LEE011 + BYL719 + Letrozole for Breast Cancer

Recruiting at 38 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

255 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

The purpose of this trial is to inform the future clinical development of the two investigational agents in ER+ breast cancer, LEE011 (CDK4/6 inhibitor) and BYL719 (PI3K-alpha inhibitor). This is a multi-center, open-label Phase Ib study. The Phase Ib dose escalation will estimate the MTD and/or RP2D for three regimens: two double combinations, LEE011 with letrozole and BYL719 with letrozole, followed by triple combinations of LEE011 + BYL719 with letrozole (Arms 3 and 4). The Phase Ib dose escalation part will be followed by Phase Ib dose expansions to further characterize the safety, tolerability, PK and preliminary clinical anti-tumor activity of the combinations. Optional crossover for patients who have progressed while on dose escalation or dose expansion with doublet treatment on Arms 1 or 2 to be treated with the triplet combination (Arm 3) after the determination of the RP2D for Arm 3; is no longer permitted after protocol amendment 6. Approximately 270 adult women with ER+/HER2- locally advanced or metastatic breast cancer will be enrolled.

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 the combination of LEE011, BYL719, and Letrozole safe for humans?

Letrozole, one of the drugs in the combination, is generally safe for humans with mostly mild side effects like hot flashes, joint pain, and nausea. It has been widely used in breast cancer treatment and is approved in many countries. ^{1 2 3 4 5}

What makes the drug combination of LEE011, BYL719, and Letrozole unique for breast cancer treatment?

The combination of LEE011 (a CDK4/6 inhibitor), BYL719 (a PI3K inhibitor), and Letrozole (an aromatase inhibitor) is unique because it targets multiple pathways involved in breast cancer cell growth, potentially offering a more comprehensive approach to treatment compared to using Letrozole alone. ^{2 6 7 8 9}

What data supports the effectiveness of the drug Letrozole for breast cancer?

Research shows that Letrozole significantly improves disease-free survival in postmenopausal women with hormone-responsive early breast cancer compared to tamoxifen, and it is effective as both adjuvant and extended adjuvant therapy. ^{2 5 6 10 11}

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 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 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]

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]

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, 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, 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]

Citations

1. England pubmed.ncbi.nlm.nih.gov

Adjuvant letrozole versus tamoxifen according to centrally-assessed ERBB2 status for postmenopausal women with endocrine-responsive early breast cancer: supplementary results from the BIG 1-98 randomised trial. [2018]

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

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

3. India pubmed.ncbi.nlm.nih.gov

Results of letrozole in postmenopausal women after tamoxifen treatment for advanced breast cancer. [2019]

4. New Zealand pubmed.ncbi.nlm.nih.gov

Letrozole: a review of its use in postmenopausal women with breast cancer. [2018]

5. New Zealand pubmed.ncbi.nlm.nih.gov

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

6. Japan 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]. [2018]

7. England pubmed.ncbi.nlm.nih.gov

The FACE trial: letrozole or anastrozole as initial adjuvant therapy? [2018]

8. Netherlands 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. [2022]

9. England pubmed.ncbi.nlm.nih.gov

The aromatase inhibitor letrozole and inhibitors of insulin-like growth factor I receptor synergistically induce apoptosis in in vitro models of estrogen-dependent breast cancer. [2022]

10. Netherlands pubmed.ncbi.nlm.nih.gov

Letrozole as primary medical therapy for locally advanced and large operable breast cancer. [2022]

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

An overview of letrozole in postmenopausal women with hormone-responsive breast cancer. [2018]