| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| metastatic breast cancer HER2- HR+ PIK3CA+ |
|
| E.1.1.1 | Medical condition in easily understood language |
| metastatic breast cancer HER2- HR+ PIK3CA+ |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 evaluate if there are differences in exposure adjusted incidence rates of grade 3 or 4 hyperglycemia between treatment with alpelisib in the evening at 22:00h with fasting period of five hours and suggestion for low carbohydrate diet in combination with fulvestrant compared to alpelisib administered according to EMA approved recommendation for posology and method of administration and fulvestrant, within the first 3 months or 30 days after the treatment discontinuation whichever comes first in men and postmenopausal women with HR+, HER2 negative, PIK3CA mutated metastatic breast cancer, who progressed on previous hormone therapy
|
|
| E.2.2 | Secondary objectives of the trial |
1) To evaluate if there are differences in time to the first grade 3 or
4 hyperglycemia event between treatment arms
2) To evaluate if there are differences in incidence of alpelisib
induced any grade hyperglycemia between treatment arms within
first 3 months from treatment start date
3) To evaluate if there are differences in efficacy between treatment
arms
4) To evaluate if there are long-term differences in incidence and
severity of alpelisib induced hyperglycemia between treatment
arms
5) To evaluate other types of toxicity between treatment arms
within the first 3 months and in a long term |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Key Inclusion criteria:
1. Patient is an adult male or female (≥ 18 years of age) with advanced (loco regionally 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. Written informed consent
4. If female, then the patient is postmenopausal. Postmenopausal status is defined either by:
- Prior bilateral oophorectomy
- Age ≥60
- Age <60 and amenorrhea 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
5. Patient has evidence of recurrence or progression during or after AI therapy (i.e. letrozole, anastrozole, exemestane) or AI and CDK 4/6i therapy (ribociclib, palbociclib, abemaciclib). AI therapy does not need to be the latest treatment regimen.
Version1 dated 01Mar2021
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Protocol CBYL719A01T Croatian Cooperative Group for Clinical Research in Oncology
6. Patient has a histologically and/or cytologically confirmed diagnosis of ER+ and/or PgR+ breast cancer by local laboratory.
7. Patient has adequate bone marrow and organ function as defined by the following laboratory values:
1) Absolute neutrophil count ≥ 1.5 × 109/L
2) Platelets ≥ 100 × 109/L
3) Hemoglobin ≥ 9.0 g/dL
4) Potassium, magnesium and calcium (corrected for serum albumin)
within normal limits or ≤ grade 1 according to National Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 if judged clinically not significant by the Treating Physician, or corrected with supplements
5) INR ≤ 1.5
6) Creatinine clearance > 50% LLN
7) In absence of liver metastases, alanine aminotransferase (ALT)
and aspartate aminotransferase (AST) ≤ 2.5 × ULN. If the patient has liver metastases, ALT and AST ≤ 5 × ULN
8) Total serum bilirubin < ULN (or ≤ 1.5 × ULN if liver metastases are present, or total bilirubin ≤ 3.0 × ULN and direct bilirubin in normal range for patients with Gilbert’s syndrome)
9) Fasting plasma glucose (FPG) ≤ 140 mg/dL (7.7 mmol/L)* and glycosylated Hemoglobin (HbA1c) ≤ 6.4% (both criteria have to be met) 10) Fasting Serum Amylase ≤ 2 × ULN
11) Fasting Serum Lipase ≤ ULN |
|
| E.4 | Principal exclusion criteria |
Key Exclusion 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 established diagnosis of diabetes mellitus type I or uncontrolled type II.
3) Patient has a known history of Steven Johnson’s syndrome or toxic epidermal necrolysis.
4) Patient has a known history of Human Immunodeficiency Virus (HIV) infection.
5) Patient has had surgery within 14 days prior to starting program drug or has not recovered from major adverse reactions.
6) Patient has not recovered to grade 1 or better (except for alopecia) from related adverse reactions of prior antineoplastic therapies.
7) 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.
8) Patient has central nervous system (CNS) involvement, except for patients fulfilling the following 3 criteria:
- completed prior therapy (including radiation and/or surgery) for CNS metastases ≥ 28 days prior to the start of program treatment and
- CNS tumor is clinically stable at the start of program treatment and
- patient is not receiving steroids and/or enzyme inducing anti-epileptic medications for brain metastases
9) Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of alpelisib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
10) 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, interstitial lung disease, unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤6 months prior to enrolment, serious uncontrolled cardiac arrhythmia, symptomatic pericarditis, etc.).
11) Patient who is concurrently being treated with drugs known to be strong inhibitors or inducers of the isoenzyme CYP3A; switching to different medications prior to start of program treatment is allowed within the last 5 days prior to starting program treatment.
12) Patient is currently receiving or has received systemic corticosteroids ≤ 2 weeks prior to start of program treatment, or who have not fully recovered from adverse reactions 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).
13) 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Exposure-adjusted incidence rate of grade 3 or 4 hyperglycemia within the first 3 months or 30 days after the treatment discontinuation whichever comes first |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Recruitment period: 10 months
Time for data clearance and analysis: 3 months Duration of the entire trial: 24 months |
|
| E.5.2 | Secondary end point(s) |
1) Median time to the first grade 3 or 4 hyperglycemia from the
first dose of study treatment until 30 days from permanent treatment discontinuation
2) Exposure-adjusted incidence rate of any grade hyperglycemia within the first 3 months or 30 days after the treatment discontinuation whichever comes first
3) ORR from randomization to 30 days after the treatment discontinuation
PFS from randomization to the end of the study
4) Exposure-adjusted incidence rate of all grade hyperglycemia,
and grade 3 and 4 hyperglycemia from alpelisib treatment start
until 30 days after the permanent treatment discontinuation
5) Exposure-adjusted incidence rate of any grade toxicities within
the first 3 months or 30 days after the treatment discontinuation whichever comes first, and throughout the treatment until 30 days from permanent treatment discontinuation |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Recruitment period: 10 months
Time for data clearance and analysis: 3 months Duration of the entire trial: 24 months |
|
| 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 | No |
| 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 | 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | No |
| 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 | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
Patients will be treated with alpelisib + fulvestrant until disease progression (assessed by RECIST 1.1), unacceptable toxicity, death or discontinuation from treatment for any other reason.
The end of the study is defined as 30 days after the patient permanently discontinues treatment in both cohorts and all the Definition end of trial procedures are completed.
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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