A Trial of BKM120 (a PI3K Inhibitor) in Patients With Triple Negative Metastatic Breast Cancer

• Sponsor: SOLTI Breast Cancer Research Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT01629615
• Collaborator: Novartis Pharmaceuticals (Industry), Dana-Farber Cancer Institute (Other), Stand Up To Cancer (Other)
• Enrollment: 50
• Locations: 7
• Arm: 1
• Duration (Months): 40
• Patients Per Site: 7.1
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the clinical activity of BKM120 in patients with metastatic triple-negative breast cancer.

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

Detailed Description

This is a prospective, non-randomized, open-label, multicenter, single-arm exploratory study of single agent BKM120 in the treatment of metastatic triple negative breast cancer patients.

Patients will first undergo screening, tumor measurement and collection of available tumor block from the primary tumor and/or a metastatic site. Available tumor block is required in all patients 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.

Following confirmation of eligibility criteria, subjects will be enrolled. BKM120 will then be administered in a 100mg dose, orally, once daily, in a continuous schedule. A treatment cycle is defined as 28 days for the purposes of scheduling procedures and evaluations.

Treatment with BKM120 will continue until disease progression, unacceptable toxicity that precludes any further treatment, and/or discontinuation of the treatment by investigator or patient decision.

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 (a PI3K Inhibitor) in Patients With Triple Negative Metastatic Breast Cancer
• Study Start Date: Jun 1, 2012
• Actual Primary Completion Date: Oct 1, 2015
• Actual Study Completion Date: Oct 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: BKM120	Drug: BKM120; BKM120 oral capsules. 100 mg daily in cycles of 28 days, until disease progression

Outcome Measures

Primary Outcome Measures

1. Rate of Clinical Benefit [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 percentage 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 the 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 [2 years]

   Overall survival was defined as the time from date of study enrollment until death from any cause.

3. Frequency and Severity of Adverse Events [Adverse events (AEs) were assessed every 2 weeks for the first 2 cycles and every cycle thereafter. Participants were followed for AEs on average approximately 2 months.]

   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 4.

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 TNBC (Stage IV disease), previously documented by histological analysis, which is ER-negative and PR-negative by IHC and HER2 negative by IHC or FISH/CISH.

• Subjects must have received maximum two prior chemotherapy regimens for metastatic breast cancer.

• Availability of a representative tumor specimen (primary or metastasis, archival tissue or fresh biopsy for patients with biopsiable tumor) at baseline.

• At least one measurable lesion by RECIST 1.1

• Age ≥ 18 years at the day of consenting to the study

• ECOG performance status ≤ 2

• Adequate bone marrow and organ function as defined by the following laboratory values: ANC ≥ 1.0 x 109/L, platelets ≥ 100 x 109/L, hemoglobin ≥ 9.0 g/dL, INR ≤ 2; serum potassium between 3.0mmol/L and 5.5 mmol/L; Corrected serum calcium between8.0mg/dL and 11.5mg/dL (OR between 1.0mmol/L and 1.5mmol/L of Ionized calcium); serum magnesium between 1.2mg/dL and 3.0 mg/dL; serum creatinine ≤ 1.5 x ULN, ALT and AST within normal range (or ≤ 3.0 x ULN if liver metastases are present); serum bilirubin within normal range (or ≤ 1.5 x ULN if liver metastases are present; or total bilirubin ≤ 3.0 x ULN with direct bilirubin within normal range in patients with well documented Gilbert Syndrome); fasting plasma glucose (FPG) ≤ 140 mg/dL or ≤ 7.8 mmol/L.

Exclusion Criteria:

• Previous treatment with PI3K inhibitors

• Symptomatic CNS metastases

• Patients with controlled and asymptomatic CNS metastases may participate in this trial. As such, the patient must have completed any prior treatment for CNS metastases

28 days (including radiotherapy and/or surgery) prior to enrollment in this study. Patients with previously treated brain metastases, who are on a stable low dose corticosteroids treatment are eligible

• Concurrent malignancy or malignancy within 3 years of study enrollment (with the exception of adequately treated basal or squamous cell carcinoma or non-melanomatous skin cancer). An exception to this rule are those patients with documented germline mutations in BRCA1 or 2, who may have previous history of cancer

• Any of the following mood disorders as judged by the Investigator or a Psychiatrist, or meets the cut-off score of ≥ 10 in the PHQ-9 or a cut-off of ≥ 15 in the GAD-7 mood scale, respectively, or selects a positive response of '1, 2, or 3' to question number 9 regarding potential for suicidal thoughts ideation in the PHQ-9 (independent of the total score of the PHQ-9)

1. Patients with a history or active episodes of major depression, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, history of suicide attempts or suicidal thoughts (eg. Risk of hurting or harming others) or patients with severe personality disorders (as defined by the DSM-IV) are not eligible. Note: For patients who are treated with psychotropic drugs at baseline, the dose and schedule shall not be changed during the 6 weeks prior to initiation of treatment with the study drug.

2. ≥ CTCAE v 4.0 grade 3 anxiety

• Patients on concurrent use of other approved or investigational antineoplastic and / or chemotherapy or any continuous or intermittent treatment with therapeutic agents of low molecular weight (excluding monoclonal antibodies) in ≤ 21 days prior to enrollment in this study or who have not recovered from the effects such therapy will not be eligible.

• Radiotherapy ≤ 28 days prior to enrollment in this study or failure to recover from side effects of such therapy at the time of initiation of screening procedures.

• Major surgery within 28 days prior to starting study drug or has not recovered from major side effects of the surgery

• Poorly controlled diabetes mellitus (HbA1c > 8%)

• Active cardiac disease including any of the following:

1. Left Ventricular Ejection Fraction (LVEF) < 50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO)Note: ECHO/MUGA is only required at baseline if patient has a history of abnormal cardiac test results

2. QTc > 480 msec on screening ECG (using the QTcF formula

3. Angina pectoris that requires the use of anti-anginal medication

4. Ventricular arrhythmias except for benign premature ventricular contractions

5. Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication

6. Conduction abnormality requiring a pacemaker

7. Valvular disease with documented compromise in cardiac function

8. Symptomatic pericarditis

• History of cardiac dysfunction including any of the following;

1. Myocardial infarction within the last 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LVEF function

2. History of documented congestive heart failure (New York Heart Association functional classification III-IV)

3. Documented cardiomyopathy

• Treatment with QT prolonging medication known to have a risk to induce Torsades de Pointes, and the treatment cannot be discontinued or switched to a different medication prior to starting study drug

• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of BKM120 (e.g., uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)

• Chronic treatment with steroids or another immunosuppressive agent. Note: Topical applications (e.g., rash), inhaled sprays (e.g., obstructive airways diseases), eye drops or local injections (e.g., intra-articular) are allowed. Patients with previously treated brain metastases, who are on a stable low dose corticosteroids treatment (e.g., dexamethasone 2 mg/day, prednisone 10 mg/day) for at least 14 days before start of study treatment, are eligible

• Other concurrent severe and/or uncontrolled medical condition that would, in the investigator's judgment contraindicate her participation in the clinical study (e.g., chronic pancreatitis, active chronic hepatitis etc.)

• History of non-compliance to medical regimen

• Current treatment with drugs known to be moderate and strong inhibitors or inducers of isoenzyme CYP3A, and the treatment cannot be discontinued or switched to a different medication prior to starting study drug

• Known history of HIV (testing not mandatory) infection

• Pregnant or nursing (lactating) woman

• Woman of child-bearing potential unwilling to observe total sexual abstinence or to use a double barrier method for birth control throughout the trial. Reliable contraception should be maintained throughout the study and for 6 months after study drug discontinuation

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Dana-Farber at Faulkner Hospital	Boston	Massachusetts	United States	02130
2	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
3	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
4	Hospital Universitario Vall d´Hebron	Barcelona		Spain	08035
5	Hospital Universitario 12 de Octubre	Madrid		Spain	28041
6	Instituto Valenciano de Oncología	Valencia		Spain	46009
7	Hospital Clínico Universitario de Valencia	Valencia		Spain	46010

Sponsors and Collaborators

• SOLTI Breast Cancer Research Group
• Novartis Pharmaceuticals
• Dana-Farber Cancer Institute
• Stand Up To Cancer

Investigators

• Study Chair: Jose Baselga, MD, Massachusetts General Hospital
• Study Chair: Eric Winer, MD, Dana-Farber Cancer Institute
• Principal Investigator: Jordi Rodon, MD, Hospital Universitario Vall d´Hebron

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• SOLTI Breast Cancer Research Group

Publications

• Saura C, Lin N, Ciruelos E, Lluch A, Gavilá J, Winer E, Baselga J, Rodón J. A phase II, non-randomized, multicenter, exploratory trial of single agent BKM120 in patients with triple-negative metastatic breast cancer. Poster session presented at: 35th Annual San Antonio Breast Cancer Symposium (SABCS); 2012 December 4th-8th; San Antonio, Texas, United States.

• Responsible Party: SOLTI Breast Cancer Research Group
• ClinicalTrials.gov Identifier: NCT01629615
• Other Study ID Numbers: CBKM120ZES02T/SOLTI-1103; 2011-006083-45
• First Posted: Jun 27, 2012
• Last Update Posted: Oct 28, 2020
• Last Verified: Oct 1, 2020

• Keywords provided by SOLTI Breast Cancer Research Group: breast cancer; metastatic; triple negative breast cancer; BKM120; SOLTI; PI3K inhibitor
• Additional relevant MeSH terms: Breast Neoplasms

Study Results

Participant Flow

Arm/Group Title	BKM120
Arm/Group Description	BKM120: BKM120 oral capsules. 100 mg daily in cycles of 28 days, until disease progression
Period Title: Overall Study
STARTED	50
COMPLETED	50
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	BKM120
Arm/Group Description	BKM120: BKM120 oral capsules. 100 mg daily in cycles of 28 days, until disease progression
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%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	12 24%
Not Hispanic or Latino	37 74%
Unknown or Not Reported	1 2%
Region of Enrollment (participants) [Number]
United States	27 54%
Spain	23 46%

Outcome Measures

1. Primary Outcome

Title	Rate of Clinical Benefit
Description	Clinical benefit rate (CBR) was defined as the percentage 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 the 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

Intent-to-treat population was all recruited population that receives the study treatment

Arm/Group Title	BKM120
Arm/Group Description	BKM120: BKM120 oral capsules. 100 mg daily in cycles of 28 days, until disease progression
Measure Participants	50
Complete response	0 0%
Partial response	0 0%
Stable disease > 4 months	6 12%
Stable disease < 4 months	11 22%
Progressive disease	20 40%
No evaluable	13 26%

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

Progression-free survival was analyzed in the intent-to-treat population, defined as all recruited population that receives the study treatment.

Arm/Group Title	BKM120
Arm/Group Description	BKM120: BKM120 oral capsules. 100 mg daily in cycles of 28 days, until disease progression
Measure Participants	50
Median (95% Confidence Interval) [Months]	1.8

3. Secondary Outcome

Title	Overall Survival
Description	Overall survival was defined as the time from date of study enrollment until death from any cause.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

Overall survival was analyzed in the Intent-to-treat population, defined as all recruited population that receives the study treatment

Arm/Group Title	BKM120
Arm/Group Description	BKM120: BKM120 oral capsules. 100 mg daily in cycles of 28 days, until disease progression
Measure Participants	50
Median (95% Confidence Interval) [Months]	11.2

4. Secondary Outcome

Title	Frequency and Severity of Adverse Events
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 4.
Time Frame	Adverse events (AEs) were assessed every 2 weeks for the first 2 cycles and every cycle thereafter. Participants were followed for AEs on average approximately 2 months.

Outcome Measure Data

Analysis Population Description

The safety population was defined as all the patients who received at least one dose of the study drug

Arm/Group Title	BKM120
Arm/Group Description	BKM120: BKM120 oral capsules. 100 mg daily in cycles of 28 days, until disease progression
Measure Participants	50
Serious Adverse events	17 34%
Other Adverse events	44 88%

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	Safety assessments consisted of monitoring by investigators and recording all adverse events, serious adverse events, and the regular monitoring of laboratory evaluations, physical examination, weight, vital signs, and ECG. Adverse events were assessed according to the Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0.
Arm/Group Title	BKM120
Arm/Group Description	BKM120: BKM120 oral capsules. 100 mg daily in cycles of 28 days, until disease progression
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%)
Dyspepsia	2/50 (4%)
Diarrhea	9/50 (18%)
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.