Dietary Changes + Canagliflozin for Metastatic Breast Cancer

Recruiting at 8 trial locations

Overseen By Neil Iyengar, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must be taking: Metformin

Must not be taking: Sulfonylureas, Meglitinides, SGLT2 inhibitors, Insulin

Disqualifiers: Type 1 diabetes, Uncontrolled type 2 diabetes, Vegetarian, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

15 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it mentions that you cannot be on anti-hyperglycemic medications other than metformin. If you are taking other diabetes medications, you may need to stop them.

What data supports the effectiveness of the drug combination of Alpelisib and Fulvestrant for metastatic breast cancer?

Research shows that combining Alpelisib with Fulvestrant improves progression-free survival (the time during and after treatment that a patient lives with the disease without it getting worse) in patients with metastatic hormone receptor-positive, PIK3CA-mutant breast cancer. ^{1 2 3 4 5}

Is the combination of dietary changes and Canagliflozin safe for treating metastatic breast cancer?

The combination of alpelisib and fulvestrant, used for treating metastatic breast cancer, has been associated with high rates of side effects like high blood sugar, rash, and diarrhea, which sometimes require hospitalization. Managing high blood sugar with very low carbohydrate diets and medications like sodium-glucose co-transporter-2 inhibitors (SGLT2i) has shown some success in individual cases. ^{5 6 7 8 9}

How is the treatment with dietary changes and Canagliflozin for metastatic breast cancer different from other treatments?

This treatment is unique because it combines dietary changes with Canagliflozin, a drug typically used for diabetes, to potentially improve outcomes in metastatic breast cancer. The focus on dietary changes, such as a whole food, plant-based diet, aims to enhance quality of life and may complement the effects of cancer drugs like Alpelisib and Fulvestrant. ^{1 10 11 12 13}

What is the purpose of this trial?

The purpose of this study to find out whether a very low carbohydrate diet (ketogenic diet), a low carbohydrate diet, or the study drug canagliflozin can prevent high blood sugar and may improve the effectiveness of cancer therapy in people who are receiving standard treatment with alpelisib and fulvestrant for their metastatic PIK3CA-mutant breast cancer.

Research Team

Neil Iyengar, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

This trial is for adults with metastatic HR-positive, HER2-negative breast cancer that has PIK3CA mutations. They must have had disease progression after endocrine therapy, be able to swallow pills, and follow a strict diet. Excluded are those underweight, with certain allergies or other cancers, uncontrolled diabetes, multiple chemotherapy treatments in the metastatic setting, or on specific diets.

Inclusion Criteria

My cancer has a PIK3CA mutation.

My breast cancer is HR-positive and HER2-negative.

My cancer can be measured by scans or I have at least one bone lesion.

Exclusion Criteria

You have an allergy or intolerance to eggs, gluten, nuts, or milk that would make it hard for you to follow the diet.

My diabetes is not under control (A1c is 8.0 or higher).

Currently participating in a study of an investigational agent

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either a ketogenic diet, low carbohydrate diet, or SGLT2i therapy in combination with standard cancer treatment

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Alpelisib
• Canagliflozin
• Fulvestrant
• Ketogenic Diet
• Low Carbohydrate Diet

Trial Overview The study tests if a very low carbohydrate (ketogenic) diet, a low carbohydrate diet, or the drug canagliflozin prevents high blood sugar and improves effectiveness of standard treatment with alpelisib and fulvestrant in patients with specific breast cancer mutations.

Participant Groups

Group I: SGLT2i Therapy Experimental Treatment 3 Interventions

Postmenopausal women and men with histologically-confirmed, HR-positive, HER2-negative, PIK3CA mutant MBC who have received no more than 1 line of endocrine-based therapy in the metastatic setting will be eligible. Participants on this arm will be assigned to SGLT2i therapy each in combination with SOC endocrine therapy (fulvestrant) and PI3K inhibition (alpelisib)

Group II: Low Carbohydrate Diet Experimental Treatment 4 Interventions

Postmenopausal women and men with histologically-confirmed, HR-positive, HER2-negative, PIK3CA mutant MBC who have received no more than 1 line of endocrine-based therapy in the metastatic setting will be eligible. Participants on this arm will be assigned to Low Carbohydrate Diet/LCD therapy each in combination with SOC endocrine therapy (fulvestrant) and PI3K inhibition (alpelisib)

Group III: Ketogenic Diet Experimental Treatment 4 Interventions

Postmenopausal women and men with histologically-confirmed, HR-positive, HER2-negative, PIK3CA mutant MBC who have received no more than 1 line of endocrine-based therapy in the metastatic setting will be eligible. Participants on this arm will partake in a ketogenic diet in combination with SOC endocrine therapy (fulvestrant) and PI3K inhibition (alpelisib)

Alpelisib is already approved in United States, European Union for the following indications:

Approved in United States as Piqray for:

• Hormone receptor-positive, HER2-negative, PIK3CA-mutated, advanced or metastatic breast cancer following progression on or after an endocrine-based regimen

Approved in European Union as Piqray for:

• Hormone receptor-positive, HER2-negative, PIK3CA-mutated, locally advanced or metastatic breast cancer in combination with fulvestrant

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Findings from Research

In a study of 521 premenopausal and postmenopausal patients with endocrine-resistant metastatic breast cancer, those treated with palbociclib and fulvestrant showed a higher rate of prolonged benefit (29%) compared to those on placebo and fulvestrant (15%).

Long-term responders to palbociclib-fulvestrant tended to have less disease burden at baseline and lower rates of certain mutations, but no specific molecular or clinical factors were identified as predictors of long-term benefit.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predictors of prolonged benefit from palbociclib plus fulvestrant in women with endocrine-resistant hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer in PALOMA-3. Cristofanilli, M., DeMichele, A., Giorgetti, C., et al.[2022]

In the FLIPPER trial, the combination of palbociclib and fulvestrant significantly improved progression-free survival (PFS) in postmenopausal women with HR+/HER2- advanced breast cancer compared to placebo and fulvestrant.

Patient-reported outcomes indicated that while global health status and quality of life (QoL) were maintained during treatment with palbociclib/fulvestrant, the time to deterioration in QoL was longer with placebo/fulvestrant, suggesting that palbociclib/fulvestrant is a beneficial treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quality of life with palbociclib plus fulvestrant versus placebo plus fulvestrant in postmenopausal women with endocrine-sensitive hormone receptor-positive and HER2-negative advanced breast cancer: patient-reported outcomes from the FLIPPER trial. Tibau, A., Martínez, MT., Ramos, M., et al.[2023]

In a phase II study involving 190 postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer, the combination of palbociclib and fulvestrant significantly improved one-year progression-free survival (PFS-1y) rates (83.5% vs. 71.9% for placebo) and median PFS (31.8 months vs. 22.0 months).

While the palbociclib/fulvestrant combination showed better efficacy, it was associated with higher rates of grade 3-4 adverse events, particularly neutropenia (68.1% vs. 0% in the placebo group), indicating a need for careful monitoring of side effects in patients receiving this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized phase II study of fulvestrant plus palbociclib or placebo in endocrine-sensitive, hormone receptor-positive/HER2-advanced breast cancer: GEICAM/2014-12 (FLIPPER). Albanell, J., Martínez, MT., Ramos, M., et al.[2022]

In a study of 247 patients with metastatic hormone receptor-positive, PIK3CA-mutant breast cancer, 61.5% developed any-grade hyperglycemia after treatment with alpelisib, with a median onset time of just 16 days.

Patients receiving alpelisib as standard care experienced significantly higher rates of hyperglycemia compared to those in clinical trials, highlighting the importance of monitoring and optimizing glycemic status before starting treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incidence, risk factors, and management of alpelisib-associated hyperglycemia in metastatic breast cancer. Shen, S., Chen, Y., Carpio, A., et al.[2023]

In a retrospective analysis of 33 patients with HR+, HER2- metastatic breast cancer, the combination of alpelisib and fulvestrant showed worse outcomes in heavily pretreated patients compared to those receiving it as a first-line treatment, with significant rates of disease progression and treatment discontinuation.

Adverse effects were common, with hyperglycemia (66.7%), rash (45.5%), and diarrhea (72.7%) leading to hospitalizations and pharmacological treatment, raising concerns about the tolerability of this regimen in real-world settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and safety of alpelisib in breast cancer: A real-world analysis. Miller, J., Armgardt, E., Svoboda, A.[2023]

Alpelisib, when combined with fulvestrant, significantly improves progression-free survival (PFS) in postmenopausal women and men with hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer, showing a median PFS of 11 months compared to 5.7 months with placebo.

The treatment is specifically effective for patients with PIK3CA mutations, as no PFS benefit was observed in those without these mutations, highlighting the importance of genetic testing in treatment decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Alpelisib Plus Fulvestrant for Patients with HR-positive, HER2-negative, PIK3CA-mutated, Advanced or Metastatic Breast Cancer. Narayan, P., Prowell, TM., Gao, JJ., et al.[2022]

Alpelisib is an effective treatment for advanced breast cancer in patients with specific genetic mutations, but it often causes hyperglycemia, which can lead to treatment complications.

In a case series of 3 patients, dietary changes and the use of sodium-glucose co-transporter-2 inhibitors (SGLT2i) were successful in managing hyperglycemia, suggesting potential strategies for improving patient outcomes during alpelisib therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treating Alpelisib-Induced Hyperglycemia with Very Low Carbohydrate Diets and Sodium-Glucose Co-Transporter 2 Inhibitors: A Case Series. Blow, T., Hyde, PN., Falcone, JN., et al.[2021]

Preliminary findings indicate that combining intermittent fasting or a fasting-mimicking diet with endocrine therapy may enhance the effectiveness of treatment for hormone receptor-positive breast cancer.

This combination approach could also help in reducing side effects associated with the endocrine therapy, suggesting a potential strategy for improving patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fasting May Complement Endocrine Therapy. [2021]

References

1. United States pubmed.ncbi.nlm.nih.gov

Impact of metformin on metastases in patients with breast cancer and type 2 diabetes. [2018]

2. England pubmed.ncbi.nlm.nih.gov

Predictors of prolonged benefit from palbociclib plus fulvestrant in women with endocrine-resistant hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer in PALOMA-3. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Quality of life with palbociclib plus fulvestrant versus placebo plus fulvestrant in postmenopausal women with endocrine-sensitive hormone receptor-positive and HER2-negative advanced breast cancer: patient-reported outcomes from the FLIPPER trial. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Randomized phase II study of fulvestrant plus palbociclib or placebo in endocrine-sensitive, hormone receptor-positive/HER2-advanced breast cancer: GEICAM/2014-12 (FLIPPER). [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Incidence, risk factors, and management of alpelisib-associated hyperglycemia in metastatic breast cancer. [2023]

6. England pubmed.ncbi.nlm.nih.gov

The efficacy and safety of alpelisib in breast cancer: A real-world analysis. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Alpelisib Plus Fulvestrant for Patients with HR-positive, HER2-negative, PIK3CA-mutated, Advanced or Metastatic Breast Cancer. [2022]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Evaluation of alpelisib-induced hyperglycemia prophylaxis and associated risk factors in PIK3CA-mutated hormone-receptor positive, human epidermal growth factor-2 negative advanced breast cancer. [2023]

9. United States pubmed.ncbi.nlm.nih.gov

Treating Alpelisib-Induced Hyperglycemia with Very Low Carbohydrate Diets and Sodium-Glucose Co-Transporter 2 Inhibitors: A Case Series. [2021]

10. United States pubmed.ncbi.nlm.nih.gov

Fasting May Complement Endocrine Therapy. [2021]

11. United States pubmed.ncbi.nlm.nih.gov

A Whole Food, Plant-Based Randomized Controlled Trial in Metastatic Breast Cancer: Feasibility, Nutrient, and Patient-Reported Outcomes. [2023]

12. United States pubmed.ncbi.nlm.nih.gov

Diabetes Risk Reduction Diet and Survival after Breast Cancer Diagnosis. [2022]

13. United States pubmed.ncbi.nlm.nih.gov

The Effects of Diabetes and Glycemic Control on Cancer Outcomes in Individuals With Metastatic Breast Cancer. [2023]