E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
|
E.1.1.1 | Medical condition in easily understood language |
|
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 | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10006206 |
E.1.2 | Term | Breast carcinoma NOS |
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 |
In women with ER-positive breast cancer about to undergo surgery, does two week's pretreatment with a new drug (the PI3K inhibitor GDC-0941, given in combination with the estrogen-blocker anastrozole) increase the benefits of anastrozole in slowing down tumour cell growth, as measured by laboratory measurements on tumour cells?
|
|
E.2.2 | Secondary objectives of the trial |
• Does the new combination kill cancer cells more effectively than anastrozole alone?
• Is the new combination more effective than anastrozole alone in shrinking the breast cancer?
• Is it possible to link any apparent benefits of using GDC-0941 to the biomarker status of the patient, perhaps leading to a strategy of tailored drug therapy to be examined in future studies?
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Women must meet ALL of the following criteria:
• Histologically-confirmed breast cancer involving a palpable tumour of any size, or a tumour with an ultrasound-assessed diameter of ≥ 1.0 cm
• Estrogen receptor (ER) positive tumours with ≥1% of tumour cells positive for ER on immunohistochemical staining or an immunhistochemistry score (Allred) of 3 or higher
• *No prior systemic treatment regimens for the new primary breast cancer currently under investigation; prior treatment for previous breast cancer is allowed as long as it was completed at least 1 year prior to inclusion into this trial.* • Postmenopausal, defined as 1) age ≥ 55y and 1y or more of amenorrhea, OR 2) age < 55y and 1y or more of amenorrhea, with an estradiol assay <20 pg/mL, OR 3) age < 55y with prior hysterectomy but intact ovaries with an estradiol level <20 pg/mL, OR 4) Status after bilateral oophorectomy (≥ 28 days prior to first study treatment).
• Adequate hematologic function (ANC ≥ 1500 cells/µl + platelet count ≥ 100000/µl).
• Serum creatinine concentration < 1.5 x ULN; AST, ALT, bilirubin level < 1.5 x ULN; Fasting plasma glucose level < 7.8 mmol/L.
• ECOG performance status 0-2
• Written informed consent prior to admission to the study
|
|
E.4 | Principal exclusion criteria |
• Male gender • *Inflammatory breast cancer.* • HER2-positive tumours with 3+ intensity on IHC staining for HER2 or amplification of the HER2 gene on ISH. • Evidence of distant metastases. • *Previous systemic or local treatment for the new primary breast cancer currently under investigation (including surgery, radiotherapy, cytotoxic and endocrine treatments); prior treatment for previous breast cancer is allowed as long as it was completed at least 1 year prior to inclusion into this trial.* •*Previous systemic treatment for other neoplasms within 1 year prior to inclusion into this trial.* • Clinically significant pulmonary dysfunction. • Uncontrolled Type 1 or 2 diabetes mellitus (diabetic patients must have been on a stable regimen of oral anti-hyperglycemic therapy for at least 3 weeks duration and must have home monitoring levels without fasting blood glucose >8.9 mmol/L or hypoglycemia for one week prior to study entry) • Serious intercurrent medical or psychiatric illness, including serious active infection. • Concurrent treatment with other experimental drugs or participation in another clinical trial with any investigational drug within 30 days prior to study entry. • Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that, in the investigator’s opinion, gives reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Change in tumour cell proliferation measured by Ki67 immunohistochemical assessment (%) in biopsy samples taken at diagnosis and day 15. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
At baseline and on day 15. |
|
E.5.2 | Secondary end point(s) |
The secondary outcome measures for this study are: • Increase in apoptosis: Changes in the tumour (TUNEL assay) measured at diagnosis and on day 15. • Change in tumour cell proliferation after discontinuation of GDC-0941 as measured by Ki67 IHC (%) on day 15 and on the day of definitive surgery *(if surgery is not performed on Day 15 +/- 2 days*) • Clinical objective response. • Pathological response and residual cancer burden.
The safety outcome measures for this study are as follows: • Incidence of serious adverse events • Incidence of all adverse events of all grades • Adverse events leading to anastrozole or GDC-0941 discontinuation • Changes in vital signs and clinical laboratory results during and following study drug administration • Changes in ECG measurements
Exploratory Outcome Measures Exploratory outcome measures may include genome-wide measurements in tumour DNA and RNA, including mutational status, RNA gene-expression values, DNA copy number, and protein expression and phosphorylation. Exploratory analysis may include, but will not be limited to, the following: • Presence of activating PI3KCA mutations in tumour specimens taken at surgery by PCR and/or sequencing • Level of PTEN expression in tumour biopsy specimens taken at baseline, after 15 (+/-2) days of treatment and at surgery by IHC and/or reverse phase protein array (RPPA) • Level of expression and phosphorylation of candidate proteins (including but not limited to Akt, PTEN, S6, p70S6, PRAS40, EGFR, HER2, HER3, ERK1/2, GSK3ab, ER, MEK1-2, p27, 4EBP1) in tumour biopsy specimens taken at baseline, after 15 (+/-2) days of treatment and at surgery by IHC, reverse-phase protein arrays and/or coincidence detection assay • Gene copy number of PTEN and other candidate genes in tumour specimens taken at surgery • Presence of activating PI3KCA mutations from plasma DNA • Presence of PI3K/PTEN-regulated gene expression signature in tumour biopsy specimens taken at baseline, after 15 days (+/-2 days) of treatment and at surgery by gene expression microarrays or Fluidigm Microfluid Platform • Presence of Luminal A and Luminal B breast cancer markers through transcriptional profiling • Molecular profiling of tumour biopsy specimens taken at baseline, after 15 (+/-2) days of treatment and at surgery including mRNA (e.g. by microarrays), microRNA (e.g. by microarrays or PCR), protein expression/phosporylation (e.g. mass spectroscopy), re-sequencing, and promoter methylation (e.g. by methylation microarrays and Pyrosequencing)
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
At baseline, on day 15 and at surgery *(if surgery is not performed on Day 15 +/- 2 days)* |
|
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 | Yes |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | 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 | 4 |
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 | No |
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
|
30 days after the last patient receives the last dose of the investigational medicinal product (IMP). |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
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 | 2 |
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 |