Clinical trial NCT02404844: Trial of BKM120/Tamoxifen-combination in Patients With HR-pos, HER2-neg Breast Cancer
Official title: Molecularly Stratified Parallel Cohort, Single Arm Phase II Trial of the Phosphoinositide 3-kinase (PI3K) Inhibitor Buparlisib (BKM120) in Combination With Tamoxifen in Patients With Hormone Receptor-positive, HER2-negative Inoperable (Locally Advanced or Metastatic) Breast Cancer With Prior Exposure to Antihormonal Therapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Breast Cancer
Lead sponsor: University Hospital, Essen
Sponsor class: OTHER
Collaborators: name: iOMEDICO AG
name: Novartis Pharmaceuticals
First posted: 2015-04-01
Enrollment: 48
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a clinical trial with a molecularly stratified parallel cohort, single arm design to explore the efficacy and safety of BKM120 in combination with tamoxifen in patients with ER/PR-positive, HER2-negative breast cancer with prior exposure to antihormonal therapy, and different biomarker profiles, two of them potentially indicative of constitutive PI3K pathway activation.

Detailed description: This is a clinical trial with a molecularly stratified parallel cohort, single arm design to explore the efficacy and safety of BKM120 in combination with tamoxifen in patients with ER/PR-positive, HER2-negative breast cancer with prior exposure to antihormonal therapy, and different biomarker profiles, two of them potentially indicative of constitutive PI3K pathway activation:

* PIK3CA mutation/preserved PTEN expression
* PIK3CA wildtype or mutation/ loss of PTEN expression
* PIK3CA wildtype/preserved PTEN expression. This trial will explore, if the combination of BKM120 and tamoxifen can overcome resistance to antihormonal therapies. BKM120 is selective for class I PI3K enzymes with no mTOR inhibitory activity that has entered Phase II and III clinical trials. The tumor suppressor PTEN is the most important negative regulator of the PI3K signaling pathway. Therefore, in addition the trial will prospectively evaluate PIK3CA mutations and/or loss of PTEN expression as predictive biomarkers for clinical benefit from combined treatment with BKM120 and tamoxifen.

Eligibility criteria: Inclusion Criteria:

* Patient has histologically and/or cytologically confirmed diagnosis of breast cancer
* Patient has radiologic or objective evidence of inoperable locally advanced, or metastatic breast cancer
* Patient has a known hormone receptor status HR-positive (ER and/or PR positive) and HER2-negative status
* Patient has a representative archival formalin-fixed tumor biopsy (metastasis or primary tumor)
* Patient has prior exposure to antihormonal therapy
* Patient has received ≤ 2 prior antihormonal treatments in the metastatic setting
* Prior treatment with tamoxifen in the (neo-)adjuvant setting is allowed but has to be discontinued for at least 1 year.
* Patient may have received up to one prior chemotherapy in the metastatic setting
* Measurable or non-measurable lesions according to RECIST v1.1 criteria
* Patient has an Eastern Cooperative Oncology Group (ECOG) performance status score ≤ 2

Exclusion Criteria:

* Patient has received previous treatment with a PI3K- or AKT-inhibitor or mTOR-inhibitors
* Prior treatment with Tamoxifen in the metastatic setting. Treatment with tamoxifen in the (neo-)adjuvant setting is allowed, but has to be discontinued for at least 1 year
* Patient has symptomatic CNS metastases
* Patient has a medically documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation (e.g. risk of doing harm to self or others), or patients with active severe personality disorders (defined according to DSM-IV).
* Patient has a known history of HIV infection (testing not mandatory) infection

Primary outcomes:
measure: Progression free survival (PFS)-rate in the full population, after 6 months
timeFrame: 6 months
Secondary outcomes:
measure: Progression free survival (PFS)- rate in the subpopulations after 6 months of combination therapy
timeFrame: 6 months
measure: Progression-free survival (PFS)
timeFrame: 6 months
measure: 1 year overall survival (OS) rate
timeFrame: 1 year
measure: 2 years overall survival (OS) rate
timeFrame: 2 years
measure: Overall response rate (ORR)
timeFrame: 6 months
measure: Disease control rate (DCR)
timeFrame: 6 months
measure: Number of Participants with Adverse Events as a Measure of Safety and Tolerability
timeFrame: From date of informed consent to +30 days from last application of study medication
measure: Incidence and severity of depressive episodes during the course of treatment
timeFrame: From date of informed consent to +30 days from last application of study medication
measure: Incidence and severity of depressive episodes during the course of treatment
timeFrame: From date of informed consent to +30 days from last application of study medication
Other outcomes:
measure: Identification of genomic signatures associated with clinical outcome in response to PI3K pathway-directed therapy with tamoxifen and buparlisib in ER/PR-positive breast cancer.
timeFrame: 2 years
measure: Validation of a proprietary technology for highly sensitive and specific mutation detection of circulating free tumor DNA
timeFrame: 2 years
Locations:
city: Freiburg
country: Germany
facility: iOMEDICO AG
state: Baden-Württemberg
Study officials:
affiliation: University Hospital, Essen
name: Anja Welt, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bendell JC, Rodon J, Burris HA, de Jonge M, Verweij J, Birle D, Demanse D, De Buck SS, Ru QC, Peters M, Goldbrunner M, Baselga J. Phase I, dose-escalation study of BKM120, an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors. J Clin Oncol. 2012 Jan 20;30(3):282-90. doi: 10.1200/JCO.2011.36.1360. Epub 2011 Dec 12.
citation: Rodon J, Brana I, Siu LL, De Jonge MJ, Homji N, Mills D, Di Tomaso E, Sarr C, Trandafir L, Massacesi C, Eskens F, Bendell JC. Phase I dose-escalation and -expansion study of buparlisib (BKM120), an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors. Invest New Drugs. 2014 Aug;32(4):670-81. doi: 10.1007/s10637-014-0082-9. Epub 2014 Mar 21.