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Estrogen Receptor-positive Breast CancerPhase 1NCT01339442

BKM120 and Fulvestrant for Treating Postmenopausal Patients With Estrogen Receptor-Positive Stage IV Breast Cancer

A Phase 1 study testing BKM120, Fulvestrant and biopsy in people with Estrogen Receptor-positive Breast Cancer and Recurrent Breast Cancer, run by Washington University School of Medicine at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

This phase I trial will determine the Maximum Tolerated Dose (MTD) of BKM120 when given together with fulvestrant in treating postmenopausal patients with estrogen receptor-positive (ER+) stage IV breast cancer. The toxicity profile of this combination therapy will also be described. Read more about this study

Who is it for?
Ages 18 years and older, women only
What is being tested?
BKM120, Fulvestrant and biopsy
Type of treatment
Surgery or procedure
Could I receive a placebo?
No, everyone receives an active treatment
How many people
31 participants
Where
1 siteUnited States
Study dates
14 Nov 2011to 28 Dec 2016
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • Women only
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Patient must be ≥ 18 years of age
  • Patient must be a postmenopausal woman, defined by one of the following criteria:
  • Women ≥ 60 years
  • Women aged 45-59 years with spontaneous cessation of menses ≥ 12 months prior to registration
  • Women aged 45-59 years with cessation of menses of duration < 12 months or secondary to hysterectomy AND an follicle-stimulating hormone (FSH) level in the postmenopausal range according to institutional standards (or > 34.4 IU/L if institutional range is not available) prior to registration
  • Women aged 45-59 years on hormonal replacement therapy who have discontinued hormonal therapy AND an FSH level in the postmenopausal range according to institutional standards (or > 34.4 IU/L if institutional range is not available) prior to registration
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  • Status post bilateral surgical oophorectomy
  • Patient must have a negative serum pregnancy test within 48 hours before starting study treatment (if a woman of childbearing potential)
  • Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status =< 2
  • Patient must have histologically or cytologically confirmed invasive breast cancer that is stage IV or metastatic (histologic/cytologic confirmation of recurrence preferred, but not required)
  • Patient must have a representative tumor tissue specimen available; archival tissue is allowed
  • Either the primary or the metastatic tumor must be positive for estrogen receptor (>= 1% tumor cell staining by immunohistochemistry or an Allred Score of >= 3 by immunohistochemistry)
  • Patient must have at least one site of measurable disease as per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria
  • Patient must have had no more than 3 lines of systemic therapy (including endocrine therapy) for metastatic disease to be eligible for phase IB and the last 10 patients of Cohort C; there is no limitation on the numbers of prior systemic therapies for phase IA and the first 2 patients of Cohort C
  • Patients who are currently taking fulvestrant without disease progression are eligible
  • Patient must have a life expectancy of >= 12 weeks
  • Patient must have adequate oran function as defined as:
  • Absolute neutrophil count (ANC) >= 1500/uL
  • Platelet count >= 100,000/uL
  • Hemoglobin >= 9 g/dL
  • Serum creatinine =< 1.5 x upper limit of normal (ULN)
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within normal range (or =< 3.0 x ULN if liver metastases are present)
  • Serum bilirubin =< ULN (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)
  • Serum amylase =< ULN
  • Serum lipase =< ULN
  • Magnesium >= the lower limit of normal
  • Potassium within normal limits for the institution
  • Patient must have international normalized ratio (INR) =< 2
  • Patient must have fasting plasma glucose =< 120 mg/dL (6.7 mmol/L)
  • Patient must have total calcium (corrected for serum albumin) within normal limits (bisphosphonate use for malignant hypercalcemia control is not allowed)
  • Patient must be able and willing to sign the consent form

Who cannot join

  • Patient must not have received prior treatment with a P13K inhibitor
  • Patient must not have a known hypersensitivity to BKM120 or to its excipients
  • Patient must not have untreated brain metastases; however, patients with metastatic central nervous system (CNS) tumors may participate in this trial if the patient is:
  • 4 weeks from therapy completion (including radiation and/or surgery)
  • Clinically stable at the time of study entry
  • Not receiving corticosteroid therapy
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  • Patient must not have acute or chronic liver disease, renal disease, or pancreatitis
  • Patient must not have any of the following mood disorders as judged by the Investigator or a Psychiatrist
  • 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 (immediate risk of doing harm to others)
  • Greater than or equal to Common Terminology Criteria for Adverse Events (CTCAE) grade 3 anxiety
  • Patient must not meet the cut-off score of >= 10 in the Patient Health Questionnaire (PHQ-9) or a cut-off of >= 15 in the Generalized Anxiety Disorder (GAD)-7 mood scale, respectively, or select a positive response of 1, 2, or 3 to question number 9 regarding potential for suicidal thoughts in the PHQ-9 (independent of the total score of the PHQ-9)
  • Patient must not have >= grade 2 diarrhea
  • Patient must not have active cardiac disease including any of the following:
  • Left ventricular ejection fraction (LVEF) < 50% as determined by Multiple Grated acquisition (MUGA) scan or echocardiogram (ECHO)
  • QTc > 480 msec on screening electrocardiogram (ECG) (using the QTcF formula)
  • Angina pectoris that requires the use of anti-anginal medication
  • Ventricular arrhythmias except for benign premature ventricular contractions
  • Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication
  • Conduction abnormality requiring a pacemaker
  • Valvular disease with document compromise in cardiac function
  • Symptomatic pericarditis
  • Patient must not have a history of cardiac dysfunction including any of the following:
  • Myocardial infarction within the last 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LVEF function
  • History of documented congestive heart failure (New York Heart Association functional classification III-IV)
  • Documented cardiomyopathy
  • Patient must not have poorly controlled diabetes mellitus or steroid-induced diabetes mellitus (defined by fasting glucose >120 mg/dL or hemoglobin [Hb] A1c > 7%)
  • Patient must not have any other concurrent severe and/or uncontrolled concomitant medical conditions (e.g., active or uncontrolled infection) that could cause unacceptable safety risks or compromise compliance with the protocol
  • Patient must not have significant symptomatic deterioration of lung function; if clinically indicated, pulmonary function tests including measures of predicted lung volumes; diffusion capacity of carbon monoxide (DLco), oxygen (O2) saturation at rest on room air should be considered to exclude pneumonitis or pulmonary infiltrates
  • Patient must not have impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of BKM120 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection); patients with unresolved diarrhea will be excluded as previously indicated
  • Patient must not have been treated with any hematopoietic colony-stimulating growth factors (e.g., filgrastim [G-CSF], sargramostim [GM-CSF]) =< 2 weeks prior to starting study drug; erythropoietin or darbepoetin therapy, if initiated at least 2 weeks prior to enrollment, may be continued
  • Patient must not have taken herbal medications and certain fruits within 7 days prior to starting study drug; herbal medications include, but are not limited to: St. Johns wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng; fruits include the CYP3A inhibitors Seville oranges, grapefruit, pummelos, or exotic citrus fruits
  • Patient must not be currently receiving treatment with medication with a known risk to prolong the QT interval or inducing Torsades de Pointes unless the treatment can either be discontinued or switched to a different medication prior to starting study drug; please refer to Table 5-2 for a list of prohibited QT prolonging drugs with risk of Torsades de Pointes
  • Patient must not be receiving 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 stable low dose corticosteroids treatment (e.g. dexamethasone 2 mg/day, prednisolone 10 mg/day) for at least 14 days before start of study treatment are eligible
  • Patient must not be currently treated with drugs known to be moderate or strong inhibitors or inducers of isoenzyme cytochrome P450, family 3, subfamily A (CYP3A) unless the treatment can be discontinued or switched to a different medication prior to starting study drug (please note that co-treatment with weak inhibitors of CYP3A is allowed)
  • Patient must not have received chemotherapy or targeted anticancer therapy =< 4 weeks (6 weeks for nitrosourea, antibodies or mitomycin-C) prior to starting study drug
  • Patient with any residual toxicities may not be enrolled unless all toxicities recover to =< grade 1 before starting the trial
  • Patient must not have received any continuous or intermittent small molecule therapeutics (excluding monoclonal antibodies) =< 5 effective half lives prior to starting study drug; patient must have recovered from side effects of such therapy
  • Patient must not have received wide field radiotherapy =< 4 weeks or limited field radiation for palliation =< 2 weeks prior to starting study drug; patient must have recovered from side effects of such therapy
  • Patient must not have undergone major surgery =< 2 weeks prior to starting study drug; patient must have recovered from side effects of such therapy
  • Patient must not be currently taking therapeutic doses of warfarin sodium or any other Coumadin-derivative anticoagulant
  • Patient must not have a known diagnosis of human immunodeficiency virus (HIV) infection
  • Patient must not have a history of another malignancy within 3 years, except cured basal cell carcinoma of the skin or excised carcinoma in situ of the cervix

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Washington University School of Medicine

    St Louis, Missouri, 63110

Other trials in United States

About this study

Official title: A Phase 1 Trial of BKM 120, a Novel Oral Selective Phosphatidylinositol-3-kinase (PI3K) Inhibitor, in Combination With Fulvestrant in Postmenopausal Women With Estrogen Receptor Positive Metastatic Breast Cancer

This phase I trial will determine the Maximum Tolerated Dose (MTD) of BKM120 when given together with fulvestrant in treating postmenopausal patients with estrogen receptor-positive (ER+) stage IV breast cancer. The toxicity profile of this combination therapy will also be described. Inhibition of PI3K by BKM120 may enhance programmed cell death (apoptosis) in estrogen receptor positive (ER+) breast cancer cells. Giving fulvestrant together with BKM 120 may enhance this apoptotic effect, providing a novel therapeutic strategy for patients with metastatic ER+ breast cancer.

Read the detailed description

PRIMARY OBJECTIVES:

  1. To determine the maximum tolerated dose (MTD) of BKM120 (PI3K inhibitor BKM120) in combination with fulvestrant.

II. To evaluate the toxicity profile of BKM120 in combination with fulvestrant.

SECONDARY OBJECTIVES:

  1. To evaluate the toxicity profile of BKM120 in combination with fulvestrant when administered for at least 3 months.

II. To determine the steady state blood concentrations of BKM120 when combined with fulvestrant.

III. To evaluate the anti-tumor effect (partial response [PR], complete response [CR], stable disease [SD], and progressive disease [PD]) of BKM120 in combination with fulvestrant in patients with ER+ metastatic breast cancer.

TERTIARY OBJECTIVES:

  1. To examine baseline tumor specimens for phosphatidylinositol 3-kinase (PI3K) pathway abnormalities, and to correlate with treatment response.

II. To examine the PIK3 catalytic alpha polypeptide (PIK3CA) mutation status in circulating deoxyribonucleic acid (DNA) at baseline and following study therapy and to correlate with tumor tissue PIK3CA status and treatment response.

III. To determine effects of study therapy on fasting C-peptide and glucose. IV. To evaluate target inhibition by BKM120 on serial tumor biopsies collected before and following study therapy.

  1. To evaluate the effect of BKM120 in combination with fulvestrant on tumor cell proliferation and apoptosis.

VI. To obtain preliminary pilot data to evaluate the effect of BKM120 on tumor cell proliferation, as measured by FLT-PET/CT (Phase IB)

OUTLINE: This is a dose-escalation study of PI3K inhibitor BKM120. Patients receive PI3K inhibitor BKM120 orally (PO) once daily (QD) on days 1-28 (if enrolled in Phase IA or Cohort C) or on a 5 days on/2 days off schedule (if enrolled in Phase IB). All patients will receive fulvestrant intramuscularly (IM) on days 1 and 15 of Cycle 1 and day 1 of all subsequent cycles. Cycles repeat ever 28 days in the absence of disease progression or unacceptable toxicity.

Two OPTIONAL FLT-PET/CT scans: the first one done at baseline before the start of BKM120 and the second one done between Day 16 and Day18 after BKM120 is started. After completion of study treatment, patients are followed up for 28 days.

Being tested
BKM120, Fulvestrant, biopsy
Medical subject headings
Breast Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • BKM120Drug

    Also called PI3K_Inhibitor_BKM120

  • FulvestrantDrug

    Also called Faslodex, ICI 182,780

  • biopsyProcedure or surgery

    Also called biopsies

    Correlative studies

Study groups in NCT01339442
Study groupRoleWhat they receive
Dose Level 1 - Phase 1AExperimentalBKM120 80 mg PO daily. Fulvestrant 500 mg IM on Days 1 \& Day 15 during Cycle 1 then on Day 1 of each subsequent cycle.
Receives: Drug: BKM120; Drug: Fulvestrant; Procedure: biopsy
Dose Level 2 - Phase IAExperimentalBKM120 100 mg PO daily. Fulvestrant 500 mg IM on Days 1 \& Day 15 during Cycle 1 then on Day 1 of each subsequent cycle.
Receives: Drug: BKM120; Drug: Fulvestrant; Procedure: biopsy
Phase IBExperimentalBKM120 (dose to be determined in Phase IA)PO 5 days on/ 2 days off per week. Fulvestrant 500 mg IM on Days 1 \& Day 15 during Cycle 1 then on Day 1 of each subsequent cycle.
Receives: Drug: BKM120; Drug: Fulvestrant; Procedure: biopsy
Cohort CExperimentalBKM120 (dose determined in Phase IA) PO daily. Fulvestrant 500 mg IM on Day 1 and Day 15 during Cycle 1 then monthly on Day 1 of subsequent cycles.
Receives: Drug: BKM120; Drug: Fulvestrant; Procedure: biopsy

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. MTD of BKM120 in combination with fulvestrant

    Highest dose level at which no more than 1 of 6 patients develops a dose-limiting toxicity

    Measured: 28 days (completion of cycle 1)

  2. Number of participants with adverse events after treatment with BKM120 in combination with fulvestrant

    Measured: 28 days after completion of treatment

Secondary outcomes (7)

  1. Anti-tumor effect (PR, CR, SD and PD) of BKM120 in combination with fulvestrant

    Measured: End of treatment (approximately 3 months)

  2. Steady state blood concentration of BKM120

    Measured: Baseline, Cycle 2 Day 1, Cycle 3 Day 1

  3. Tumor PI3K pathway abnormalities in tissue from previous biopsy or collected at baseline

    Measured: Baseline

  4. Effects of study therapy on blood levels of fasting C-peptide

    Measured: Baseline, Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 Day 1

  5. Effects of study therapy on blood levels of glucose

    Measured: Baseline, Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 2 Day 15, Cycle 3 Day 1, End of Treatment

  6. Samples will be analyzed for markers of PI3K signaling (including pAKT, pS6, Cyclin D1, subcellular localization of FOXO3a, phosphoproteomics), tumor cell proliferation (Ki67) and apoptosis (cleaved caspase 3 or TUNEL staining).

    Measured: Baseline

  7. Examine the PIK3CA mutation status in circulating DNA at baseline thru last treatment

    Measured: Baseline or Cycle 1 Day 1 and Day 1 of each subsequent cycle

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted20 Apr 2011 (estimated)
  2. Study start14 Nov 2011
  3. Primary completion21 Dec 2016
  4. Study completion28 Dec 2016

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
31 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01339442
Sponsor's protocol ID
201105445
Other IDs
NCI-2011-00583
Status last verified
Jan 2017
First submitted
13 Apr 2011
Last updated
25 Jan 2017
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing BKM120, Fulvestrant and biopsy in people with Estrogen Receptor-positive Breast Cancer and Recurrent Breast Cancer, run by Washington University School of Medicine at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 31 inclusion and 42 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 25 Jan 2017. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

MTD of BKM120 in combination with fulvestrant (time frame: 28 days (completion of cycle 1)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01339442.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Jan 2017.

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