Trial of BKM120/Tamoxifen-combination in Patients With HR-pos, HER2-neg Breast Cancer

Breast Cancer Clinical Trial

— PIKTAM  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02404844
• Other study ID #: iOM-02282
• Secondary ID: 2014-000599-24CB
• Status: Completed
• Phase: Phase 2
• First received: February 20, 2015
• Last updated: April 19, 2018
• Start date: December 2014
• Est. completion date: October 19, 2017

Study information

• Verified date: April 2018
• Source: University Hospital, Essen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 48
• Est. completion date: October 19, 2017
• Est. primary completion date: September 19, 2017
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

Drug:
• BKM120
daily oral
• Tamoxifen
daily oral

Locations

Country	Name	City	State
Germany	iOMEDICO AG	Freiburg	Baden-Württemberg

Sponsors (3)

Lead Sponsor	Collaborator
University Hospital, Essen	iOMEDICO AG, Novartis Pharmaceuticals

Country where clinical trial is conducted

Germany, 

References & Publications (2)

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. — View Citation

Rodon J, Braña 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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.	Finding of genomic signatures associated with clinical outcome in response to PI3K pathway-directed therapy with tamoxifen and buparlisib in ER/PR-positive breast cancer.	2 years
Other	Validation of a proprietary technology for highly sensitive and specific mutation detection of circulating free tumor DNA	Finding of specific mutation detection of circulating free tumor DNA	2 years
Primary	Progression free survival (PFS)-rate in the full population, after 6 months	PFS is defined as time from date of start of treatment to the date of the event, defined as the first documented disease progression or death due to any cause per local investigator assessment	6 months
Secondary	Progression free survival (PFS)- rate in the subpopulations after 6 months of combination therapy	PFS is defined as time from date of start of treatment to the date of the event, defined as the first documented disease progression or death due to any cause per local investigator assessment	6 months
Secondary	Progression-free survival (PFS)	PFS in subpopulations and full population. PFS is defined as time from date of start of treatment to the date of the event, defined as the first documented disease progression or death due to any cause per local investigator assessment	6 months
Secondary	1 year overall survival (OS) rate	OS is defined as time from date of start of treatment to the date of death from any cause.	1 year
Secondary	2 years overall survival (OS) rate	OS is defined as time from date of start of treatment to the date of death from any cause.	2 years
Secondary	Overall response rate (ORR)	ORR is defined as the proportion of patients with best overall response of complete response (CR) or partial response (PR) (RECIST v1.1).	6 months
Secondary	Disease control rate (DCR)	DCR is defined as the proportion of patients with best overall response of complete response (CR) or partial response (PR) or stable disease (SD) lasting more than 12 weeks (RECIST v1.1).	6 months
Secondary	Number of Participants with Adverse Events as a Measure of Safety and Tolerability	Type, frequency and severity of adverse events per CTCAE v4.03	From date of informed consent to +30 days from last application of study medication
Secondary	Incidence and severity of depressive episodes during the course of treatment	Change in depressive episodes assessed by PHQ-9 questionnaire	From date of informed consent to +30 days from last application of study medication
Secondary	Incidence and severity of depressive episodes during the course of treatment	Change in depressive episodes assessed by GAD-7 questionnaire	From date of informed consent to +30 days from last application of study medication