E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Hormone Receptor Positive Locally Advanced or Metastatic Breast Cancer |
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E.1.1.1 | Medical condition in easily understood language |
Breast Cancer
Breast Tumors
Neoplasm Metastasis
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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 | 14.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10027475 |
E.1.2 | Term | Metastatic 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 |
To provide an estimate of the relative efficacy of Arm A (AMG 479 in combination with
endocrine therapy [exemestane or fulvestrant] versus Arm B (AMG 479 placebo in combination with endocrine therapy [exemestane or fulvestrant]) as measured by the PFS hazard ratio. This estimate will be precise enough to provide guidance for further development of AMG 479.for use in the planning of a phase 3 study in this patient population. Additionally, this study will provide qualitative estimates of PFS for treatment arms A and B. |
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E.2.2 | Secondary objectives of the trial |
To investigate the effect of AMG 479 compared with placebo when administered in combination with exemestane or fulvestrant on:
• the safety and tolerability
• the impact to patient reported outcomes (PROs)
• the pharmacokinetics (PK) of AMG 479
• additional efficacy measures including clinical benefit rate, objective response rate, duration of response, time to progression (TTP), time-to-response, time-to-treatment failure, and survival time |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Disease related
• Histologically or cytologically confirmed carcinoma of the breast with locally advanced or metastatic disease not amenable to surgery or radiation with curative intent (based on medical history review)
• Confirmation of hormone receptor (ER and/or progesterone receptor) positive disease using institutional standards for analysis of the primary tumor tissue or tissue obtained thereafter (based on medical history review)
• Amenable to receive endocrine therapy as per investigator discretion
• Disease progression while receiving prior endocrine therapy for locally advanced or metastatic breast cancer or recurrence while receiving prior endocrine therapy as adjuvant treatment or within 12 months of treatment discontinuation.
• Measurable or non-measurable disease, as defined by RECIST criteria
• Eastern Cooperative Oncology Group (ECOG, refer to Appendix I) performance status of 0 or 1
• Documented life expectancy greater than 3 months
Demographic
• Woman ≥ 18 years old
• Postmenopausal as defined by any of the following criteria:
- History of bilateral oophorectomy, or
- Age ≥ 55 years old, or
- ≥ 45 years old with amenorrhea for ≥ 12 months, or
- ≥ 45 years old with amenorrhea and follicle stimulating hormone concentrations within postmenopausal range, or
- Follicle stimulating hormone concentrations within postmenopausal range in patients previously treated with bilateral ovarian radiation, or patients with chemotherapy induced amenorrhea
Laboratory
• Hematological function, as follows:
- Absolute neutrophil count (ANC) ≥ 1.0 x 109/L
- Platelet count ≥ 100 x 109/L
- Hemoglobin ≥ 9 g/dL
• Partial thromboplastin ≤ 1.3 x upper limit of normal (ULN) and international normalized ratio (INR) ≤ 1.5, unless subject is on anticoagulation therapy. Subjects on therapeutic anticoagulation are eligible if they will be prescribed exemestane as their endocrine therapy on the study, there is no bleeding and they are on a stable dose of anticoagulation therapy (eg, on coumadin with an INR of 2 to 3) for at least 7 days before randomization.
• Renal function, as follows:
- Serum creatinine ≤ 1.5 x the ULN or calculated creatinine clearance (by Cockcroft-Gault formula) ≥ 40 mL/min
• Hepatic function, as follows:
- Aspartate aminotransferase (AST) ≤ 2.5 x ULN
- Alanine aminotransferase (ALT) ≤ 2.5 x ULN
- Alkaline phosphatase ≤ 2.5 x ULN (≤ 5 x ULN with bone/liver metastases)
- Bilirubin ≤ 1.5 x ULN or if total bilirubin < 3 X ULN if subject has UGT1A1 promoter polymorphism (ie, Gilbert syndrome) confirmed by genotyping or Invader® UGT1A1 Molecular Assay prior to randomization.
• Adequate glycemic function, for subjects with known diabetes (Type 1 or 2), as
follows:
- Must be controlled with a glycosylated hemoglobin (HgbA1c) of < 8.0%
- Documented fasting blood sugars < 160 mg/dL. Diabetic subjects who have recently had their glycemic control regimens adjusted and have documented fasting blood glucose concentrations < 160 mg/dL may be considered, regardless of HgbA1c value, if per investigator discretion are considered to have adequate glycemic function |
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E.4 | Principal exclusion criteria |
Disease Related
• HR-unknown, or -negative disease (based on medical history review)
• Not amenable to receive endocrine therapy, including but not limited to, inflammatory breast cancer, rapidly progressing disease, or symptomatic visceral
disease
• Central nervous system metastases, unless previously treated by either radiation therapy and/or surgical resection, who are clinically stable off corticosteroids before randomization
• Prior malignancy except the following is allowable:
• Malignancy treated with curative intent and with no known active disease present for ≥ 3 years before enrollment and felt to be at low risk for recurrence by the treating physician
• Adequately treated non-melanomatous skin cancer or lentigo maligna without evidence of disease
• Adequately treated cervical carcinoma in situ without evidence of disease
Medications
• More than 1 prior endocrine regimen for metastatic breast cancer, or locally advanced breast cancer. There are no restrictions for their administration in the neoadjuvant or adjuvant settings, except subjects should not have previously been treated with the endocrine therapy planned for use in this study
• More than 1 prior regimen including immunotherapy (eg, vaccines), antibody therapy (eg, trastuzumab, bevacizumab), small-molecule therapy (eg, lapatinib) for metastatic breast cancer, or locally advanced breast cancer, although there are no restrictions for their administration in the neoadjuvant or adjuvant settings
• More than 1 prior regimen including chemotherapy for metastatic breast cancer,
or locally advanced breast cancer, although there are no restrictions for their administration in the neoadjuvant or adjuvant settings
• For subjects with measurable disease, previous radiation therapy to a lesion being used for RECIST assessment, unless it has subsequently progressed after completion of therapy
• Administration of prior endocrine anticancer therapies within 1 week of randomization
• Administration of other prior anticancer therapies within 2 weeks of randomization
• Toxicities related to prior anticancer treatment (except alopecia) have not resolved to common terminology criteria for adverse events version 3.0 (CTCAE V 3.0) defined ≤ grade 1 before randomization
• Prior treatment with investigational treatment targeted to IGF axis including, but not limited to, CP 751,871, IM-A12, RO4858696
• Previous exposure to AMG 479
• Currently receiving systemic antibiotic therapy for the treatment of an active infection
• Requirement for other endocrine therapy including:
- systemic hormone-replacement therapy or intravaginal estrogen
- megestrol acetate
General
• History of bleeding diathesis
• Known positive test for human immunodeficiency virus, or chronic hepatitis B or C infection
• Any co-morbid medical condition that may put the subject at significant risk for toxicity
• Major surgical procedure within 28 days of randomization
• Minor surgical procedures within 7 days of randomization, although placement of central access device, fine needle aspiration, thoracentesis or paracentesis > 1 day before randomization is acceptable
• Inability to tolerate IV drug administration
• Has not yet completed at least 30 days before randomization since ending other investigational device or drug study(s)
• Subject has known sensitivity to any of the products to be administered during dosing
• Subject previously randomized to this study
• Subject will not be available for follow-up assessments
• Subject has any kind of disorder that compromises the ability of the subject to give written informed consent and/or to comply with study procedures
• Unable to initiation study treatment within 3 days of randomization |
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E.5 End points |
E.5.1 | Primary end point(s) |
To provide an estimate of the relative efficacy of Arm A (AMG 479 in combination with endocrine therapy [exemestane or fulvestrant] versus Arm B (AMG 479 placebo in combination with endocrine therapy [exemestane or fulvestrant]) as measured by the PFS hazard ratio. This estimate will be precise enough to provide guidance for further development of AMG 479.for use in the planning of a phase 3 study in this patient population. Additionally, this study will provide qualitative estimates of PFS for treatment arms A and B. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Time from starting treatment to progression |
|
E.5.2 | Secondary end point(s) |
Clinical benefit (confirmed CR, or confirmed PR, or SD for ≥ 24 weeks as measured by modified RECIST per local review), ORR (confirmed CR + confirmed PR as measured by modified RECIST per local review), duration of response, TTP, time-to-response, time-to-treatment failure, and survival. Incidence of adverse events, abnormal laboratory values, and incidence of anti-AMG 479 antibody formation. PK parameters of AMG 479. Breast cancer related symptoms, HRQOL, and skin toxicity burden. These secondary endpoints will assist in determining the effect on the safety, the efficacy profile, and breast cancer related symptoms in subjects receiving AMG 479 or placebo in combination with endocrine therapy (fulvestrant or exemestane). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Timepoints as detailed above (E.5.2) |
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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 | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
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 | 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 | Yes |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 25 |
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 | No |
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 |
Australia |
Canada |
France |
Germany |
Ireland |
Spain |
Switzerland |
United Kingdom |
United States |
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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
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The end of the clinical study is when all subjects have completed the long-term follow-up (up to a maximum of 48 months from the date the last subject is enrolled), withdrawn of consent, lost-to-follow up or died.
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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 | 5 |
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 | 5 |
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 |