E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
HER2-positive advanced breast cancer |
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E.1.1.1 | Medical condition in easily understood language |
Advanced breast cancer that is distinguished from other breast cancer types by stage and the presence of molecules that respond to certain treatments |
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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 | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10072737 |
E.1.2 | Term | Advanced breast cancer |
E.1.2 | System Organ Class | 100000004864 |
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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 |
Safety run-in Part 1:
To confirm the recommended dose of alpelisib in combination with trastuzumab and pertuzumab for Part 2
Double-blind, randomized, placebo-controlled Part 2:
To determine whether treatment with alpelisib in combination with trastuzumab and pertuzumab prolongs PFS compared to placebo in combination with trastuzumab and pertuzumab in adult patients with HER2-positive advanced breast cancer with a PIK3CA mutation |
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E.2.2 | Secondary objectives of the trial |
Safety run-in Part 1:
- To determine the safety and tolerability of alpelisib in combination with trastuzumab and pertuzumab
- To characterize exposure of alpelisib when administered in combination with trastuzumab and pertuzumab
Double-blind, randomized, placebo-controlled Part 2:
- To determine whether treatment with alpelisib in combination with trastuzumab and pertuzumab prolongs OS in adult patients with HER2-positive advanced breast cancer with a PIK3CA mutation
- To assess safety and tolerability
- To assess additional efficacy parameters
- To characterize exposure of alpelisib in combination with trastuzumab and pertuzumab
- To evaluate PROs of alpelisib in combination with trastuzumab and pertuzumab
- To evaluate the association between PIK3CA mutation status as measured in ctDNA at baseline with PFS upon treatment with alpelisib
- To evaluate alpelisib in combination with trastuzumab and pertuzumab with respect to time to deterioration of ECOG performance status |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Subject has histologically-confirmed HER2-positive breast cancer that is advanced (loco-regionally not amenable to surgery t or metastatic).
- Subject has received pre-study induction therapy with up to and including 6 cycles of a taxane (docetaxel, paclitaxel, or nab-paclitaxel), plus trastuzumab and pertuzumab. A minimum of 4 cycles of taxane is permitted if discontinuation was due to toxicity
- Subject has an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
- Subject has adequate bone marrow and organ function
- Applies only to Part 2: Subject has a PIK3CA mutation(s) present in tumor tissue prior to enrollment, as determined by a Novartis designated central
laboratory. |
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E.4 | Principal exclusion criteria |
- Subject with inflammatory breast cancer at screening.
- Subject with evidence of disease progression during the pre-study induction therapy and prior to first dose of alpelisib (or alpelisib/alpelisib matching-placebo for Part 2)
- Subject with an established diagnosis of diabetes mellitus type I or not controlled type II based on FPG and HbA1c (see inclusion criteria 7).
- Subject has a known history of acute pancreatitis within 1 year of screening or past medical history of chronic pancreatitis
- Subject has clinically significant, uncontrolled heart disease and/or recent cardiac events
- Subject has a history of Steven-Johnson Syndrome (SJS), erythema multiforme (EM) or Toxic Epidermal Necrolysis (TEN).
- Subject has currently documented pneumonitis/interstitial lung disease |
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E.5 End points |
E.5.1 | Primary end point(s) |
Part 1: Safety-run in
- Incidence of DLTs during the first 6 weeks of treatment for each dose level associated with administration of alpelisib in combination with trastuzumab and pertuzumab
Part 2: Double-blind, randomized, placebo-controlled
- PFS based on local investigator assessment and using RECIST 1.1 criteria, defined as the time from the date of randomization to the date of the first documented progression or death due to any cause |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part 1: 6 weeks
Part 2: up to approximately 38 months |
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E.5.2 | Secondary end point(s) |
Part 1:
- Safety: Incidence, type, and severity of adverse events per Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 criteria including changes in laboratory values, vital signs, liver assessments and cardiac assessments
- Tolerability: dose interruptions, reductions, dose intensity, and duration of exposure for all drug components
- Summary statistics of alpelisib concentrations by timepoint and dose level
Part 2:
- OS, as defined as the time from date of randomization to date of death due to any cause |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Part 1: up to approximately 38 months
Part 2: up to approximately 70 months |
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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 | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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) | 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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 146 |
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 |
Argentina |
Austria |
Belgium |
Brazil |
Bulgaria |
Canada |
China |
Colombia |
Czech Republic |
Finland |
France |
Germany |
Greece |
Hungary |
Israel |
Italy |
Lebanon |
Malaysia |
Netherlands |
Poland |
Romania |
Russian Federation |
Singapore |
Slovakia |
Spain |
Sweden |
Taiwan |
Thailand |
Turkey |
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
|
Study completion is defined as when the last subject finishes their safety and efficacy follow-up periods (as applicable) and any repeat assessments associated with these visits have been documented and followed-up appropriately by the Investigator or, in the event of an early study termination decision, the date of that decision. |
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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 | 9 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 11 |
E.8.9.2 | In all countries concerned by the trial years | 9 |
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 | 0 |