arms.

Overall survival is defined as the time interval between the date of randomization and the date of death from any cause
Timepoint [1] 310064 0
Time Frame: up to 42 months
Secondary outcome [2] 310719 0
To compare clinical benefit rate (CBR) between arms, as determined by the total number of patients who achieve a complete or partial response plus those patients who have stable disease for at least 12 weeks evaluated using MRI/CT scans.
Timepoint [2] 310719 0
Time Frame: MRI/CT scans obtained at baseline and every 6 weeks up to 42 Months
Secondary outcome [3] 310721 0
To estimate time to response and response duration evaluated using MRI/CT scans.
Timepoint [3] 310721 0
Time Frame: MRI/CT scans obtained at baseline and every 6 weeks up to 42 Months
Secondary outcome [4] 310722 0
To evaluate and compare the nature, severity, and frequency of toxicities, including neuropathy between the two arms by evaluating adverse events from the time of first treatment.

Adverse events will be assessed in accordance with NCI Common Terminology Criteria for Adverse Events (CTCAE) v4
Timepoint [4] 310722 0
Time Frame: Baseline, every three weeks during treatment and every six weeks after end of treatment for up to 42 months post enrolment.
Secondary outcome [5] 310723 0
To compare the quality of life between the two arms.

Quality of life will be assessed using the EORTC-C15-PAL and FACT-Taxane questionnaires plus additional study specific questions.
Timepoint [5] 310723 0
Time frame:
Baseline,
One week after both the first and second treatments,
On the day of the fourth treatment and then every 12 weeks while on treatment.
Every six weeks after end of treatment for up to 42 months post enrolment.
Secondary outcome [6] 310724 0
To determine the incremental cost effectiveness and cost utility ratios using a health utilities assessment questionnaire (EQ-5D questionnaire).
Timepoint [6] 310724 0
Time frame:
Baseline,
One week after both the first and second treatments,
On the day of the fourth treatment and
Then every 12 weeks while on treatment and
Six weeks after end of treatment.
Secondary outcome [7] 310725 0
To correlate the expression of tissue markers (at diagnosis) with outcomes and response. Diagnostic tumor tissue will be analysed to assess this outcome.
Timepoint [7] 310725 0
Time Frame: Baseline after consent has been obtained. Outcomes and response assessed for up to 42 months.
Secondary outcome [8] 310726 0
To assess genetic polymorphisms that may impact on response or toxicity to the taxanes. A whole blood sample is collected for this assessment.
Timepoint [8] 310726 0
Time Frame: Baseline after consent has been obtained. Outcomes and response assessed for up to 42 months.
Secondary outcome [9] 310727 0
To assess the effect modification of clinico-demographic factors using health and demographics questionnaires (Questionnaire has been designed specifically for this study).
Timepoint [9] 310727 0
Time frame: Questionnaire administered at baseline. Outcomes and response assessed for up to 42 months.

Eligibility
Key inclusion criteria
1.Histologically or cytologically confirmed diagnosis of TCC of the urinary tract (bladder, urethra, ureter, renal pelvis) and metastatic or locally advanced inoperable disease extent (T4, N2, N3 or M1 disease)
Note: Mixed histologies (except small cell) permitted if predominately TCC by IHC.
2. Patients must have evidence of metastatic disease, but measurable disease is not mandatory. To be considered evaluable for the overall response rate (complete and partial response), patients must have at least one measurable lesion as follows:
*X-ray, physical exam greater than or equal to 20 mm
*Conventional CT scan, MRI greater than or equal to 20 mm
*Spiral CT scan greater than or equal to 10 mm
3. Male or female, 18 years of age or older.
4. ECOG performance status less than or equal to 2 at study entry
5. Adequate hematological, renal and hepatic functions as defined by the following required laboratory values obtained within 14 days prior to randomization. If anemic, patients should be asymptomatic and should not be decompensated.
*Absolute neutrophil count (ANC) greater than or equal to 1.5 x10^9/L (1,500 cells/mm3)
*Platelet count greater than or equal to 90 x10^9/L (100,000/mm3)
*Hemoglobin greater than or equal to 90 g/L
*Calculated creatinine clearance greater than 25 mL/min (Cockcroft and Gault formula)
*Total bilirubin less than or equal to 1.5 times the upper limit of normal (less than or equal to 2.5X if Gilbert's disease)
*ALT (SGPT) less than or equal to 3 x ULN or less than or equal to 5 x ULN if hepatic metastases are present
6. Patients may have had prior neoadjuvant or adjuvant therapy for completely resected disease, provided it was completed at least 12 months prior to randomization. Patients must have recovered from any acute toxic effects to less than or equal to Grade 2 from any prior treatments. Neoadjuvant or adjuvant chemotherapy will be considered to have been first line therapy in the metastatic setting if the patient progressed within 12 months of the last dose.
7. Patients must have received one and only one prior chemotherapeutic regimen which included a platinum (at least one cycle) for metastatic/recurrent disease. Treatment must have been discontinued at least 4 weeks prior to randomization in this study. Patients must have recovered from any acute toxic effects to less than or equal to Grade 2 from any prior treatments
8. Patients may not have had any prior therapy with a taxane in any setting.
9. Patients may have had prior investigational agents but these must have been discontinued at least 4 weeks prior to randomization. Patients must have recovered from any acute toxic effects less than or equal to Grade 2 from any prior treatments.
10. Prior treatments with radiation therapy in the adjuvant and/or metastatic setting are permitted provided that at least 2 weeks have elapsed since the last fraction of radiation therapy and all treatment related adverse events are less than or equal to Grade 1 at the time of randomization.
11. Patients may have had prior surgery provided that at least 4 weeks elapsed between the end of surgery and randomization onto the study. Patients must have recovered from any acute toxic effects less than or equal to Grade 2 from any prior treatments.
12. Patients may have peripheral neuropathy from previous treatments assuming it is less than or equal to Grade 2.
13. Patient is able (i.e. sufficiently fluent) and willing to complete the health and demographic, quality of life, and health utilities questionnaires in either English or French. The baseline assessment must be completed within required timelines, prior to registration/randomization. Inability (illiteracy in English or French, loss of sight, or other equivalent reason) to complete the questionnaires will not make the patient ineligible for the study. However, ability but unwillingness to complete the questionnaires will make the patient ineligible.
14. Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to enrollment in the trial to document their willingness to participate.
15. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within 7 days prior to randomization. In addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy, bilateral tubal ligation or vasectomy/vasectomized partner. However, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures.
16. Patients must be accessible for treatment and follow up. Patients registered on this trial must be treated and followed at the participating centre. This implies there must be reasonable geographical limits (for example: 1.5 hour's driving distance) placed on patients being considered for this trial. Investigators must assure themselves the patients registered on this trial will be available for complete documentation of the treatment, adverse events, response assessment and follow-up.
17. In accordance with NCIC CTG policy, protocol treatment is to begin within 5 working days of patient randomization.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion Criteria:
1. A candidate for potentially curative surgery or radiotherapy.
2. Patients with brain metastases are ineligible if they meet at least one of the following criteria:
a. diagnosis within 3 months from randomization
b. untreated brain metastases
c. unstable brain metastasis as defined by:
*cavitation or hemorrhage in the brain lesion
*symptomatic state
*daily prednisone or equivalent use greater than 10 mg
Patients do not need CT/MRI scans to rule out brain metastases unless there is a clinical suspicion of CNS metastases.
3. Any evidence of severe or uncontrolled systemic diseases which include known cases of hepatitis B or C or human immunodeficiency virus (HIV). Patients with active or uncontrolled infections, or with serious illnesses or medical conditions which would not permit the patient to be managed according to the protocol. Screening for chronic conditions is not required, although patients known to have such conditions at screening should not be included.
4. Women who are pregnant or breastfeeding.
5. Patients with history of allergic or hypersensitivity reactions to any study drug or their excipients or with a history of allergic reactions attributed to compounds with similar chemical composition to any of the study drugs.
6. Planned concomitant participation in another clinical trial of an experimental agent, vaccine or device. Concomitant participation in observational studies is acceptable.
7. Patients with a history of other malignancies, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumours curatively treated with no evidence of disease for greater than or equal to 5 years. Prior prostate cancer is allowed provided that it is an incidental finding at cystoprostatectomy with a PSA of less than 0.5 ng/mL at randomization or a prior diagnosis of low risk prostate cancer at any time as defined by less than or equal to T2, a Gleason Score of 6 or less and PSA of less than 10 ng/mL.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
All randomizations will be done centrally through the NCIC CTG web-based, password-operated Electronic Data Capture (EDC) system when a patient meets all the eligibility criteria.
Subjects will be stratified by:
1. Centre
2. ECOG performance status (0, 1 versus 2)
3. Liver metastases (yes versus no)
4. Lymph node metastases only (yes versus no)
5. Hemoglobin (less than 100 g/L versus greater than 100 g/L)
6. Interval from last platinum based chemotherapy (less than 6 months versus greater than 6 months)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Correlative Study and Pharmacogenomics Analyses
For all consenting patients, archival diagnostic tumour tissue and baseline whole blood will be collected and banked.
The following analyses will be performed for each treatment regimen. Descriptive statistics will be used to summarize biomarkers for responders versus to assess relationship between response and biomarkers, a logistic regression analysis will be performed with effects for biomarker and treatment regimen in the model. To assess the relationship of overall survival (and PFS) with biomarkers, a Cox regression analysis will be used with effects for biomarker and treatment regimen in the model. In addition, for SPARC and other biomarkers with binary measures, survival will be summarized by median survival time for each biomarker category along with the hazard ratio. For each treatment regimen, the Kaplan-Meier curve for survival will be presented graphically for each biomarker category and differences in the curves will be tested using the log-rank test.
Health and Demographic Questionnaire Analyses
Much of the analyses of this questionnaire involve the inclusion of elements of the HDQ as confounders or potential interactors with QoL, health economics, correlative, co-morbidity and baseline patient characteristics, and other HDQ elements for the primary and secondary outcome measures. As such, these analyses are described in the appropriate correlative, QoL, and health economic sections. The HDQ data will also be used in a descriptive manner (i.e. comparing the BL.12 trial population with demographic data derived from the larger non-trial population of patients). When quantitative analyses are needed to understand how the HDQ variable affects other potential confounders or primary and secondary outcomes, regression methods will be utilized.

Assuming a median survival of 4 months with paclitaxel, the study is designed to detect a one third reduction in the hazard of progression with nab-paclitaxel (PFS HR equal to 0.67) which translates into a 50 percent median PFS improvement of 2 months (i.e. from 4 to 6 months). Using a 1- sided 5 percent significance test with 81percent power, 155 events are required. This will be achieved with an accrual rate of 5.5 patients per month for 36 months with a follow-up period of 4 months. The estimated sample size will be approximately 199 patients which will allow for lost to follow-up or withdrawal of consent.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 5757 0
Ballarat Health Services (Base Hospital) - Ballarat Central
Recruitment hospital [2] 5758 0
Ashford Cancer Centre: Adelaide Cancer Centre - Kurralta Park
Recruitment hospital [3] 5759 0
Border Medical Oncology - Albury
Recruitment hospital [4] 5760 0
Calvary Mater Newcastle - Waratah
Recruitment hospital [5] 5761 0
Concord Repatriation Hospital - Concord
Recruitment hospital [6] 5762 0
Box Hill Hospital - Box Hill
Recruitment hospital [7] 5763 0
Epworth Freemasons - Melbourne
Recruitment hospital [8] 5764 0
Epworth Richmond - Richmond
Recruitment hospital [9] 5765 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [10] 5766 0
Barwon Health - Geelong Hospital campus - Geelong
Recruitment hospital [11] 5767 0
Liverpool Hospital - Liverpool
Recruitment hospital [12] 5768 0
Frankston Hospital - Frankston
Recruitment hospital [13] 5769 0
Port Macquarie Base Hospital - Port Macquarie
Recruitment hospital [14] 5770 0
Royal Hobart Hospital - Hobart
Recruitment hospital [15] 5771 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [16] 5772 0
St Vincents & Mercy Private Hospital - Mercy campus - East Melbourne
Recruitment hospital [17] 5773 0
The Townsville Hospital - Douglas
Recruitment hospital [18] 5774 0
Sunshine Hospital - St Albans
Recruitment hospital [19] 5775 0
Prince of Wales Hospital - Randwick
Recruitment hospital [20] 5776 0
Albury Wodonga Health - Albury campus - Albury
Recruitment hospital [21] 5777 0
Murray Valley Private Hospital - Wodonga
Recruitment hospital [22] 7839 0
Peninsula Oncology Centre - Frankston
Recruitment hospital [23] 7840 0
Nambour General Hospital - Nambour
Recruitment postcode(s) [1] 15777 0
3199 - Frankston
Recruitment postcode(s) [2] 15778 0
4560 - Nambour

Funding & Sponsors
Funding source category [1] 289817 0
Other Collaborative groups
Name [1] 289817 0
CCTG (Canadian Cancer Trials Group)
Address [1] 289817 0
Cancer Clinical Trials Division
Cancer Research Institute
Queen's University
10 Stuart Street
Kingston, ON K7L 3N6
Country [1] 289817 0
Canada
Primary sponsor type
University
Name
NHMRC CTC (National Health and Medicine Research Council Clinical Trial Centre) at the University of Sydney.
Address
The Chris O'Brien Lifehouse,
Level 6, 119-143 Missenden Road
Camperdown
NSW 2050
Country
Australia
Secondary sponsor category [1] 288509 0
Other Collaborative groups
Name [1] 288509 0
ANZUP Cancer Trials Group (Australia and New Zealand Urogenital and Prostate Cancer Trials Group)
Address [1] 288509 0
The Chris O'Brien Lifehouse,
Level 6, 119-143 Missenden Road
Camperdown
NSW 2050
Country [1] 288509 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 291554 0
Health Canada
Ethics committee address [1] 291554 0
Office of Clinical Trials (OCT)
Therapeutic Products Directorate
Health Products and Food Branch
Address Locator: 3105A
Health Canada
Ottawa, Ontario
K1A 0K9
Ethics committee country [1] 291554 0
Canada
Date submitted for ethics approval [1] 291554 0
Approval date [1] 291554 0
03/06/2014
Ethics approval number [1] 291554 0
9427-N1119-109C
Ethics committee name [2] 291555 0
SLHD Ethics Review Committee (RPAH Zone)
Ethics committee address [2] 291555 0
Research Development Office
Royal Prince Alfred Hospital
Missenden Road
CAMPERDOWN NSW 2050
Ethics committee country [2] 291555 0
Australia
Date submitted for ethics approval [2] 291555 0
10/07/2014
Approval date [2] 291555 0
30/09/2014
Ethics approval number [2] 291555 0
X14-0217 and HREC/14/RPAH/283, AU/1/5649115

Summary
Brief summary
The purpose of this study is to evaluate the effects of nab-paclitaxel compared to paclitaxel in patients with advanced urothelial cancer.
Who is it for?
You may be eligible to join this study if you are aged 18 years or above, and have been diagnosed with metastatic or locally advanced transitional cell carcinoma (TCC) of the urinary tract (bladder, urethra, ureter, renal, pelvis), which has progressed on or after a platinum containing regimen.
Study details
Participants in this study will be randomly (by chance) allocated to one of two groups. Participants in one group will receive intravenous infusions of the chemotherapy drug Paclitaxel every 21 days. Participants in the other group will receive intravenous infusions of the chemotherapy drug Nab-Paclitaxel every 21 days. Treatment will continue indefinitely as long as you are responding and able to tolerate the drug well.

All participants will be followed-up for up to 42 months in order to evaluate disease response, survival, toxicity, and quality of life. This research is being done because currently there is no effective treatment for advanced urothelial cancer that has progressed after prior chemotherapy.
Trial website
(none)
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 50834 0
Dr Ben Tran
Address 50834 0
Freemasons Medical Centre
Suite 117 Level 1
320 Victoria Parade
East Melbourne VIC 3002
Country 50834 0
Australia
Phone 50834 0
+61 (0) 3 9416 1154
Fax 50834 0
Email 50834 0
ben.tran@petermac.org
Contact person for public queries
Name 50835 0
Ms Anna Walsh
Address 50835 0
NHMRC Clinical Trials Centre, THE UNIVERSITY OF SYDNEY
The Chris O'Brien Lifehouse, Level 6, 119-143 Missenden Road Camperdown NSW 2050
Country 50835 0
Australia
Phone 50835 0
+61 2 9562 5322
Fax 50835 0
Email 50835 0
anna.walsh@ctc.usyd.edu.au
Contact person for scientific queries
Name 50836 0
Dr Ben Tran
Address 50836 0
Freemasons Medical Centre
Suite 117 Level 1
320 Victoria Parade
East Melbourne VIC 3002
Country 50836 0
Australia
Phone 50836 0
+61 (0) 3 9416 1154
Fax 50836 0
Email 50836 0
ben.tran@petermac.org

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary