BKM120 and Fulvestrant for Treating Postmenopausal Patients With Estrogen Receptor-Positive Stage IV 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.
Estrogen Receptor-positive Breast Cancer
Recurrent Breast Cancer
Stage IV Breast Cancer
Drug: PI3K inhibitor BKM120
|Study Design:||Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|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|
- MTD of BKM120 in combination with fulvestrant [ Time Frame: 1 month ] [ Designated as safety issue: Yes ]Highest dose level at which no more than 1 of 6 patients develops a dose-limiting toxicity
- Number of participants with adverse events after treatment with BKM120 in combination with fulvestrant [ Time Frame: 5 months ] [ Designated as safety issue: Yes ]
- Anti-tumor effect (PR, CR, SD and PD) of BKM120 in combination with fulvestrant [ Time Frame: 5 months ] [ Designated as safety issue: No ]
- Steady state blood concentration of BKM120 [ Time Frame: 3 months ] [ Designated as safety issue: No ]
- Tumor PI3K pathway abnormalities in tissue from previous biopsy or collected at baseline [ Time Frame: 1 day ] [ Designated as safety issue: No ]
- Effects of study therapy on blood levels of fasting C-peptide [ Time Frame: 5 months ] [ Designated as safety issue: No ]
- Effects of study therapy on blood levels of glucose [ Time Frame: 5 months ] [ Designated as safety issue: No ]
- 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). [ Time Frame: 5 months ] [ Designated as safety issue: No ]
- Examine the PIK3CA mutation status in circulating DNA at baseline thru last treatment [ Time Frame: 5 months ] [ Designated as safety issue: No ]
- FLT-PET/CT effect of BKM120 on tumor cell proliferation [ Time Frame: 18 days ] [ Designated as safety issue: No ]To obtain preliminary pilot data to evaluate the effect of BKM120 on tumor cell proliferation, as measured by FLT-PET/CT
|Study Start Date:||November 2011|
|Estimated Primary Completion Date:||April 2014 (Final data collection date for primary outcome measure)|
Experimental: Treatment (enzyme inhibitor and hormone therapy)
Patients receive PI3K inhibitor BKM120 PO QD on days 1-28 (for patients enrolled to the 80 mg cohort and at the MTD) and on a 5 days on, 2 days off schedule (for patients enrolled to the 100 mg cohort) and fulvestrant 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.
Drug: PI3K inhibitor BKM120
Other Names:Drug: fulvestrant
Other Names:Procedure: biopsy
Other Name: biopsies
I. 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.
I. 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.
I. 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.
V. 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.
|Contact: Cynthia Ma, M.D., Ph.D.||email@example.com|
|United States, Missouri|
|Washington University School of Medicine||Recruiting|
|Saint Louis, Missouri, United States, 63110|
|Contact: Cynthia X. Ma 314-362-8903 firstname.lastname@example.org|
|Principal Investigator: Cynthia X. Ma|
|Sub-Investigator: Teresa Deshields, Ph.d.|
|Principal Investigator:||Cynthia Ma||Siteman Cancer Center at Washington University|