Managed Access Program to Provide Access to Alpelisib for Patients With Advanced Breast Cancer

The purpose of this Cohort Treatment Plan is to allow access to alpelisib for patients diagnosed with HR-positive, HER2-negative advanced breast cancer with mutated phosphoinositide 3-kinase who progressed on or after AI treatment. The patient's Treating Physician should follow the suggested treatment guidelines and comply with all local health authority regulations.


Eligibility Criteria:
Inclusion Criteria:

Patients eligible for inclusion in this Treatment Plan have to meet all of the following criteria:

Written patient informed consent must be obtained prior to start of treatment.

1. Patient is an adult male or female (≥ 18 years of age) with advanced (locoregionally recurrent not amenable to curative therapy or metastatic) hormone receptor-positive, HER2-negative breast cancer
2. Patient has documented evidence of a mutation in the PIK3CA gene as determined in tumor tissue or plasma by a local laboratory.
3. If female, then the patient is postmenopausal. Postmenopausal status is defined either by:

   * Prior bilateral oophorectomy
   * Age ≥60
   * Age \<60 and amenorrheic for ≥12 months in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression and Follicle-stimulating Hormone (FSH) and estradiol in the postmenopausal range per local normal range
4. Patient has evidence of recurrence or progression during or after AI therapy (i.e. letrozole, anastrozole, exemestane). AI therapy does not need to be the latest treatment regimen.
5. Patient has a histologically and/or cytologically confirmed diagnosis of ER+ and/or PgR+ breast cancer by local laboratory.
6. Patient has adequate bone marrow and organ function as defined by laboratory values:

   * Fasting plasma glucose (FPG) ≤ 140 mg/dL (7.7 mmol/L) and Glycosylated Hemoglobin (HbA1c) ≤ 6.4% (both criteria have to be met)

Exclusion criteria

Patients eligible for this Treatment Plan must not meet any of the following criteria:

1. Participant has received prior treatment with any PI3K, mTOR or AKT inhibitor.
2. Participant has a known hypersensitivity to alpelisib, or to any of the excipients of alpelisib.
3. Participant has had major surgery within 14 days prior to treatment start and/or has not recovered from major side effects.
4. Participant with an established diagnosis of diabetes mellitus type I or not controlled type II (based on FG and HbA1c).
5. Participant has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection) based on physician discretion.
6. Participant has currently documented pneumonitis/interstitial lung disease (the chest CT scan performed before start of treatment for the purpose of tumor assessment should be reviewed to confirm that there are no relevant pulmonary complications present).
7. Participant with Child Pugh score B or C.
8. Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 160 mmHg and/or Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, with or without anti-hypertensive medication. Initiation or adjustment of antihypertensive medication(s) is allowed prior to screening.
9. Participant has clinically significant, uncontrolled heart disease and/or recent cardiac events including any of the following:

   * History of angina pectoris, coronary artery bypass graft (CABG), symptomatic pericarditis, or myocardial infarction within 6 months prior to the start of treatment
   * History of documented congestive heart failure (New York Heart Association functional classification III-IV)
   * Left Ventricular Ejection Fraction (LVEF) \< 50% at screening as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO)
   * Clinically significant cardiac arrhythmias, (e.g., ventricular tachycardia), complete left bundle branch block, high grade AV block (e.g. bifascicular block, Mobitz type II and third degree AV block without pacemaker in place
   * Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome, or Fridericia QT correction formula (QTcF) \> 470 msec at screening (mean of triplicate ECGs).
10. Participant has any other concurrent severe and/or uncontrolled medical condition that would, in the physician's judgment, contraindicate participation in the MAP (e.g., chronic active hepatitis \[testing not mandatory unless required by local regulations or requirements\], severe hepatic impairment, etc.).
11. Participant is currently receiving any of the following medications and cannot be discontinued 7 days prior to the start of the treatment:

    * Strong CYP3A4 inducers
    * Inhibitors of BCRP.
12. Participant has a history of acute pancreatitis within 1 year of screening or past medical history of chronic pancreatitis.
13. Participant with unresolved osteonecrosis of the jaw.
14. Participant has a history of severe cutaneous reaction, such as Stevens-Johnson Syndrome (SJS), Erythema Multiforme (EM), Toxic Epidermal Necrolysis (TEN), or Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).
15. Participant has received radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to treatment, and who has not recovered to grade 1 or better from related side effects of such therapy (with the exception of alopecia).
16. Participant is currently receiving or has received systemic corticosteroids ≤ 2 weeks prior to starting drug, or who have not fully recovered from side effects of such treatment. Note: The following uses of corticosteroids are permitted: single doses, topical applications (e.g., for rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local injections (e.g., intra-articular).
17. Participant has not recovered from all toxicities related to prior anticancer therapies to NCI CTCAE version 4.03 Grade ≤1. Exception to this criterion: participant with any grade of alopecia are allowed to enter the MAP.
18. Participant has a concurrent malignancy or malignancy within 3 years of start of treatment, with the exception of adequately treated, basal or squamous cell carcinoma, non-melanomatous skin cancer, or curatively resected cervical cancer.
19. Participant has central nervous system (CNS) involvement which was not previously treated and not fulfilling the following 3 criteria to be eligible for the MAP:

    * Completed prior therapy (including radiation and/or surgery) for CNS metastases ≥ 28 days prior to the treatment and
    * CNS tumor is clinically stable at the time of treatment start and
    * Participant is not receiving steroids and/or enzyme inducing anti-epileptic medications for brain metastases.
20. Subject has any other concurrent severe and/or uncontrolled medical condition that would, in the physician's judgment, contraindicate subject participation in MAP (e.g., chronic active hepatitis \[testing not mandatory unless required by local regulations or requirements\], severe hepatic impairment.
21. Participant is not able to understand and to comply with instructions and requirements, including oral administration of treatment.
22. Participant is a nursing (lactating) or pregnant as confirmed by a positive serum (hCG) test prior to initiating treatment.
23. Participant is a woman of child-bearing potential defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during treatment and at least for 1 week after the last dose of the treatment. Highly effective contraception methods include:

    * Total abstinence (when this is in line with the preferred and usual lifestyle of the participant). Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception
    * Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or bilateral tubal ligation at least 6 weeks before taking treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
    * Male sterilization (at least 6 months prior to screening). For female participants the vasectomized male partner should be the sole partner for that participant
    * Use of oral (estrogen and progesterone), injected or implanted combined hormonal method of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or forms of hormonal contraception that have comparable efficacy (failure rate \<1%), for example hormonal vaginal ring or transdermal hormone contraception. In case of use or oral contraception, women should have been stable on the same pill for a minimum of 3 months before taking treatment.

    Note: Women are considered postmenopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (i.e., age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or bilateral tubal ligation at least 6 weeks before starting treatment In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.

    If local regulations to prevent pregnancy deviate from the contraception methods listed above, local regulations apply and will be described in the informed consent form (ICF).
24. Participant is a sexually active male unwilling to use a condom during intercourse while taking treatment, and for 1 week after the last dose of treatment. A condom is required for all sexually active male participants to prevent them from fathering a child AND to prevent delivery of treatment via seminal fluid to their partner. In addition, male participants must not donate sperm during MAP and up to the time period specified above.