Primary: The primary objective is to determine whether treatment with alpelisib in combination with fulvestrant prolongs progression free survival (PFS) compared to treatment with placebo in combination with fulvestrant based on local radiological…
ID
Source
Brief title
Condition
- Breast neoplasms malignant and unspecified (incl nipple)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
PFS
Secondary outcome
OS, centrally assessed PFS, ORR, time to deterioration of ECOG performance
status, adverse events, quality of life, PK parameters, association between
PIK3CA mutation status and PFS.
Background summary
Pre-clinical data showing potential for cell death in addition to decreased
proliferation have been observed when PI3K inhibitors are given in combination
with hormonal therapy, in particular fulvestrant. Furthermore promising
clinical activity has been observed with single agent alpelisib in heavily
pre-treated ER+ metastatic breast cancer patients and when alpelisib was given
in combination with fulvestrant or AI to HR+ HER2-negative metastatic breast
cancer patients.
The purpose of this study is to determine whether treatment with alpelisib plus
fulvestrant prolongs progression-free survival compared to fulvestrant and
placebo in men and postmenopausal women with hormone receptor positive,
HER2-negative advanced breast cancer, who received prior treatment with an
aromatase inhibitor either as (neo)adjuvant or for advanced disease.
Study objective
Primary:
The primary objective is to determine whether treatment with alpelisib in
combination with fulvestrant prolongs progression free survival (PFS) compared
to treatment with placebo in combination with fulvestrant based on local
radiological assessment for each of the following cohorts
1. patients with PIK3CA mutant status
2. patients with PIK3CA non-mutant status
Secondary:
The key secondary objective is to determine whether treatment with alpelisib in
combination with fulvestrant prolongs overall survival (OS).
Other secondary objectives are centrally assessed PFS, overall response rate
(ORR), time to deterioration of ECOG performance status, safety and
tolerability, quality of life, PK, association between PIK3CA mutation status
and PFS.
Study design
Randomized, phase III, double-blind, placebo controlled trial comparing
* the combination of fulvestrant 500 mg IM per 4 weeks + alpelisib 300 mg daily
orally
* fulvestrant 500 mg IM per 4 weeks + placebo.
28-days screening phase, treatment phase until progression or unacceptable side
effects and a post-treatment phase which includes safety, efficacy, and
survival follow-up.
Subjects will be assigned to one of the following cohorts:
* Cohort I; PIK3CA mutant: Patients with a confirmed PIK3CA mutation.
* Cohort II; PIK3CA non-mutant: Patients without evidence of PIK3CA mutation.
In each cohort, patient will be randomly assigned to one of the two study
treatments in a 1:1 ratio.
Randomization will be stratified by the following factors:
* Lung and/or liver metastases (yes versus no)
* Previous treatment with any CDK4/6 inhibitor (yes versus no) (the total
number of subjects pre-treated with any CDK4/6 inhibitor will be limited to 30%
of the overall study population).
Approx. 560 subjects.
Intervention
Treatment with fulvestrant with or without alpelisib.
Study burden and risks
Risk: Adverse effects of fulvestrant with or without alpelisib.
Burden: Cycles of 4 weeks. Cycle 1: 3 visits, cycle 2: 2 visits, from cycle 3
onwards 1 visit. Duration mostly 3-4 and occasionally up to 8 hours. (in case
part of the first 200 patients worlwide on the day of PK blood draw during 8
uhours post dose).
2 IM injections of 5 mL with fulvestrant every 4 weeks (plus 2 extra injections
during cycle 1, day 15)
Physical examination: start and end of treatment, once per cycle (exception:
twice during cycle 1 and 2).
Blood draws (fasting, 20-40 ml/occasion): start and end of treatment, once per
cycle (exception: twice during cycle 1 and 2).(10-25ml for biomarker analysis)
ECG: start and end of treatment, twice during cycle 1 and every 2nd cycle
thereafter.
Echocardiogram/MUGA-scan: start and end of treatment, once during cycle 5 and
every 4th cycle thereafter.
0-2 tumor biopsies (1 may be archival sample, the other is optional)(for
biomarker analysis)
Optional skin biopsy in case of rash.
CT-/MRI-scan: every 8 weeks during first 18 months and every 12 weeks
thereafter. Skin photographs in case of skin lesions.
Questionnaires QLQ-C30, EQ-5D-5L, BPI-SF (pain): every 8 weeks during first 18
months and every 12 weeks thereafter.
Optional storage and use of the remaining blood and tissue for future research.
Raapopseweg 1
Arnhem 6824 DP
NL
Raapopseweg 1
Arnhem 6824 DP
NL
Listed location countries
Age
Inclusion criteria
* Postmenopausal (see protocol page 62 for details) females and males * 18
years of age.
* Adequate tumor tissue for analysis of PIK3CA mutational status. Identified
PIK3CA status.
* Histologically and/or cytologically confirmed diagnosis of ER+ and/or PgR+
HER2- breast cancer.
* Advanced disease. See protocol page 62 for details.
* Recurrence or progression of disease during or after aromatase inhibitor
therapy (i.e. letrozole, anastrozole, exemestane).
* Measurable disease or *1 predominantly lytic bone lesion. See protocol page
62 for details.
* ECOG performance status 0-1.
Exclusion criteria
* Symptomatic visceral disease or ineligibility for endocrine treatment.
* Prior treatment with chemotherapy (except for neoadjuvant/ adjuvant
chemotherapy), fulvestrant, any PI3K, mTOR or AKT inhibitor.
* Child pugh score B or C.
* CNS involvement. Exceptions: see protocol page 64 for details.
* Diabetes mellitus type I or not controlled type II.
* Documented pneumonitis. See protocol page 64 for details.
* Clinically significant uncontrolled heart disease. See protocol page 64 for
details.
* Treatment with drugs with a known risk to prolong the QT interval or induce
Torsade de Pointes. Use of herbal preparations. Unless discontinued at least 14
days prior to start of study treatment.
* Systemic corticosteroids * 2 weeks prior to starting study drug, or who have
not fully recovered from side effects of such treatment.
* Sexually active males unless they are sterilized or use a condom during
intercourse during the use of study treatment and 8 months thereafter.
* History of acute pancreatitis within1 year of screening or past medical
history of chronic
pancreatitis
* Patient who relapsed with documented evidence of progression more than
12 months from
completion of (neo)adjuvant endocrine therapy with no treatment for metastatic
disease
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2015-000340-42-NL |
| ClinicalTrials.gov | NCT02437318 |
| CCMO | NL53653.028.15 |