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

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

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.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: BKM120; Drug: Tamoxifen

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.

• Study Type: Interventional
• Enrollment (Actual): 48
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Baden-Württemberg
    • Freiburg, Baden-Württemberg, Germany, 79108
      • iOMEDICO AG

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BKM120 + Tamoxifen; BKM120 (Buparlisib): 100 mg/day, orally, on a continuous dosing schedule without interruption starting on day 1 in 28 day cycle Tamoxifen: 20 mg/day, orally, on a continuous dosing schedule without interruption starting on day 1 in 28 day cycle	Drug: BKM120; daily oral; Other Names: Buparlisib; Drug: Tamoxifen; daily oral

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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
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
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
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
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
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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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

Collaborators and Investigators

• Sponsor: University Hospital, Essen
• Collaborators: Novartis Pharmaceuticals; iOMEDICO AG
• Investigators: Principal Investigator: Anja Welt, MD, University Hospital, Essen

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: December 1, 2014
• Primary Completion (Actual): September 19, 2017
• Study Completion (Actual): October 19, 2017

Study Registration Dates

• First Submitted: February 20, 2015
• First Submitted That Met QC Criteria: March 26, 2015
• First Posted (Estimate): April 1, 2015

Study Record Updates

• Last Update Posted (Actual): April 20, 2018
• Last Update Submitted That Met QC Criteria: April 19, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Hormone Antagonists; Bone Density Conservation Agents; Estrogen Antagonists; Selective Estrogen Receptor Modulators; Estrogen Receptor Modulators; Tamoxifen
• Other Study ID Numbers: iOM-02282; 2014-000599-24 (EudraCT Number); CBKM120ZDE02T (Other Grant/Funding Number: Novartis Pharma GmbH); AIO-MAM-0114/ass (Other Grant/Funding Number: AIO)