| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
metastatic or recurrent locally advanced breast cancer that
is ER-, PR- (or unknown) and HER2- or known BRCA1/BRCA
2 carriers. |
|
| E.1.1.1 | Medical condition in easily understood language |
metastatic or recurrent locally advanced breast cancer that
is ER-, PR- (or unknown) and HER2- or known BRCA1/BRCA
2 carriers. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 13.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027475 |
| E.1.2 | Term | Metastatic breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Objective tumour response rate (CR + PR): Response will be evaluated after three and six cycles of chemotherapy using modified RECIST criteria (see Appendix 2), with appropriate clinical assessment and radiological investigations. There will be a ‘response evaluation committee’ to independently assess all claimed responses |
|
| E.2.2 | Secondary objectives of the trial |
Time to progression (TTP): This will be defined according to RECIST criteria and will be
measured from randomisation until the confirmation of progression.
• Progression Free Survival (PFS): This will be defined according to RECIST criteria and will be measured from randomisation until the confirmation of progression or death.
• Response to second line protocol therapy on progression will be assessed using RECIST criteria as described for the primary endpoint.
Time to Treatment Failure (TTF): This will be defined as time from randomisation to
discontinuation of protocol treatment for any reason, or progression of disease as defined by RECIST.
• Overall Survival (OS): This will be defined as time from randomisation until death from any cause in the intention to treat population.
• Toxicity: This will be assessed throughout the treatment period using the NCI CTC AE v3.0
• Frequency of development of symptomatic new cerebral metastases |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
•Either:
• Histologically confirmed ER-, PR-, HER2- primary invasive breast cancer
Allred/quick score <3 or H score <10 or ER and PR negative, if other cut-offs used (e.g., 1%, 5% or
10%), see Appendix 3. HER2 negative defined as immunohistochemistry scoring 0 or 1+ for
HER2, or 2+ and non-amplified for HER2 gene by FISH or CISH; see Appendix 3.
or:
• PR unknown but ER- and HER2-, and otherwise eligible. Please arrange urgent PR
testing. If PR unknown and PR testing is not possible within a reasonable timeframe,
the patient is eligible for the trial provided that ER and HER2 status are negative and
all other eligibility criteria are met.
or:
• Confirmed BRCA1 or 2 mutation carrier, with any ER, PR and HER2 status
plus:
• Measurable confirmed metastatic or recurrent locally advanced disease unsuitable for
local therapy but suitable for taxane chemotherapy.
TNT Protocol Version 3.0, 18 June 2009
10
NB: Patients who have not received anthracycline based chemotherapy in the
adjuvant setting or for locally advanced disease may have received a non-taxane,
anthracycline regimen as their first treatment at relapse and are eligible to enter the
trial at confirmed progression after the anthracycline treatment
• Patients with stable, treated brain metastases will be eligible providing informed
consent can be given and that other sites of measurable disease are present
• Patients with bone metastases currently receiving bisphosphonates for palliation will
be eligible providing other sites of measurable disease are present
• ECOG Performance Status 0, 1 or 2 (see Appendix 4)
• Adequate haematology, biochemical indices (FBC, U & Es)
• LFTs = Normal bilirubin, AST and/or ALT ≤3 x ULN if Alk Phos >5 x ULN (or an
isolated elevation AST/ALT of ≤5 x ULN)
• Adequate renal function – Glomerular Filtration Rate (GFR) of >25mls per minute
(see Appendix 5)
• Written informed consent, able to comply with treatment and follow-up. |
|
| E.4 | Principal exclusion criteria |
Original primary tumour or subsequent relapse known to be positive for any of ER,
PR, or HER2 receptors (defined above and in Appendix 3) unless patient is a known
BRCA1 or BRCA 2 mutation carrier
• Patients unfit for chemotherapy or those with neuropathy >grade 1 (sensory or motor)
• Known allergy to platinum compounds or to mannitol
• Known sensitivity to taxanes
• Patients with inoperable locally advanced disease suitable for local radiotherapy or an
anthracycline containing regimen.
• Previous chemotherapy for metastatic disease other than an anthracycline as in
inclusion criteria above.
• Previous exposure to a taxane in adjuvant chemotherapy within 12 months of trial
entry
• Previous treatment with a taxane for recurrent locally advanced disease which was
not completely excised.
• Previous treatment with a platinum chemotherapy drug
• LFTs = Abnormal bilirubin (> ULN) and/or AST and/or ALT >3 x ULN with Alk Phos >5
x ULN, or an isolated elevation AST/ALT of >5 x ULN.
• Patients with a life expectancy of less than 3 months
TNT Protocol Version 3.0, 18 June 2009
11
• Previous malignancies other than adequately treated in situ carcinoma of the uterine
cervix or basal or squamous cell carcinoma of the skin, unless there has been a
disease-free interval of at least 10 years
• Previous or synchronous second breast cancer (unless also confirmed ER-, PR-
/unknown and HER2-)
• Patients with bone limited disease
• Other serious uncontrolled medical conditions or concurrent medical illness likely to
compromise life expectancy and/or the completion of trial therapy
• Pregnant, lactating or potentially childbearing women not using adequate
contraception
(documentation of a negative serum HCG pregnancy test should be available for premenopausal
women with intact reproductive organs, or women less than two years
after the menopause. Fertile women and their partners must use a medically
acceptable contraceptive throughout the treatment period and for six months following
cessation of treatment. Subjects must be made aware before entering the trial of the
risk in becoming pregnant). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
PRIMARY ENDPOINT
Objective tumour response rate (CR + PR): Response will be evaluated after three and six cycles of chemotherapy using modified RECIST criteria (see Appendix 2), with appropriate clinical assessment and radiological investigations. There will be a ‘response evaluation committee’ to independently assess all claimed responses.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Response will be evaluated after three and six cycles of chemotherapy using modified RECIST criteria (see Appendix 2 of protocol), with appropriate clinical assessment and radiological investigations. There will be a ‘response evaluation committee’ to independently assess all claimed responses.
|
|
| E.5.2 | Secondary end point(s) |
SECONDARY ENDPOINTS
• Time to progression (TTP): This will be defined according to RECIST criteria and will be measured from the start of treatment until the confirmation of progression.
• Progression Free Survival (PFS): This will be defined according to RECIST criteria and will be measured from the start of treatment until the confirmation of progression or death.
• Response to second line protocol therapy on progression will be assessed using RECIST criteria as described for the primary endpoint.
• Time to Treatment Failure (TTF): This will be defined as time from randomisation to
discontinuation of protocol treatment for any reason, or progression of disease as defined by RECIST.
• Overall Survival (OS): This will be defined as time from randomisation until death from any cause in the intention to treat population.
• Toxicity: This will be assessed throughout the treatment period using the NCI CTC AE v3.0 (see Appendix 6 of trial protocol).
• Frequency of development of symptomatic new cerebral metastases
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Until evidence of disease progression (on second line protocol therapy) or treatment withdrawal due to any drug-related serious adverse event or patient choice. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 140 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
Definition of the end of the trial is 30 days after the last patient receives the last dose of the investigational medicinal product.
However patients will be followed up longer term, the duration of time for which patient follow up data will be collected is dependent on future funding arrangements.
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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