Clinical trial NCT03962647: A 2-Week Ketogenic Diet in Combination With Letrozole to Modulate PI3K Signaling in ER+ Breast Cancer
Official title: A Pilot and Feasibility Neoadjuvant Study of a 2-Week Ketogenic Diet in Combination With Letrozole to Modulate PI3K Signaling in ER+ Breast Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: EARLY_PHASE1
Conditions: Estrogen Receptor-positive Breast Cancer
Lead sponsor: Vanderbilt-Ingram Cancer Center
Sponsor class: OTHER
First posted: 2019-05-24
Enrollment: 31
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a neoadjuvant study to determine the feasibility and tolerability of 2 weeks of a very low carbohydrate ketogenic diet in combination with letrozole for patients with early stage operable ER+disease.

Detailed description: Primary Objective:

• To evaluate the feasibility and tolerability of a 2 week ketogenic diet in combination with endocrine therapy prior to surgery for early stage ER+ breast cancer.

Secondary Objectives

* To determine whether endocrine therapy in combination with a dietary intervention to reduce insulin pathway signaling results in enhanced inhibition of cancer cell proliferation (measured byKi67)
* To determine the effectiveness of 2 weeks of a ketogenic diet to reduce measures of insulin/PI3Kpathway activation in breast tumors
* To measure changes in weight and body composition after 2 weeks of a ketogenic diet
* To measure changes in insulin resistance after 2 weeks of a ketogenic diet
* To measure the effectiveness of a ketogenic diet in combination with endocrine therapy to induce and maintain a ketogenic state.

Outline:

Participants will have baseline metabolic parameters measured and will begin a 2-week diet consisting of meal replacement shakes to induce a ketogenic state. Patients will also receive letrozole 2.5 mg daily. At the end of 2 weeks, metabolic parameters will again be measured and patients will proceed with surgical treatment of their breast cancer. A tumor biopsy from the surgical specimen will be obtained to measure cell proliferation compared with the pre-treatment diagnostic biopsy.

Eligibility criteria: Inclusion Criteria:

* All participants must provide written informed consent.
* Patients must have histologically confirmed primary invasive mammary carcinoma

  * The tumor must be estrogen receptor positive
  * The tumor must be HER2 negative (negative IHC or FISH)
  * The primary tumor size must be at least 2 mm in size.
* Patients must be post-menopausal defined by any of the following:

  * Subjects at least 55 years of age.
  * Subjects younger than 55 years of age and amenorrheic for at least 12 months or serum follicle-stimulating hormone (FSH) levels and estradiol levels in the post-menopausal range by local lab criteria
  * Subjects with history of bilateral oophorectomy or prior radiation castration with amenorrhea for at least 6 months.
* Patients must have clinical stage I, II, or III invasive mammary carcinoma planning to undergo surgical treatment with either segmental resection or total mastectomy.
* Patients must have BMI \>= 30.
* A core biopsy from the time of diagnosis must be available.
* Mammogram or ultrasound required prior to screening
* Patients must have adequate organ function based on the following laboratory parameters:

  * Serum creatinine \<= 1.5x ULN
  * SGOT, SGPT \<= 4x ULN (unless known steatohepatitis)
  * Serum albumin \>= 2.0 g/dL
  * Total serum bilirubin \<= 1.5x ULN (or \<= 3x ULN if known Gilbert's syndrome)

Exclusion Criteria:

Patients with locally advanced disease who are candidates for other preoperative (chemo)therapy at the time of initial evaluation. This includes patients with inflammatory breast cancer.

* Evidence of distant metastatic disease (stage IV).
* Serious medical illness that in the judgment of the treating physician places the patient at high risk of operative mortality.
* Serious medical illness that in the judgment of the treating physician would preclude the use of a ketogenic diet.
* Severe uncontrolled malabsorption condition or disease (e.g. grade II/III diarrhea, severe malnutrition, short gut syndrome).
* Diabetes mellitus requiring insulin therapy.
* Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent.
* Participation in any other neoadjuvant therapeutic clinical trial.
* Concurrent anti-cancer therapy other than endocrine therapy (e.g. chemotherapy, radiotherapy, immunotherapy, or any other biologic therapy).
* Concurrent treatment with an investigational agent.
* Use of an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first day of dietary intervention.

Primary outcomes:
measure: Patients who complete the dietary intervention
timeFrame: After 2 weeks of a ketogenic diet
Secondary outcomes:
measure: Measure enhanced inhibition of cancer cell proliferation
timeFrame: After 2 weeks of a ketogenic diet
measure: Reduction in measures of insulin/P13K pathway activation
timeFrame: After 2 weeks of a ketogenic diet
measure: Measure changes in body composition
timeFrame: After 2 weeks of a ketogenic diet
measure: Measure changes in body composition
timeFrame: After 2 weeks of a ketogenic diet
measure: Measure changes in body composition
timeFrame: After 2 weeks of a ketogenic diet
measure: Measure changes in body composition
timeFrame: After 2 weeks of a ketogenic diet
measure: Measure changes in insulin resistance
timeFrame: After 2 weeks of a ketogenic diet
Other outcomes:
Locations:
city: Nashville
country: United States
facility: Vanderbilt-Ingram Cancer Center
state: Tennessee
Study officials:
affiliation: Vanderbilt Medical Center
name: Brent Rexer, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: