E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Advanced triple negative breast cancer |
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E.1.1.1 | Medical condition in easily understood language |
Advanced triple negative breast neoplasm |
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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 | 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 | 10006187 |
E.1.2 | Term | Breast cancer |
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 |
Part A and Part B2 •to determine whether treatment with alpelisib in combination with nab-paclitaxel prolongs Progression Free Survival (PFS) compared to placebo in combination with nab-paclitaxel Part B1 •to assess the antitumour activity of alpelisib in combination with nab-paclitaxel based on the Overall Response Rate (ORR) with confirmed response at 6 months via local radiology assessments
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E.2.2 | Secondary objectives of the trial |
Part A and Part B2 key secondary objective: •to determine whether treatment with alpelisib in combination with nab-paclitaxel prolongs OS Part A and Part B2 secondary objectives: •To evaluate safety and tolerability •To further evaluate the efficacy of alpelisib in combination with nab-paclitaxel measuring the ORR, CBR, DOR and TTR based on local radiological assessments•To characterize exposure of alpelisib and nab-paclitaxel •To evaluate PROs •To evaluate the association between PIK3CA mutation status as measured in ctDNA at baseline with PFS upon treatment with alpelisib •To evaluate the time to definitive deterioration of the ECOG performance status from baseline Part B1 secondary objectives: •To evaluate safety and tolerability•To further evaluate the efficacy measuring the CBR with confirmed response, DOR with confirmed response and TTR based on local radiological assessments •To characterize exposure of alpelisib and nab-paclitaxel when administered in combination |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Subject has histologically confirmed diagnosis of advanced (loco-regionally recurrent and not amenable to curative therapy, or metastatic (stage IV)) TNBC - Subject has either a measurable disease per RECIST 1.1 criteria or, if no measurable disease is present, then at least one predominantly lytic bone lesion or mixed lytic-blastic bone lesion with identifiable soft tissue component (that can be evaluated by CT/MRI) must be present Part B1: patients must have measurable disease - Subject has adequate tumor tissue to identify the PIK3CA mutation status (either carrying a mutation or without a mutation) and the PTEN loss status; both of which will determine whether the subject can be allocated to Part A - PIK3CA mutation regardless of PTEN status; or to Part B - PTEN loss without a PIK3CA mutation - Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 - Subject has received no more than one line of therapy for metastatic disease. - Subject has adequate bone marrow and organ function |
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E.4 | Principal exclusion criteria |
- Subject has received prior treatment with any PI3K, mTOR or AKT inhibitor - Subject has a known hypersensitivity to alpelisib, nab-paclitaxel or to any of their excipients - Subject has not recovered from all toxicities related to prior anticancer therapies to NCI CTCAE version 4.03 Grade ≤1; with the exception of alopecia - Subject has central nervous system (CNS) involvement - Subject with an established diagnosis of diabetes mellitus type I or uncontrolled type II based on Fasting Plasma Glucose and HbA1c - Subject has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection) based on investigator discretion - Subject has a history of acute pancreatitis within 1 year of screening or past medical history of chronic pancreatitis - Subject has currently documented pneumonitis/interstitial lung disease - Subject has a history of severe cutaneous reactions, such as Steven-Johnson Syndrome (SJS), erythema multiforme (EM),Toxic Epidermal Necrolysis (TEN) or Drug Reaction with Eosinophilia and Systemic Syndrome (DRESS) - Subject with unresolved osteonecrosis of the jaw Other protocol-defined inclusion/exclusion criteria apply |
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression-free Survival (PFS) Per Investigator Assessment in Study part A Progression-free Survival (PFS) Per Investigator Assessment in Study part B2 Overall Response Rate (ORR) based on local radiology assessments in subjects with measurable disease at baseline in study Part B1 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part A : Once approximately 192 PFS events in Study Part A had been observed, up to 35 months
PartB2 : Once approximately 192 PFS events in Study Part A had been observed, up to 22 months
Part B1 up to 6 months |
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E.5.2 | Secondary end point(s) |
Overall Survival (OS) in Study Part A Overall Survival (OS) in Study Part B2 Overall response rate (ORR) with confirmed response in Study Part A and B2 Clinical benefit rate (CBR) with confirmed response, in Study Parts A, B1 and B2 Time to response (TTR), in Study Parts A, B1 and B2 Duration of Response (DOR) with confirmed response, in Study Parts A, B1 and B2 Time to definitive deterioration of the ECOG performance status from baseline, in Study Parts A and B2 Overall Survival (OS) in Study Part B2 Progression-free Survival (PFS) Per Investigator Assessment in Study part B1 Safety and Tolerability of alpelisib in Combination With nab-paclitaxel in study Parts A, B1 and B2 Summary statistics of plasma alpelisib concentrations by time point in study Parts A, B1 and B2 Day 8 and Day 15 of Cycle 1, then Day 1 of Cycles 2, 4 and 6 Summary statistics of plasma paclitaxel concentrations by time point in study Parts A and B1 Day 8 of Cycle 1, then Day 1 of Cycles 2 and 4 Change from baseline in the global health status/QoL scale score of the EORTC QLQ-C30 in study Parts A and B1 Time to 10% definitive deterioration in the global health status/QOL scale score of the EORTC QLQ-C30 in study Parts A and B1 PFS based on local radiology assessments using RECIST 1.1 criteria for subjects by PIK3CA mutation status measured in baseline ctDNA in study Parts A and B2 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Part A up to 66 months Part B2 up to 41 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 | 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 | 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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 105 |
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 |
Australia |
Austria |
Brazil |
Bulgaria |
Canada |
China |
Colombia |
Croatia |
France |
Germany |
Hungary |
India |
Israel |
Italy |
Kenya |
Korea, Republic of |
Lebanon |
Malaysia |
Mexico |
Norway |
Peru |
Poland |
Romania |
Russian Federation |
Saudi Arabia |
Serbia |
Slovakia |
Slovenia |
South Africa |
Spain |
Switzerland |
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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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Study completion is defined as when the last subject, regardless of Study Part, 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 | 4 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 8 |