Managed Access Program to Provide Access to Alpelisib for Patients With Advanced Breast Cancer
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 (loco regionally recurrent not amenable to
 curative therapy or metastatic) breast cancer with mutated phosphoinositide 3-kinase. The
 patient's Treating Physician should follow the suggested treatment guidelines and comply with
 all local health authorityregulations.
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 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 the following
 laboratory values:

 1. Absolute neutrophil count ≥ 1.5 × 1.000.000.000/L

 2. Platelets ≥ 100 × 1.000.000.000/L

 3. Hemoglobin ≥ 9.0 g/dL

 4. Calcium (corrected for serum albumin) within normal limits or ≤ grade 1 according
 to NCI-CTCAE version 4.03 if judged clinically not significant by the Treating
 Physician, or corrected with supplements

 5. INR ≤ 1.5

 6. Creatinine clearance ≥ 35 mL/min using Cockcroft-Gault formula

 7. In absence of liver metastases, alanine aminotransferase (ALT) and aspartate
 aminotransferase (AST) ≤ 3 × ULN. If the patient has liver metastases, ALT and
 AST ≤ 5 × ULN (elevated AST or ALT values must be stable for 2 weeks, without
 evidence of biliary obstruction by imaging)

 8. Total serum 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 × ULN or direct bilirubin ≤ 1.5 × ULN

 9. Potassium within normal limits, or corrected with supplements

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

 *For patients with FPG ≥ 100 mg/dL and/or HbA1c ≥5.7% (i.e. threshold for
 prediabetes), recommend lifestyle changes according to ADA or similar local
 diabetes guidelines, i.e. dietary advice (e.g. small frequent meals, low
 carbohydrate content, high fiber, balancing carbohydrate intake over the course
 of the day, three small meals and 2 small snacks rather than one large meal) and
 exercise. A consultation with a diabetologist is highly recommended.

 11. Fasting Serum amylase ≤ 2 × ULN

 12. Fasting Serum lipase ≤ ULN

 Exclusion Criteria:

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

 1. Patient has history of hypersensitivity to any drugs or metabolites of PI3K inhibitor
 or any of the excipients of alpelisib.

 2. Patient with uncontrolled diabetes mellitus type I or not controlled type II (based on
 FPG and HbA1c, see inclusion criterion 6)

 3. Patient has a known history of severe cutaneous reactions like Steven Johnson's
 syndrome (SJS), Erythema Multiforme (EM), Toxic Epidermal Necrolysis (TEN), or Drug
 Reaction with Eosinophilia and Systemic Symptoms (DRESS)

 4. Patient has a known history of Human Immunodeficiency Virus (HIV) infection.

 5. Patient has not recovered to grade 1 or better (except for alopecia) from related side
 effects of prior antineoplastic therapies.

 6. Patient has other prior or concurrent malignancy, with the exception of adequately
 treated basal or squamous cell skin cancer or other in situ cancer, or any other
 cancer from which the patient has been disease-free for ≥ 3 years.

 7. Patient has central nervous system (CNS) involvement, except for patients fulfilling
 the following 3 criteria:

 1. Completed prior therapy (including radiation and/or surgery) for CNS metastases ≥
 28 days prior to the start of program treatment and

 2. CNS tumor is clinically stable at the start of program treatment and

 3. Patient is not receiving steroids and/or enzyme inducing anti-epileptic
 medications for brain metastases

 8. Patient who has other concurrent severe and/or uncontrolled medical conditions that
 would, in the Treating Physician's judgment, contraindicate administration of
 alpelisib (e.g. active or uncontrolled severe infection, chronic active hepatitis,
 immunocompromised, acute or chronic pancreatitis, uncontrolled high blood pressure,
 intersticial lung disease, severe GI impairment, etc) based on treating physician's
 discretion

 9. Subject has currently documented pneumonitis/interstitial lung disease

 10. History of acute pancreatitis within 1 year of screening or past medical history of
 chronic pancreatitis

 11. Patients with unresolved osteonecrosis of the jaw

 12. Patient who is concurrently receiving any of the following medications and cannot be
 discontinued 7 days prior to the start of the treatment:

 1. Strong inducers of CYP3A4

 2. Inhibitors of BCRP

 13. Patient is currently receiving or has received systemic corticosteroids ≤ 2 weeks
 prior to start of program treatment, 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).

 14. Male patient who does not apply highly effective contraception during the treatment
 with alpelisib and through the duration as defined below after the final dose of
 alpelisib.

 Sexually active males should use a condom during intercourse while taking drug and for
 at least 4 weeks after stopping alpelisib and should not father a child in this
 period. A condom is required to be used also by vasectomized men in order to prevent
 delivery of the drug via seminal fluid.

 15. Patient is not able to understand and to comply with treatment instructions and
 requirements