Primary: To determine whether treatment with BKM120 plus fulvestrant prolongs PFS based on local investigator assessment compared to treatment with placebo plus fulvestrant for all patients regardless of PI3K pathway activation status (unkown status…
ID
Source
Brief title
Condition
- Breast neoplasms malignant and unspecified (incl nipple)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Progression free survival.
Secondary outcome
Secondary: PFS based on ctDNA, Overall survival based on ctDNA, Overall
response rate based on ctDNA, Clinical benefit rate based on ctDNA, Safety, PK,
Quality of life, time to definitive deterioration of the ECOG PS of the score
of the baseline
Background summary
There are currently no treatments specifically approved for breast cancer after
recurrence or progression on mTORi treatment. Hormonal therapy, in particular
fulvestrant, remains one of the valid options in that setting.
A significant number of HR+ HER2- breast cancer patients are expected to have
an activated PI3K pathway, either de novo (as diagnosed on archival samples) or
after exposure to anticancer therapies. In these latter patients, PI3K pathway
can be considered turned on irrespective of molecular alterations observed on
archival sample. This pathway can play a critical role in inducing resistance
to endocrine therapies and mTORi therapies. Promising pre-clinical and clinical
activity has been observed with single agent BKM120 in breast cancer together
with the combined effect with fulvestrant in the pre-clinical setting.
Moreover, use of the pan PI3Ki BKM120 may be a way to overcome resistance to
mTORi by targeting the PI3K pathway upstream. Therefore the addition of BKM120
to fulvestrant may be an effective treatment in HR+ HER2- MBC patients who have
relapsed after mTORi treatment.
The purpose of this pivotal multi-center, double blind, two-arm, randomized
phase III study is to determine whether treatment with BKM120 plus fulvestrant
prolongs PFS compared to treatment with placebo plus fulvestrant in
postmenopausal women with HR+ HER2- AI pretreated locally advanced or MBC whose
disease has progressed on mTORi containing regimen for the following
populations: i) all patients regardless of PI3K pathway activation status
(unknown status is allowed) (full population) and ii) PI3K pathway activated
sub-population.
Study objective
Primary: To determine whether treatment with BKM120 plus fulvestrant prolongs
PFS based on local investigator assessment compared to treatment with placebo
plus fulvestrant for all patients regardless of PI3K pathway activation status
(unkown status is allowed) (full population) and for PI3K pathway activated
sub-population.
Secondary: PFS based on ctDNA, Overall survival based on ctDNA, Overall
response rate based on ctDNA, Clinical benefit rate based on ctDNA, Safety, PK,
Quality of life, time to definitive deterioration of the ECOG PS of the score
of the baseline
Study design
Multicenter randomized double blind placebo controlled parallel group phase III
study.
Essay of existing or fresh tumor tissue for PI3K activation status.
Randomization (2:1) to treatment with:
• Fulvestrant 500 mg intramuscularly every 4 weeks (plus after 1st 2 weeks) +
BKM120 daily 100 mg orally.
• Fulvestrant 500 mg intramuscularly every 4 weeks (plus after 1st 2 weeks) +
Placebo.
Until disease progression.
Follow-up for survival.
Interim-analysis planned (see protocol section 10.7, protocol page 131).
Independent DMC.
420 patients
Intervention
Treatment with BKM120 or placebo in combination with fulvestrant.
Study burden and risks
Risk: Adverse events of study medication.
Burden: Study duration in principle until disease progression. weekly visits
during 1st 2 courses of 4 weeks; 4-weekly thereafter. Follow-up for survival
every 3 weeks.
Diary about medication intake during the whole study.
Physical examination every 4 weeks.
Blood draws 30-50 ml/week during treatment period.
PK blood sampling (2 ml/sample):
1st 100 patients:
• Day 1 course 1: 3-4 samples in 6-9 h.
• Day 15 course 1 and day 1 courses 2, 3 and 4: 1 sample.
Urine sample during screening.
ECG every 4 weeks.
Echocardiography or MUGA-scan every 12 weeks.
Tumor evaluations as during regular treatment, every 6 weeks.
Questionnaires (2 on mood changes, 2 on quality of life) (nearly) every visit.
Pregnancy test during screening and end of study.
Lung function test only if needed.
Tumor biopsy during screening (PI3K activation) only if no archival tumor
material is available
Optional tumor biopsy 2x for biomarker research.
Optional availability of remaning tumor material for future research on BKM120
and/or breast cancer.
Raapopseweg 1
Arnhem 6824DP
NL
Raapopseweg 1
Arnhem 6824DP
NL
Listed location countries
Age
Inclusion criteria
Postmenopausal women breast cancer that is locally advanced or metastatic HER2 negative disease, and a known positive hormone receptor status (common breast cancer classification tests);Patient has adequate tumor tissue for the analysis of PI3K related biomarkers.
Evidence of progression to the combination of mTORi and endocrine therapy given as the last therapy prior to study entry;Adequate bone marrow and organ function;Other protocol defined criteria may apply
Exclusion criteria
More than 1 prior chemotherapy given for locally advanced or metastatic disease;Previous treatment with PI3K inhibitors, AKT inhibitors or fulvestrant;Symptomatic CNS metastases;Concurrent malignancy or malignancy within 3 years prior to start of study treatment;Certain drugs or radiation within 2-4 weeks of enrollment - Increasing or chronic treatment (> 5 days) with corticosteroids or another immunosuppressive agent;Active heart (cardiac) disease or a history of cardiac dysfunction as defined in the protocol;Hypersensitivity to fulvestrant excipients;Certain scores on an anxiety and depression mood questionnaire given at screening;Other protocol defined criteria may apply
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 | EUCTR2012-002571-34-NL |
| ClinicalTrials.gov | NCT01633060 |
| CCMO | NL41871.068.12 |