| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced or Metastatic Her-2-positive Breast Cancer |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065430 |
| E.1.2 | Term | HER-2 positive breast cancer |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.0 |
| 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 |
| The dose escalation part will determine the maximum tolerated dose (MTD) and a recommended Phase II dose (or dose range as appropriate) of BMS-754807 administered orally on a once daily schedule in combination with trastuzumab administered at standard doses intravenously on a weekly basis. The primary objective for the dose expansion part is to assess the anti-tumor response rate of the combination. |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the safety and tolerability of the combination regimen.
• To assess the effect of the combination therapy on glucose metabolism.
• To explore whether co-medication with an oral anti-hyperglycemic agent can enable adequate tolerability of the combination therapy if BMS-754807 doses induce hyperglycemia.
For additional exploratory objectives see Protocol section 2.3. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Signed Written Informed Consent
2) Target Population
a) Subjects with locally advanced or metastatic Her-2-positive breast tumors who have failed at least one trastuzumab containing regimen in the advanced or metastatic setting. Prior treatment with other Her-2-targeted agents (e.g. lapatinib, pertuzumab, trastuzumab DM-1, neratinib etc) is allowed. When treatment with Her-2- targeted therapy has stopped, progression should occur within 6 months after last er-2-targeted treatment to be eligible for the dose expansion phase.
b) Histologic or cytologic diagnosis of Her-2-positive breast cancer. Her-2-positivity is defined as either 3+ on immunohistochemistry (uniform, intense membrane staining of > 30% of invasive tumor cells) or FISH-positive (>2.2 ratio: (HER2 gene signals to chromosome 17 signals)) based on local laboratory results.
c) Ability to comply with visits/procedures required by the protocol.
d) Life expectancy of at least 3 months.
e) Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (Appendix 2)
f) A tumor paraffin tissue block or 20 - 30 unstained slides from the tumor tissue block, cut within one week of shipment, must be provided for biomarker and predictive marker analyses. (This tissue does not need to be obtained fresh at the time of screening. Obtaining archived tumor material or unstained slides from an archived tumor block will suffice to meet this requirement. Archived tumor tissue must be provided during the screening, if a new biopsy is needed this should also occur during screening).
g) Subjects in the dose expansion phase must have measurable disease as defined by RECIST criteria (Appendix 3).
3) Previous Treatment
a) Prior anti-cancer treatments are permitted (ie. chemotherapy, radiotherapy, hormonal, or immunotherapy).
b) Toxicity related to prior anti-cancer therapy and/or surgery must either have resolved, returned to baseline or been deemed irreversible except for alopecia. Four (4) weeks must have elapsed between surgery and/or last dose of prior anti-cancer therapy and the initiation of study therapy.
c) Prior to enrollment (within 4 weeks) or anytime during study participation, radiation therapy is allowed to a limited field (eg painful bone metastasis, painful lumps) after consultation with the medical monitor, if it is not the sole site of measurable and/or assessable disease.
4) Age and Sex
Women, ages 18 years and above.
Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study [and for up to 3 months after the last dose of investigational product] in such a manner that the risk of pregnancy is minimized. |
|
| E.4 | Principal exclusion criteria |
1) Sex & Reproductive Status
a)WOCBP unwilling or unable to use acceptable method to avoid pregnancy for the entire study period & for up to 3 months after the last dose of investigational product (IP)
b)WOCBP using a prohibited contraceptive method
c)Pregnant or breastfeeding women
d)Women with positive pregnancy test on enrollment or prior IP administration
2) Target Disease Exceptions
a)Subj. with known symptomatic brain metastasis. Subj. with controlled brain metastasis will be allowed. Subj. with signs or symptoms suggestive of brain metastasis, unless brain metastases are ruled out by CT or MRI
b)Any condition requiring chronic use of steroids. Inhalation steroids for mild pulmonary disease eg not leading to exclusion based on other criteria allowed
3) Medical History & Concurrent Diseases
a)Serious uncontrolled medical disorder or active infection, which would impair the ability of the subj. to receive protocol therapy
b)Any disorder with dysregulation of glucose homeostasis incl. but not limited to history of Type 1 or 2 Diabetes Mellitus or prediabetic symptoms, incl. polyuria or polydipsia and delayed healing of wounds, excl. prior hyperglycemia in pregnancy
c)History of glucose intolerance or conditions with an ancillary effect on glucose, eg Cushing syndrome, pheochromocytoma, acromegaly, aldosteronism, or hyperthyroidism (excl. hyperthyroidism treated and adequately controlled for ≥4 weeks before entering the study)
d)Current or recent (within 3 months) gastrointestinal disease that could impact study drug absorption
e)Major surgery within 4 weeks of study drug administration
f)Gastrointestinal surgery that could impact study drug absorption
g)Inability to swallow oral medication
h)Inability to be venipunctured and/or tolerate venous access
i)Uncontrolled or significant cardiovascular disease incl.:
•Myocardial infarction within 6 months
•Uncontrolled angina within 3 months
•Congestive heart failure within 3 months
•LVEF ≤ the institutional lower limit of normal
•Previous treatment discontinuation because of significant cardiotoxicity in adjuvant or metastatic setting (interruptions with restart upon recovery allowed)
•Diagnosed or suspected congenital long QT syndrome
•Any history of clinically significant ventricular arrhythmias; controlled AF is not an excl. criterion
j)Subj. with concomitant second malignancies (exc. non-melanoma skin cancers & adequately treated in-situ carcinoma of the cervix), unless complete remission achieved at least 5 years prior to study entry & no additional therapy required/anticipated to be required during study
k)Any other sound medical psychiatric and/or social reason as determined by Investigator
4) Physical & Lab Test Findings
a)Fasting blood glucose levels indicating diabetes defined as fasting glucose ≥7.0 mmol/L (126 mg/dL)
b)Inadequate bone marrow function defined as:
•Absolute neutrophil count <1,500 cells/mm³
•Platelet count <100,000 cells/mm³
•Hemoglobin <9.0 g/dL (5.6 mmol/L)
c)Inadequate hepatic function defined as:
•Total bilirubin >1.5 times the institutional upper limit of normal (IULN).
•Alanine transaminase (ALT) and aspartate transaminase (AST) >2.5 times the IULN (ALT & AST <=5 times IULN acceptable if elevation is due to tumor involvement of the liver)
d)Inadequate renal function defined as: Serum creatinine >1.5 times the IULN.
e)Abnormalities in serum sodium, potassium, calcium and magnesium levels ≥ Grade II
5) Allergies & Adverse Drug Reactions
a)History of allergy to compounds chemically related to BMS-754807
b)History of any significant drug allergy
6) Prohibited Treatments and/or Therapies
a)Prior exposure to BMS-754807
b)Exposure to any IP or placebo within 4 weeks of study drug administration
c)Concurrent chemotherapy, hormonal therapy, immunotherapy regimens or radiation therapy standard or investigational; except: radiation therapy to a limited field, if it is not the sole site of measurable and/or assessable disease, is allowed any time during study, after medical monitor consultation
d)N/A per Protocol Amd 03
e)Prior treatment with trastuzumab &anthracyclines given concurrently in metastatic or adjuvant setting (sequential treatment allowed)
f)N/A per Protocol Amd 03
g)Treatment with (investigational) IGF-1R monoclonal antibodies or tyrosine kinase inhibitors (for dose expansion cohort only)
h)Drugs or interventions generally accepted to have a risk of causing Torsades de Pointes (see IB)
i)Strong CYP3A4 inhibitors (see IB)
j)Strong CYP3A4 inducers prohibited (see IB)
h)Chronic use of steroids (low dose inhalation steroids allowed)
For above criteria h), i) and j), subj. must have a wash-out period of at least 5 days or at least 5 half-lives of the drug (whichever is longer) prior to the first dose of BMS-754807
7) Other
a)Prisoners/involuntarily incarcerated subj.
b)Subj. compulsorily detained for treatment of psychiatric or physical illness |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Efficacy Measures:
Tumor response will be determined for all subjects by radiological responses assessed by CT scan or MRI as defined by RECIST criteria. Radiological tumor assessments to evaluate response and progression will be done every 8 weeks or more frequently if indicated.
• Safety Outcome Measures:
Toxicity will be evaluated according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Safety assessments will be based on medical review of adverse event reports and the results of vital sign measurements, ECGs, echocardiography, physical examinations, and clinical laboratory tests. The incidence of observed adverse events will be tabulated and reviewed for potential significance and clinical importance. Subjects will be evaluated for safety if they have received any study drug.
• Pharmacokinetic Measures:
Nine blood samples will be collected from each subject including four samples on Day 1, three samples on Day 8 (Day 1 of Week 2) and one sample each on Days 15 and 22 (Day 1 of Weeks 3 and 4) for the measurement of BMS-754807 plasma concentration. The plasma concentration versus time data from this study will be combined with data from other studies to conduct a population pharmacokinetic evaluation of BMS-754807. Results of population pharmacokinetic analyses will be reported separately. A separate pharmacokinetic evaluation of plasma BMS-754807 concentrations is not planned for this study.
• Metabolic Measures:
Metabolic measures including but not limited to the occurrence of hyperglycemia or hypoglycemia will be monitored by measurement of serum glucose and/or home glucose monitoring. These metabolic measures will also be used to assess whether hyperglycemia can be controlled when subjects are co-medicated with an oral anti-hyperglycemic agent at BMS-754807 doses that induce hyperglycemia.
• Pharmacodynamic Measures:
Serum levels of hormones and ligands such as human growth hormone (HGH), insulin, C-peptide, IGF-1 and IGF-2 may indicate inhibition of the IR and IGF-1R. Serum samples will be obtained and collected on Days 1, 8, 29 and every 8 weeks thereafter.
• Exploratory Measures:
Tumor-material obtained at baseline will be studied by immunohistochemistry (IHC) for markers such as expression or activity of IGF-1R, IR, IGF-1, IGF-2, EGFR, HER2 and AKT and CTCs will be obtained at pre-specified time points to explore predictive or PD markers of the effect of BMS-754807 and trastuzumab |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| Exploratory PD and Predictive Biomarkers; Exploratory Metabolite Analysis |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| MTD and a recommended Phase II dose |
|
| 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 | No |
| E.8.1.1 | Randomised | Information not present in EudraCT |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 7 |
| 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 last visit for each subject will be defined as the follow-up visit which will occur approximately 30 days after the subject discontinues treatment.
The end of the trial will thus occur 30 days after the last subject discontinues from the study. |
|
| 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 | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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