E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Premenopausal ER-positive, PgR-positive early breast cancer |
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E.1.1.1 | Medical condition in easily understood language |
Early breast cancer that is oestrogen receptor positive and progesterone receptor positive, in patients that are premenopausal. |
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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 | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10070577 |
E.1.2 | Term | Oestrogen receptor positive breast cancer |
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 |
The primary objective is to evaluate the response to treatment as measured by changes in the Ki67 proliferation index after 2 weeks of treatment in ER positive, PgR positive, HER2 negative breast cancer. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives in this study are: - To determine changes in the pro-aptoptic marker cleaved caspase 3 after 2 weeks of treatment - To determine changes in ER, PgR (steroid nuclear receptors), FoxA1 (pioneer factor), Cyclin D1 (ER regulated gene) and RANKL (putative PgR target gene) protein and mRNA expression after 2 weeks of treatment - To determine changes in circulating steroidogenic hormones after two weeks of treatment. - To determine the pharmacokinetics of tamoxifen and N-desmethyltamoxifen (DMT). - To establish the safety and tolerability of progesterone plus tamoxifen. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Women 16 years of age and above • New diagnosed histologically confirmed breast cancer • Premenopausal as defined by the following criteria: o gonadotrophin levels (luteinizing hormone and follicle stimulating hormone) and oestradiol levels within the local laboratory’s reference range for premenopausal females • Ability to provide menstrual cycle information • ER positive (Allred ≥3) • PgR positive (Allred ≥3) • HER2 negative (IHC 1+ or 2+ and HER2/CEP17 ratio of <2) • Tumour measuring ≥14mm in longest diameter by ultrasound (US)/mammogram examination • Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2 • Adequate bone marrow function defined by Hb≥10 g/dl, WBC≥3.0 x109, PLT≥100 x109/L. • Adequate renal function defined by a serum creatinine ≤1.5 x ULN. Adequate liver function defined by total bilirubin ≤ 1.5 ULN (patients with Gilbert’s syndrome exempted), either ALT or AST ≤1.5 ULN and ALP ≤1.5 ULN • Written informed consent, able to comply with treatment and follow-up • Currently using adequate contraception, and willing to continue use of this for the duration of the trial and for one year following end of treatment.
Adequate contraception is defined as either:
a. Total abstinence: When this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception.
b. Sterlisation: have had surgical tubal ligation at least six weeks before taking study treatment.
c. Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate). For female study subjects, the vasectomized male partner should be the sole partner for that patient.
d. Placement of a copper intrauterine device (IUD)
e. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository.
Note: Hormonal contraceptive methods (e.g. oral, injected and implanted) are not permitted. |
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E.4 | Principal exclusion criteria |
• Inoperable breast cancer • Inflammatory tumours • Evidence of metastatic disease • Prior endocrine therapy or chemotherapy for breast cancer • Any history of invasive malignancy within 5 years of starting study treatment (other than adequately treated basal cell carcinoma or squamous cell carcinoma of the skin and cervical carcinoma in situ) • Concomitant use (defined as use within 12 weeks prior to entry) of OCP or any other oestrogen-containing medication or supplement • History of thromboembolic disease • Known carrier of genetic defects predisposing to thromboembolic disorders • Any medical condition that would prevent the use of low molecular weight heparin for venous thromboembolism prophylaxis • Uncontrolled abnormalities of serum potassium, sodium, calcium or magnesium levels • Evidence of bleeding diathesis • Evidence of uncontrolled active infection • Evidence of significant medical condition or laboratory finding which, in the opinion of the investigator, makes it undesirable for the patient to participate in the trial • Pregnant or lactating women |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary outcome measure is the Ki67 proliferation index. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Samples will be taken at baseline and after 14(+4) days of treatment (ending the day before or the day of surgery) |
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E.5.2 | Secondary end point(s) |
• Changes in the pro-aptoptic marker cleaved caspase 3 after 2 weeks of treatment. • Changes in ER, PgR (steroid nuclear receptors), FoxA1 (pioneer factor), Cyclin D1 (ER regulated gene) and RANKL (putative PgR target gene) protein and mRNA expression after two weeks of treatment. • Changes in circulating steroidogenic hormones after two weeks of treatment. • Pharmacokinetics of tamoxifen and N-desmethyltamoxifen (DMT). • Safety and tolerability of progesterone plus tamoxifen.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Baseline and 14(+4) days of treatment |
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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 | No |
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 | No |
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 | No |
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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Control arm - tamoxifen only |
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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 | 13 |
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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 1 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 1 |