| 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 |
|
| 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') |
|
| 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 | 18.0 |
| 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 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| 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) |
|
| 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 carboplatin to gemcitabine/carboplatin in subjects with TNMBC, as assessed by independent blinded radiologist(s) using RECIST 1.1 guidelines. |
|
| 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 adenocarcinoma of the breast
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 (ASCO/CAP Guidelines 2013 preferred; Wolff, 2007 acceptable):
i. IHC 0 or 1 or FISH negative (or equivalent negative test). Subjects with IHC 2 must have a negative FISH (or equivalent negative test).
4. Subjects with prior breast cancer history of different phenotypes (ie, ER/PgR/HER2 positive) must have pathologic confirmation of triple negative disease in at least one of the current sites of metastasis
5. Subjects must have received prior adjuvant or neoadjuvant anthracycline therapy, unless (a) anthracycline treatment was not indicated or was not the best treatment option in the opinion of the treating physcian, and b) remains not indicated or not the best treatment option for metastatic disease. Newly diagnosed subjects presenting with TNMBC are eligible if anthracycline treatment is not indicated or not the best treatment option
6. Subjects with measurable disease, defined by RECIST 1.1 guidelines
7. Life expectancy ≥ 16 weeks from randomization
8. 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.
9. Prior neoadjuvant or adjuvant chemotherapy, if given, must have been completed at least 6 months before start of study treatment (or 12 months if it contained taxane, gemcitabine or platinum agents), all related toxicities resolved, and documented evidence of disease progression per RECIST 1.1 guidelines is required
10. Prior radiotherapy must have completed before randomization, with full recovery from acute radiation side effects. At least 1 measurable lesions must be completely outside the radiation portal or there must be unequivocal radiologic or clinical exam proof of PD within the radiation portal (RECIST 1.1)
11. At least 30 days from major surgery before the start of study treatment, with full recovery
12. ECOG performance status 0–1
13. Subject has the following blood counts at screening:
- ANC ≥ 1.5 x 10^9/L
- platelets ≥ 100 x 10^9/L
- Hemoglobin ≥ 9 g/dL
14. 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 serum bilirubin ≤ ULN; or total bilirubin <= 3.0 x ULN with direct bilirubin within normal range in subjects with documented Gilbert's syndrome
- creatinine clearance > 60 mL/min (by Cockroft-Gault)
15. Females of child-bearing potential [defined as a sexually mature women 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:
- Negative serum pregnancy test result at screening (performed by central lab) confirmed by local negative urine pregnancy dipstick within 72 h before first dose of IP); pregnancy test with sensitivity of at least 25 mIU/mL
- Either commit to true abstinence* from heterosexual contact (which must be reviewed on a monthly basis) or agree to use, and be able to comply with, two physician approved effective contraception methods (oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner)andwithout interruption for 28 days or longer as required by local guidelines, prior to starting study drug, during the study therapy (including dose interruptions), and for 28 days after discontinuation of the study or longer as required by local guidelines
16. Females must abstain from breastfeeding during study participation and for 28 days or longer as required by local guidelines, after IP discontinuation
17. Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures are conducted
18. Able to adhere to the study visit schedule and other protocol requirements
|
|
| E.4 | Principal exclusion criteria |
1. Male subjects.
2. Concurrent chemotherapy or any other anti-tumor therapy for breast cancer. Prior immunotherapy & monoclonal antibody therapy are acceptable.
3. Subjects who received prior cytotoxic chemotherapy after incomplete resection of locoregional recurrent disease.
4. History of, or known current evidence of brain metastasis, including leptomeningeal involvement.
5. Subjects with bone as the only site of metastatic disease
6. Subjects with regional lymph node as the only site of metastatic disease as per AJCC TNM
7. Serious intercurrent medical or psychiatric illness, including serious active infection
8. History of class II-IV congestive heart failure or myocardial infarction within 6 months of randomization.
9. History of other primary malignancy in the last 5 years. Subjects
with prior breast cancer history are eligible, however the most recently obtained biopsy must demonstrate triple negative disease (source documented). Subjects with prior history of in situ cancer or basal or localized squamous cell skin cancer are eligible.
10. Subjects with a history of interstitial lung disease, history of slowly progressive dyspnea and unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonary hypersensitivity pneumonitis or multiple uncontrolled or unstable allergies which, in the opinion of the investigator, may lead to serious complications.
11. Peripheral neuropathy Grade ≥ 2 by NCI CTCAE v4.0
12. Subjects who have received an investigational product within the previous 4 weeks prior to randomization
13. 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
14. Pregnant or nursing women
15. Subjects with prior hypersensitivity to nab-paclitaxel, gemcitabine, carboplatin or any other platin, or nucleoside analogue agents
16. Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study
17. Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if she were to participate in the study
18. Any condition that confounds the ability to interpret data from the study
19. History of seropositive human immunodeficiency virus (HIV)
20. Subjects who are receiving immunosuppressive or myelosuppressive medications that would, in the opinion of the investigator, increase the risk of serious neutropenic complications
|
|
| 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. |
|
| 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 |
|
| 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
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 3 |
| 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 |
| Australia |
| Austria |
| Brazil |
| Canada |
| France |
| Germany |
| Greece |
| Italy |
| Japan |
| Portugal |
| 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
|
| 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 | 6 |
| 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 | 6 |
| 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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