E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Advanced Metastatic Breast Cancer (MBC) |
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E.1.1.1 | Medical condition in easily understood language |
Advanced Metastatic Breast Cancer (MBC) |
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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 | 10057654 |
E.1.2 | Term | Breast cancer female |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 | 10006202 |
E.1.2 | Term | Breast cancer stage IV |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10055113 |
E.1.2 | Term | Breast cancer metastatic |
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 of the dose-evaluation phase (Phase 1) is to evaluate the safety and tolerability of 3 dose levels of MEDI 573 in combination with an AI in subjects with hormone receptor positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative MBC.
The primary objective of the randomization phase (Phase 2) is to evaluate the progression-free survival (PFS) of subjects with HR+, HER2-negative MBC treated with MEDI-573 and an AI versus treatment with an AI alone.
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E.2.2 | Secondary objectives of the trial |
To describe the safety and tolerability of MEDI-573 when used in combination with an AI
To evaluate the anti-tumor activity of MEDI-573 when used in combination with an AI versus treatment with an AI alone
To evaluate overall survival (OS) in subjects treated with MEDI-573 when used in combination with an AI versus treatment with an AI alone
To describe the pharmacokinetics (PK) of MEDI-573 when used in combination with an AI
To evaluate the pharmacodynamics of MEDI-573 when used in combination with an AI on circulating levels of insulin-like growth factor I (IGF-I) and insulin-like growth factor II (IGF-II)
To evaluate the immunogenicity (IM) of MEDI-573 when used in combination with an AI
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Histologically-confirmed MBC not deemed amenable to curative surgery or curative radiation therapy (subjects with bone metastases are eligible but enrollment will be capped at approximately 30 subjects)
Tumors are positive for ER, PgR, or both
Tumors must be negative for HER2 (by FISH, CISH or ICH)
Female gender and age ≥ 18 years at time of study entry
Postmenopausal
Karnofsky Performance Status ≥ 70
Life expectancy of ≥ 6 months
Adequate organ and marrow function
Suitable candidate for AI therapy
Consent to allow collection of available paraffin-embedded tumor tissue
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E.4 | Principal exclusion criteria |
Subjects who received prior chemotherapy, hormonal therapy, immunotherapy or biologic therapy for advanced or metastatic disease with the following exceptions:
Prior adjuvant therapy with an AI and/or tamoxifen is allowed, provided treatment ended at least 2 weeks prior to the first dose of MEDI-573
Prior neoadjuvant and/or adjuvant chemotherapy for breast cancer is allowed
Extensive symptomatic visceral disease including hepatic involvement and pulmonary lymphangitic spread of tumor, or disease that is considered by the investigator to be rapidly progressing or life threatening (eg, subjects who are intended for chemotherapy)
Active brain metastases with the exception of subject has been treated and are asymptomatic and there has been no evidence of CNS progression for at least 4 weeks of first dose of MEDI-573
Evidence of ongoing spinal cord compression or leptomeningeal carcinomatosis
Unresolved toxicities from prior therapy with the exception of alopecia that have not resolved to ≤ Grade 1 at the time of starting study treatment
Receipt of any investigational therapy within 30 days or 5 half-lives, prior to recieving study treatment
Previous treatment with agents that target the IGF receptor
History of allergy or reaction attributed to compounds of chemical or biologic composition similar to those of MEDI-573 or AI
Use of immunosuppresive med other than steroids within 7d before 1st dose of study drug
History of another invasive malignancy within 5 years except for curatively resected nonmelanoma skin cancer or carcinoma in situ of the cervix
Poorly controlled diabetes mellitus
History of cardiac disease within past 6 mo
Active hepatic liver or biliary disease (with exceptions)
Known immunodeficiency virus or hep B or C (active, previously treated)
Active infection
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E.5 End points |
E.5.1 | Primary end point(s) |
Phase 1b (Dose-evaluation Phase)
The primary endpoints for safety are the number of subjects with a DLT as well as the adverse events (AEs) and serious adverse events (SAEs) occurring during the protocol-specified period.
Phase 2 (Randomization Phase)
The primary endpoint is PFS, measured from randomization until the documentation of disease progression (according to Response Evaluation Criteria in Solid Tumors, Version 1.1) or death due to any cause, whichever occurs first.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
After the first cycle (3 weeks) subjects will be evaluated every 9 weeks for safety and for disease progression |
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E.5.2 | Secondary end point(s) |
Efficacy
Endpoints include objective response rate, time to response, duration of response, time to progression, OS, and change in tumor size. Response Evaluation Criteria in Solid Tumors (version 1.1) guidelines will be used to evaluate tumor response.
Safety
The safety endpoints include AEs, SAEs, and changes in clinical laboratory evaluations from baseline.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Timepoint(s) of evaluation for Safety and Tolerability of MEDI-573 in Phase 2: Multiple safety visits during the first cycle, then every 9 weeks until disease progression.
Timepoints for evaluation for the Pharmacokinetic, Pharmacodynamic and Immunogenicity endpoints: Multiple timepoints during the first cycle, then every 9 weeks during treatment.
Timepoints for evaluation for Efficacy endpoints: Subjects will be evaluated for tumor response or progression at regular 9-week intervals until progression of disease. After disease progression, subjects will be followed for overall survival every 12 weeks until death or until the end of the study.
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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 | 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 | No |
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.8.2.4 | 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 | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 65 |
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 |
Belgium |
Canada |
France |
Germany |
Hungary |
Israel |
Poland |
Spain |
United Kingdom |
United States |
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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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The end of the study will be when the last subject still on treatment as of 10Jul2016 finishes the 60-day (+/- 3 days) safety follow-up |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | 5 |
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 |