E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
ER, PgR, and HER2 negative (triple negative) metastatic breast cancer |
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E.1.1.1 | Medical condition in easily understood language |
breast cancer that has spread to other parts of the body and does not respond to hormonal or anti-HER2 therapy ('triple negative disease') |
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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 | 16.1 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10006289 |
E.1.2 | Term | Benign and malignant breast neoplasms |
E.1.2 | System Organ Class | 100000004872 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10055113 |
E.1.2 | Term | Breast cancer metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
- Phase 2: evaluate the benefit and risk profiles of the two nab-paclitaxel experimental arms and identify the nab-paclitaxel combination that will be used in the Phase 3.
- Phase 3: compare the progression-free survival (PFS) of nab-paclitaxel plus either gemcitabine or carboplatin to gemcitabine/carboplatin in subjects with TNMBC, as assessed by independent blinded radiologist(s) using RECIST 1.1 guidelines. |
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E.2.2 | Secondary objectives of the trial |
- Phase 2:
● safety
● investigator-determined progression free survival (PFS)
● investigator-determined overall response rate (ORR)
● Overall survival (OS)
- Phase 3:
● Compare safety and tolerability of each treatment regimen
● Compare Overall Response Rate (ORR), determined by independent blinded radiologist(s)
● Compare Overall Survival (OS)
● Compare Disease Control Rate (CR, PR and SD ≥ 16 weeks)
● Compare Duration of Response |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
A subject will be eligible for inclusion in this study only if all of the following criteria are met:
1. Female subjects, age ≥ 18 years at the time informed consent is signed
2. Pathologically confirmed metastatic adenocarcinoma of the breast
a. Paraffin fixed primary or metastatic site tumor sample (most recently obtained) is required for central laboratory biomarker evaluation
3. Pathologically confirmed as triple negative, source documented, defined as both of the following
a. Estrogen Receptor (ER) and Progesterone Receptor (PgR) negative: < 1% of tumor cell nuclei are immunoreactive in the presence of evidence that the sample can express ER or PgR (positive intrinsic controls) (Hammond, 2010)
b. HER2 negative (Wolff, 2007):
i. Immunohistochemistry (IHC) 0 or 1+, or
ii. IHC 2+ and confirmed negative by Flourescence In Situ Hybridization (FISH), (FISH HER2/CEP17 ratio < 1.8), or
iii. Average HER2 gene copy number of < 4 signals/nucleus for test systems without and internal control probe
4. Subjects must have received prior adjuvant or neoadjuvant anthracycline therapy; or anthracycline treatment must be clinically contraindicated.
5. Subjects with measurable disease, defined by RECIST 1.1 guidelines
6. No prior cytotoxic chemotherapy for metastatic breast cancer. Prior immunotherapy and/or monoclonal antibody therapy are acceptable. Prior treatments must have been discontinued at least 30 days prior to start of study treatment and all related toxicities must have resolved to ≤ Grade 1.
7. Prior neoadjuvant or adjuvant chemotherapy, if given, must have been completed at least 30 days before start of study treatment with all related toxicities resolved, and documented evidence of disease progression per RECIST 1.1 guidelines is required
8. Prior radiotherapy must have completed at least 2 weeks before randomization, with full recovery. The measurable disease (target lesions) must be completely outside the radiation portal or there must be unequivocal radiologic or clinical exam proof of progressive disease within the radiation portal
9. At least 30 days from major surgery before the start of study treatment, with full recovery
10. ECOG performance status 0–1
11. Subject has the following blood counts at screening:
- ANC ≥ 1500/mm2 ;
- platelets ≥ 100,000/mm2 ;
- Hemoglobin ≥ 9 g/dL
12. Subject has the following blood chemistry levels at screening:
- AST (SGOT), ALT (SGPT) ≤ 2.5 x upper limit of normal range (ULN); if hepatic metastases present ≤ 5.0 x ULN
- total bilirubin ≤ ULN (subjects with Gilbert's syndrome can have bilirubin of up to 1.5 x ULN)
- alkaline phosphatase ≤ 2.5 x ULN (unless bone metastases are present in the absence of liver metastasis)
- creatinine clearance > 60 mL/min (by Cockroft-Gault)
13. Females of child-bearing potential [defined as a sexually mature woman who (1) have not undergone hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) or (2) have not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time during the preceding 24 consecutive months)] must:
- Agree to the use of two physician-approved contraceptive methods (oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner) while on study medication;
and for 28 days following the last dose of study medication; and
- Negative serum pregnancy test result at screening (performed by central lab) confirmed by local negative urine pregnancy dipstick within 72 hours prior to the first dose of IP); pregnancy test with sensitivity of at least 25 mIU/mL
14. Females must abstain from breastfeeding during study participation and 28 days after IP discontinuation
15. Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures are conducted
16. Able to adhere to the study visit schedule and other protocol requirements
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E.4 | Principal exclusion criteria |
1. Male subjects with breast cancer.
2. Concurrent chemotherapy or any other anti-tumor therapy for breast cancer. Prior immunotherapy & monoclonal antibody therapy are acceptable.
3. Concurrent or prior anticoagulation therapy within 7 days of first dose of study treatment
4. History of, or known current evidence of brain metastasis, including leptomenigeal involvement.
5. Subjects with bone as the only site of metastatic disease
6. Serious intercurrent medical or psychiatric illness, including serious active infection
7. History of class II-IV congestive heart failure or myocardial infarction within 6 months of beginning study treatment
8. History of other primary malignancy in the last 5 years. Subjects with prior history of in situ cancer or basal or localized squamous cell skin cancer are eligible. Subjects with other malignancies are eligible if they were cured by surgery alone or surgery plus radiotherapy and have been continuously disease-free for at least 5 years
9. Subjects with a history of interstitial lung disease, history of slowly progressive dyspnea and unproductive cough, sarcoidosis, silicosis, idopathic pulmonary fibrosis, pulmonary hypersensitivity pneumonitis or multiple allergies
10. Peripheral neuropathy Grade ≥ 2 by NCI CTCAE v4.0
11. Subjects who have received an investigational product within the previous 4 weeks prior to study randomization
12. Subject is currently enrolled, or will enroll in a different clinical study in which investigational therapeutic procedures are performed or investigational therapies are administered while participating in this study
13. Pregnant or nursing women
14. Subjects with prior hypersensitivity to nab-paclitaxel, gemcitabine, carboplatin or any other platin, or nucleoside analogue agents
15. Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study
16. Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if she were to participate in the study
17. Any condition that confounds the ability to interpret data from the study
18. History of seropositive human immunodeficiency virus (HIV) or subjects who are receiving immunosuppressive or myelosuppressive medications that would, in the opinion of the investigator, increase the risk of serious neutropenic complications
19. Initiation of bisphosphonate for bone metastasis therapy while on study. Subjects receiving bisphosphonate therapy initiated ≥ 1 day prior to starting IP are eligible. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Phase II: Progression-Free Survival (PFS) based on investigator assessment of response using RECIST 1.1 guidelines.
Phase III: Progression-Free Survival (PFS) based on an independent blinded radiologist(s) assessment using RECIST 1.1 guidelines. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
- in phase II: when approximately 144 PFS events have ocurred
- in phase III: when 330 PFS events or 217 deaths have ocurred, whichever is later |
|
E.5.2 | Secondary end point(s) |
- phase II:
● Efficacy: Overall Response Rate (ORR), investigator-determined, using RECIST 1.1 guidelines; percentage of subjects who initiated Cycle 6; overall Survival
● Safety: Incidence/Grade of TEAEs, serious adverse events (SAEs), laboratory abnormalities; incidence of subjects experiencing dose modifications (dose interruptions and
reductions); percentage of subjects who discontinued for adverse event
- Phase III:
key secondary endpoints: ORR with a confirmed complete or partial response; OS;
others: efficacy (investigator assessment of PFS; disease control rate; duration of response in subjects with objective CR or PR), safety (incidence of TEAEs, SAEs, laboratory abnormalities) |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
phase II: efficacy and safety at cut-off date of follow-up period
phase III: efficacy and safety at cut-off date of follow-up period; final analysis of overall survival after approximately 309 deaths |
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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 | No |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
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 | Yes |
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 | Yes |
E.8.2.3.1 | Comparator description |
carboplatin + gemcitabine |
|
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 62 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Canada |
France |
Greece |
Italy |
Japan |
Austria |
Portugal |
Australia |
Brazil |
Germany |
Spain |
United Kingdom |
United States |
|
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
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after approximately 309 deaths required to conduct the final overall survival assessment |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |