| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Locally recurrent or metastatic hormone receptor positive (HR+) breast cancer and either:
• HER2+ disease with progression while on adjuvant antiendocrine therapy or at any time after adjuvant antiendocrine therapy, or
• HER2- disease with progression while on adjuvant antiendocrine therapy or within 6 months of completing adjuvant antiendocrine therapy. |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027475 |
| E.1.2 | Term | Metastatic breast cancer |
|
| 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 the clinical benefit rate (CBR) in patients receiving the BMS-690514/letrozole combination relative to the lapatinib/letrozole combination. |
|
| E.2.2 | Secondary objectives of the trial |
• To compare progression free survival (PFS) of BMS-690514/letrozole with lapatinib/letrozole
• To estimate objective response rate (ORR) of BMS-690514/letrozole with lapatinib/letrozole
• To assess the safety and tolerability of BMS-690514 combined with letrozole
Exploratory Objectives:
• To explore the population pharmacokinetics of BMS-690514 when BMS-690514 and letrozole are concomitantly administered.
• To explore associations between efficacy and candidate biomarkers (including, but not limited to, ER-low histoscore, PTEN protein loss, PIK3CA mutation status, VEGF-A polymorphism status) as measured in tumor tissue, plasma and whole blood.
• To explore the pharmacodynamic effects of BMS-690514 and lapatinib on biomarkers of ErbB and VEGFR activity. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Signed Written Informed Consent
Target Population
2) Histologically documented invasive breast cancer, positive for ER+ and/or PgR+ in greater than or equal to 10% of tumor cells with tumor tissue from prior surgery available for analysis of ER/PR, EGFR, HER2, PTEN and PIK3CA
3) Patients must have previously received adjuvant treatment for their breast cancer using tamoxifen, anastrozole or exemestane. Sequential use of antihormonal agents is permitted.
a) Patients with HER2- disease must have developed disease progression or recurrence while receiving or within 6 months of completing adjuvant treatment prior to the first dose of randomized study medication
b) Patients with HER2+ disease must have developed disease progression or recurrence while receiving or at any time after receiving adjuvant treatment with prior to the first dose of randomized study medication
4) Patients who received cytotoxic chemotherapy (in the adjuvant, neoadjuvant or metastatic settings) are required to have completed therapy at least 4 weeks prior to the first dose of randomized study medication.
5) Patients who received adjuvant therapy using trastuzumab alone or in combination with either chemotherapy or an aromatase inhibitor are required to have completed therapy at least 2 weeks prior to the first dose of randomized study medication.
a) Patients with newly diagnosed metastatic breast cancer that is HER2+ and HR+ who do not receive treatment with trastuzumab plus aromatase inhibitor standard-of-care therapy (where this is considered an approved use of the combination) are eligible for this study with careful documentation of the reason why trastuzumab-based therapy was not used
6) Patients may have received radiotherapy to a limited area only within 2 weeks prior to the initiation of randomized therapy but this cannot be the sole site of disease and cannot be used as a target lesion
7) ECOG performance status of 0 or 1
8) Patients have disease that is either measurable or non-measurable, including bone only disease without a soft tissue component.
a) Measurable lesions include measurable lytic or lytic/blastic lesions as noted in the RECIST 1.1 criteria. See Appendix 6.
9) Adequate bone marrow function defined as:
a) Absolute neutrophil count > 1500/mm³.
b) Hemoglobin > 10 g/dL (The use of erythropoietin stimulating agents is permitted)
c) Platelet count > 100,000/mm³
10) Adequate renal parameters defined as:
a) Serum creatinine ≤ 1.2 mg/dL or a 24-hour urinary creatinine clearance > 60 mL/min. For patients over the age of 70, a 24-hour urine collection for creatinine clearance must be performed and must indicate a creatinine clearance of > 60 mL/minute.
b) Serum magnesium > 1.5 mg/dL or > 0.5 mmol/L (supplementation to achieve this is acceptable).
c) Serum potassium > 3.5 mEq/L (supplementation to achieve this is acceptable).
11) Adequate hepatic parameters defined as:
a) AST ≤ 2.5 times the institutional ULN
b) ALT ≤ 2.5 times the institutional ULN
c) Alkaline phosphatase ≤ 2 times the institutional ULN
d) Total bilirubin ≤ 2 times the institutional ULN
12) In the presence of documented liver metastases, the hepatic parameters will be defined as:
a) AST ≤ 3.5 times the institutional ULN
b) ALT ≤ 3.5 times the institutional ULN
c) Alkaline phosphatase ≤ 2.5 times the institutional ULN
d) Total bilirubin ≤ 2.5 times the institutional ULN
13) Patients must be able to take oral medications on an empty stomach (1 hour before or 2 hours after a meal)
14) Patients who have CNS metastases are permitted onto this study if they are asymptomatic and require only low dose steroids (equivalent to 4 mg of dexamethasone or less) and if these metastases are documented as non-progressing at the time of study entry.
15) Visceral metastases (eg, liver, lung) are permitted if asymptomatic and if they do not affect the patient’s ECOG performance status
16) Able to comply with visits/procedures required by the protocol
Age and Reproductive Status
17) Postmenopausal women who are amenorrheic for greater than 12 consecutive months without another cause (ie, pregnancy) and women with a documented serum follicle stimulating hormone (FSH) level of greater than 35 mIU/mL.
a) Women who underwent bilateral oophorectomy or prior radiation castration and are experiencing amenorrhea for at least 6 months are permitted. Bilateral oophorectomy for the initial treatment of premenopausal women with MBC is not permitted as this would constitute first-line hormonal therapy
b) Women who are not of childbearing potential (ie, who are postmenopausal or
surgically sterile; see Section 3.3.3 for the definition of WOCBP) ages ≥ 18
c) Women must have a negative serum pregnancy test (minimum sensitivity 25 IU/L
or equivalent units of HCG) prior to the start of investigational product.
d) Women must not be breastfeeding |
|
| E.4 | Principal exclusion criteria |
Target Disease Exceptions
18) Patients who have received prior hormonal therapy for metastatic disease
19) Patients who have received prior hormonal therapy with letrozole for adjuvant disease
20) Not Applicable - This criterion has been deleted per Amendment 02. Patients who present with blastic bony metastatic disease as their only manifestation of recurrent or metastatic breast cancer
21) Patients who have symptomatic brain metastases
22) Patients who have signs or symptoms suggestive of spinal cord compression or any other medical condition that requires immediate radiotherapy, surgery or high dose steroid therapy
23) Other concurrent chemotherapy, hormonal therapy, immunotherapy regimens or radiotherapy, standard or investigational
24) Any history of hemoptysis > 10mL/day within the last 10 days
Medical History and Concurrent Diseases
25) Concurrent or previous malignancies (except for non-melanoma skin cancers, in situ bladder cancer, cervical cancer/dysplasia or any other in situ malignancies) are excluded unless a complete remission was achieved at least 3 years prior to randomization and no additional therapy is required or anticipated to be required during the study period
26) Prior treatment with any tyrosine kinase inhibitor (marketed or investigational)
27) Uncontrolled or significant cardiovascular disease including:
a) Myocardial infarction within 6 months
b) Uncontrolled angina within 6 months
c) Class III-IV New York Heart Association (NYHA) congestive heart failure
d) Uncontrolled hypertension (systolic blood pressure of greater than 150 mmHg or diastolic blood pressure above 90 mmHg for 24 hours) despite optimized antihypertensive therapy.
28) Any history of uncontrolled diarrhea, Crohn’s disease or ulcerative colitis that may be exacerbated by EGFR tyrosine kinase inhibitors
29) Any serious or uncontrolled medical disorder or active infection that would impair the ability of the patient to receive protocol therapy (This includes any possible risks of interactions that may interfere with the control of the medical disorder that is
unrelated to the patient’s breast cancer.)
30) Any surgery within 4 weeks of initiation of randomized therapy
31) Any non-healing wounds or skin ulcers
32) Inability to swallow tablets, malabsorption syndrome or gastrointestinal surgery that results in inability to properly absorb protocol therapy
33) Patients with a documented diagnosis of HIV
34) Any psychiatric or other disorders such as dementia that would prohibit the patients from understanding or rendering informed consent or from fully complying with protocol treatment and follow-up
35) Inability to tolerate multiple blood sampling/or tolerate venous access
36) Any other medical, psychiatric, and/or social reason as determined by the investigator.
Physical and Laboratory Test Findings
37) Cardiac ejection fraction that is below the institutional range of normal as measured by echocardiogram or MUGA
Allergies and Adverse Drug Reaction
38) History of allergy to EGFR/HER2/VEGFR tyrosine kinase inhibitors
Sex and Reproductive Status
39) Women of child-bearing potential or have not undergone menopause
40) Men with breast cancer
Other Exclusion Criteria
41) Prisoners or subjects who are involuntarily incarcerated
42) Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is to compare the CBR in patients receiving the BMS-690514/letrozole combination relative to the lapatinib/letrozole combination. |
|
| 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 | Yes |
| 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 | 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 | 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 6 |
| 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 | 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
|
The trial will end when the event rate for the secondary endpoint of Progression-Free Survival (PFS) is met.
Any patients who are still on trial that were not part of the event rate analysis would continue on the study until disease progression. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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