Metastatic Breast CancerPhase 2NCT05025735
Alpelisib, Fulvestrant and Dapagliflozin for the Treatment of HR+, HER2 -, PIK3CA Mutant Metastatic Breast Cancer
A Phase 2 study testing Dapagliflozin 10Mg Tab in people with Metastatic Breast Cancer and HER2-negative Breast Cancer, run by Saint Luke's Health System at 1 site in United States.
Trial summary
This will be a single arm, open label pilot to test the combination of dapagliflozin, a commercially available SGLT-2 inhibitor, in combination with alpelisib + fulvestrant in patients with HR+/HER2- mBC. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Metastatic Breast Cancer, HER2-negative Breast Cancer
- What is being tested?
- Dapagliflozin 10Mg Tab
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 25 participants
- Where
- 1 siteUnited States
- Study dates
- 25 Aug 2021to Jul 2023
- Phase
- Phase 2
- 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 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients > 18 years old with stage IV or locally advanced, unresectable Stage III breast cancer that is:
- ER and/or PR positive by local laboratory evaluation
- HER2 negative as defined by: either IHC status of 0, 1+ ; IHC of 2+ with FISH negative by ASCO/CAP guidelines.
- If female, post-menopausal status as defined by
- Prior bilateral oophorectomy
- Age > 60
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- Age <60 and amenorrheic for 12 or more months in the absence of chemotherapy, tamoxifen, toremifene; or ovarian suppression and Follicle-stimulating Hormone (FSH) and estradiol in the postmenopausal range per local normal range.
- Current use of LHRH agonist for ovarian suppression and estradiol and FSH documented in the post-menopausal range.
- PIK3CA activating mutation identified by a either in a CLIA certified tumor genomic assay or ctDNA assay.
- Patients may be:
- relapsed with documented evidence of progression while on (neo) adjuvant endocrine therapy or within 12 months from completion of (neo)adjuvant endocrine therapy with no treatment for metastatic disease
- relapsed with documented evidence of progression more than 12 months following/completion of (neo)adjuvant endocrine therapy and then subsequently progressed with documented evidence of progression while on or after only one line of endocrine therapy for metastatic disease
- newly diagnosed advanced breast cancer, then relapsed with documented evidence of progression while on or after only one line of endocrine therapy
- Prior endocrine treatment must have included a CDK4/6 inhibitor
- ECOG performance status 0-2
- Patient has adequate bone marrow and organ function as defined by the following laboratory values:
- Absolute neutrophil count ≥ 1.0 × 109/L
- Platelets ≥ 75 × 109/L
- Hemoglobin ≥ 8.0 g/dL
- Calcium (corrected for serum albumin) and magnesium within normal limits or ≤ grade 1 according to NCI-CTCAE version 4.03 if judged clinically not significant by the investigator
- Potassium within normal limits, or corrected with supplements
- Creatinine Clearance 35 ≥ mL/min using Cockcroft-Gault formula
- In absence of liver metastases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 × ULN. If the patient has liver metastases, ALT and AST ≤ 5 × ULN
- Total bilirubin < ULN except for patients with Gilbert's syndrome who may only be included if the total bilirubin is ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 × ULN≤
- Fasting plasma glucose (FPG) ≤ 200 and Glycosylated Hemoglobin (HbA1c) ≤ 6.5%
- Fasting Serum amylase ≤ 2 × ULN
- Fasting Serum lipase ≤ ULN
Who cannot join
- Patient has not recovered from all toxicities related to prior anticancer therapies to NCI CTCAE version 4.03 Grade ≤1. Exception to this criterion: patients with any grade of alopecia are allowed to enter the study.
- Patient with symptomatic visceral disease or any disease burden that makes the patient ineligible for endocrine therapy per the investigator's best judgment.
- Patients with Type I diabetes or history of diabetic ketoacidosis
- Patient has received prior treatment with chemotherapy in the metastatic setting, fulvestrant, any PI3K, mTOR or AKT inhibitor
- Patient has a known hypersensitivity to alpelisib or fulvestrant, or to any of the excipients of alpelisib or fulvestrant.
- Patient is concurrently using other anti-cancer therapy.
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- Patient has had surgery within 14 days prior to starting study drug or has not recovered from major side effects of surgery.
- Patient has central nervous system (CNS) involvement that does not meet ALL of the following criteria:
- completed prior therapy (including radiation and/or surgery) for CNS metastases ≥ 14 days prior to the start of study and
- CNS tumor is clinically stable at the time of screening and
- patient is not receiving steroids and/or enzyme inducing anti-epileptic medications for brain metastases
- Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
- Patient is following a ketogenic diet and unwilling to change diet.
- Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the investigator's judgment, contraindicate patient participation in the clinical study.
- Patient has currently documented pneumonitis (the chest CT scan performed at baseline for the purpose of tumor assessment should be reviewed to confirm that there are no relevant pulmonary complications present).
- Patient is currently receiving or has received systemic corticosteroids 7 days prior to starting study drug, or who have not fully recovered from side effects of such treatment.
- Note: The following uses of corticosteroids are permitted: single doses, topical applications (e.g., for rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local injections (e.g., intra-articular).
- Sexually active males unless they are sterilized (at least 6 months prior to screening) or use a condom during intercourse while taking drug and for at least 8 months after stopping alpelisib and/or fulvestrant. .
- Participation in a prior investigational study within 14 days prior to the start of study treatment or within 5 half-lives of the investigational product, whichever is longer.
- Not able to understand and to comply with study instructions and requirements.
- History of acute pancreatitis within1 year of screening or past medical history of chronic pancreatitis.
Trial locations and contacts
1 site in 1 country.
United States1 site, 1 recruiting
- Recruiting
Saint Luke's Cancer Institute
Kansas City, Missouri, 64111
Kelley Aldrich, RN, 816-932-2677, kaldrich@saint-lukes.org
Timothy J Pluard, MD
About this study
This will be a single arm, open label pilot to test the combination of dapagliflozin, a commercially available SGLT-2 inhibitor, in combination with alpelisib + fulvestrant in patients with HR+/HER2- mBC. The objective of this study is to determine if the addition of dapagliflozin to the combination of alpelisib and fulvestrant leads to significant reduction in all-grade hyperglycemia.
Read the detailed description
Alpelisib is a p110α specific PI3K inhibitor that has shown significant clinical benefit in patients with HR+/HER2 negative mBC harboring activating PIK3CA mutations. The SOLAR-1 study randomized patients with MBC progressing after aromatase inhibitor therapy patients had a PFS of 11 months with fulvestrant plus alpelisib versus 5.7 months with fulvestrant alone. Alpelisib was associated with a 65% incidence of hyperglycemia, including 37% Grade 3 or 4 hyperglycemia.
Hyperglycemia is an expected effect of PI3K inhibitors given the pivotal role of PI3K in mediating the response to insulin in multiple tissues. Blocking insulin signaling by p110α inhibitors leads to glycogen breakdown in the liver along with decreased glucose uptake in peripheral tissues. The resulting hyperglycemia causes a compensatory response of increase insulin secretion by the pancreas.
Cantley and colleagues have shown in animal models that treatment with BYL-719(alpelisib) results in rapid increase in plasma glucose level and a compensatory increase in insulin.
They went on to show that this rebound hyperinsulinemia was able to rescue KPC tumor allografts from BYL-719 inhibition as evidenced by increasing phosphorylation of downstream effectors in the PI3K pathway, pAKT and PS6. Pretreatment of the mice with an SGLT-2 inhibitor decreased the hyperglycemia and hyperinsulinemia following treatment with BYL-719. Importantly, the response of the KPC tumor allografts to treatment was concordant with reduction in insulin levels.3
This provides a rationale for combining dapagliflozin with alpelisib in the treatment of HR+, PIK3CA mutant MBC. If concurrent treatment with dapagliflozin can abrogate the alpelisib induced hyperglycemia and subsequent rebound hyperinsulinemia it may significantly improve the therapeutic efficacy of alpelisib.
- Being tested
- Dapagliflozin 10Mg Tab
- Keywords
- Metastatic Breast Cancer, HER2 Negative, HR Positive
- Medical subject headings
- Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Dapagliflozin 10Mg TabDrug
Hyperglycemia is an expected effect of PI3K inhibitors given the pivotal role of PI3K in mediating the response to insulin in multiple tissues. Blocking insulin signaling by p110α inhibitors leads to glycogen breakdown in the liver along with decreased glucose uptake in peripheral tissues. The resulting hyperglycemia causes a compensatory response of increase insulin secretion by the pancreas.
If concurrent treatment with dapagliflozin can abrogate the alpelisib induced hyperglycemia and subsequent rebound hyperinsulinemia it may significantly improve the therapeutic efficacy of alpelisib.
| Study group | Role | What they receive |
|---|---|---|
| Phase 2 study of Fulvestrant, alpelisib and dapagliflozin | Experimental | A cycle length is defined as 28 days.
Fulvestrant 500 mg intramuscular, Cycle 1, Day 1 and Day 15; Cycle 2 and beyond 500 mg Intramuscular Day 1.
Alpelisib 300 mg by mouth, daily, continuously beginning on Cycle 1, Day 1.
Dapagliflozin 10 mg by mouth, daily, continuously beginning Cycle 1, Day 3. Receives: Drug: Dapagliflozin 10Mg Tab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Incidence of all grade hyperglycemia as assessed by CTCAE v5.0
Measured: Through study completion, an average of 1 year.
Secondary outcomes (3)
Incidence of Grade 3/4 hyperglycemia as assessed by CTCAE v5.0
Measured: Through study completion, an average of 1 year.
Overall response rate (ORR) as assed by RECIST 1.1 in patients with measurable disease
Measured: Through study completion, an average of 1 year.
Progression free survival
Measured: Through study completion, an average of 1 year.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Aug 2021
- Study start25 Aug 2021
- Primary completionDec 2022 (estimated)
- Study completionJul 2023 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Metastatic Breast CancerStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- open label pilot to test the combination of dapagliflozin, a commercially available SGLT-2 inhibitor, in combination with alpelisib + fulvestrant in patients with HR+/HER2- mBC.
- Masking
- None (open label)
- Enrolment
- 25 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Saint Luke's Health System
- Sponsor type
- University, hospital or other
- Collaborators
- Novartis Pharmaceuticals
- Responsible party
- Sponsor
- Investigators
- Timothy J Pluard, MD, Principal investigator, Saint Luke's Cancer Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05025735
- Sponsor's protocol ID
- CBYL719A0US03T
- Status last verified
- Oct 2021
- First submitted
- 26 Jun 2021
- Last updated
- 19 Oct 2021
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 19 Oct 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Alpelisib, Fulvestrant and Dapagliflozin for the Treatment of HR+, HER2 -, PIK3CA Mutant Metastatic Breast Cancer
- ClinicalTrials.gov ID
- NCT05025735
- Acronym / sponsor ID
- CBYL719A0US03T
- Keywords
- Metastatic Breast Cancer, HER2 Negative, HR Positive
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 25 participants (estimated)
- Lead sponsor
- Saint Luke's Health SystemUniversity, hospital or other
- Collaborators
- Novartis Pharmaceuticals
- Study start
- 25 Aug 2021 (actual)
- Primary completion
- Dec 2022 (estimated)
- Study completion
- Jul 2023 (estimated)
- First posted
- 27 Aug 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This will be a single arm, open label pilot to test the combination of dapagliflozin, a commercially available SGLT-2 inhibitor, in combination with alpelisib + fulvestrant in patients with HR+/HER2- mBC. The objective of this study is to determine if the addition of dapagliflozin to the combination of alpelisib and fulvestrant leads to significant reduction in all-grade hyperglycemia.
Detailed description
Alpelisib is a p110α specific PI3K inhibitor that has shown significant clinical benefit in patients with HR+/HER2 negative mBC harboring activating PIK3CA mutations. The SOLAR-1 study randomized patients with MBC progressing after aromatase inhibitor therapy patients had a PFS of 11 months with fulvestrant plus alpelisib versus 5.7 months with fulvestrant alone. Alpelisib was associated with a 65% incidence of hyperglycemia, including 37% Grade 3 or 4 hyperglycemia.
Hyperglycemia is an expected effect of PI3K inhibitors given the pivotal role of PI3K in mediating the response to insulin in multiple tissues. Blocking insulin signaling by p110α inhibitors leads to glycogen breakdown in the liver along with decreased glucose uptake in peripheral tissues. The resulting hyperglycemia causes a compensatory response of increase insulin secretion by the pancreas.
Cantley and colleagues have shown in animal models that treatment with BYL-719(alpelisib) results in rapid increase in plasma glucose level and a compensatory increase in insulin.
They went on to show that this rebound hyperinsulinemia was able to rescue KPC tumor allografts from BYL-719 inhibition as evidenced by increasing phosphorylation of downstream effectors in the PI3K pathway, pAKT and PS6. Pretreatment of the mice with an SGLT-2 inhibitor decreased the hyperglycemia and hyperinsulinemia following treatment with BYL-719. Importantly, the response of the KPC tumor allografts to treatment was concordant with reduction in insulin levels.3
This provides a rationale for combining dapagliflozin with alpelisib in the treatment of HR+, PIK3CA mutant MBC. If concurrent treatment with dapagliflozin can abrogate the alpelisib induced hyperglycemia and subsequent rebound hyperinsulinemia it may significantly improve the therapeutic efficacy of alpelisib.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- open label pilot to test the combination of dapagliflozin, a commercially available SGLT-2 inhibitor, in combination with alpelisib + fulvestrant in patients with HR+/HER2- mBC.
| Arm | Type | Receives |
|---|---|---|
| Phase 2 study of Fulvestrant, alpelisib and dapagliflozin | Experimental | Drug: Dapagliflozin 10Mg TabA cycle length is defined as 28 days. Fulvestrant 500 mg intramuscular, Cycle 1, Day 1 and Day 15; Cycle 2 and beyond 500 mg Intramuscular Day 1. Alpelisib 300 mg by mouth, daily, continuously beginning on Cycle 1, Day 1. Dapagliflozin 10 mg by mouth, daily, continuously beginning Cycle 1, Day 3. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (27 listed)
- Patients > 18 years old with stage IV or locally advanced, unresectable Stage III breast cancer that is:
- If female, post-menopausal status as defined by
- PIK3CA activating mutation identified by a either in a CLIA certified tumor genomic assay or ctDNA assay.
- Patients may be:
- ECOG performance status 0-2
Key exclusion criteria (21 listed)
- Patient has not recovered from all toxicities related to prior anticancer therapies to NCI CTCAE version 4.03 Grade ≤1. Exception to this criterion: patients with any grade of alopecia are allowed to enter the study.
- Patient with symptomatic visceral disease or any disease burden that makes the patient ineligible for endocrine therapy per the investigator's best judgment.
- Patients with Type I diabetes or history of diabetic ketoacidosis
- Patient has received prior treatment with chemotherapy in the metastatic setting, fulvestrant, any PI3K, mTOR or AKT inhibitor
- Patient has a known hypersensitivity to alpelisib or fulvestrant, or to any of the excipients of alpelisib or fulvestrant.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Dapagliflozin 10Mg TabHyperglycemia is an expected effect of PI3K inhibitors given the pivotal role of PI3K in mediating the response to insulin in multiple tissues. Blocking insulin signaling by p110α inhibitors leads to glycogen breakdown in the liver along with decreased glucose uptake in peripheral tissues. The resulting hyperglycemia causes a compensatory response of increase insulin secretion by the pancreas. If concurrent treatment with dapagliflozin can abrogate the alpelisib induced hyperglycemia and subsequent rebound hyperinsulinemia it may significantly improve the therapeutic efficacy of alpelisib. | Drug | Phase 2 study of Fulvestrant, alpelisib and dapagliflozin |
Primary outcome
Incidence of all grade hyperglycemia as assessed by CTCAE v5.0
Time frame: Through study completion, an average of 1 year.
3 secondary outcomes
Incidence of Grade 3/4 hyperglycemia as assessed by CTCAE v5.0
Time frame: Through study completion, an average of 1 year.
Overall response rate (ORR) as assed by RECIST 1.1 in patients with measurable disease
Time frame: Through study completion, an average of 1 year.
Progression free survival
Time frame: Through study completion, an average of 1 year.
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Oct 2021.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Timothy J Pluard, MD principal investigator
Saint Luke's Cancer Institute
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Dapagliflozin 10Mg Tab in people with Metastatic Breast Cancer and HER2-negative Breast Cancer, run by Saint Luke's Health System 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 27 inclusion and 21 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: status not confirmed, as of the sponsor's last update on 19 Oct 2021. 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 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Kelley Aldrich, RN (816-932-2677, slci1research@saint-lukes.org), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Incidence of all grade hyperglycemia as assessed by CTCAE v5.0 (time frame: Through study completion, an average of 1 year.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 19 Oct 2021.