Preventing High Blood Sugar in Patients Being Treated for PIK3CA-mutant Metastatic Breast Cancer
This phase II trial tests whether dietary interventions can prevent high blood sugar in patients with PIK3CA-mutant breast cancer that has spread to other places in the body (metastatic). Ketogenic (very low carbohydrate) and low carbohydrate diets may help prevent high blood sugar by reducing the amount of sugar from foods that is stored in the muscles and liver. Canagliflozin works on the kidneys to help the kidneys get rid of more sugar in the urine, instead of absorbing the sugar into the blood. This study may help doctors determine whether a very low carbohydrate diet (ketogenic diet), a low carbohydrate diet, or canagliflozin can prevent high blood sugar and may improve the effectiveness of cancer therapy in patients receiving standard treatment with alpelisib and fulvestrant for metastatic PIK3CA-mutant breast cancer.
Inclusion Criteria
- Histologically confirmed metastatic hormone receptor (HR)-positive, HER2-negative breast cancer. HR positive is defined by ER status >10% immunohistochemical (IHC) staining of any intensity. HER2 negativity is defined as the following as per the 2018 American Society of Clinical Oncology and College of American Pathologists guidelines: * IHC score of 0 or 1+ or * Single-probe average HER2 copy number of < 4 signals/cell or * Dual-probe HER2/CEP17 ratio < 2 with an average HER2 copy number of < 4 signals/cell or * IHC 0, 1+, or 2+ and dual-probe HER2/CEP17 ratio >= 2 with an average HER2 copy number of < 4 signals/cell or * IHC 0 or 1+ and dual-probe HER2/CEP17 ratio < 2 with an average HER2 copy number of >= 6 signals/cell or * IHC 0 or 1+ and dual-probe HER2/CEP17 ratio < 2 with an average HER2 copy number of >= 4 and < 6 signals/cell
- Presence of one or more activating PIK3CA mutations in tumor tissue
- Measurable or non-measurable disease per RECIST v1.1 OR at least one predominantly lytic bone lesion must be present
- Written informed consent provided
- Female or male >= 18 years of age
- Adequate archived tumor tissue for the analysis of PIK3CA mutational status or evaluable circulating tumor deoxyribonucleic acid (DNA) (ctDNA) for analysis of PIK3CA mutation status
- Recurrence or progression of disease during or after endocrine-based therapy
- Eastern Cooperative Oncology Group performance status of 0 or 1
- Life expectancy >= 6 months
- Hemoglobin >= 9.0 g/dL (without blood transfusion within 7 days of laboratory test used to determine eligibility)
- Absolute neutrophil count >= 1.5 x 10^9/L (without granulocyte colony stimulating factor support within 2 weeks of laboratory test used to determine eligibility)
- Platelet count >= 100 x 10^9/L (without transfusion within 2 weeks of laboratory test used to determine eligibility)
- Total bilirubin (TB) =< 1.0 x institutional upper limit of normal (ULN; Patients with known Gilbert’s disease who have TB =< 3 x ULN may be enrolled)
- Aspartate transaminase/alanine transaminase =< 2.5 x ULN with normal alkaline phosphatase (=< 5 x ULN for patients with liver metastases) OR =< 1.5 x ULN in conjunction with alkaline phosphatase > 2.5 x ULN
- Fasting blood glucose =< 140 mg/dL and HbA1c < 8% (both criteria have to be met) and not on anti-hyperglycemic medications other than metformin (i.e., metformin is allowable if fasting blood glucose and HbA1c parameters are met)
- Able to swallow oral medication
- Willing to be randomized to any of the diet arms and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations
- Women must be of postmenopausal status. Postmenopausal status is defined by any one of the following criteria: * Prior bilateral oophorectomy or current ovarian suppression with a gonadotropin-releasing hormone (GnRH) agonist * Age >= 60 years * Age < 60 years and amenorrheic for at least 12 months (spontaneous cessation of menses for 12 consecutive months or more in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression) and follicle-stimulating hormone and estradiol levels in the postmenopausal range without an alternative cause
Exclusion Criteria
- Multiple prior lines of chemotherapy in the metastatic setting (one line of chemotherapy is allowed. Also prior treatment with CDK4/6 inhibitors is allowed)
- Currently participating in a study of an investigational agent
- Current participation in a formalized weight loss program or currently consuming a ketogenic diet
- Body mass index < 20 kg/m^2
- Known hypersensitivity to alpelisib, fulvestrant, canagliflozin, or to any of the excipients of alpelisib or fulvestrant
- Concurrent malignancy (basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or cervical cancer in situ that have undergone curative intent therapy are allowed)
- Type 1 diabetes mellitus
- Uncontrolled type 2 diabetes mellitus (hemoglobin A1c >= 8.0)
- Type 2 diabetes mellitus requiring treatment with a sulfonylurea, meglitinide, SGLT2 inhibitors or insulin
- Vegetarian or vegan eating habits
- Allergy or intolerance to egg, gluten, nut or milk protein that would interfere with adherence to diet
- Individuals with impaired decision making capacity
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT05090358.
PRIMARY OBJECTIVE :
I. To determine the grade 3/4 hyperglycemia-free rate at 12 weeks, as assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0.
SECONDARY OBJECTIVES:
I. 6 and 12 month objective response rate (ORR) assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
II. 6 month and 12 month progression free survival (PFS) rates assessed by RECIST v1.1.
III. Alpelisib adherence assessed by relative dose intensity (RDI) and discontinuation rate.
IV. Changes in systemic hormones and metabolites related to glucose homeostasis (i.e. glucose, insulin, c-peptide, hemoglobin [Hb]A1C, beta-hydroxybutyrate).
V. Changes in weight and body composition will be assessed using standard of care (SOC) cross sectional imaging (computed tomography [CT] or positron emission tomography [PET]/CT).
VI. To evaluate the effects of the interventions on quality of life (QOL) using the Functional Assessment of Cancer Therapy–Breast (FACT-B).
EXPLORATORY OBJECTIVES:
I. Explore the change in serum metabolomics from baseline to 12 weeks.
II. Explore the change in histologic markers of PI3K signaling, proliferation, and apoptosis including P-INSR, P-AKT, P-S6, Ki67, cleaved caspase 3 (CC3), and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) in:
IIa. Tumor: paired pre- (SOC) and post-treatment tumor tissues in patients who consent for the optional post-treatment biopsy of the tumors.
IIb. Buccal cell samples at baseline and 4 weeks.
III. Explore the change in tumor, adipose, and skeletal muscle 18F-fluorodeoxyglucose (18F-FDG) uptake using SOC positron emission tomography (PET) imaging.
OUTLINE: Patients are randomized to 1 of 3 arms.
ARM I: Patients receive fulvestrant intramuscularly (IM) on days 1, 15, and 29 and then once monthly. Beginning on day 15, patients receive alpelisib orally (PO) once daily (QD). Patients also receive ketogenic diet consisting of 3 pre-packaged meals and 2 snacks per day for 12 weeks. Patients then meet with a dietician and may continue or switch to low carbohydrate diet. Treatment continues for 1 year in the absence or disease progression of unacceptable toxicity.
ARM II: Patients receive fulvestrant IM on days 1, 15, and 29 and then once monthly. Beginning on day 15, patients receive alpelisib PO QD. Patients also receive low carbohydrate diet consisting of 3 pre-packaged meals and 2 snacks per day for 12 weeks. Patients then meet with a dietician and may continue or switch to ketogenic diet. Treatment continues for 1 year in the absence of disease progression or unacceptable toxicity.
ARM III: Patients receive fulvestrant IM on days 1, 15, and 29 and then once monthly. Beginning on day 15, patients receive alpelisib PO QD and canagliflozin PO QD Treatment continues for 1 year in the absence of disease progression or unacceptable toxicity.
Patients in all arms undergo computed tomography (CT) scan or magnetic resonance imaging (MRI), and fludeoxyglucose-positron emission tomography (FDG-PET) at 12 weeks, and undergo tissue collection at screening.
Patients will be followed up once a month for 12 months.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationMemorial Sloan Kettering Cancer Center
Principal InvestigatorSherry Shen
- Primary ID21-123
- Secondary IDsNCI-2021-11861
- ClinicalTrials.gov IDNCT05090358