Combo Therapy for Breast Cancer

Recruiting at16 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Olema Pharmaceuticals, Inc.

Must not be taking: PI3K inhibitors, mTOR inhibitors

Disqualifiers: Heart disease, Liver disease, HIV, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial tests a new drug, OP-1250, combined with either ribociclib or alpelisib in cancer patients. It aims to see if these combinations are safe and can better stop cancer growth.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, it does mention that you should not have received prior treatment with certain drugs like OP-1250, PI3K inhibitors, or mTOR inhibitors, depending on the treatment group.

What data supports the effectiveness of the drug combination therapy for breast cancer?

Alpelisib has shown promising results in treating hormone receptor-positive metastatic breast cancer with PIK3CA mutations, and ribociclib has been effective in increasing progression-free survival in similar breast cancer cases. These drugs have demonstrated efficacy in clinical trials, supporting their use in combination therapy for breast cancer. ^{1 2 3 4 5}

Is the combo therapy for breast cancer safe for humans?

Ribociclib (Kisqali) and Alpelisib have been studied in combination with other treatments for breast cancer and have shown manageable safety profiles, though they can cause some side effects. Alpelisib, for example, has been associated with clinically relevant adverse events, meaning it can cause noticeable side effects in some patients. ^{2 5 6 7 8}

What makes the combo therapy with Alpelisib, OP-1250, and Ribociclib unique for breast cancer?

This combo therapy is unique because it combines Alpelisib, a PI3K inhibitor targeting specific mutations, with Ribociclib, a CDK4/6 inhibitor, to overcome resistance in hormone receptor-positive breast cancer. This approach targets multiple pathways involved in cancer growth, potentially improving treatment effectiveness compared to using these drugs individually. ^{1 2 3 4 9}

Research Team

Mark Shilkrut, M.D., PhD

Principal Investigator

Olema Pharmaceuticals, Inc.

Daniela Vecchio, PhD

Principal Investigator

Olema Pharmaceuticals, Inc.

Eligibility Criteria

This trial is for adults over 18 with advanced or metastatic HR+/HER2- breast cancer, who've had no more than one prior chemo and up to two hormone therapies. They should have a life expectancy of at least 6 months and be able to follow the study plan. Exclusions include other cancers, heart disease, liver disease not in early stages, recent serious blood clots or stroke, lung conditions like pneumonitis, or HIV.

Inclusion Criteria

Willing and able to participate and comply with all study requirements

Evaluable disease (measurable and non-measurable)

I am fully active or can carry out light work.

Exclusion Criteria

I have had pneumonitis or lung disease affecting the tissue and space around the air sacs.

I am HIV positive.

I haven't had a stroke or brain blood vessel issue in the last 6 months.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Evaluate the safety and pharmacokinetics of OP-1250 in combination with ribociclib, alpelisib, or everolimus to determine the RP2D

28 days

Visits every 28 days

Dose Expansion

Further evaluate the safety and pharmacokinetics of OP-1250 at the RP2D and provide an exploratory estimate of anti-tumor activity

Up to 1 year

Visits every 28 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 35 days

Treatment Details

Interventions

• Alpelisib (PI3K Inhibitor)
• OP-1250 (Other)
• Ribociclib (CDK4/6 Inhibitor)

Trial Overview The study tests OP-1250 combined with either ribociclib (Treatment Group 1) or alpelisib (Treatment Group 2). It's an open-label Phase 1b trial meaning both researchers and participants know which treatment is given. The goal is to assess safety and effectiveness of these combinations in treating breast cancer.

Participant Groups

Group I: OP-1250 with Ribociclib Experimental Treatment 2 Interventions

Treatment Group 1: OP-1250 in combination with ribociclib (KISQALI®, Novartis Pharmaceuticals Corporation).

Group II: OP-1250 with Everolimus Experimental Treatment 2 Interventions

Treatment Group 3: OP-1250 in combination with everolimus

Group III: OP-1250 with Alpelisib Experimental Treatment 2 Interventions

Treatment Group 2: OP-1250 in combination with alpelisib (PIQRAY®, Novartis Pharmaceuticals Corporation)

Who Is Running the Clinical Trial?

Olema Pharmaceuticals, Inc.

Lead Sponsor

Trials

5

Recruited

970+

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

Alpelisib (PIQRAY®) is the first PI3K inhibitor approved for treating hormone receptor-positive metastatic breast cancer with PIK3CA mutations, showing promising clinical results that support its use in overcoming endocrine resistance.

The review highlights the pharmacodynamic and pharmacokinetic properties of alpelisib, along with safety and efficacy data from the Phase III SOLAR-1 trial, which led to its FDA approval, indicating its potential as a tailored treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alpelisib in the treatment of metastatic HR+ breast cancer with PIK3CA mutations. Mavratzas, A., Marmé, F.[2021]

Ribociclib, a CDK 4/6 inhibitor, significantly improves median progression-free survival (PFS) in women with HR+/HER2- metastatic breast cancer when used in combination with endocrine therapy, with PFS ranging from 8 to 13 months across three phase III trials.

The treatment is well tolerated, particularly in elderly patients, and while it has some dose-limiting toxicities like neutropenia and QTc prolongation, it maintains health-related quality of life and reduces pain scores.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ribociclib in HR+/HER2- Advanced or Metastatic Breast Cancer Patients. Rascon, K., Flajc, G., De Angelis, C., et al.[2020]

In the MONALEESA-3 trial, the addition of ribociclib to fulvestrant significantly improved median progression-free survival (PFS) from 12.8 months to 20.5 months in patients with hormone receptor-positive, HER2-negative advanced breast cancer, indicating its efficacy as a treatment option.

The SANDPIPER trial showed that taselisib combined with fulvestrant extended PFS in patients with PIK3CA mutations, but it also resulted in a higher rate of severe adverse events (32% vs 9%), highlighting the need to balance efficacy with safety in treatment decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ASCO 2018 highlights: metastatic breast cancer. Rinnerthaler, G., Gampenrieder, SP., Greil, R.[2020]

Alpelisib (Piqray™) is an oral PI3K inhibitor specifically targeting PI3Kα, showing efficacy in treating hormone receptor-positive, HER2-negative breast cancer in patients with a PIK3CA mutation.

The drug has been approved in the USA for use in combination with fulvestrant, marking a significant milestone in its development for breast cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alpelisib: First Global Approval. Markham, A.[2020]

In a study of 554 Italian patients with hormone receptor-positive, HER2-negative advanced breast cancer, ribociclib combined with letrozole showed a clinical benefit rate of 71.7% and a median time to progression of 26.7 months, indicating effective treatment outcomes.

The treatment was associated with manageable safety profiles, with 98.9% of patients experiencing all-grade adverse events, primarily neutropenia, but health-related quality of life scores remained stable during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Ribociclib in Combination with Letrozole in Patients with HR+, HER2- Advanced Breast Cancer: Results from the Italian Subpopulation of Phase 3b CompLEEment-1 Study. De Laurentiis, M., Caputo, R., Mazza, M., et al.[2022]

The study established the recommended phase 2 doses (RP2D) for alpelisib (350 mg) and buparlisib (100 mg) when combined with tamoxifen and goserelin in premenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer, showing that both combinations were well-tolerated.

Patients treated with alpelisib experienced a longer progression-free survival of 25.2 months compared to 20.6 months for those on buparlisib, suggesting that alpelisib may be a more effective option for this patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase Ib Study of Alpelisib or Buparlisib Combined with Tamoxifen Plus Goserelin in Premenopausal Women with HR-Positive HER2-Negative Advanced Breast Cancer. Lu, YS., Lee, KS., Chao, TY., et al.[2021]

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 a phase Ib study involving 26 patients with metastatic ER+ breast cancer, the combination of alpelisib and letrozole was found to be safe, with a maximum-tolerated dose of 300 mg/d and manageable side effects like hyperglycemia and fatigue.

The treatment showed a clinical benefit rate of 35%, particularly benefiting patients with PIK3CA mutations, where 44% experienced a lack of disease progression for at least 6 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase Ib Study of Alpelisib (BYL719), a PI3Kα-Specific Inhibitor, with Letrozole in ER+/HER2- Metastatic Breast Cancer. Mayer, IA., Abramson, VG., Formisano, L., et al.[2022]

References

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

Alpelisib in the treatment of metastatic HR+ breast cancer with PIK3CA mutations. [2021]

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

Ribociclib in HR+/HER2- Advanced or Metastatic Breast Cancer Patients. [2020]

3. Austria pubmed.ncbi.nlm.nih.gov

ASCO 2018 highlights: metastatic breast cancer. [2020]

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

Alpelisib: First Global Approval. [2020]

5. France pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Ribociclib in Combination with Letrozole in Patients with HR+, HER2- Advanced Breast Cancer: Results from the Italian Subpopulation of Phase 3b CompLEEment-1 Study. [2022]

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

A Phase Ib Study of Alpelisib or Buparlisib Combined with Tamoxifen Plus Goserelin in Premenopausal Women with HR-Positive HER2-Negative Advanced Breast Cancer. [2021]

7. Switzerland 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. [2023]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Health-related quality of life of postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer treated with ribociclib + letrozole: results from MONALEESA-2. [2022]

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

A Phase Ib Study of Alpelisib (BYL719), a PI3Kα-Specific Inhibitor, with Letrozole in ER+/HER2- Metastatic Breast Cancer. [2022]