BKM120 For Triple Negative Breast Cancer

• Sponsor: Dana-Farber Cancer Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT01790932
• Collaborator: (none)
• Enrollment: 50
• Locations: 4
• Arm: 1
• Actual Duration (Months): 39
• Patients Per Site: 12.5
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

Triple negative breast cancer (TNBC) has an aggressive phenotype and poor prognosis. This tumor type characterized by lack of expression of estrogen receptor (ER), progesterone receptor (PR) and no amplification of the human epidermal growth factor 2 (HER2) accounts for 15% of breast cancers. Limited treatment options exist in the clinic as hormonal therapies and HER2-trageted agents have proven ineffective. BKM120 is a drug that works by blocking a protein called phosphatidylinositol-3-kinase (PI3K) which may contribute to cancer growth. This drug has been used in experiments in the laboratory and information from these research studies suggests that BKM120 may help to prevent cancer cells from growing. In this research study, the investigators are looking to see if BKM120 works to stop breast cancer cells from growing.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: BKM120	Phase 2

Detailed Description

Study plan Two investigator-initiated protocols (one for US, one for Spain) will be enrolling in parallel. The first 50 participants will be recruited concurrently in US and Spain.

Stage 1 Stage 1 will include up to 50 participants with advanced TN disease. Available tumor block is required in all participants per inclusion criteria. Analysis of this tumor block will be used for correlation of predictive markers and clinical response in order to define potential subpopulation that benefit from BKM120. In Stage 1, all participants will have biopsies done at baseline, cycle 1 day 28/cycle 2 day 1 and end of treatment to analyze drug effect in the PI3K and mitogen-activated protein kinases (MAPK) pathway. This will aid to understand the pharmacodynamic effects of BKM120 in tumors with similar genetic background (triple negative disease). The enrollment of Stage 1 will ensure that at least 10 paired evaluable biopsies are obtained. After the enrollment of the first 29 evaluable subjects enrolled overall in Stage 1 (considering the US and the Spanish protocol), the Steering Committee will perform an interim analysis of safety and efficacy. If absolutely no activity is observed, the clinical trial will close and no more subjects will be enrolled. If there are early signs of activity (one patient or more achieving clinical benefit response), enrollment will proceed until 50 participants are enrolled in Stage 1. After 50 patients have been enrolled, we will analyze preliminary responses to treatment depending on the molecular status of each patient.

Stage 2 Were the trial to continue at the end of Stage 1, 50 participants would have been treated and their clinical status and response to therapy will be available. Also, paraffin blocks from these participants will have been analyzed for predictive markers of treatment effect. If there is clinical activity observed in Stage 1 and this analysis shows preliminary signs of response in a subpopulation based on the presence or absence of tumor PI3K pathway alterations, participant pre-selection may be implemented for Stage 2 (justified in an amendment before proceeding to Stage 2.

Study Design

• Study Type: Interventional
• Actual Enrollment: 50 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Trial of BKM120 in Patients With Triple Negative Metastatic Breast Cancer
• Actual Study Start Date: Jun 1, 2012
• Actual Primary Completion Date: Sep 1, 2015
• Actual Study Completion Date: Sep 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: BKM120 BKM120: 100 mg capsule once daily each day of a 28 day cycle . Treatment with BKM120 will continue until disease progression, unacceptable toxicity or withdrawal for other reasons.	Drug: BKM120; Other Names: Buparlisib

Outcome Measures

Primary Outcome Measures

1. Clinical Benefit Rate [Disease was evaluated radiologically at baseline and every 2 cycles on treatment then every 3 months up to 2 years. Participants in this study cohort were followed for response on average approximately 2 months.]

   Clinical benefit rate (CBR) was defined as the proportion of participants achieving complete response (CR), partial response (PR), or stable disease (SD) for 4 months or longer based on RECIST 1.1 criteria on treatment. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PD is at least a 20% increase in sum LD of target lesions (smallest sum LD reference), new lesions, and/or unequivocal progression of existing non-target lesions. Stable disease (SD) is defined as any condition not meeting the above criteria.

Secondary Outcome Measures

1. Progression Free Survival [Disease was evaluated radiologically at baseline and every 2 cycles on treatment then every 3 months up to 2 years. Participants in this study cohort were followed for PFS on average approximately 2 months.]

   Progression-free survival (PFS) based on the Kaplan-Meier (KM) method is defined as the duration of time from study entry to documented disease progression (PD) or death. Participants alive without PD are censored at the date of last disease assessment. Per RECIST 1.1 criteria: PD is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions.

2. Overall Survival [Participants were assessed every 3 months post-treatment up to 2 years. Average survival follow-up for the study cohort was 13.8 months.]

   Overall survival (OS) is defined as the duration of time from study entry to death or date last known alive and estimated using the KM method.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Pathologically and radiologically confirmed metastatic triple negative breast cancer

• Up to two prior lines of chemotherapy for metastatic breast cancer

• Availability of a representative tumor specimen

• At least one measurable lesion

Exclusion Criteria:

• Have received previous treatment with PI3K inhibitors

• Symptomatic central nervous system (CNS) metastases (controlled and asymptomatic CNS metastases are acceptable)

• Concurrent malignancy or has a malignancy within 3 years of study enrollment

• Any of the following mood disorders: active major depressive episode, bipolar disorder, obsessive-compulsive disorder, schizophrenia, history of suicidal attempt or ideation, homicidal ideation, greater than or equal to Common Toxicity Criteria for Adverse Events (CTCAE) grade 3 anxiety

• Concurrently using other approved or investigational antineoplastic agent and/or chemotherapy within 21 days prior to enrollment in this study

• Has received radiation therapy within 28 days prior to enrollment in this study or has not recovered from side effects of such therapy

• Major surgery within 28 days of starting therapy or has not recovered from major side effects of a previous surgery

• Poorly controlled diabetes mellitus

• History of cardiac dysfunction

• Currently receiving treatment with QT prolonging medication and the treatment cannot be discontinued or switched to a different medication

• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of BKM120

• Receiving chronic treatment with steroids or another immunosuppressive agent

• Other concurrent severe and/or uncontrolled medical condition that would contraindicate participation in this study

• History of non-compliance to a medical regimen

• Currently being treated with drugs known to be moderate or strong inhibitors or inducers of isoenzyme Cytochrome P450, family 3, subfamily A (CYP3A)

• Known history of human immunodeficiency virus (HIV)

• Pregnant or breastfeeding

• Unwilling to observe total abstinence or to use double barrier method for birth control throughout trial

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Dana-Farber Cancer Institute at Faulkner Hospital	Boston	Massachusetts	United States	02130
2	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
3	Brigham and Women's Hospital	Boston	Massachusetts	United States	02215
4	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215

Sponsors and Collaborators

• Dana-Farber Cancer Institute

Investigators

• Principal Investigator: Nancy Lin, MD, Dana-Farber Cancer Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Nancy Lin, MD, Principal Investigator, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT01790932
• Other Study ID Numbers: 12-438
• First Posted: Feb 13, 2013
• Last Update Posted: Jan 23, 2019
• Last Verified: Jan 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Nancy Lin, MD, Principal Investigator, Dana-Farber Cancer Institute: Metastatic; Triple Negative
• Additional relevant MeSH terms: Breast Neoplasms

Study Results

Participant Flow

Recruitment Details	Participants enrolled between June 2012 and September 2014.

Arm/Group Title	BKM120
Arm/Group Description	BKM120: 100 mg capsule once daily each day of a 28 day cycle . Treatment with BKM120 will continue until disease progression, unacceptable toxicity or withdrawal for other reasons.
Period Title: Overall Study
STARTED	50
COMPLETED	0
NOT COMPLETED	50

Baseline Characteristics

Arm/Group Title	BKM120
Arm/Group Description	BKM120: 100 mg capsule once daily each day of a 28 day cycle . Treatment with BKM120 will continue until disease progression, unacceptable toxicity or withdrawal for other reasons.
Overall Participants	50
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	53
Sex: Female, Male (Count of Participants)
Female	50 100%
Male	0 0%
Region of Enrollment (Count of Participants)
United States	50 100%

Outcome Measures

1. Primary Outcome

Title	Clinical Benefit Rate
Description	Clinical benefit rate (CBR) was defined as the proportion of participants achieving complete response (CR), partial response (PR), or stable disease (SD) for 4 months or longer based on RECIST 1.1 criteria on treatment. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PD is at least a 20% increase in sum LD of target lesions (smallest sum LD reference), new lesions, and/or unequivocal progression of existing non-target lesions. Stable disease (SD) is defined as any condition not meeting the above criteria.
Time Frame	Disease was evaluated radiologically at baseline and every 2 cycles on treatment then every 3 months up to 2 years. Participants in this study cohort were followed for response on average approximately 2 months.

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all enrolled participants.

Arm/Group Title	BKM120
Arm/Group Description	BKM120: 100 mg capsule once daily each day of a 28 day cycle . Treatment with BKM120 will continue until disease progression, unacceptable toxicity or withdrawal for other reasons.
Measure Participants	50
Number (95% Confidence Interval) [proportion of participants]	0.12 0.2%

2. Secondary Outcome

Title	Progression Free Survival
Description	Progression-free survival (PFS) based on the Kaplan-Meier (KM) method is defined as the duration of time from study entry to documented disease progression (PD) or death. Participants alive without PD are censored at the date of last disease assessment. Per RECIST 1.1 criteria: PD is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions.
Time Frame	Disease was evaluated radiologically at baseline and every 2 cycles on treatment then every 3 months up to 2 years. Participants in this study cohort were followed for PFS on average approximately 2 months.

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all enrolled participants.

Arm/Group Title	BKM120
Arm/Group Description	BKM120: 100 mg capsule once daily each day of a 28 day cycle . Treatment with BKM120 will continue until disease progression, unacceptable toxicity or withdrawal for other reasons.
Measure Participants	50
Median (95% Confidence Interval) [months]	1.8

3. Secondary Outcome

Title	Overall Survival
Description	Overall survival (OS) is defined as the duration of time from study entry to death or date last known alive and estimated using the KM method.
Time Frame	Participants were assessed every 3 months post-treatment up to 2 years. Average survival follow-up for the study cohort was 13.8 months.

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all enrolled participants.

Arm/Group Title	BKM120
Arm/Group Description	BKM120: 100 mg capsule once daily each day of a 28 day cycle . Treatment with BKM120 will continue until disease progression, unacceptable toxicity or withdrawal for other reasons.
Measure Participants	50
Median (95% Confidence Interval) [months]	11.2

Adverse Events

Time Frame	Adverse events (AEs) were assessed every 2 weeks for the first 2 cycles and every cycle thereafter. Participants in this study cohort were followed for AEs on average approximately 2 months.
Adverse Event Reporting Description	Maximum grade toxicity by type was first calculated. Serious AEs were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher per Common Toxicity Criteria for Adverse Events (CTCAE) version 3. All remaining events regardless of treatment attribution were classified as Other AEs. No further data is available to specify classification of other beyond the general term.
Arm/Group Title	BKM120
Arm/Group Description	BKM120: 100 mg capsule once daily each day of a 28 day cycle . Treatment with BKM120 will continue until disease progression, unacceptable toxicity or withdrawal for other reasons.
All Cause Mortality
	BKM120
	Affected / at Risk (%)	# Events
Total	29/50 (58%)
Serious Adverse Events
	BKM120
	Affected / at Risk (%)	# Events
Total	17/50 (34%)
General disorders
Fatigue	4/50 (8%)
Infections and infestations
Papulopustular rash	1/50 (2%)
Investigations
Alanine aminotransferase increased	5/50 (10%)
Aspartate aminotransferase increased	4/50 (8%)
Metabolism and nutrition disorders
Alkalosis	1/50 (2%)
Anorexia	1/50 (2%)
Hyperglycemia	2/50 (4%)
Nervous system disorders
Nervous system disorders - Other	1/50 (2%)
Skin and subcutaneous tissue disorders
Dry skin	1/50 (2%)
Rash acneiform	1/50 (2%)
Rash maculo-papular	2/50 (4%)
Skin and subcutaneous tissue disorders - Other	1/50 (2%)
Other (Not Including Serious) Adverse Events
	BKM120
	Affected / at Risk (%)	# Events
Total	44/50 (88%)
Blood and lymphatic system disorders
Anemia	1/50 (2%)
Febrile neutropenia	2/50 (4%)
Blood and lymphatic system disorders - Other	1/50 (2%)
Eye disorders
Watering eyes	1/50 (2%)
Eye disorders - Other	1/50 (2%)
Gastrointestinal disorders
Bloating	1/50 (2%)
Constipation	5/50 (10%)
Diarrhea	9/50 (18%)
Dyspepsia	2/50 (4%)
Mucositis oral	5/50 (10%)
Nausea	16/50 (32%)
Rectal hemorrhage	1/50 (2%)
Vomiting	2/50 (4%)
Gastrointestinal disorders - Other	5/50 (10%)
General disorders
Fatigue	24/50 (48%)
Fever	1/50 (2%)
Non-cardiac chest pain	2/50 (4%)
Pain	1/50 (2%)
General disorders and administration site conditions - Other	3/50 (6%)
Hepatobiliary disorders
Hepatic failure	1/50 (2%)
Immune system disorders
Allergic reaction	1/50 (2%)
Infections and infestations
Papulopustular rash	1/50 (2%)
Upper respiratory infection	1/50 (2%)
Urinary tract infection	1/50 (2%)
Infections and infestations - Other	2/50 (4%)
Injury, poisoning and procedural complications
Fracture	1/50 (2%)
Investigations
Alanine aminotransferase increased	8/50 (16%)
Alkaline phosphatase increased	1/50 (2%)
Aspartate aminotransferase increased	6/50 (12%)
Weight loss	1/50 (2%)
Investigations - Other, specify	1/50 (2%)
Metabolism and nutrition disorders
Anorexia	14/50 (28%)
Hyperglycemia	16/50 (32%)
Hypomagnesemia	1/50 (2%)
Hyponatremia	1/50 (2%)
Musculoskeletal and connective tissue disorders
Back pain	2/50 (4%)
Myalgia	2/50 (4%)
Pain in extremity	1/50 (2%)
Musculoskeletal and connective tissue disorder - Other	2/50 (4%)
Nervous system disorders
Dizziness	2/50 (4%)
Dysgeusia	2/50 (4%)
Headache	3/50 (6%)
Peripheral sensory neuropathy	3/50 (6%)
Somnolence	2/50 (4%)
Psychiatric disorders
Anxiety	8/50 (16%)
Depression	7/50 (14%)
Insomnia	5/50 (10%)
Libido increased	1/50 (2%)
Psychiatric disorders - Other	7/50 (14%)
Renal and urinary disorders
Cystitis noninfective	1/50 (2%)
Hematuria	1/50 (2%)
Reproductive system and breast disorders
Breast pain	2/50 (4%)
Respiratory, thoracic and mediastinal disorders
Cough	2/50 (4%)
Dyspnea	4/50 (8%)
Voice alteration	1/50 (2%)
Skin and subcutaneous tissue disorders
Alopecia	1/50 (2%)
Dry skin	1/50 (2%)
Photosensitivity	1/50 (2%)
Pruritus	3/50 (6%)
Rash acneiform	5/50 (10%)
Rash maculo-papular	3/50 (6%)
Skin and subcutaneous tissue disorders - Other	2/50 (4%)
Vascular disorders
Hypertension	1/50 (2%)
Lymphedema	1/50 (2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.