Targeted Radiation Therapy for Brain Cancer

(RAPPLE Trial)

Recruiting at 5 trial locations

Overseen By Sandy Chang

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: British Columbia Cancer Agency

Must not be taking: Immunotherapy, Targeted therapy

Disqualifiers: Multiple sclerosis, Epilepsy, 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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: 1-5 days

100 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new radiation treatment for brain cancer that has spread from other parts of the body. Researchers aim to determine if a quicker, one-time treatment, called RAPid SimPLE Targeted Radiation Treatment (RAPPLE), is as effective as the usual method, which requires five sessions. The trial seeks participants with brain metastases who have not received whole-brain radiation in the last three months and whose condition is stable despite steroid use. Participants must also be able to undergo routine imaging and complete a quality of life questionnaire. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to significant advancements in cancer care.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, if you are on immunotherapy, targeted therapy, or hormone therapy, you cannot participate in the trial.

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

Research shows that patients generally tolerate targeted radiation treatment for brain tumors well. Studies comparing one high-dose treatment (8 Gy) with several smaller doses (totaling 20 Gy) found no major differences in patient-reported side effects. This suggests that both radiation treatments are relatively safe for people with brain cancer. While side effects like tiredness or headaches are common with any radiation therapy, the targeted approach aims to minimize these by focusing more precisely on the tumor. As this trial is in the middle stages, earlier research has already demonstrated a reasonable level of safety. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about these treatments for brain metastases because they offer targeted radiation therapy with potentially fewer side effects and more convenience for patients. Unlike traditional whole-brain radiation therapy, which can affect healthy brain tissue and requires multiple sessions, the 8 Gy in 1 Fraction treatment delivers a single, concentrated dose directly to the tumor using volumetric modulated arc therapy. This approach may reduce the treatment time and limit radiation exposure to healthy tissue. Similarly, the 20 Gy in 5 Fractions treatment provides a more focused and precise delivery over five sessions, aiming for effective tumor control while sparing surrounding healthy brain tissue. Both methods could significantly improve patients' quality of life by minimizing adverse effects and shortening treatment duration.

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

This trial will compare a single session of targeted radiation therapy at 8 Gy with the traditional method of 20 Gy given over five sessions. Research has shown that this single-session approach can be just as effective for patients with brain metastases, who often have a poor outlook. Previous studies indicated that the single, higher-dose treatment may offer similar results while being simpler and quicker. Both methods in this trial use a precise type of radiation treatment called Volumetric Modulated Arc Therapy, which targets the tumor while protecting healthy tissue. This could result in fewer hospital visits and possibly fewer side effects. ^{1 2 3 4 6}

Who Is on the Research Team?

Alan Nichol, MD

Principal Investigator

BC Cancer Vancouver

Are You a Good Fit for This Trial?

This trial is for adults with non-blood related cancers that have spread to the brain. Participants should have multiple brain tumors that can be targeted, a life expectancy not suitable for surgery or precise radiotherapy, and some active cancer outside the brain. They must also be able to complete questionnaires, follow up with imaging tests, start treatment within two weeks of joining, and have a performance score indicating they are still somewhat active.

Inclusion Criteria

My doctor thinks I won't live long enough for surgery to help.

My cancer is not related to blood cells.

All my brain tumors can be clearly identified and targeted for treatment.

Exclusion Criteria

Pregnancy

Inability to have a brain MRI

My cancer has spread to the lining of my brain and spinal cord.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either a single treatment of 8 Gy or five treatments of 4 Gy using volumetric modulated arc therapy to brain metastases

1-5 days

1-5 visits (in-person)

Follow-up

Participants are monitored for survival, control of brain disease, adverse events, and quality of life

1 year

What Are the Treatments Tested in This Trial?

Interventions

• RAPid SimPLE Targeted Radiation Treatment

Trial Overview The study is testing if one session of targeted radiation (8 Gy) is as effective as five sessions (20 Gy total) in extending overall survival for patients with poor prognosis due to brain metastases from other cancers. The goal is to determine whether this simpler and quicker treatment approach works just as well.

How Is the Trial Designed?

Group I: 8 Gy in 1 Fraction Volumetric Modulated Arc Therapy to Brain Metastases Experimental Treatment 1 Intervention

A single treatment of 8 Gy will be delivered using volumetric modulated arc therapy on a conventional linear accelerator in a conventional head shell without the use of stereotactic radiosurgery technique.

Group II: 20 Gy in 5 Fractions Volumetric Modulated Arc Therapy to Brain Metastases Active Control 1 Intervention

Five treatments of 4 Gy will be delivered using volumetric modulated arc therapy on a conventional linear accelerator in a conventional head shell without the use of stereotactic radiosurgery technique.

RAPid SimPLE Targeted Radiation Treatment is already approved in European Union, United States for the following indications:

Approved in European Union as RAPid SimPLE Targeted Radiation Treatment for:

• Brain metastases

Approved in United States as RAPid SimPLE Targeted Radiation Treatment for:

• Brain metastases

Who Is Running the Clinical Trial?

British Columbia Cancer Agency

Lead Sponsor

Trials

181

Recruited

95,900+

Varian Medical Systems

Industry Sponsor

Trials

63

Recruited

3,700+

Dow R. Wilson

Varian Medical Systems

Chief Executive Officer since 2012

MBA from Dartmouth's Amos Tuck School of Business, BA from Brigham Young University

Dr. Deepak Khuntia

Varian Medical Systems

Chief Medical Officer since 2020

MD from the University of Cambridge, PhD from the University of Leicester

Published Research Related to This Trial

Stereotactic radiosurgery (SRS) has been shown to improve patient outcomes and reduce toxicity compared to whole-brain radiation therapy (WBRT) for treating multiple brain metastases, based on three decades of research.

Current practices allow for the treatment of patients with 10 or more brain metastases using SRS alone, even with cumulative tumor volumes of up to 25 cm³, reflecting a shift in clinical approach due to advancements in cancer therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Guidelines for Multiple Brain Metastases Radiosurgery. Niranjan, A., Monaco, E., Flickinger, J., et al.[2019]

Fractionated stereotactic radiation therapy (FSRT) based on biological effective dose (BED) demonstrated a high local control rate of 96.3% at 6 months and 94.5% at 12 months for brain metastases from non-small cell lung cancer (NSCLC), indicating its efficacy in managing these tumors.

The treatment showed acceptable toxicity, with only 2% of patients experiencing progressive radiation injury, which improved with hyperbaric oxygen therapy, suggesting that FSRT is a promising option for patients with brain metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical outcomes of biological effective dose-based fractionated stereotactic radiation therapy for metastatic brain tumors from non-small cell lung cancer. Matsuyama, T., Kogo, K., Oya, N.[2022]

A systematic review highlighted the safety concerns and toxicity profiles of combining stereotactic body radiotherapy (SBRT) with targeted therapy or immunotherapy in patients with metastatic cancer, particularly those with oligometastatic disease.

An international consensus among 28 experts provided guidelines on risk mitigation strategies, including recommendations for potential interruptions in therapy and adjustments in radiation dosing, to enhance the safety of this combined treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metastases-directed stereotactic body radiotherapy in combination with targeted therapy or immunotherapy: systematic review and consensus recommendations by the EORTC-ESTRO OligoCare consortium. Kroeze, SGC., Pavic, M., Stellamans, K., et al.[2023]

Concurrent treatment of stereotactic radiotherapy (SRT) with BRAF-inhibitors is associated with high rates of severe toxicity, indicating a need for caution when combining these therapies.

While cranial SRT is generally well tolerated with concurrent therapies, there is a potential risk of increased severe toxicity when SRT is combined with EGFR-targeting tyrosine kinase inhibitors and bevacizumab in extra-cranial treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicity of concurrent stereotactic radiotherapy and targeted therapy or immunotherapy: A systematic review. Kroeze, SG., Fritz, C., Hoyer, M., et al.[2022]

In a study of 173 patients with resected metastatic brain disease, a 3 mm uniform expansion of the stereotactic radiation surgery (SRS) target volume significantly improved coverage of recurrent tumors, potentially enhancing local control rates.

The analysis revealed that the original SRS target volume only overlapped 69.6% of recurrent tumors, but with a 3 mm expansion, this coverage increased to 90%, suggesting that adjusting target volumes could optimize treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Local recurrence patterns after postoperative stereotactic radiation surgery to resected brain metastases: A quantitative analysis to guide target delineation. Gui, C., Moore, J., Grimm, J., et al.[2019]

Targeted therapies have shown promise in improving survival rates for patients with brain metastases, which are the most common type of brain cancer, particularly when combined with stereotactic radiosurgery.

The review highlights the importance of collaboration among different specialists, including neurosurgeons and oncologists, to optimize treatment strategies for brain metastases from various primary cancers like lung, breast, melanoma, and renal cell carcinoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improving Brain Metastases Outcomes Through Therapeutic Synergy Between Stereotactic Radiosurgery and Targeted Cancer Therapies. Rubino, S., Oliver, DE., Tran, ND., et al.[2022]

The review discusses various treatment options for newly diagnosed and recurrent brain metastases, including whole-brain radiotherapy, radiosurgery, and chemotherapy, highlighting the importance of tailoring treatments to specific patient prognostic subgroups.

Emerging therapies, such as new radiosensitizers and cytotoxic agents, are being explored to improve local control and survival rates while managing the risk of late neurotoxicity associated with these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiotherapy and chemotherapy of brain metastases. Soffietti, R., Costanza, A., Laguzzi, E., et al.[2018]

Stereotactic radiosurgery (SRS) alone is more cost-effective than upfront whole brain radiation therapy (WBRT) plus SRS for treating one to three brain oligometastases, with an incremental cost-effectiveness ratio (ICER) of $9917 per quality-adjusted life year (QALY) gained.

Both treatment options resulted in a median survival of 9 months, but SRS alone was favored for preserving neurocognitive function, making it a preferable choice based on current evidence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost-effectiveness Analysis of Stereotactic Radiosurgery Alone Versus Stereotactic Radiosurgery with Upfront Whole Brain Radiation Therapy for Brain Metastases. Kim, H., Rajagopalan, MS., Beriwal, S., et al.[2018]

Five-fraction stereotactic radiotherapy (FSRT) delivering 35 Gy was found to be safe and well-tolerated in 36 patients with brain metastases, with no severe adverse events reported and a radiation necrosis rate of 14.3%.

The treatment resulted in an impressive 1-year local control rate of 83.1% and a median overall survival of 11 months, indicating that FSRT is an effective option for managing brain metastases, whether used as a definitive or adjuvant treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Five-Fraction Stereotactic Radiotherapy for Brain Metastases-A Retrospective Analysis. Layer, JP., Layer, K., Sarria, GR., et al.[2023]

In a study of 28 children treated with stereotactic radiotherapy (SRT) for low grade astrocytomas, 43% experienced imaging changes that could mimic tumor progression, such as increased lesion size and edema, primarily occurring between 9 and 12 months post-treatment.

These treatment-related MRI changes were generally transient and resolved by 15 to 21 months, with most patients maintaining normal or stable neurological function, indicating that such changes can be distinguished from actual tumor progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Magnetic resonance imaging changes after stereotactic radiation therapy for childhood low grade astrocytoma. Bakardjiev, AI., Barnes, PD., Goumnerova, LC., et al.[2010]

Combining metastasis-directed hypofractionated radiation therapy (RT) with systemic therapies can be effective, but specific timing adjustments are necessary to minimize toxicity; for example, BRAF and MEK inhibitors should be suspended a few days before and after RT due to reported toxicities.

Certain therapies like cetuximab and osimertinib are generally safe with RT, but recommendations include suspending them during radiation treatment to reduce potential side effects, highlighting the need for careful management when integrating these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Tolerability of Metastasis-Directed Radiation Therapy in the Era of Evolving Systemic, Immune, and Targeted Therapies. Guimond, E., Tsai, CJ., Hosni, A., et al.[2022]

Targeted radiotherapy presents a promising alternative to traditional external beam radiotherapy for malignant brain tumors, as it aims to increase the precision of radiation delivery to tumor cells while minimizing damage to surrounding healthy brain tissue.

This approach could potentially enhance treatment efficacy by focusing on tumor cells specifically, reducing the risk of adverse effects associated with excessive radiation exposure to normal central nervous system tissues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted radiotherapy of brain tumours. Zalutsky, MR.[2022]

Radiotherapy can be enhanced through physical targeting methods like brachytherapy and intensity-modulated radiotherapy, which improve the distribution of radiation to maximize treatment effectiveness.

Biological targeting strategies utilize specific metabolic pathways or carrier molecules to deliver radiation more precisely to cancer cells, such as using iodine-131 for thyroid cancer or boronophenylalanine in boron neutron capture therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Physical and biological targeting of radiotherapy. Joensuu, H., Tenhunen, M.[2019]

The single-isocenter multitarget (SIMT) stereotactic radiosurgery technique demonstrated excellent local control rates of 99.0% at 1 year and 95.1% at 2 years for treating multiple brain metastases in 173 patients, with a median follow-up of 12.7 months.

The treatment showed acceptable safety profiles, with low rates of severe side effects: only 1.4% of patients experienced grade 2 radionecrosis and 0.9% experienced grade 3 or higher, indicating that SIMT SRS is both effective and safe for managing multiple brain metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-Isocenter Multitarget Stereotactic Radiosurgery Is Safe and Effective in the Treatment of Multiple Brain Metastases. Palmer, JD., Sebastian, NT., Chu, J., et al.[2022]

In a study of 20 patients with inoperable high-risk NSCLC brain metastases treated with a 5-fraction stereotactic radiosurgery (SRS) approach, local tumor control was achieved in 90% of cases at a median follow-up of 11.3 months, indicating high efficacy of the treatment.

While a total dose of 35 Gy was found to be safe and effective, a higher dose of 40 Gy increased the risk of symptomatic radionecrosis in some patients, suggesting that careful dose selection is crucial to minimize toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Five-fraction stereotactic radiosurgery (SRS) for single inoperable high-risk non-small cell lung cancer (NSCLC) brain metastases. Lischalk, JW., Oermann, E., Collins, SP., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05050929

RAPid SimPLE Targeted Radiation Treatment for Brain ... The aim of the study is to show that rapid, simple targeted radiotherapy to brain metastases with 8 Gy / 1 is non-inferior to 20 Gy / 5 in terms of overall ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10639460/

RADT-16. A RETROSPECTIVE COMPARISON OF ... Our study compares clinical outcomes after RAPPLE and whole brain radiotherapy (WBRT). METHODS. From January 2017 to December 2021, we identified patients ...

3. trialfinder.panfoundation.org trialfinder.panfoundation.org/en-US/trial/listing/304676

RAPid SimPLE Targeted Radiation Treatment for Brain ... The aim of the study is to show that rapid, simple targeted radiotherapy to brain metastases with 8 Gy / 1 is non-inferior to 20 Gy / 5 in ...

4. connect.careboxhealth.com connect.careboxhealth.com/en-US/trial/listing/304676

RAPid SimPLE Targeted Radiation Treatment for Brain ... The aim of the study is to show that rapid, simple targeted radiotherapy to brain metastases with 8 Gy / 1 is non-inferior to 20 Gy / 5 in ...

5. centerwatch.com centerwatch.com/clinical-trials/listings/condition/496/brain-metastases

Brain Metastases Clinical Research Trials The QUARTZ study randomized patients with brain metastases and poor prognosis between 20 Gy / 5 whole brain radiotherapy (WBRT) and best supportive care.

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.21.02314

Treatment for Brain Metastases: ASCO-SNO-ASTRO ... Surgery is a reasonable option for patients with brain metastases. Patients with large tumors with mass effect are more likely to benefit.