LEE011 + BYL719 + Letrozole for Breast Cancer

Not currently recruiting at 42 trial locations

Age: 18+

Sex: Female

Trial Phase: Phase 1 & 2

Sponsor: Novartis Pharmaceuticals

Must be taking: Letrozole

Must not be taking: Hormone replacement

Disqualifiers: HER2-overexpression, Active CNS metastases, Diabetes, others

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

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores new treatment combinations for women with estrogen-receptor positive (ER+) breast cancer that has spread or is locally advanced. Researchers are testing LEE011 and BYL719, both investigational drugs, with letrozole (also known as Femara, a hormone therapy) to determine the best doses and assess their safety and effectiveness. Participants may qualify if they have ER+/HER2- breast cancer and have undergone no more than one line of chemotherapy for advanced cancer. The trial includes different treatment groups, featuring combinations of two or all three drugs. This study could contribute to developing new treatment options for breast cancer in the future. 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 these investigational drugs.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications, but you cannot be on hormone replacement therapy that cannot be discontinued. It's best to discuss your specific medications with the trial team.

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

Research shows that the treatments in this trial have been safe in past studies. For LEE011 (ribociclib) combined with letrozole, previous research indicates that this combination is generally safe and well-tolerated, with manageable side effects and a good level of safety.

For BYL719 (alpelisib) combined with letrozole, studies show this combination is also safe and effective for certain types of breast cancer. However, about 50% of patients may develop a rash, which sometimes requires adjusting the dose.

Regarding the triple combination of LEE011, BYL719, and letrozole, research suggests it is acceptably safe. While some side effects might occur, they are generally manageable. This combination has shown early signs of effectiveness against breast cancer in patients who have undergone several treatments before.

In summary, the treatments in this trial have generally been well-tolerated in earlier studies, though some side effects like rash may occur. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for breast cancer because they target specific pathways that drive cancer growth, potentially offering more effective options than current treatments. While standard treatments often include hormone therapy or chemotherapy, LEE011 (also known as ribociclib) works by inhibiting cyclin-dependent kinases 4 and 6 (CDK4/6), which are crucial for cancer cell division. BYL719, or alpelisib, is a PI3K inhibitor that targets pathways involved in tumor growth and survival. When combined with letrozole, a common hormone therapy, these drugs may work synergistically to slow or stop cancer progression more effectively than existing options. This multi-targeted approach could lead to better outcomes for patients with advanced breast cancer.

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

This trial will evaluate different combinations of treatments for breast cancer. Studies have shown that combining ribociclib (LEE011) and letrozole, which participants in one arm of this trial may receive, helps patients with advanced breast cancer live longer. Specifically, patients using these drugs lived about 64 months, compared to 51 months for those using letrozole alone. Another arm of this trial will test the combination of alpelisib (BYL719) with letrozole, which research has shown to be effective and safe for patients with metastatic breast cancer. This combination resulted in an average of 5.7 months without cancer worsening in patients with a specific gene mutation (PIK3CA-mutant). The trial will also explore the combination of ribociclib, alpelisib, and letrozole, which has shown early promise and is considered safe for patients who have already tried several treatments. ^{5 6 7 8 9}

Who Is on the Research Team?

Novartis Pharmaceuticals

Principal Investigator

Novartis Pharmaceuticals

Are You a Good Fit for This Trial?

This trial is for postmenopausal women with advanced ER+/HER2- breast cancer who haven't had systemic treatment in the advanced setting, except possibly letrozole for up to one month. They can have had (neo)adjuvant therapy if they've been disease-free for over a year since completion. Exclusions include recent major surgery, other cancers within 3 years, heart issues, active brain metastases, and certain diabetes conditions.

Inclusion Criteria

I had early-stage breast cancer treatment and have been disease-free for over a year.

I may have had multiple hormone treatments but only one chemotherapy for advanced cancer.

I haven't had systemic treatment for advanced cancer, except possibly letrozole for up to a month.

Exclusion Criteria

My heart does not function properly.

I have diabetes or had gestational diabetes.

I have pancreatitis.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Phase Ib dose escalation to estimate the MTD and/or RP2D for the combinations

28 days per cycle

Multiple visits for dose adjustments and monitoring

Dose Expansion

Phase Ib dose expansions to further characterize safety, tolerability, PK, and preliminary clinical anti-tumor activity

18-24 months

Regular visits for safety and PK assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• BYL719
• LEE011
• Letrozole

Trial Overview The study tests two drugs: LEE011 (a CDK4/6 inhibitor) and BYL719 (a PI3K-alpha inhibitor), both combined with letrozole. It's an open-label Phase Ib trial aiming to find the maximum tolerated doses of these combinations and their preliminary effectiveness against breast cancer.

How Is the Trial Designed?

Group I: LEE011+ BYL719+letrozole Arm 4 Experimental Treatment 3 Interventions

LEE011-daily (dose escalating), BYL719 -daily (dose escalating), letrozole 2.5 mg/day

Group II: LEE011 + letrozole Arm 1 Experimental Treatment 2 Interventions

LEE011 - 28 day cycles (21 days followed by a 7 day break - dose escalating), letrozole - 2.5 mg/day

Group III: LEE011 + BYL719 + letrozole Arm 3 Experimental Treatment 3 Interventions

LEE011 - 28 day cycles (21 days followed by a 7 day break -dose escalating), BYL719 - daily (dose escalating), letrozole 2.5 mg/day

Group IV: BYL719 + letrozole Arm 2 Experimental Treatment 2 Interventions

BYL719 - daily (dose escalating) letrozole - 2.5 mg/day

Who Is Running the Clinical Trial?

Novartis Pharmaceuticals

Lead Sponsor

Trials

2,963

Recruited

4,275,000+

Founded

1996

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Gleevec, Cosentyx, Entresto, Kisqali

Dr. Vas Narasimhan

Novartis Pharmaceuticals

Chief Executive Officer since 2018

MD from Harvard Medical School

Dr. Shreeram Aradhye

Novartis Pharmaceuticals

Chief Medical Officer since 2021

MD

Published Research Related to This Trial

In a study of 150 breast cancer patients, those receiving sequential treatment with letrozole and tamoxifen showed a higher overall response rate and fewer adverse reactions compared to those on letrozole alone.

Both treatment methods resulted in similar survival rates, but the sequential therapy group had a significantly lower recurrence rate and better improvement in blood lipid levels, indicating a potentially better prognosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy, Safety, and Prognosis of Sequential Therapy with Tamoxifen and Letrozole versus Letrozole Monotherapy for Breast Carcinoma. Lu, X., Qian, C.[2023]

Letrozole, at both 2.5 mg and 10 mg doses, was effective as a neoadjuvant therapy for locally advanced breast cancer, with significant reductions in tumor volume observed in all patients, allowing for breast-conserving surgery.

There were no significant differences in efficacy between the two doses, and both were well-tolerated with no recordable side effects, indicating a favorable safety profile for letrozole in this treatment setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Letrozole as primary medical therapy for locally advanced and large operable breast cancer. Dixon, JM., Love, CD., Bellamy, CO., et al.[2022]

Letrozole is more effective than tamoxifen for adjuvant therapy in postmenopausal women with hormone-responsive early breast cancer, and it is well tolerated by patients.

Extended therapy with letrozole after tamoxifen treatment is more effective than placebo, making it a valuable treatment option while ongoing trials investigate the best duration and comparison with other aromatase inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Letrozole: a review of its use in the treatment of postmenopausal women with hormone-responsive early breast cancer. Keating, GM.[2021]

Letrozole is a new non-steroidal aromatase inhibitor approved in Japan for treating postmenopausal women with breast cancer, particularly effective for those with steroid receptor positive or receptor-unknown locally advanced or metastatic cases.

The drug is generally well-tolerated, with mostly mild side effects such as hot flashes and fatigue, and has shown beneficial results in large international studies for post-surgical endocrine therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Introduction of new drug: letrozole, a new non-steroidal aromatase inhibitor for the treatment of postmenopausal women with breast cancer]. Tsukagoshi, S.[2018]

In the BIG 1-98 trial, letrozole demonstrated a 19% reduction in the risk of disease-free survival events compared to tamoxifen, indicating its superior efficacy as an adjuvant therapy for early breast cancer.

Letrozole significantly reduced the risk of distant metastases (hazard ratio 0.73), establishing it as a standard treatment option for postmenopausal women with hormone-sensitive breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The evolving role of letrozole in the adjuvant setting: first results from the large, phase III, randomized trial BIG 1-98. Monnier, A.[2022]

Letrozole is an effective treatment for postmenopausal women with early-stage or advanced hormone-sensitive breast cancer, showing a 43% reduction in disease recurrences when used as extended adjuvant therapy beyond standard tamoxifen treatment.

In advanced breast cancer, letrozole outperformed tamoxifen in terms of time to disease progression (9.4 months vs. 6.0 months) and has a similar tolerability profile, making it a recommended first-line therapy according to treatment guidelines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Letrozole: a review of its use in postmenopausal women with breast cancer. Simpson, D., Curran, MP., Perry, CM.[2018]

Letrozole, a third-generation aromatase inhibitor, has been shown to be more effective than tamoxifen in delaying disease progression in hormone receptor-positive breast cancer, making it a preferred treatment option in various settings including adjuvant and neoadjuvant therapy.

Combining letrozole with other agents like lapatinib or everolimus enhances its efficacy, particularly in patients with both HR+ and HER2+ breast cancer, suggesting that dual-targeted therapies can effectively overcome treatment resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An overview of letrozole in postmenopausal women with hormone-responsive breast cancer. Barnadas, A., Estévez, LG., Lluch-Hernández, A., et al.[2018]

The FACE trial is a large-scale study involving 4000 postmenopausal women with hormone receptor-positive, node-positive breast cancer, comparing the efficacy and safety of letrozole and anastrozole over a treatment period of up to 5 years.

The primary goal of the trial is to assess disease-free survival (DFS), while secondary objectives include evaluating overall survival (OS) and the time to distant metastases, which will provide comprehensive insights into the effectiveness of both treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The FACE trial: letrozole or anastrozole as initial adjuvant therapy? Jonat, W., Mundhenke, C.[2018]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/27126994/

A Phase Ib Study of Alpelisib (BYL719), a PI3Kα ... - PubMed This phase Ib study evaluated alpelisib plus letrozole's safety, tolerability, and preliminary activity in patients with metastatic ER + breast cancer ...

2. aacrjournals.org aacrjournals.org/clincancerres/article/23/1/26/122921/A-Phase-Ib-Study-of-Alpelisib-BYL719-a-PI3K

A Phase Ib Study of Alpelisib (BYL719), a PI3Kα-Specific ... The results from this study provide evidence that alpelisib plus letrozole is safe, tolerable, and active in postmenopausal patients with ER+/HER2− metastatic ...

3. ascopubs.org ascopubs.org/doi/10.1200/jco.2014.32.15_suppl.516

SU2C phase Ib study of the PI3Kα inhibitor BYL719 with ... Conclusions: The combination of letrozole/ BYL719 is safe and tolerable in pts with AI-refractory ER+/HER2 MBC. The MTD and recommended dose for ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT05038735

NCT05038735 | Study to Assess the Efficacy and Safety of ... The purpose of this study is to complement Study CBYL719C2301 (SOLAR-1) and obtain more comprehensive data on the efficacy and safety of alpelisib (BYL719) ...

5. cancernetwork.com cancernetwork.com/view/alpelisib-letrozole-combo-sustains-efficacy-in-pik3ca-mutant-hr-her2--advanced-breast-cancer

Alpelisib/Letrozole Combo Sustains Efficacy in PIK3CA- ... With a median follow-up of 15 months, the combination of alpelisib and letrozole resulted in a median progression-free survival (PFS) of 5.7 ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5085926/

A Phase Ib Study of Alpelisib (BYL719), a PI3Kα-specific ... The combination of the PI3Kα specific inhibitor, alpelisib, and the aromatase inhibitor letrozole is safe and clinically active in patients with ER+/PIK3CA- ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7398571/

Dermatologic Adverse Events Related to the PI3Kα ... Rash develops in approximately 50% of patients receiving alpelisib for breast cancer, often requiring dose modifications. Here, we describe the ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT01870505

NCT01870505 | BYL719 Plus Letrozole or Exemestane for ... The purpose of this study is to test the safety of a drug called BYL719 at different dose levels. The investigators want to find out what effects, ...

9. ecancer.org ecancer.org/en/news/7206-aacr-2015-adding-pi3k-inhibitor-byl719-to-letrozole-was-safe-with-early-signs-of-activity-against-metastatic-er-positive-breast-cancer

AACR 2015: Adding PI3K inhibitor BYL719 to letrozole was ... AACR 2015: Adding PI3K inhibitor BYL719 to letrozole was safe, with early signs of activity against metastatic ER-positive breast cancer. 20 ...