Alpelisib + Pembrolizumab for Metastatic Breast Cancer

Overseen By Ecaterina Dumbrava, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Corticosteroids, Chemotherapy

Disqualifiers: Autoimmune disease, Active infection, Diabetes, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

50 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two drugs, alpelisib (a PI3K inhibitor) and pembrolizumab (an immunotherapy), to determine the optimal dose for treating metastatic breast cancer or melanoma. It targets patients whose cancer has spread and who have not responded to other treatments. Participants should have advanced melanoma or triple-negative breast cancer (TNBC) with brain metastases. The trial evaluates the effectiveness of this drug combination and potential side effects. 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 this new combination therapy.

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 mentions that the use of certain prohibited medications is not allowed during the study, so it's best to discuss your current medications with the study team.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that the combination of alpelisib and pembrolizumab has been studied for safety. Past research generally considers alpelisib safe. However, pembrolizumab can cause serious side effects, such as infections and heart problems. Previous studies found that pembrolizumab, when combined with other treatments, was well-tolerated by some patients. This suggests the combination might be safe, but awareness of potential risks, especially those related to pembrolizumab, is important. Prospective participants should consult a doctor to better understand the safety aspects. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about the combination of Alpelisib and Pembrolizumab for metastatic breast cancer because it offers a unique approach compared to standard treatments like chemotherapy and hormone therapy. Alpelisib specifically targets the PI3K pathway, which is often overactive in cancer cells, helping to slow down their growth. Meanwhile, Pembrolizumab is an immunotherapy that boosts the body's immune response against cancer cells. This combination aims to attack the cancer from two fronts: directly inhibiting cancer cell growth and empowering the immune system to fight the cancer more effectively.

What evidence suggests that this treatment might be an effective treatment for metastatic breast cancer?

Studies have shown that pembrolizumab, when combined with other treatments, can improve outcomes in breast cancer, including advanced forms. Research suggests that combining alpelisib with pembrolizumab, as studied in this trial, might be safe and could help treat advanced breast cancer. One report indicated that patients taking pembrolizumab experienced progression-free survival, meaning their cancer did not worsen, for over 21 months. Real-world data on alpelisib in metastatic breast cancer showed a modest response, with some patients experiencing partial tumor shrinkage. These findings suggest that using these two drugs together could be promising for treating metastatic breast cancer. ^{2 4 6 7 8}

Who Is on the Research Team?

Ecaterina E Dumbrava

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for patients with advanced breast cancer or melanoma. Participants must have a certain type of tumor and be able to take oral medication. They should not have had previous treatments that conflict with the trial drugs.

Inclusion Criteria

Has measurable disease based on the RECIST v1.1

Has a life expectancy of at least 12 weeks

I had a brain MRI within the last 28 days.

Exclusion Criteria

I have a serious illness that is not under control.

I have a history of heart problems.

Has a history of or active autoimmune disease

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Study treatment with alpelisib and pembrolizumab is administered to determine the maximum tolerated dose and recommended Phase II dose

12-16 weeks

Regular outpatient visits

Dose Expansion

Study treatment is administered to further evaluate safety and efficacy at the recommended dose

16-24 weeks

Regular outpatient visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Alpelisib + Pembrolizumab

Trial Overview The study is testing the combination of two drugs, Alpelisib and Pembrolizumab, to determine a safe dosage level for patients with metastatic breast cancer or melanoma.

How Is the Trial Designed?

Group I: Dose Expansion Experimental Treatment 1 Intervention

Study treatment will be administered on an outpatient basis.

Group II: Dose Escalation Experimental Treatment 1 Intervention

Study treatment will be administered on an outpatient basis.

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Published Research Related to This Trial

In patients with hormone receptor-positive metastatic breast cancer, higher levels of specific immune cells (effector memory CD8+ and CD4+ T cells) before treatment were associated with better responses to the combination therapy of palbociclib, pembrolizumab, and letrozole, compared to those receiving only pembrolizumab and letrozole.

The combination therapy also led to significant changes in myeloid cell composition, including increased mature dendritic cells and decreased classical monocytes, which may enhance the immune response against the cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pre-existing effector T-cell levels and augmented myeloid cell composition denote response to CDK4/6 inhibitor palbociclib and pembrolizumab in hormone receptor-positive metastatic breast cancer. Egelston, C., Guo, W., Yost, S., et al.[2021]

In a meta-analysis of 11 clinical trials involving 3713 patients, the overall incidence of fatal adverse events (FAEs) associated with pembrolizumab was found to be 1.2%, indicating a relatively low risk of severe complications from this immune checkpoint inhibitor.

The incidence of FAEs varied significantly by tumor type, with breast cancer patients experiencing a higher risk (3.1%) compared to melanoma patients (0.2%), and the combination of pembrolizumab with chemotherapy resulted in a much higher incidence of FAEs (7.0%) compared to pembrolizumab alone (0.7%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fatal Adverse Events Associated with Pembrolizumab in Cancer Patients: A Meta-Analysis. Sher, AF., Golshani, GM., Wu, S.[2020]

Pembrolizumab, an anti-PD-1 antibody, has been approved for treating unresectable or metastatic melanoma, especially in patients who have progressed after ipilimumab treatment, marking a significant advancement in immuno-oncology.

The drug has also received breakthrough status for treating non-small cell lung cancer (NSCLC) that is EGFR mutation-negative and ALK rearrangement-negative, indicating its broad potential in cancer therapy, with ongoing trials to explore its use in various tumor types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab. Khoja, L., Butler, MO., Kang, SP., et al.[2022]

Combining pembrolizumab with trastuzumab and chemotherapy has been shown to reduce tumor size in patients, indicating enhanced efficacy of the treatment.

This combination therapy can also lead to complete responses in some patients, suggesting a potential for significant improvement in cancer treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab Addition Improves Clinical Response in HER2+ Gastric Cancer. [2022]

In the KEYNOTE-355 trial, the combination of pembrolizumab and chemotherapy significantly improved progression-free and overall survival in patients with advanced triple-negative breast cancer with a PD-L1 combined positive score of at least 10.

Patient-reported outcomes showed no significant differences in quality of life or functioning between the pembrolizumab and placebo groups at week 15, indicating that while pembrolizumab is effective, it does not negatively impact patients' quality of life compared to standard chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Health-Related Quality of Life With Pembrolizumab+Chemotherapy Versus Placebo+Chemotherapy for Advanced Triple-Negative Breast Cancer: KEYNOTE-355. Cescon, DW., Schmid, P., Rugo, HS., et al.[2023]

In a phase Ib/II trial, the combination of the PD-1 inhibitor pembrolizumab with trastuzumab demonstrated clinical benefits for patients with advanced HER2-positive breast cancer who had become resistant to trastuzumab.

The study identified tumor-infiltrating lymphocyte levels as a potential biomarker, which could help predict how well patients might respond to this combined treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role for Immune Therapy in Advanced Breast Cancer. [2019]

A disproportionality analysis of 33,327 reports identified 687 cases of adverse reactions associated with alpelisib, with hyperglycaemia being the most significant adverse event, indicating a strong association with this medication.

The most frequently reported adverse events included hyperglycaemia, rash, and diarrhoea, highlighting the need for monitoring these effects in patients receiving alpelisib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events of alpelisib: A postmarketing study of the World Health Organization pharmacovigilance database. Chen, X., Wei, L., Chi, L., et al.[2022]

In a phase 3 trial involving 847 patients with untreated metastatic triple-negative breast cancer, the addition of pembrolizumab to chemotherapy significantly improved progression-free survival, especially in patients with a PD-L1 combined positive score (CPS) of 10 or more, with a median survival of 9.7 months compared to 5.6 months for placebo.

The safety profile of pembrolizumab-chemotherapy was comparable to placebo-chemotherapy, with similar rates of grade 3-5 treatment-related adverse events (68% vs. 67%), indicating that the combination therapy is both effective and manageable in terms of safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Cortes, J., Cescon, DW., Rugo, HS., et al.[2021]

In a real-life study of 108 patients with advanced non-small cell lung cancer (NSCLC) and a PD-L1 tumor proportion score of ≥50%, pembrolizumab showed a median progression-free survival of 10.1 months, similar to results from the KEYNOTE-024 trial.

The treatment was generally well-tolerated, with only 8% of patients experiencing grade 3 adverse events, and no severe (grade 4 or 5) adverse events reported, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line pembrolizumab for non-small cell lung cancer patients with PD-L1 ≥50% in a multicenter real-life cohort: The PEMBREIZH study. Amrane, K., Geier, M., Corre, R., et al.[2021]

In a phase II study involving 22 patients with BRCA1/2-related metastatic breast cancer, the combination of pembrolizumab and carboplatin showed an overall response rate (ORR) of 43% and a disease control rate (DCR) of 76%, indicating some level of efficacy, particularly in luminal tumors.

Despite the promising results, the study did not meet its primary aim of achieving an ORR of 70%, leading to its termination; however, the safety profile was acceptable with only 22.7% of patients experiencing grade ≥3 adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of pembrolizumab plus carboplatin in BRCA-related metastatic breast cancer (PEMBRACA). Cortesi, L., Venturelli, M., Cortesi, G., et al.[2023]

In a long-term study of 123 patients with advanced nonsquamous NSCLC, the combination of pembrolizumab with pemetrexed-carboplatin significantly improved the objective response rate (58% vs. 33%) and progression-free survival (24.5 months vs. 9.9 months) compared to chemotherapy alone.

Patients who completed 2 years of pembrolizumab treatment had a remarkable 92% survival rate at the data cutoff, indicating a durable clinical benefit, while the safety profile remained manageable with no new safety concerns identified.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Overall Survival From KEYNOTE-021 Cohort G: Pemetrexed and Carboplatin With or Without Pembrolizumab as First-Line Therapy for Advanced Nonsquamous NSCLC. Awad, MM., Gadgeel, SM., Borghaei, H., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7939121/

Case Report: Long-Term Response to Pembrolizumab ... The patients completed six cycles of pembrolizumab, and the PFS was more than 21 months. In conclusion, our study confirmed that antiestrogen ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.1053

Phase I study combining pembrolizumab and aromatase ... Conclusions: The combination of pembrolizumab and AI is well tolerated in patients with HR+ HER2- MBC who were not pre-selected for PD-L1. There ...

3. withpower.com withpower.com/trial/phase-2-leukemia-myeloid-11-2024-d9325

Alpelisib + Pembrolizumab for Metastatic Breast Cancer Research shows that pembrolizumab, when combined with other treatments, has improved outcomes in various types of breast cancer, such as advanced triple- ...

4. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2024-06339

Alpelisib and Pembrolizumab for the Treatment of Patients ... Giving alpelisib in combination with pembrolizumab may be safe, tolerable and/or effective in treating patients with locally advanced, unresectable, or ...

5. frontiersin.org frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.1012391/full

Real world outcomes with alpelisib in metastatic hormone ... 3/27 (11.11%) patients discontinued therapy before response assessment due to grade 3 AEs. ORR was 12.5% (3/24) and these were all PR, no CR was observed.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT06545682

Phase Ib Study of AlpeliSib With PEmbroLizumab in ... To find a recommended dose of the combination of alpelisib and pembrolizumab that can be given to patients with metastatic breast cancer or melanoma.

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

Real world outcomes with alpelisib in metastatic hormone ... The primary endpoint was progression-free survival (PFS) which was achieved with a median of 11.0 months in PIK3CA mutations carriers compared to 5.7 months in ...

8. sciencedirect.com sciencedirect.com/science/article/pii/S0959804921004950

Clinical outcomes of patients with metastatic breast cancer ... The aim of our study is to evaluate the outcomes of patients with metastatic breast cancer (BC) enrolled in Phs1 testing TT, IO and combinations.