Alpelisib + Fulvestrant for Endometrial Cancer

Recruiting at10 trial locations

Age: 18+

Sex: Female

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: GOG Foundation

Must not be taking: Fulvestrant, PIK3CA inhibitors

Disqualifiers: Diabetes, Cardiac disease, Active infection, others

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial tests a combination of two drugs, alpelisib and fulvestrant, in patients with a specific type of endometrial cancer. These patients have a genetic mutation (PIK3CA) and their cancer grows in response to estrogen. Alpelisib targets the mutation, while fulvestrant blocks estrogen, aiming to stop cancer growth. Alpelisib is the first drug of its kind approved for use with fulvestrant based on its effectiveness in treating similar types of cancer.

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.

What data supports the effectiveness of the drug combination Alpelisib and Fulvestrant for treating endometrial cancer?

The combination of Alpelisib and Fulvestrant has been shown to improve progression-free survival in patients with certain types of breast cancer, specifically those with hormone receptor-positive and PIK3CA-mutated tumors. While this data is from breast cancer studies, it suggests potential effectiveness in similar hormone-driven cancers like endometrial cancer. ^{1 2 3 4 5}

Is the combination of Alpelisib and Fulvestrant safe for humans?

The combination of Alpelisib and Fulvestrant has been studied for breast cancer, showing common side effects like high blood sugar, rash, and diarrhea, which sometimes required hospital treatment. These side effects suggest that while the treatment is used in humans, it requires careful monitoring for safety. ^{2 5 6 7 8}

How is the drug combination of Alpelisib and Fulvestrant unique for treating endometrial cancer?

The combination of Alpelisib and Fulvestrant is unique because Alpelisib is a PI3K inhibitor that targets specific gene mutations (PIK3CA) and is used alongside Fulvestrant, an estrogen receptor antagonist, to potentially improve outcomes in cancers with these mutations. This approach is novel for endometrial cancer, as it leverages a mechanism proven effective in certain breast cancers. ^{1 2 4 6 8}

Research Team

Stephanie Gaillard, MD

Principal Investigator

GOG Foundation

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Alpelisib (PI3K Inhibitor)
• Fulvestrant (Estrogen Receptor Antagonist)

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.

Participant Groups

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.

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

Findings from Research

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 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 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]

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]

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]

References

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

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

2. 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]

3. England 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. [2022]

4. United States 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. [2018]

5. United States 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. [2019]

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

Alpelisib for the treatment of PIK3CA-mutated, hormone receptor-positive, HER2-negative metastatic breast cancer. [2021]

7. United States 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. [2022]

8. England pubmed.ncbi.nlm.nih.gov

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