| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced Estrogen Receptor-Positive Breast Cancer. |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10006190 |
| E.1.2 | Term | Breast cancer invasive NOS |
|
| 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 |
| To compare progression-free survival (PFS) distribution for exemestane plus dasatinib vs exemestane plus placebo. |
|
| E.2.2 | Secondary objectives of the trial |
1) To estimate Clinical Benefit Rate (CBR) and Freedom-From-Progression at 6 months (FFP-6) in each treatment arm;
2) To estimate [in subjects evaluable for response] the Objective Response Rate, Time to Response and Response Duration in each treatment arm;
3) To assess safety and tolerability in each treatment arm;
4) To evaluate [in subjects with bone metastasis] changes in subject-reported pain
intensity and markers of bone lysis in each treatment arm. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Histologically-documented invasive breast cancer, positive for ER and/or PgR in
≥ 10% of tumor cells (institutional determination), with tumor tissue from prior
surgery available for analysis.
2) Prior therapy
a) Required: a non-steroidal aromatase inhibitor (eg NSAI, letrozole or anastrozole),
with exposure of ≥ 12 months in adjuvant setting or ≥ 4 months in advanced setting
b) Permitted: tamoxifen, fulvestrant, chemotherapy with or without trastuzumab
and/or lapatinib, bisphosphonates. Targeted antitumor therapy (eg, bevacizumab)
is allowed if given in combination with an NSAI or chemotherapy.
c) Chemotherapy in advanced setting is allowed ONLY if completed ≥ 6 months
prior to study entry and NSAI was subsequently received.
3) Recurrent or progressive advanced breast cancer (locally-advanced or metastatic),
either:
a) during or ≤ 12 months after completion of adjuvant NSAI treatment, OR
b) during NSAI treatment in advanced setting
4) Documented advanced breast cancer with ≥1 measurable or evaluable(non-measurable) tumor ≤ 28 days prior to treatment start.
a) CNS metastasis is permitted if asymptomatic without steroid requirement
≥ 8 weeks has elapsed since treatment and is documented to be non-progressing at
study entry
b) Visceral metastasis (eg, lung, liver) is permitted if asymptomatic, has no effect on
Performance Status, and is not associated with abnormal laboratory values
5) Women who are not of childbearing potential (ie, are postmenopausal or surgically
sterile) and men, ages ≥ 18.
Women are considered surgically sterile only if they have undergone hysterectomy,
bilateral tubal ligation, or bilateral oophorectomy. Post menopause is defined as:
• Amenorrhea ≥ 12 consecutive months without another cause or
• For women with irregular menstrual periods, a documented serum follicle stimulating hormone (FSH) level > 35 mIU/mL.
Women with ovarian suppression due to use of goserelin (Zoladex®) or other LH-RH
agonist MUST have a negative pregnancy test prior to investigational drug start.
6) Recovery to Grade 0 - 1 from acute toxicities of prior therapy, except alopecia
7) Performance Status 0 or 1 (see Protocol Appendix 3)
8) Able to take oral medications (dasatinib tablets must be swallowed intact) reliably
9) Signed Written Informed Consent according to Local Regulations |
|
| E.4 | Principal exclusion criteria |
1) Target Disease or Therapy Exclusions
a) Pleural or pericardial effusion or ascites (of any etiology; Grade ≥ 1) within
6 months prior to study entry. Trace or ‘minimal’ effusion is acceptable.
b) Any chemotherapy or immunotherapy < 6 months before study entry. Any
targeted therapy (eg, lapatinib) < 6 months before study entry, unless given in
combination with an NSAI.
c) Any antitumor therapy, including radiotherapy or hormonal therapy, within
15 days prior to treatment start
d) Prior exposure to exemestane, to any Src-family kinase inhibitor including
dasatinib, to agents intended to control osteolytic metastatic disease other than
bisphosphonates, or to any investigational agent for breast cancer except as in 1b
2) Medical History or Concurrent Disease
a) Concurrent or previous malignant disease requiring chemotherapy or radiation
treatment within the prior 3 years,
b) Significant bleeding disorder, including: diagnosed congenital bleeding disorders
(eg, von Willebrand’s disease); diagnosed acquired bleeding disorder within
1 year (eg, acquired anti-factor VIII antibodies), or ongoing or recent
(≤ 3 months) clinically-significant gastrointestinal bleeding,
c) Serious concomitant systemic disorder, including bacterial, fungal or viral
infection requiring intravenous therapy, which in the opinion of Investigator is
incompatible with Study,
d) Serious cardiac condition, including congestive heart failure or myocardial
infarction within 6 months, uncontrolled angina, or Class III or IV heart disease as
defined by the New York Heart Association, baseline EF ≤ 40%, diagnosed
congenital long QT syndrome, clinically-significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes), QTc
interval > 450 msec at baseline (Fridericia correction)
3) Physical and Laboratory Test Findings
a) Hematologic abnormality Grade ≥ 2
b) Hypocalcemia of Grade ≥ 1
c) Any Chemistry abnormality of Grade ≥ 2 [except Grade 2 indirect bilirubin
permitted if diagnosed Gilbert’s disease]
4) Pregnant Women and Women of Childbearing Potential (WOCBP)
WOCBP include any female who has experienced menarche and who has not
undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or
bilateral oophorectomy) and is not postmenopausal. Post menapause is defined as:
• Amenorrhea ≥ 12 consecutive months without another cause or
• For women with irregular menstrual periods, a documented serum follicle stimulating hormone (FSH) level ≥ 35 mIU/mL).
Women who are amenorrheic due to chemotherapy, who are using oral
contraceptives, other hormonal contraceptives (vaginal products, skin patches, or
implanted or injectable products), or mechanical products such as an intrauterine
device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy,
or are practicing abstinence or where their partner is sterile (eg, vasectomy) should be considered to be WOCBP. To be eligible, women must be postmenopausal based on age-related amenorrhea, surgical sterilization or ovarian suppression by use of
goserelin (Zoladex®) or other LH-RH agonist, see Inclusion 5.
5) Allergies and Adverse Drug Reactions
a) Extremely lactose intolerant, in the judgment of Treating Physician (100 mg
dasatinib contains 135 mg lactose, posing a problem only if intolerance is severe)
6) Prohibited Treatments and/or Therapies [see Protocol Section 5.5.1]
a) Is receiving any of the following concomitant medications: Category I drugs that
are generally accepted to have a risk of causing Torsades de Pointes including:
(Subjects must discontinue drug at least 7 days prior to starting dasatinib)
i) quinidine, procainamide, disopyramide
ii) amiodarone, sotalol, ibutilide, dofetilide
iii) erythromycin, clarithromycin
iv) chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide
v) cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone,
halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine.
b) Potent inhibitors of CYP3A4 isoenzyme
c) Hormone Replacement Therapy (HRT)
7) Other
a) Prisoners or subjects who are involuntarily incarcerated
b) Subjects who are compulsorily detained for treatment of either a psychiatric or
physical (eg, infectious disease) illness
Eligibility criteria for this study have been carefully considered to ensure the safety of the study subjects and to ensure that the results of the study can be used. It is imperative that subjects fully meet all eligibility criteria. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint is Progression free survival (PFS).
PFS will be defined as time from date of randomization until date PD is first reported. Subjects who die without a reported prior progression will be considered to have progressed on the day of their death. Subjects who initiate other non-study treatment for breast cancer (excluding palliative radiotherapy per Protocol Section 5.5.1) will be censored at the day of last tumor assessment prior to that other
therapy. Subjects who neither progress nor die will be censored at the day of their last on-study tumor assessment, or initiation of subsequent therapy, whichever is later. Subjects who have no on-study tumor assessments will be censored on the day they were
randomized.
|
|
| 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 | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 31 |
| 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 | Information not present in EudraCT |
| 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 |
|
| 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
| |
| 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 | 1 |
| 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 | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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