E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Metastatic or Locally Advanced HER2-positive Breast Cancer |
|
E.1.1.1 | Medical condition in easily understood language |
|
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 | 23.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10065430 |
E.1.2 | Term | HER2 positive breast cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
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) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10072740 |
E.1.2 | Term | Locally advanced breast cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
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 this study is to evaluate the efficacy, as measured by progression-free survival (PFS) assessed by independent review and overall survival (OS), of margetuximab plus chemotherapy compared with trastuzumab plus chemotherapy in patients with advanced HER2+ breast cancer who have received at least 2 prior lines of anti-HER2 directed therapy in the metastatic setting, or in case of having received (neo)adjuvant pertuzumab, at least 1 prior line of antiHER2 directed therapy in the metastatic setting, and who have received at least one, and no more than three, lines of therapy overall in the metastatic setting.
|
|
E.2.2 | Secondary objectives of the trial |
•To evaluate PFS, as assessed by study investigators, of margetuximab plus chemotherapy vs. trastuzumab plus chemotherapy in these patients. •To evaluate by independent review the objective response rate (ORR) of margetuximab plus chemotherapy vs. trastuzumab plus chemotherapy in these patients.
|
|
E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Infusion Sub-Study (Protocol amend 3, 26 January 2018) Sub-study cohort of about 78 patients will be added to the main study to evaluate the safety and tolerability of sequential reductions in margetuximab infusion duration from 120 minutes in Cycle 1 to 30 minutes in Cycles 2 and beyond. The primary objective of the infusion sub-study is to determine the safety and tolerability of margetuximab administered at a reduced infusion time in Cycle 2 and beyond. The incidence of Grade 3 or greater infusion-related reactions (IRRs) by the end of Cycle 2 is the primary outcome measure. The secondary outcome measure is the incidence of all Grade IRRs in all sub-study patients.
|
|
E.3 | Principal inclusion criteria |
1. Male or female patients ≥ 18 years of age. 2. Have histologically-proven metastatic or locally-advanced relapsed/refractory HER2+ breast cancer based on the most recently available tumor biopsy collected from the patient. Tumors may be estrogen receptor (ER)/progesterone receptor (PR) positive or negative. 3. Have received at least 2 prior lines of anti-HER2 directed therapy in the metastatic setting, or in case of having received (neo)adjuvant pertuzumab, at least 1 prior line of anti-HER2 directed therapy in the metastatic setting. In either case, patients must have received prior treatment with pertuzumab in the (neo)adjuvant or metastatic setting. Prior radiotherapy, hormonal therapies, and other anti-HER2 therapies are allowed. 4. Have received treatment with at least one, and no more than three, lines of therapy overall in the metastatic setting. 5. Resolution of all chemotherapy or radiation-related toxicities to ≤ Grade 1 (with exception of ≤ Grade 2 alopecia, stable sensory neuropathy, or stable electrolyte disturbances that are managed by supplementation). 6. Have life expectancy ≥ 12 weeks. 7. Have acceptable laboratory parameters. 8. Female patients of childbearing potential must have negative pregnancy test performed within 14 days of randomization and a negative serum or urine pregnancy test on the day of first study treatment. All subjects must agree to use highly effective contraceptive measures.
Inclusion Criteria for the Infusion Sub-Study: 1. Patients will meet all entry criteria for the randomized portion of the study with the exception of inclusion criteria #3 and #4 above (which correspond to #4 and #5 in the Protocol). 2. Patients must have received at least 4 prior lines of therapy for metastatic disease. Hormonal therapies will not be considered when determining the number of previous lines of therapy in the metastatic setting. Prior neo-adjuvant or adjuvant therapy that resulted in relapse within 6 months of the completion of therapy will be considered a line of treatment for metastatic disease. Eligible patients must have progressed on or following the most recent line of therapy. Dose interruptions, delays, pauses during previous therapy, or changes in therapy to manage toxicity will not constitute a new line of therapy provided disease progression did not occur. 3. Patients must have received prior trastuzumab, pertuzumab, and TDM1. |
|
E.4 | Principal exclusion criteria |
1. Patients with known, untreated brain metastasis. Patients with signs or symptoms of brain metastasis must have a CT or MRI performed within 4 weeks prior to randomization to specifically exclude the presence of radiographically-detectable brain metastases. 2. History of uncontrolled seizures within 6 months of randomization. 3. History of prior allogeneic bone marrow, stem-cell, or solid organ transplantation. 4. History of clinically significant cardiovascular disease 5. Clinically-significant pulmonary compromise, including a requirement for supplemental oxygen use to maintain adequate oxygenation. 6. Any condition that would be a contraindication to receiving trastuzumab as described in the approved local label or a condition that would prevent treatment with the physician's choice of chemotherapy. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Progression-free survival as determined by independent radiological review. Overall survival defined as the number of days from randomization to the date of death (from any cause).
|
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
For PFS: 24 months from the start of the study For OS: 36 months from the start of the study
|
|
E.5.2 | Secondary end point(s) |
Overall response rate (ORR) as determined by independent radiological review PFS as determined by study investigators
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
For ORR: 36 months from the start of the study. For PFS: 24 months from the start of the study
|
|
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 | 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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 117 |
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 |
Canada |
Israel |
Korea, Republic of |
United States |
Austria |
Belgium |
Czechia |
Denmark |
Finland |
France |
Germany |
Italy |
Poland |
Portugal |
United Kingdom |
Netherlands |
Spain |
Switzerland |
|
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
|
The end of this study is defined as when the last patient visit occurs or one year after the final survival analysis, whichever occurs first. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 1 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 30 |