| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| PIK3CA mutated HER2+ advanced or relapsed breast cancer (BC) previously treated with trastuzumab and trastuzumab emtansine (T-DM1) |
|
| E.1.1.1 | Medical condition in easily understood language |
| PIK3CA mutated and HER2 positive metastatic breast cancer (ABC), previously treated with trastuzumab T-DM1 |
|
| 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 | 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 | 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.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
-To determine whether the PI3K inhibitor alpelisib + trastuzumab improve efficacy, as measured by PFS, compared to trastuzumab + chemotherapy of physician's choice (vinorelbine, capecitabine or eribulin) in previously treated HER2+/HR- PIK3CA mutated advanced breast cancer patients.
-To determine whether the PI3K inhibitor alpelisib + trastuzumab + fulvestrant improve efficacy, as measured by PFS, compared to trastuzumab + hemotherapy of physician's choice (vinorelbine, capecitabine or eribulin) in previously treated HER2+/HR+ PIK3CA mutated advanced breast cancer patients. |
|
| E.2.2 | Secondary objectives of the trial |
-To compare additional measures of efficacy between treatment arms per cohort of
patients:
Overall survival (OS).
Objective response rate (ORR).
-To compare safety and tolerability between treatment arms per cohort of patients. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Written informed consent prior to any specific study procedures, showing patient willingness to comply with all study procedures.
2.Histologically or cytologically documented locally recurrent inoperable or metastatic breast cancer with HER2+ status based on local laboratory determination, preferably on the most recent available FFPE tumor sample, and according to American Society of Clinical Oncology (ASCO)/Collegue of American Pathologists (CAP) international guidelines valid at the time of the assay. In case of discordance in HER2+ status in different biopsies, the result from the most recent biopsy will be used.
3.Documented HR status based on local laboratory, preferably on the most recent available FFPE tumor sample, and according to ASCO/CAP international guidelines valid at the time of the assay. In case of discordance in HR status in different biopsies, the result from the most recent biopsy will be used. HR+ will be defined as ≥1% positive cells by immunohistochemistry for Estrogen Receptor (ER) and/or Progesterone Receptor (PgR). HR- will be defined as <1% positive cells by immunohistochemistry for both ER and PgR. For the purpose of this study, patients with ER and PgR expression between 1 and 10% (considered to be HR low by the most recent ASCO/CAP guidelines) will be eligible for inclusion in the HR- cohort.
4.Patients with a PIK3CA tumor mutation at central laboratory determination, preferably on the most recent available FFPE tumor sample.
5.At least 1 but no more than 5 prior lines of anti-HER2 based therapy for metastatic breast cancer (MBC). Maintenance therapy will not count as an additional line of therapy.
6.At least 1 prior line of trastuzumab in the metastatic setting, or in the (neo)adjuvant setting (provided the patient relapsed while on therapy or within 6 months after completing adjuvant trastuzumab).
7.Female or male patient is at least 18 years of age.
8.Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1.
9.Patients can be either males or premenopausal/perimenopausal or postmenopausal females. In the HR+ cohort, males and females who are not post-menopausal must have been on a gonadotropin-releasing hormone (GnRH) agonist (e.g. goserelin or leuprorelin) for at least 28 days prior to starting study treatment.
10.Measurable disease or at least one evaluable bone lesion, lytic or mixed (lytic+blastic), which has not been previously irradiated and is assessable by computer tomography (CT)/magnetic resonance imaging (MRI) in the absence of measurable disease according to RECIST 1.1 criteria.
11.Life expectancy ≥ 12 weeks.
12.Adequate organ and marrow function defined as follows:
-Absolute neutrophil count (ANC) ≥ 1,500/mm3 (1.5x109/L).
-Platelets ≥ 100,000/mm3 (100x109/L).
-Hemoglobin ≥ 9g/dL (90g/L).
-Calcium (corrected for serum albumin) and magnesium within normal limits or ≤ grade 1.
-Creatinine <1.5 x upper limit of normal (ULN) or creatinine Clearance ≥ 35 mL/min using Cockcroft-Gault formula (if creatinine is ≥1.5 ULN).
-Total bilirubin < 2 x ULN (any elevated bilirubin should be asymptomatic at enrollment) except for patients with Gilbert’s syndrome who may only be included if the total bilirubin is ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN.
-Potassium within normal limits, or corrected with supplements.
-Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x ULN. If patient has liver metastasis, AST and ALT ≤ 5.0 x ULN.
-Fasting serum amylase ≤ 2.0 x ULN.
-Fasting serum lipase ≤ ULN.
-Fasting plasma glucose (FPG) < 140 mg/dL (7.7 mmol/L) and glycosylated hemoglobin (HbA1c) < 6.5%.
13.Resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to NCI-CTCAE version 5.0 grade ≤ 1 (except alopecia or other toxicities not considered a safety risk for the patient at investigator´s discretion).
14.Adequate cardiac function as defined by left ventricular ejection fraction (LVEF) of ≥ 50% measured by echocardiography or multi-gated acquisition (MUGA) scans.
“Please consult the complete criteria in the protocol” |
|
| E.4 | Principal exclusion criteria |
1.Have received more than 5 previous lines of anti-HER2 based therapy for MBC, or prior fulvestrant.
2.Symptomatic visceral disease or any disease burden that makes the patient ineligible for experimental therapy per the investigator’s best judgment.
3.Symptomatic central nervous system (CNS) metastases. However, patients with CNS metastases who have been adequately treated, are asymptomatic and do not require corticosteroid or anti-epileptic medication are eligible.
4.Presence of leptomeningeal carcinomatosis.
5.Other invasive malignancy (different from the current breast cancer) at the time of enrollment or previous diagnosis of a completely removed malignancy within 3 years prior to randomization except for adequately treated (including complete surgical removal) of International Federation of Gynecology and Obstetrics (FIGO) stage I grade 1 endometrial cancer, basal or squamous cell carcinoma of the skin, thyroid cancer limited to thyroid gland, in situ carcinoma of the cervix, and grade 1-2 early stage bladder cancer defined as T1 or less, without nodal involvement (N0).
6.Patients with an established diagnosis of diabetes mellitus type I or not controlled type II (FPG ≥ 140 mg/dL [7.7 mmol/L] or HbA1c ≥ 6.5%), or history of gestational diabetes (as per ACOG guidelines) or documented steroid-induced diabetes mellitus.
7.Prior treatment with any mTOR, AKT or PI3K inhibitor.
8.Patients treated within the last 7 days prior to treatment initiation with:
-Drugs that are strong inducers of CYP3A4.
-Drugs that are inhibitors of BCRP (Breast Cancer Resistance Protein).
9.Patients who received before randomization:
-Any investigational agent within 4 weeks.
-Chemotherapy within a period of time that is shorter than the cycle duration used for that treatment (e.g. < 3 weeks for fluorouracil, doxorubicine, epirubicine or < 1 week for weekly chemotherapy).
-Biologic therapy (e.g., antibodies, other than trastuzumab which is permitted): within 4 weeks prior to starting study treatment.
-Endocrine therapy: tamoxifen or aromatase inhibitor (AI) within 2 weeks prior to starting study treatment.
-Corticosteroids within 2 weeks prior to starting study treatment.
-Radiotherapy within 2 weeks prior to starting study treatment. Patients who received prior radiotherapy to >25% of bone marrow are not eligible regardless of when it was administered.
-Major surgery or other anti-cancer therapy not previously specified within 4 weeks prior to starting study treatment.
10.Patient has clinically significant, uncontrolled heart disease and/or recent cardiac events.
11.Bleeding diathesis (i.e., disseminated intravascular coagulation [DIC], clotting factor deficiency) or long-term (> 6 months) anticoagulant therapy, other than antiplatelet therapy and low dose coumarin derivatives, provided that the International Normalised Ratio (INR) is less than 1.5.
12.History of clinically significant bowel disease including abdominal fistula, or gastrointestinal perforation.
13.Difficulties to swallow tablets, malabsorption syndrome disease significantly affecting gastrointestinal function, resection of the stomach or small bowel, or active inflammatory bowel disease (e.g., ulcerative diseases).
14.Known hypersensitivity to trastuzumab, alpelisib or fulvestrant or any of their excipients. If known hypersensitivity to all three cytostatics (vinorelbine, capecitabine and eribulin), the patient will not be eligible.
15.Known positive serology for Human Immunodeficiency Virus (HIV), or active infection for hepatitis B or hepatitis C.
16.Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
21.Patient is nursing (lactating) or is pregnant as confirmed by a positive serum human Chorionic Gonadotropin (hCG) test prior to initiating study treatment.
“Please consult the complete criteria in the protocol” |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| PFS: Time from randomization to objective disease progression based on the investigator’s assessment according to the response evaluation criteria for solid tumors (RECIST) version 1.1., or death from any cause. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Two interim analyses and the primary analysis based on the primary endpoint of PFS will be conducted.
A first interim analysis will be conducted at approximately 25% information (approximately 30 PFS events).
A second interim analysis for inefficacy monitoring will be conducted at approximately 50% (approximately 60 PFS events).
The interim analyses are expected to occur before completion of enrollment.
The primary analysis of targeted PFS events is estimated at 44 months since first patients randomized. |
|
| E.5.2 | Secondary end point(s) |
-OS: time from randomization to death from any cause.
-OR: complete or partial response as best overall response based on the investigator’s assessment according to RECIST version 1.1.
-Safety and tolerability: adverse events (AEs) grades will be defined by the National Cancer Institute common terminology criteria for adverse events (NCI-CTCAE) version 5.0. AE terms will be coded according to the MedDRA dictionary. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The data cut-off date for the final analysis will occur approximately 12-15 months after the primary analysis, estimated to be approximately 59 months from the inclusion of the first patient, in order to estimate OS. |
|
| 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 | No |
| 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) | 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 | 10 |
| 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 |
|
| 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
|
|
| 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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
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