Alpelisib + Fulvestrant for Endometrial Cancer

Recruiting at 10 trial locations

Overseen By Jennifer Klein, MEd

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: GOG Foundation

Must not be taking: Fulvestrant, PIK3CA inhibitors

Disqualifiers: Diabetes, Cardiac disease, Active infection, 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: 4

Duration: Until disease progression or unacceptable toxicity

51 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination of treatments, alpelisib (Piqray) and fulvestrant (Faslodex), for endometrial cancer with a specific genetic mutation (PIK3CA-mutated ER-positive). The study aims to determine how effectively this combination can shrink tumors in individuals whose cancer is unlikely to be cured by surgery or radiation. It is suitable for those with advanced endometrial cancer with this genetic profile who have already tried other treatments. Participants must be able to swallow pills and should not have previously taken fulvestrant. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, such as strong CYP3A4 inducers and inhibitors of BCRP, at least 7 days before starting the treatment. There is also a washout period of at least 21 days for chemotherapy and 14 days for radiotherapy before beginning the trial. If you are on these or similar medications, you may need to stop them.

Is there any evidence suggesting that the combination of alpelisib and fulvestrant is likely to be safe for humans?

Research has shown that combining alpelisib and fulvestrant benefits patients with certain types of breast cancer. One study found this combination effective for patients with hormone receptor-positive breast cancer that has a specific change in the PIK3CA gene. The FDA has approved this treatment for this use, considering it relatively safe.

Earlier studies indicate that common side effects include high blood sugar, diarrhea, and nausea, but these were usually manageable. Every treatment carries risks, and individual reactions can vary. Consulting a doctor is crucial to understand how these findings might apply to one's health. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for endometrial cancer?

Researchers are excited about alpelisib and fulvestrant for endometrial cancer because they target the disease in a unique way. Unlike standard treatments that often focus on hormones or chemotherapy, alpelisib inhibits a specific pathway known as PI3K, which is frequently overactive in many cancers. Fulvestrant complements this by blocking estrogen receptors, which can drive cancer growth. This combination has the potential to more precisely target and slow down the progression of endometrial cancer, offering hope for more effective management.

What evidence suggests that the combination of alpelisib and fulvestrant could be effective for endometrial cancer?

This trial will evaluate the combination of alpelisib and fulvestrant for treating a specific type of endometrial cancer with a PIK3CA mutation that is ER-positive. Studies have shown that using alpelisib and fulvestrant together can help treat this type of cancer. In some research, 28% of patients with similar cancers experienced tumor shrinkage, and some patients' cancer remained stable for a period. This treatment targets certain pathways in cancer cells, helping to stop or slow tumor growth. These findings suggest that this treatment could be a promising option for patients with this type of endometrial cancer. ^{1 2 5 6 7}

Who Is on the Research Team?

Stephanie Gaillard, MD

Principal Investigator

GOG Foundation

Are You a Good Fit for This Trial?

This trial is for adults with recurrent or primary endometrioid endometrial cancer that's ER-positive and PIK3CA-mutated. Participants must have measurable disease, be recovered from prior treatments, have good performance status (ECOG 0-1), controlled blood sugar levels, and adequate organ function. They can't have had certain previous inhibitors, other cancer types or treatments, uncontrolled diabetes type II, serious infections or conditions that could interfere with the study.

Inclusion Criteria

I am not pregnant and use effective birth control.

I've had chemotherapy for early-stage cancer or for a pelvic recurrence.

My endometrial cancer is ER positive and has a PIK3CA mutation.

Exclusion Criteria

I currently have an active infection.

I am currently experiencing active bleeding or have a condition that greatly increases my risk of bleeding.

You are either pregnant or currently breastfeeding.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive alpelisib 300mg orally daily and fulvestrant 500mg IM on specified days of each 28-day cycle

Until disease progression or unacceptable toxicity

Visits every 4 weeks for toxicity assessment, every 8 weeks for response assessment

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

What Are the Treatments Tested in This Trial?

Interventions

• Alpelisib
• Fulvestrant

Trial Overview The trial tests a combination of an alpelisib pill and fulvestrant injection in patients to see how well it works against specific mutations in endometrial cancer. The main goal is to measure the objective response rate (ORR) - basically how many patients see their tumors shrink or disappear after treatment.

How Is the Trial Designed?

Group I: Apelisib and Fulvestrant Experimental Treatment 2 Interventions

alpelisib 300mg orally daily of each 28-day cycle fulvestrant 500mg IM on Day 1 and Day 15 of Cycle 1, then 500mg IM on Day 1 of each 28-day cycle.

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?

GOG Foundation

Lead Sponsor

Trials

48

Recruited

18,500+

Novartis

Industry Sponsor

Trials

1,646

Recruited

2,778,000+

Vasant Narasimhan

Novartis

Chief Executive Officer since 2018

MD from Harvard Medical School, Bachelor's in Biological Sciences from University of Chicago, Master's in Public Policy from John F. Kennedy School of Government

Shreeram Aradhye

Novartis

Chief Medical Officer since 2022

MD from Yale University, MSc in Clinical Epidemiology from University of Pennsylvania

Published Research Related to This Trial

In the phase III SANDPIPER study involving 516 postmenopausal women with PIK3CA-mutant breast cancer, taselisib combined with fulvestrant significantly improved progression-free survival (7.4 months) compared to placebo plus fulvestrant (5.4 months), indicating its efficacy in this patient population.

Despite the efficacy in extending progression-free survival, the taselisib combination had a concerning safety profile, with higher rates of serious adverse events (32.0% vs. 8.9% in placebo) and more treatment discontinuations (16.8% vs. 2.3% in placebo), suggesting limited clinical utility.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase III randomized study of taselisib or placebo with fulvestrant in estrogen receptor-positive, PIK3CA-mutant, HER2-negative, advanced breast cancer: the SANDPIPER trial. Dent, S., Cortés, J., Im, YH., 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]

Alpelisib, a PI3K-alpha inhibitor, has been approved for use with fulvestrant in patients with HR+/HER2- breast cancer that have PIK3CA mutations, showing improved progression-free survival compared to fulvestrant alone in a phase III trial.

While alpelisib offers a significant benefit in delaying disease progression, its safety profile necessitates careful patient selection and monitoring, particularly regarding glycemic levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alpelisib for the treatment of PIK3CA-mutated, hormone receptor-positive, HER2-negative metastatic breast cancer. Leenhardt, F., Alexandre, M., Jacot, W.[2021]

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 study involving 587 postmenopausal women with advanced breast cancer, fulvestrant showed similar efficacy to tamoxifen in patients with hormone receptor-positive tumors, with no significant differences in time to progression (TTP) or objective response rates.

While tamoxifen had a slightly better overall efficacy in the general population, both treatments were well tolerated, indicating that fulvestrant can be a viable option for patients with ER+ and/or PgR+ tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of fulvestrant versus tamoxifen for the treatment of advanced breast cancer in postmenopausal women previously untreated with endocrine therapy: a multinational, double-blind, randomized trial. Howell, A., Robertson, JF., Abram, P., et al.[2022]

In a study of 35 patients with advanced or recurrent endometrial cancer, fulvestrant showed marginal activity, resulting in 4 partial responses and 8 cases of stable disease, with a median time to progression of 2.3 months.

The treatment was well tolerated, suggesting good safety, but the authors recommend exploring a higher dose of 500 mg every 4 weeks to potentially enhance its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of fulvestrant 250 mg/month in patients with recurrent or metastatic endometrial cancer: a study of the Arbeitsgemeinschaft Gynäkologische Onkologie. Emons, G., Günthert, A., Thiel, FC., et al.[2018]

In a phase II study involving 60 postmenopausal women with advanced HER2-negative, hormone receptor-positive breast cancer, the combination of taselisib and fulvestrant showed clinical activity, particularly in patients with PIK3CA mutations, achieving a best confirmed response rate of 38.5%.

The treatment was associated with a high incidence of adverse events, with 50% of patients experiencing grade ≥3 adverse events, but no new safety concerns were identified, indicating that taselisib plus fulvestrant is a potentially safe option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Study of Taselisib (GDC-0032) in Combination with Fulvestrant in Patients with HER2-Negative, Hormone Receptor-Positive Advanced Breast Cancer. Dickler, MN., Saura, C., Richards, DA., et al.[2019]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05154487

NCT05154487 | A Study of Alpelisib and Fulvestrant to ... This is a 2 stage multi-center study designed to evaluate the efficacy of the combination of alpelisib and fulvestrant in patients with PIK3CA-mutated ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.TPS5639

GOG3069: Phase 2 study of alpelisib and fulvestrant for ... GOG3069 is a phase II trial designed to evaluate the efficacy and safety of alpelisib and fulvestrant in a biomarker-selected endometrial cancer patient ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10046539/

Do Not Forget about Hormonal Therapy for Recurrent ... They found a similar ORR of 10%, with no responses in the ER-negative group (ER-negative arm was closed early). In the ER-positive group, PFS was 3.8 months and ...

4. gynecologiconcology-online.net gynecologiconcology-online.net/article/S0090-8258(24)00139-2/fulltext

Alpelisib for PIK3CA-mutated advanced gynecological ... Overall, 10 patients (28%) achieved a PR and 12 patients (33%) had SD with alpelisib. The greatest benefit of alpelisib was observed in the endometrial cancer ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S1048891X24163542

TP005/#1564 Gog-3069: phase 2 study of alpelisib and ... GOG3069 is a phase II trial evaluating the efficacy and safety of alpelisib + fulvestrant in biomarker-selected endometrial cancer patients. Methods. GOG ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9631302/

Real world outcomes with alpelisib in metastatic hormone ... It has received FDA approval in May 2019 for patients with metastatic HR-positive breast cancer with PIK3CA mutation who have received prior endocrine therapy.

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.e13058

metastatic breast cancer in real-world clinical practice. The results of using alpelisib with fulvestrant confirm its effectiveness in real-world clinical practice in patients with pre-treated HR+HER2- negative ...