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 (full…
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
Overall survival, Overall response rate, Clinical benefit rate, Safety, PK,
Quality of life.
Time to deterioration ECOG performance
Background summary
Therapies which interfere with the estrogen receptor (ER) functions such as
tamoxifen have significantly contributed to mortality reduction in advanced
breast cancer, but at best 50-60% of hormone receptor positive patients have a
benefit from this therapy. Consequently, a number of other therapeutic options
have been developed for the treatment of locally advanced or metastatic breast
cancer (MBC) including aromatase inhibitors (AIs) that reduce peripheral
estrogen synthesis and fulvestrant which is an ER antagonist.
There are currently no treatments specifically approved after recurrence or
progression on an AI. Current clinical practice and treatment guidelines
include fulvestrant and exemestane as available options.
A significant number of ER-positive HER2-negative breast cancer patients are
expected to have an activated PI3K pathway, and this pathway can play a
critical role in inducing resistance to endocrine therapies. The PI3K signaling
regulates diverse cellular functions, including cell proliferation, survival,
translational regulation of protein synthesis, glucose metabolism, cell
migration, and angiogenesis. PI3K signaling also serves a central role in the
pathogenesis of numerous forms of neoplasia. Evidence suggests that the PI3K
pathway may play a role in primary and/or acquired resistance to systemic
antineoplastic therapy in MBC.
Evidence suggestes that PI3K pathway could be a critical therapeutic target for
the treatment of patients with ER positive metastatic breast cancer. Hence, the
pan-PI3K inhibitor BKM120 as a treatment option potentially addresses an unmet
medical need in such patients. BKM120 is a potent and highly specific oral PI3K
inhibitor.
A pan PI3K inhibitor in combination with an endocrine agent might present a
benefit in advanced breast cancer patient population who is ER-positive,
HER2-negative and refractory to AI. 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. The
concept of combining a PI3K/AKT/mTOR pathway inhibitor treatment with an AI has
also been supported in the clinical setting: promising improvements in terms of
PFS have been observed recently with the combination of everolimus (mTORi) and
exemestane compared to exemestane alone in MBC patients after prior endocrine
therapy. Therefore the addition of BKM120 to fulvestrant may be an effective
treatment in ER-positive HER2-negative MBC patients.
The purpose of this study is to determine whether treatment with BKM120 plus
fulvestrant prolongs PFS compared to treatment with placebo plus fulvestrant in
postmenopausal women with hormone receptor-positive HER2-negative locally
advanced or MBC whose disease has progressed on or after AI for all patients
regardless of PI3K pathway activation status and 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
(full population) and for PI3K pathway activated sub-population.
Secondary: Overall survival, Overall response rate, Clinical benefit rate,
Safety, PK, Quality of life.
Time to deterioration ECOG performance
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 (1:1) 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 127).
Independent DMC.
~842 patients (at least 334 with PI3K activation).
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. Bi-weekly visits
during 1st 3 courses of 4 weeks; 4-weekly thereafter. Follow-up for survival
every 3 weeks.
Physical examination every 4 weeks.
Blood draws mostly 30-40 ml/week during treatment period.
PK blood sampling (2 ml/sample):
1st 68 patients:
* Day 1 course 2: 9 samples in 9 h.
* Next morning: 1 sample.
* Day 1 course 3: 1 sample.
Next 132 patients:
* Day 15 course 1: 3 samples in 6 uur. Optional after 9 h.
* Day 15 course 2 and day 1 course 3: 1 sample.
1st 200 patients:
* Day 1 course 1-5: 1 sample.
Urine sample during screening.
ECG every 4 weeks.
Echocardiography or MUGA-scan every 16 weeks.
Tumor evaluations as during regular treatment, every 8 weeks.
Questionnaires (2 on mood changes, 2 on quality of life) (nearly) every visit.
Tumor biopsy during screening (PI3K activation), only in case no tissue from
prior biopsy available.
Optional tumor biopsy 1x for biomarker research.
Raapopseweg 1
Arnhem 6824 DP
NL
Raapopseweg 1
Arnhem 6824 DP
NL
Listed location countries
Age
Inclusion criteria
* Women (* 18 years) with histologically confirmed ER-positive and/or PgR-positive and HER2-negative inoperable locally advanced or metastatic breast cancer.
* Known PI3K pathway status (Novartis central lab).
* Postmenopausal (see protocol page 47 for details).
* Refractory to aromatase inhibitors (see protocol page 47 for details).
* (Non) measurable disease as per RECIST 1.1 criteria.
* Patient has adequate bone marrow and organ function
* Fasting plasma glucose * 6.7 mmol/L, HbA1c * 8%.
* ECOG performance status 0-2.
Exclusion criteria
* Previous treatment with a PI3K inhibitor
* More than one chemotherapy line for metastatic disease (see protocol page 48 for details).
* Symptomatic CNS metastases.
* Wide field radiotherapy * 4 weeks or limited field radiation for palliation * 2 weeks prior to starting study drug.
* Chronic treatment (> 5 days) with corticosteroids or another immunosuppressive agent, as chronic administration of corticosteroids (> 5 days) can induce CYP3A4. Exceptions see protocol page 49.
* Coumarin derived anti-coagulant. Therapy with heparin, LMWH, or fondaparinux is allowed
* Drugs known to be moderate or strong inhibitors or inducers of isoenzyme CYP3A.
* Score * 12 on the PHQ-9 questionnaire.
* Response of *1, 2 or 3* to question number 9 on the PHQ-9 questionnaire regarding potential for suicidal thoughts or ideation (independent of the total score of the PHQ-9).
* GAD-7 mood scale score * 15.
* Documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of or current risk of doing harm to self or others.
* * CTCAE grade 3 anxiety.
* Active cardiac disease or a history of cardiac dysfunction. See protocol page 49-50 for details.
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 | EUCTR2011-005524-17-NL |
| ClinicalTrials.gov | NCT01610284 |
| CCMO | NL40888.091.12 |