Stereotactic Radiosurgery + Immunotherapy for Meningioma

Overseen By Neuro-Oncology New Patient Coordinator

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Nancy Ann Oberheim Bush, MD

Must not be taking: Anti-PD-1, Anti-PD-L1

Disqualifiers: Pregnancy, Brainstem tumors, Metastasis, 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

Compensation: Varies

Number of Visits: 14

Duration: 6 weeks per cycle

37 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment combination for individuals whose meningioma, a type of brain tumor, has returned after surgery and radiation. It combines stereotactic radiosurgery, a precise form of radiation, with pembrolizumab (also known as KEYTRUDA or MK-3475), an immune-boosting drug that helps the body detect and fight cancer cells. The researchers aim to determine if this combination can prevent the tumor from growing again. Individuals with recurrent meningioma who have previously undergone surgery and radiation might be suitable for this trial. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important medical advancements.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you must not have had certain treatments like systemic immunosuppressive drugs within 3 months before starting the trial, and you should not be on another clinical trial for 4 weeks before joining this one.

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

Research has shown that combining pembrolizumab with stereotactic radiosurgery may help treat recurring meningioma. Stereotactic radiosurgery, a precise method targeting tumors with radiation, has been safely used for brain tumors. However, it can sometimes cause swelling around the tumor, which might require medical care.

Pembrolizumab is approved for treating other cancers, such as skin and lung cancer, and most people tolerate it well. Some may experience side effects like tiredness, skin rash, or mild digestive issues. Serious side effects are less common but can occur.

Both treatments have been studied separately, and researchers have confidence in their safety. However, using them together is new, so it's important to consider the benefits and risks. This trial aims to learn more about the safety and effectiveness of this combination for meningioma. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about pembrolizumab combined with stereotactic radiosurgery for treating recurrent meningioma because this approach targets the immune system in a unique way. Unlike standard treatments, which often involve surgery and conventional radiation, pembrolizumab is an immunotherapy that empowers the body's immune system to fight the tumor by blocking the PD-1 pathway, potentially enhancing the effectiveness of stereotactic radiosurgery. This combination could offer a more precise and potentially long-lasting response compared to traditional methods.

What evidence suggests that stereotactic radiosurgery and pembrolizumab might be effective for recurrent meningioma?

Research has shown that stereotactic radiosurgery effectively treats meningiomas, a type of brain tumor. This method uses precise radiation beams to target the tumor without surgery. Studies have found it promising for managing both non-cancerous and recurrent brain tumors.

In this trial, participants with recurrent meningioma will receive stereotactic radiosurgery combined with pembrolizumab. One study found that 48% of patients with recurrent meningioma did not experience tumor growth for six months with pembrolizumab, suggesting it may help slow tumor growth. Pembrolizumab aids the immune system in identifying and attacking cancer cells. Using these treatments together in this trial might enhance their effectiveness against recurrent meningioma. ^{1 6 7 8 9}

Who Is on the Research Team?

Nancy Oberheim Bush, MD, PhD

Principal Investigator

University of California, San Francisco

Steve Braunstein, MD

Principal Investigator

University of California, San Francisco

Are You a Good Fit for This Trial?

Adults with recurrent grade II or III meningioma, previously treated with surgery and radiotherapy. Participants must be in good health otherwise, not pregnant or breastfeeding, willing to use contraception, and have no other active cancers or severe psychiatric issues. They should not have had recent immunosuppressive treatments or live vaccines.

Inclusion Criteria

It's been over 28 days since my surgery and I've fully recovered without any ongoing health issues.

I agree to use birth control and not donate sperm for 120 days after my last treatment dose.

You had a stereotactic biopsy more than 7 days ago.

Exclusion Criteria

I am not on high-dose steroids or other drugs that weaken my immune system.

I have had pneumonitis treated with steroids or currently have it.

I have not had active treatment for another cancer, except for certain skin cancers or localized cancers, in the last 3 years.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive stereotactic radiosurgery and pembrolizumab. Pembrolizumab is administered intravenously on days 1 and 22, with cycles repeating every 6 weeks.

6 weeks per cycle

2 visits (in-person) per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up occurs at 30 days post-treatment, every 12 weeks for 2 years, and then every 6 months for up to 5 years.

Up to 5 years

Regular visits every 12 weeks, then every 6 months

Extension

Participants may receive up to 17 additional cycles of pembrolizumab if there is progressive disease after initial treatment.

Up to 17 cycles

What Are the Treatments Tested in This Trial?

Interventions

• Pembrolizumab
• Stereotactic Radiosurgery

Trial Overview The trial is testing the combination of stereotactic radiosurgery (precise radiation therapy) and pembrolizumab (an immune system-boosting drug) to see if it can improve survival without cancer growth in patients with recurring brain tumors called meningiomas.

How Is the Trial Designed?

Group I: Treatment for recurrent meningioma (pembrolizumab, stereotactic radiosurgery) Experimental Treatment 2 Interventions

Participants with recurrent grade II or III meningioma will receive stereotactic radiosurgery. in conjunction with pembrolizumab 200mg IV infusion on day 1 (to -1) of radiation and then every 3 weeks. Participants may be eligible for up to 17 additional cycles of pembrolizumab depending on disease status after completion of first course.

Pembrolizumab is already approved in United States, European Union, United Kingdom for the following indications:

Approved in United States as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in European Union as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in United Kingdom as KEYTRUDA for:

• Untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1

Who Is Running the Clinical Trial?

Nancy Ann Oberheim Bush, MD

Lead Sponsor

Trials

1

Recruited

40+

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

Published Research Related to This Trial

In a study of 241 patients with skull base meningiomas treated with LINAC-based stereotactic radiosurgery (SRS), the long-term tumor control rate was 91.2% after a median follow-up of 102 months, indicating SRS is an effective treatment option.

The study found that previous surgery increased the risk of tumor progression, while adverse effects were linked to the maximum radiation dose to the brainstem and the tumor's location in the cerebellopontine angle.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term Experience of LINAC Single-Dose Radiosurgery for Skull Base Meningiomas: A Retrospective Single-Center Study of 241 Cases. Ortiz García, IM., Rodríguez Valero, P., Jorques Infante, AM., et al.[2023]

In a study of 220 skull base meningiomas treated with different radiation techniques, there was no significant difference in tumor control or clinical response among stereotactic radiosurgery (SRS), hypofractionated stereotactic radiotherapy (hFSRT), and fractionated stereotactic radiotherapy (FSRT).

The median follow-up was 32 months, and the results suggest that treatment can be tailored based on tumor size and location, as all methods achieved high rates of radiographic control (91-95%) and clinical response (89-100%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparative study of stereotactic radiosurgery, hypofractionated, and fractionated stereotactic radiotherapy in the treatment of skull base meningioma. Han, J., Girvigian, MR., Chen, JC., et al.[2022]

Stereotactic radiosurgery (SRS) demonstrated a high five-year tumor control probability of 92.7% for benign meningiomas, indicating it is a safe and effective treatment option for these tumors.

Fractionated stereotactic radiation therapy (FSRT) also proved to be effective, particularly for larger tumors or those near critical structures, with similar three-year tumor control rates compared to SRS, suggesting it is a viable alternative for patients who cannot undergo SRS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single dose versus fractionated stereotactic radiotherapy for meningiomas. Lo, SS., Cho, KH., Hall, WA., et al.[2022]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating advanced melanoma, showing an overall response rate of 24% in a trial of 89 patients, with 86% of responses lasting at least 6 months.

While there are potential immune-mediated side effects, the benefits of prolonged tumor response durations were deemed to outweigh these risks, marking an improvement over existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. Chuk, MK., Chang, JT., Theoret, MR., et al.[2021]

Pembrolizumab, an immune checkpoint inhibitor, can cause pneumonitis in 1%-5% of patients, and this case report highlights an atypical presentation of this side effect in a patient with metastatic squamous cell carcinoma.

The patient was successfully treated with steroid therapy after ruling out other potential causes, leading to complete resolution of the pneumonitis, emphasizing the importance of recognizing and managing atypical cases of checkpoint inhibitor-pneumonitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. Jeon, WJ., Nguyen, J., Castillo, DR., et al.[2023]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating unresectable or metastatic melanoma based on two clinical trials involving 1,374 patients, showing significant improvements in overall survival compared to ipilimumab, with hazard ratios indicating a reduced risk of death.

Patients receiving pembrolizumab also experienced significant improvements in progression-free survival, although some immune-mediated adverse reactions like hypothyroidism and pneumonitis were noted, highlighting the importance of monitoring for side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma. Barone, A., Hazarika, M., Theoret, MR., et al.[2022]

Stereotactic radiosurgery (SRS) for World Health Organization grade 2 meningiomas showed promising outcomes, with a 3-year progression-free survival (PFS) of 63.1% in a good-prognostic group, indicating its efficacy in carefully selected patients.

Factors such as age over 50 years and multiple prior surgeries were associated with reduced PFS, suggesting that patient selection based on these criteria can optimize treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of WHO Grade 2 Meningiomas With Stereotactic Radiosurgery: Identification of an Optimal Group for SRS Using RPA. Kowalchuk, RO., Shepard, MJ., Sheehan, K., et al.[2021]

Gross-total resection is the preferred treatment for meningiomas, but radiation therapy is recommended for inoperable or incompletely resected grade 1 tumors, and for all grade 2 or 3 lesions post-surgery.

Both fractionated stereotactic radiotherapy and stereotactic radiosurgery provide excellent tumor control rates of over 90% for benign meningiomas, with low toxicity, making them effective options for treating these tumors, especially those near critical structures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Stereotactic radiotherapy for intracranial meningioma]. Delannes, M., Maire, JP., Sabatier, J., et al.[2018]

Stereotactic radiosurgery has emerged as a viable first-line treatment for select meningiomas, especially small tumors in difficult or high-risk locations, providing local control rates similar to those achieved with traditional surgery.

Techniques such as Gamma knife and Linear Accelerator-based radiosurgery, as well as brachytherapy with radioactive seeds, are highlighted as effective stereotactic methods for managing meningiomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stereotactic Therapies for Meningiomas. Tuleasca, C., Ruess, D., Ruge, M., et al.[2023]

In a study of 25 patients with melanoma brain metastases treated with pembrolizumab (PB) combined with stereotactic radiosurgery (SRS), the treatment was well tolerated, with only a 6.8% incidence of radiation necrosis observed.

The combination therapy achieved local control in 80% of brain metastases and resulted in a median overall survival of 15.3 months, suggesting a promising efficacy for this treatment approach in patients with metastatic melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tolerance and outcomes of stereotactic radiosurgery combined with anti-programmed cell death-1 (pembrolizumab) for melanoma brain metastases. Nardin, C., Mateus, C., Texier, M., et al.[2019]

In a study of 35 patients with malignant meningiomas treated with stereotactic radiosurgery (SRS) using CyberKnife, local control rates were high, with 97% at 12 months for atypical meningiomas, indicating that SRS is an effective treatment option.

The study also found that age was a risk factor for local failure, suggesting that younger patients may have better outcomes with SRS for malignant meningiomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Image-Guided Robotic Radiosurgery for Treatment of Recurrent Grade II and III Meningiomas. A Single-Center Study. Acker, G., Meinert, F., Conti, A., et al.[2020]

In a study of 50 patients with meningiomas treated with cobalt-60 gamma knife stereotactic radiosurgery, the 2-year tumor control rate was an impressive 96%, indicating high efficacy of this treatment.

Stereotactic radiosurgery was found to be a safe and effective option for patients with symptomatic meningiomas, especially for those who were not suitable candidates for surgical resection due to age or medical conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gamma knife radiosurgery of meningiomas. Kondziolka, D., Lunsford, LD., Coffey, RJ., et al.[2018]

A study of 5,406 meningioma patients showed that stereotactic radiosurgery (SRS) is more commonly used for grade 1 tumors, while external beam radiation therapy (EBRT) is primarily used for grade 3 tumors, indicating a tailored approach based on tumor grade.

Survival rates were higher for patients treated with SRS compared to those receiving EBRT, with 5-year survival rates of 89.2% for SRS versus 72.6% for EBRT, although the difference was not statistically significant after adjusting for other factors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trends in the use of radiation for meningioma across the United States. Matani, H., Abel, S., Yu, A., et al.[2022]

Pembrolizumab, a PD-1 inhibitor used in cancer treatment, can lead to rare but serious immune-related adverse events, including type 1 diabetes mellitus, occurring in about 0.2% of cases.

A review of 42 cases revealed that patients may develop diabetic ketoacidosis during treatment, highlighting the need for blood glucose monitoring and awareness of this potential side effect among clinicians.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. Clotman, K., Janssens, K., Specenier, P., et al.[2022]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39429970/

A phase II, open-label, single-arm trial of pembrolizumab ... Our results showed that pembrolizumab failed to improve PFS-6 in patients with aggressive meningioma or anaplastic SFT.

2. nature.com nature.com/articles/s41467-022-29052-7

Phase 2 study of pembrolizumab in patients with recurrent ... Our study has met its primary endpoint and achieved a PFS-6 rate of 0.48 (90% exact CI: 0.31–0.66) and a median PFS of 7.6 months (90% CI: 3.4– ...

3. academic.oup.com academic.oup.com/noa/article/6/1/vdae154/7758765

A phase II, open-label, single-arm trial of pembrolizumab for ... The second study on pembrolizumab reported a PFS-6 rate of 48%, hinting at a potential utility in this setting. Herein, we present the results ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/35289329/

Phase 2 study of pembrolizumab in patients with recurrent and ... Our study has met its primary endpoint and achieved a PFS-6 rate of 0.48 (90% exact CI: 0.31-0.66) and a median PFS of 7.6 months (90% CI: 3.4- ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT04659811

Study Details | NCT04659811 | Stereotactic Radiosurgery ... This phase II trial studies the effect of stereotactic radiosurgery and pembrolizumab in treating patients with meningioma that has come back (recurrent).

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10526192/

Novel Advances in Treatment of Meningiomas: Prognostic and ... Meningiomas are considered benign lesions and are frequently linked to a lower quality of life. Total surgical resection is the gold standard treatment.

7. mdpi.com mdpi.com/2072-6694/17/17/2750

Stereotactic Radiosurgery for Recurrent Meningioma Conclusions: SRS may represent a reasonable salvage option for carefully selected patients with recurrent meningioma, particularly following surgery alone.

8. advancesradonc.org advancesradonc.org/article/S2452-1094(22)00204-4/fulltext

Efficacy and Safety of Primary Stereotactic Radiosurgery ... Primary stereotactic radiosurgery for intraventricular meningiomas remains controversial owing to the potential for life-threatening peritumoral edema.

9. academic.oup.com academic.oup.com/noa/article/5/Supplement_1/i67/7190032

Radiotherapy and radiosurgery for meningiomas Neurological symptom improvement following radiotherapy has been reported in 23–89% of cases,56–58 although surgery offers faster and more ...