Palbociclib for Brain Metastasis

Recruiting at 1 trial location

Overseen By Priscilla Brastianos, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Massachusetts General Hospital

Must not be taking: CYP3A inhibitors, CYP3A inducers, QT prolonging drugs

Disqualifiers: HIV, Uncontrolled illness, Pregnancy, others

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

Prior Safety Data This treatment has passed at least one previous human trial

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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: As long as no intolerable side effects or disease progression

45 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness and safety of palbociclib (also known as Ibrance), alone or combined with pembrolizumab, for treating cancer that has spread to the brain or central nervous system (CNS). The study aims to determine how well these drugs slow or stop the growth of these cancer metastases. Participants may qualify if they have a solid tumor or breast cancer with measurable disease in the CNS and have experienced progression after previous treatments. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial requires that you do not take medications that are moderate or strong inhibitors or inducers of CYP3A isoenzymes, as these can interact with the study drugs. You should consult with your doctor about your current medications to see if they fall into this category.

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

Research has shown that palbociclib is generally well-tolerated by patients. In one study, 82.2% of patients managed their disease effectively with palbociclib, and it also showed promise in controlling cancer that has spread to the brain. This indicates the drug can be effective with manageable side effects.

When combined with pembrolizumab, earlier findings suggest palbociclib may help treat cancer in the brain. A report noted that most patients experienced benefits without severe side effects, indicating the combination is safe.

Overall, both palbociclib alone and with pembrolizumab have been shown to be safe options, with the combination offering additional benefits for some patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about palbociclib because it offers a novel approach to treating brain metastasis by specifically targeting a different aspect of cancer cell growth. Unlike traditional treatments like surgery, radiation, or chemotherapy, which aim to remove or kill cancer cells directly, palbociclib works as a CDK4/6 inhibitor. This means it disrupts the cancer cell cycle, preventing the cells from dividing and growing. Additionally, in one experimental arm, palbociclib is combined with pembrolizumab, an immunotherapy drug. This combination could potentially enhance the body's immune response against cancer cells, offering a two-pronged attack that is different from any existing standard of care.

What evidence suggests that this trial's treatments could be effective for brain metastasis?

Research has shown that palbociclib may help treat cancer that has spread to the brain by targeting specific pathways that aid cancer growth. Studies found that patients treated with palbociclib lived for an average of 6.4 months and experienced cancer progression after about 9 weeks. This suggests palbociclib might temporarily slow the spread of brain cancer. In this trial, participants in Cohort 1 will receive palbociclib alone.

Participants in Cohort 2 will receive a combination of palbociclib and pembrolizumab. Early results for this combination are encouraging. Some patients with breast cancer that spread to the brain experienced significant tumor shrinkage, with 13% having no detectable cancer and others showing partial improvement. This combination might help the body fight cancer more effectively than palbociclib alone. ^{1 3 6 7 8}

Who Is on the Research Team?

Priscilla K. Brastianos

Principal Investigator

Massachusetts General Hospital

Are You a Good Fit for This Trial?

This trial is for adults over 18 with recurrent brain metastases from any solid tumor. They must have measurable disease in the CNS, stable corticosteroids use, and normal organ/marrow function. Excluded are those on other investigational drugs, with uncontrolled illnesses, pregnant/breastfeeding women, prior CDK4/6 inhibitor treatment, recent chemotherapy/immunotherapy/radiotherapy or taking drugs affecting CYP3A enzymes.

Inclusion Criteria

I have a brain lesion that is at least 10 mm big.

My cancer diagnosis was confirmed through tissue or cell analysis.

I can care for myself but may not be able to do active work.

Exclusion Criteria

I have been treated with a CDK4/6 inhibitor before.

Pregnancy or breastfeeding

I have stable levels of body salts and minerals.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive palbociclib daily for 21 days per 28-day cycle in Cohort 1, and palbociclib with pembrolizumab every 21 days in Cohort 2

As long as no intolerable side effects or disease progression

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 2 years

What Are the Treatments Tested in This Trial?

Interventions

• Palbociclib

Trial Overview

The study tests palbociclib as a potential treatment for progressive brain metastases. It's supported by Pfizer and includes participants who've shown alterations in the CDK pathway. The drug's effectiveness will be measured against specific criteria for CNS lesion progression.

How Is the Trial Designed?

Group I: Cohort 2 (Palbociclib in Combination with Pembrolizumab) Experimental Treatment 2 Interventions

Cohort 2 involves screening for eligibility, study treatment and study visits, and follow up. Participants in Cohort 2 will receive study drugs palbociclib and pembrolizumab. Palbociclib is taken orally once per day for 21 days (Day 1-21) of each 28-day cycle. Pembrolizumab will be administered as an intravenous (IV) infusion once every 21 days. Participants may receive study drugs as long as they do not meet the criteria for ending treatment (no intolerable side effects and disease is not progressing), and will be followed for up to 2 years after they stop study treatment. Up to 15 participants will be enrolled in Cohort 2.

Group II: Cohort 1 (Palbociclib) Experimental Treatment 1 Intervention

This arm involves screening for eligibility, study treatment and study visits, and follow up. Cohort 1 participants will receive palbociclib daily at a pre-determined dose for 21 days (Day 1-21) per 28-day cycle. Palbociclib is taken orally. Participants may receive study drug as long as they do not meet the criteria for ending treatment (no intolerable side effects and disease is not progressing). Participants will be followed for up to 2 years after their treatment with the study drug ends. Up to 30 participants will be enrolled in Cohort 1.

Palbociclib is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Ibrance for:

• HR-positive, HER2-negative advanced or metastatic breast cancer

Approved in European Union as Ibrance for:

• HR-positive, HER2-negative locally advanced or metastatic breast cancer

Approved in Canada as Ibrance for:

• HR-positive, HER2-negative advanced or metastatic breast cancer

Approved in Japan as Ibrance for:

• HR-positive, HER2-negative advanced or recurrent breast cancer

Who Is Running the Clinical Trial?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Pfizer

Industry Sponsor

Trials

4,712

Recruited

50,980,000+

Known For

Vaccine Innovations

Top Products

Viagra, Zoloft, Lipitor, Prevnar 13

Albert Bourla

Pfizer

Chief Executive Officer since 2019

PhD in Biotechnology of Reproduction, Aristotle University of Thessaloniki

Patrizia Cavazzoni

Pfizer

Chief Medical Officer

MD from McGill University

Published Research Related to This Trial

In a real-world study of 54 patients with advanced non-squamous non-small cell lung cancer, the combination of carboplatin, pemetrexed, and pembrolizumab showed a higher disease control rate (86.7%) compared to carboplatin and pemetrexed alone (54%).

Patients with brain metastases treated with the combination therapy had a significantly lower progression rate (33.3%) compared to those receiving only carboplatin and pemetrexed (91.7%), indicating that this regimen may be particularly effective for this challenging patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A tertiary care cancer center experience with carboplatin and pemetrexed in combination with pembrolizumab in comparison with carboplatin and pemetrexed alone in non-squamous non-small cell lung cancer. Afzal, MZ., Dragnev, K., Shirai, K.[2023]

In a study of 191 patients with metastatic breast cancer receiving palbociclib, the median progression-free survival was 22.8 months for first-line treatment, indicating significant efficacy of the drug in delaying disease progression.

While 47% of patients experienced severe neutropenia, the overall survival rate at 24 months was 74.2% for first-line treatment, suggesting that palbociclib is effective but requires monitoring for potential adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A real-world study of the first use of palbociclib for the treatment of advanced breast cancer within the UK National Health Service as part of the novel Ibrance® Patient Program. Palmieri, C., Musson, A., Harper-Wynne, C., et al.[2023]

In a phase II study involving 12 patients with HER2+ metastatic breast cancer and brain metastases, palbociclib combined with trastuzumab showed no significant responses, with the best outcome being stable disease in 6 patients and a median progression-free survival of only 2.2 months.

The study found that patients with stable or responding systemic disease had lower circulating tumor DNA (ctDNA) variant allele fractions and fewer alterations compared to a larger cohort, suggesting that ctDNA levels may correlate with disease progression in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase II Single-arm Study of Palbociclib in Patients With HER2-positive Breast Cancer With Brain Metastases and Analysis of ctDNA in Patients With Active Brain Metastases. Shah, AN., Santa-Maria, CA., Mukhija, D., et al.[2023]

Palbociclib, when combined with endocrine therapy, shows a promising clinical response in patients with hormone receptor-positive breast cancer that has metastasized to the brain, despite the lack of prior phase 3 trial data for this specific group.

This combination treatment offers a potential new management strategy for a patient population that typically has a poor prognosis, highlighting the need for further research in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Substantial Response from Adding Palbociclib to Endocrine Therapy in Brain Metastasis from Hormone Receptor-Positive, HER2-Negative Breast Cancer: Case Reports. Abusanad, A., Al Hashem, H.[2021]

In a study of 37 non-small-cell lung cancer patients with brain metastases, concurrent treatment with PD-1 pathway inhibitors and stereotactic radiosurgery (SRS) resulted in significantly improved overall survival (87.3% at 1 year) compared to those receiving SRS before or after PD-1 therapy.

The combination therapy also showed favorable local control of brain lesions, with a 1-year local control rate of 100% for lesions treated concurrently with PD-1 inhibitors, indicating that this approach is both effective and well tolerated, with no severe toxicities reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved Overall Survival and Locoregional Disease Control With Concurrent PD-1 Pathway Inhibitors and Stereotactic Radiosurgery for Lung Cancer Patients With Brain Metastases. Schapira, E., Hubbeling, H., Yeap, BY., et al.[2021]

In a phase 2 trial involving 57 patients with untreated and recurrent brain metastases, pembrolizumab showed an intracranial benefit rate of 42.1%, indicating its potential effectiveness in treating this challenging condition.

The median overall survival for patients receiving pembrolizumab was 8.0 months, with some patients experiencing survival beyond 2 years, although over half of the participants reported grade-3 or higher adverse events, highlighting the need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in brain metastases of diverse histologies: phase 2 trial results. Brastianos, PK., Kim, AE., Giobbie-Hurder, A., et al.[2023]

The interim analysis of a basket trial shows that the CDK inhibitor palbociclib is effective in treating patients with progressive brain metastases that have CDK alterations, meeting its primary endpoint.

This study highlights the importance of molecular testing of archival brain metastasis tissue to guide the selection of targeted therapies that can penetrate the central nervous system.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Palbociclib demonstrates intracranial activity in progressive brain metastases harboring cyclin-dependent kinase pathway alterations. Brastianos, PK., Kim, AE., Wang, N., et al.[2023]

Pazopanib significantly reduced the size of brain metastases in breast cancer models, showing a 73% decline in large metastases and a 39% decline in micrometastases, indicating its efficacy in preventing brain metastasis formation.

The drug acts directly on tumor cells by inhibiting B-Raf activation, which is crucial for cancer cell proliferation, suggesting a new mechanism of action for pazopanib beyond its known antiangiogenic effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pazopanib reveals a role for tumor cell B-Raf in the prevention of HER2+ breast cancer brain metastasis. Gril, B., Palmieri, D., Qian, Y., et al.[2022]

Citations

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pmc.ncbi.nlm.nih.gov

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Combination of Palbociclib and Endocrine Therapy in ...

The disease control rate and the intracranial disease control rate were 82.2% and 50%, respectively. A longer progression-free survival was ...

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advances.massgeneral.org

advances.massgeneral.org/oncology/journal.aspx?id=2303

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Palbociclib demonstrates intracranial activity in progressive brain metastases harboring cyclin-dependent kinase pathway alterations.

4.

sciencedirect.com

sciencedirect.com/science/article/pii/S0960977625004655

metastatic breast cancer: A Flatiron Health database analysis

In the current study, approximately 15 % of patients treated with palbociclib had a reduced starting dose (100/75 mg/day); per protocols, this did not occur in ...

5.

academic.oup.com

academic.oup.com/oncolo/article/30/8/oyae274/7825842

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Analysis of SEER-Medicare data reported worse median overall survival (OS) among patients with HR+/HER2− MBC brain metastasis (9.4 months) ...

6.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC9553912/

Real-world study of overall survival with palbociclib plus ...

Progression-free survival (95% CI) is 19.3 (17.5–20.7) versus 13.9 (12.5–15.2) months, respectively (hazard ratio, 0.70 [95% CI, 0.62–0.78]; P < ...

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clinicaltrials.gov

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The purpose of this study is to see if the study drug is effective in patients with brain metastasis, who have HER2-positive breast cancer. Detailed Description.

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Palbociclib in Hormone-Receptor–Positive Advanced ...

At the time of the interim analysis, data on overall survival were immature, with a total of 28 deaths: 19 patients (5.5%) in the palbociclib– ...