Evexomostat + Alpelisib + Fulvestrant for Breast Cancer

(Amelia-1 Trial)

Recruiting at 11 trial locations

Overseen By James M Shanahan

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: SynDevRx, Inc.

Must be taking: Alpelisib, Capivasertib, Fulvestrant

Must not be taking: Insulin, Corticosteroids, Sulfonylureas, others

Disqualifiers: Inflammatory breast cancer, Brain metastasis, Type 1 diabetes, others

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

Compensation: Varies

Number of Visits: 1

Duration: 6 months

52 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new drug combination for advanced or metastatic breast cancer. The researchers aim to determine if adding evexomostat (also known as SDX-7320) to standard treatments can enhance safety and effectiveness. Specifically, they assess reduced blood sugar spikes and evaluate the treatment's efficacy against cancer. The trial seeks men and postmenopausal women with specific genetic markers linked to breast cancer and advanced cancer that is difficult to treat. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new drug combination.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications at least 7 days before starting the treatment, specifically strong CYP3A4 inducers, inhibitors of BCRP, and sulfonylureas. If you are on these medications, you will need to discuss alternatives with your doctor.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that evexomostat, one of the treatments in this trial, has been safe in past studies. Patients with advanced cancer tolerated it well, with most experiencing no severe side effects. Some even showed stable disease, which is encouraging. Another study found that evexomostat improved insulin resistance, a condition where the body doesn't use insulin properly.

The other treatments in the trial, alpelisib and capivasertib, are standard treatments already used for certain types of cancer, so their safety is well-established. However, they can sometimes cause high blood sugar levels. This study explores whether evexomostat can address that issue.

Overall, previous research has shown promising safety for the treatments in this trial. However, like any clinical trial, there are risks, and discussing participation with a doctor is important to determine if joining is appropriate. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Evexomostat is unique because it works by targeting the hypoxia-inducible factor (HIF) pathway, which is different from most standard breast cancer treatments that typically focus on hormone receptors or HER2. This new mechanism might help in cutting off the tumor's blood supply, potentially starving it and slowing its growth. Researchers are excited about Evexomostat because it offers a novel approach that could complement existing therapies and improve outcomes for patients who may not respond well to current options like chemotherapy, hormone therapy, or targeted treatments.

What evidence suggests that this trial's treatments could be effective for breast cancer?

Research has shown that evexomostat, one of the treatments in this trial, may help manage advanced breast cancer when combined with other treatments. A previous study found that evexomostat was well-tolerated and helped stabilize the disease in patients with metastatic cancer. This trial examines evexomostat in combination with drugs like alpelisib and fulvestrant to determine if these combinations can slow cancer growth and manage side effects such as high blood sugar. Early results appear promising, but further research is needed to confirm these benefits. ^{1 2 4 6 7}

Who Is on the Research Team?

Medical Team

Principal Investigator

SynDevRx, Inc.

Are You a Good Fit for This Trial?

This trial is for adult women with advanced HR+/HER2- breast cancer, specifically those who have a PIK3CA mutation and are postmenopausal. Participants should not have brain malignancies or sensitivities to the drugs being tested, nor should they have uncontrolled diabetes or previous treatments with similar drugs.

Inclusion Criteria

My cancer has a PIK3CA mutation confirmed by an FDA-approved test.

I am postmenopausal.

I am fully active or can carry out light work.

Exclusion Criteria

I have been treated with PI3K/Akt/mTOR inhibitors or fulvestrant.

I have been diagnosed with inflammatory breast cancer.

You are allergic to evexomostat, fulvestrant, or alpelisib or any of their ingredients.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-treatment

14-day pre-treatment phase of evexomostat plus fulvestrant before adding either alpelisib or capivasertib

2 weeks

1 visit (in-person)

Treatment

Participants receive the triplet therapy consisting of evexomostat, alpelisib or capivasertib, and fulvestrant for up to 7 cycles

6 months

Monthly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

What Are the Treatments Tested in This Trial?

Interventions

• Evexomostat

Trial Overview The study tests a combination of three drugs: Evexomostat, Alpelisib, and Fulvestrant in women with a specific gene mutation linked to aggressive breast cancer. It aims to see if Evexomostat can reduce high blood sugar caused by Alpelisib and improve its effectiveness against tumors.

How Is the Trial Designed?

Group I: Evexomostat Experimental Treatment 1 Intervention

Each subject will receive repeat doses (C1, C2…) for 28-day cycles. Participants may continue on study drug until disease progression, unacceptable toxicity, or other withdrawal criteria is met.

Who Is Running the Clinical Trial?

SynDevRx, Inc.

Lead Sponsor

Trials

3

Recruited

140+

Published Research Related to This Trial

In a study of 76 women with hormone receptor-positive, HER2-negative metastatic breast cancer, alpelisib combined with endocrine therapy demonstrated a median progression-free survival of 5.2 months, indicating its effectiveness in a real-world setting.

However, about 31.6% of patients had to permanently discontinue alpelisib due to adverse events, with hyperglycemia being the most common serious side effect, highlighting the need for careful monitoring of patients on this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Cohort Study of the Antitumor Efficacy and Toxicity Profile of Alpelisib for Metastatic or Locally Advanced HR+, HER2- Breast Cancer: A Single-Institution Experience. Sarfraz, H., Bari, S., Whiting, J., et al.[2023]

In the phase III SOLAR-1 trial involving 571 patients, alpelisib combined with fulvestrant showed significant efficacy in treating PIK3CA-mutated advanced breast cancer, with a median progression-free survival of 12.5 months at higher dose intensities compared to 5.8 months with placebo.

Common adverse events included hyperglycemia and rash, which were effectively managed through early identification and preventive measures, leading to reduced severity and lower treatment discontinuation rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Time course and management of key adverse events during the randomized phase III SOLAR-1 study of PI3K inhibitor alpelisib plus fulvestrant in patients with HR-positive advanced breast cancer. Rugo, HS., André, F., Yamashita, T., et al.[2022]

In the NEO-ORB study involving 257 postmenopausal women with HR+ early breast cancer, the addition of alpelisib to letrozole did not significantly improve the objective response rate compared to placebo, with rates of 43% for alpelisib versus 45% for placebo in the PIK3CA-mutant cohort.

Although the primary objective was not met, the combination treatment did show a greater decrease in phosphorylated AKT levels in PIK3CA-mutant tumors, suggesting some biological activity, but overall pathologic complete response rates remained low across all groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase II Randomized Study of Neoadjuvant Letrozole Plus Alpelisib for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer (NEO-ORB). Mayer, IA., Prat, A., Egle, D., et al.[2023]

Fulvestrant is an effective estrogen receptor antagonist for postmenopausal women with advanced breast cancer who have progressed after previous endocrine therapies, as demonstrated in a Compassionate Use Programme with diverse patient cases.

Clinical experience from the Compassionate Use Programme aligns with clinical trial data, indicating that fulvestrant is a valuable treatment option even for patients with challenging disease characteristics, such as visceral metastases and HER2-positive breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Case studies of fulvestrant ("Faslodex") in postmenopausal women with advanced breast cancer. Abram, P., Maass, N., Rea, D., et al.[2018]

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]

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]

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]

In a study of 54 postmenopausal women with metastatic breast cancer, fulvestrant demonstrated clinical benefit in 38.9% of patients, with a median time to progression of 6.4 months, indicating its efficacy even after multiple prior treatments.

Fulvestrant was well tolerated, with no severe toxicities (grade 3/4) reported, suggesting it is a safe option for patients with advanced breast cancer who have limited treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fulvestrant ('Faslodex') in heavily pretreated postmenopausal patients with advanced breast cancer: single centre clinical experience from the compassionate use programme. Mlineritsch, B., Psenak, O., Mayer, P., et al.[2018]

Fulvestrant was well tolerated and provided clinical benefit to 21% of heavily pre-treated postmenopausal women with advanced breast cancer, with 42% achieving stable disease for at least 12 weeks.

The efficacy of fulvestrant was similar whether given after disease progression or as maintenance therapy, with a median time to progression of 3 months and no significant toxicities reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fulvestrant in heavily pre-treated patients with advanced breast cancer: results from a single compassionate use programme centre. Catania, C., Ascione, G., Adamoli, L., et al.[2018]

In a study involving 451 postmenopausal women with advanced breast cancer, fulvestrant was found to be as effective as anastrozole in terms of time to progression, with median times of 5.5 months for fulvestrant and 5.1 months for anastrozole.

Both treatments were well tolerated, with low withdrawal rates due to adverse events (3.2% for fulvestrant and 1.3% for anastrozole), indicating that fulvestrant is a safe and effective option for patients who have progressed on prior endocrine therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. Howell, A., Robertson, JF., Quaresma Albano, J., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12183619/

A Phase 1 Safety Study of Evexomostat (SDX-7320) in ... Evexomostat (SDX-7320) was well-tolerated with prolonged stable disease and metastatic control in an open-label, phase I safety study.

2. aacrjournals.org aacrjournals.org/clincancerres/article/31/12_Supplement/P3-08-18/753953

Abstract P3-08-18: The AmeliaTM-1 study: A phase 1b/2 study ... A phase 1b/2 study assessing the safety and efficacy of evexomostat (SDX-7320) plus a PI3K/Akt inhibitor and fulvestrant in patients with advanced HR+/Her2- ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05455619

NCT05455619 | Evexomostat Plus PI3K or AKT Inhibitor ... This is a Phase 1b/2, open-label, parallel-arms pilot study in men and post-menopausal women with hormone receptor positive (HR+), HER2- advanced or metastatic ...

4. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2022-08559

A Study of SDX-7320 in Combination with Eribulin for ... Giving evexomostat in combination with eribulin may be more effective at treating metastatic TNBC than standard chemotherapy on its own. Eligibility Criteria ...

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.TPS1129

The Amelia-1 study: A phase 1b/2 trial of evexomostat ... Restoring insulin sensitivity and reducing systemic insulin levels improved the efficacy of alpelisib in animal models of breast cancer.

6. my.clevelandclinic.org my.clevelandclinic.org/clinical-trials/2238-a-phase-1b2-study-assessing-the-safety-and-efficacy-of-evexomostat-sdx-7320-in-combination-with-a-pi3k-pathway-inhibitor-plus-fulvestrant-in-postmenopausal-women-with-advanced-breast-cancer-and-pi3k-pathway-alterations-who-have-progressed

Clinical Trials A Phase 1b/2 Study Assessing the Safety and Efficacy of Evexomostat (SDX-7320) in Combination with a PI3K Pathway Inhibitor plus Fulvestrant in ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40444533/

A Phase 1 Safety Study of Evexomostat (SDX-7320) in ... Evexomostat (SDX-7320) was well-tolerated with prolonged stable disease and metastatic control in an open-label, phase I safety study.