Carmustine + Retifanlimab + Radiation for Glioblastoma

Overseen By Lawrence Kleinberg, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Must not be taking: Probiotics, Immunosuppressants

Disqualifiers: Recurrent GBM, Metastatic disease, Autoimmune, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 6-8 weeks

50 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores new treatment options for adults recently diagnosed with glioblastoma, an aggressive brain cancer. Researchers are testing the safety and effectiveness of combining carmustine wafers (a type of chemotherapy implant), radiation therapy, and the drug retifanlimab (an immunotherapy), with or without the chemotherapy drug temozolomide. Suitable participants have had carmustine wafers placed during surgery and are on a steady or reducing dose of steroids. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, it does mention that you should not have any serious or uncontrolled medical disorders that could interfere with the study, and you cannot use other anti-cancer treatments. It's best to discuss your current medications with the study team.

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

Research shows that retifanlimab is generally well-tolerated. The FDA has already approved it for treating a type of anal cancer. Studies indicate that side effects are manageable, with common ones including tiredness and skin reactions.

When combined with radiation, past patients have demonstrated that retifanlimab can be safe. Some side effects have been reported, but they were often mild or moderate. Radiation therapy, a common cancer treatment, has known side effects such as skin changes and tiredness.

For those considering joining a trial, it's important to know that the safety of retifanlimab, especially when used with other treatments like temozolomide, has been studied. Temozolomide, a chemotherapy drug often used with radiation for brain tumors, is generally well-tolerated, though it can cause nausea and low blood counts.

In summary, retifanlimab appears to have a good safety record based on current studies. Side effects exist but are usually not severe. It's always crucial to discuss any concerns with the medical team before joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for glioblastoma because they offer a fresh approach compared to the standard options like radiation therapy combined with temozolomide. Retifanlimab, an immunotherapy drug, is being tested in combination with radiation therapy, with or without temozolomide, to potentially boost the body's immune response against cancer cells. This is different from traditional chemotherapy, which directly attacks cancer cells but can also harm healthy cells. By harnessing the power of the immune system, these new combinations could lead to more effective and possibly less toxic treatments for glioblastoma.

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

Research has shown that using retifanlimab with radiation therapy yields promising results for treating glioblastoma, a type of brain cancer. Past studies have linked this combination to improved survival rates for patients with recurring glioblastoma. Retifanlimab, a form of immunotherapy, enhances the immune system's ability to identify and combat cancer cells. When combined with radiation, it may enhance the overall effectiveness of the treatment.

In this trial, participants in Arm A will receive retifanlimab and radiation therapy. Arm B will include retifanlimab, radiation therapy, and temozolomide, a chemotherapy drug that has been shown to extend patient survival with prolonged use. Arm C will involve radiation therapy and temozolomide, the standard of care. Combining these treatments could provide a more effective approach to fighting glioblastoma, offering hope for better outcomes. ^{6 7 8 9 10}

Who Is on the Research Team?

Lawrence Kleinberg, MD

Principal Investigator

Johns Hopkins University

Are You a Good Fit for This Trial?

Adults over 18 with newly-diagnosed Grade IV Glioblastoma who've had carmustine wafers placed during surgery. They haven't had other GBM treatments, can sign consent, and are on stable or decreasing steroids. Women must not be pregnant or nursing, and men must use effective contraception. Participants need normal organ/marrow function, a Karnofsky Performance Status of ≥60, and no prior malignancies within 3 years (with some exceptions).

Inclusion Criteria

I agree to use birth control to prevent pregnancy for 6 months after my last dose.

I have mostly recovered from my surgery.

Subjects must be willing and able to comply with scheduled visits, treatment schedule, study procedures, and other requirements of the study

Exclusion Criteria

I had a brain bleed greater than Grade 1, but it's now resolved.

I am currently on antibiotics or antifungal treatment for an infection.

Taking Probiotic dietary supplements

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive carmustine wafers, retifanlimab, and radiation therapy, with or without temozolomide

6-8 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 2 years

What Are the Treatments Tested in This Trial?

Interventions

• Carmustine Wafer
• Radiation Therapy
• Retifanlimab
• Temozolomide

Trial Overview The trial is testing the combination of carmustine wafers with radiation therapy and retifanlimab immunotherapy, with or without temozolomide chemotherapy in adults after surgical placement of carmustine for glioblastoma treatment. The goal is to assess safety and survival outcomes.

How Is the Trial Designed?

Group I: Arm C- Radiation Therapy and Temozolomide Experimental Treatment 2 Interventions

Participants will receive Radiation Therapy and Temozolomide which is the Standard of Care.

Group II: Arm B- Retifanlimab, Radiation Therapy and Temozolomide Experimental Treatment 3 Interventions

Participants will receive Retifanlimab, Radiation Therapy and Temozolomide.

Group III: Arm A- Retifanlimab and Radiation Therapy Experimental Treatment 2 Interventions

Participants will receive Retifanlimab and Radiation Therapy.

Radiation Therapy is already approved in European Union, United States, Canada, Japan, China, Switzerland for the following indications:

Approved in European Union as Radiation Therapy for:

• Cancer treatment
• Palliative care
• Oropharyngeal cancer
• Breast cancer
• Prostate cancer
• Lung cancer
• Brain tumors

Approved in United States as Radiation Therapy for:

• Cancer treatment
• Palliative care
• Oropharyngeal cancer
• Breast cancer
• Prostate cancer
• Lung cancer
• Brain tumors

Approved in Canada as Radiation Therapy for:

• Cancer treatment
• Palliative care
• Oropharyngeal cancer
• Breast cancer
• Prostate cancer
• Lung cancer
• Brain tumors

Approved in Japan as Radiation Therapy for:

• Cancer treatment
• Palliative care
• Oropharyngeal cancer
• Breast cancer
• Prostate cancer
• Lung cancer
• Brain tumors

Approved in China as Radiation Therapy for:

• Cancer treatment
• Palliative care
• Oropharyngeal cancer
• Breast cancer
• Prostate cancer
• Lung cancer
• Brain tumors

Approved in Switzerland as Radiation Therapy for:

• Cancer treatment
• Palliative care
• Oropharyngeal cancer
• Breast cancer
• Prostate cancer
• Lung cancer
• Brain tumors

Who Is Running the Clinical Trial?

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Lead Sponsor

Trials

578

Recruited

33,600+

Incyte Corporation

Industry Sponsor

Trials

408

Recruited

66,800+

Steven Stein

Incyte Corporation

Chief Medical Officer since 2015

MD from University of Witwatersrand

Hervé Hoppenot

Incyte Corporation

Chief Executive Officer since 2014

MBA from ESSEC Business School

Published Research Related to This Trial

In a study of 40 patients with inoperable glioblastoma multiforme, the combination of carmustine (BCNU) and temozolomide showed a promising objective response rate of 42.5%, indicating its potential effectiveness as a first-line chemotherapy before and after radiotherapy.

The treatment was generally well-tolerated, with manageable grade 3-4 toxicities such as thrombocytopenia and neutropenia, and no patients discontinued treatment due to side effects, suggesting a favorable safety profile for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide in combination with BCNU before and after radiotherapy in patients with inoperable newly diagnosed glioblastoma multiforme. Barrié, M., Couprie, C., Dufour, H., et al.[2022]

The combination of carmustine (BCNU) and interferon alpha-2a (IFN-a) with radiation therapy is feasible and shows effectiveness in treating high-grade gliomas, with a median survival of 44 months for patients in the study.

The maximum tolerated dose (MTD) was established as IFN-a 12 x 10(6) units/m2 on specific days during a 7-week cycle, but significant nonhematological toxicities, such as lethargy and flu-like symptoms, were common, leading to dose adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I evaluation of radiation combined with recombinant interferon alpha-2a and BCNU for patients with high-grade glioma. Rajkumar, SV., Buckner, JC., Schomberg, PJ., et al.[2019]

In a study of 96 lung cancer patients who received thoracic radiotherapy (TRT) after PD-(L)1 inhibitor treatment, nearly 49% developed symptomatic treatment-related pneumonitis, indicating a significant safety concern with this treatment sequence.

Independent risk factors for developing pneumonitis included pulmonary emphysema and lung V20 exposure, highlighting the need for careful patient selection and monitoring when using TRT after PD-(L)1 inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of thoracic radiotherapy after PD-(L)1 inhibitor treatment in patients with lung cancer. Chen, Y., Liu, X., Huang, Z., et al.[2022]

In a study of 179 patients with brain metastases, those receiving stereotactic radiation therapy (SRT) combined with immune checkpoint inhibitors (ICI) showed significantly improved local control of brain lesions (98% vs. 89.5%) compared to SRT alone, indicating a potential synergistic effect.

Importantly, the combination of SRT and ICI did not increase the risk of symptomatic radiation necrosis, with similar rates of radiation necrosis (7% for SRT-ICI vs. 4% for SRT alone), suggesting that this treatment approach is safe.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune checkpoint inhibition in patients treated with stereotactic radiation for brain metastases. Kowalski, ES., Remick, JS., Sun, K., et al.[2021]

Carmustine wafers (Gliadel) and temozolomide (Temodal) have been approved for treating glioblastoma, with temozolomide showing a median survival benefit of 2 months when used with radiotherapy, and a two-year survival rate of 26.5% compared to 10.4% with radiotherapy alone.

In patients who undergo complete tumor resection, the two-year survival rate can reach 38%, highlighting the potential effectiveness of these treatments in younger patients with good performance status.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[What type of adjuvant chemotherapy should be proposed for the initial treatment of glioblastoma?]. Ducray, F., Honnorat, J.[2018]

In a phase I trial involving 38 patients with extensive-stage small cell lung cancer, the combination of pembrolizumab and thoracic radiotherapy was found to be safe, with no dose-limiting toxicities observed in the first 35 days of treatment.

The median progression-free survival was 6.1 months and overall survival was 8.4 months, suggesting that while the safety profile is promising, further studies are needed to fully understand the efficacy of this combined treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Trial of Pembrolizumab and Radiation Therapy after Induction Chemotherapy for Extensive-Stage Small Cell Lung Cancer. Welsh, JW., Heymach, JV., Chen, D., et al.[2023]

Radiotherapy (RT) has been a key treatment for cancer for over a century, and recent evidence suggests it can enhance the effectiveness of immunotherapy, particularly with immune checkpoint inhibitors (ICIs).

A collaborative workshop organized by major cancer organizations highlighted the need for further research to optimize the combination of RT and immunotherapy, as early clinical experiences show promise but require more investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incorporating Radiation Oncology into Immunotherapy: proceedings from the ASTRO-SITC-NCI immunotherapy workshop. Marciscano, AE., Walker, JM., McGee, HM., et al.[2019]

In a study of 467 patients with malignant glioma, radiotherapy alone or combined with chemotherapy significantly improved survival compared to semustine alone, indicating the importance of radiotherapy in post-surgical treatment.

The combination of carmustine and radiotherapy showed the best survival outcomes, although the difference in survival compared to semustine plus radiotherapy was not statistically significant, suggesting further research is needed to optimize chemotherapy options alongside radiotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery. Walker, MD., Green, SB., Byar, DP., et al.[2022]

In a study of 179 patients with non-small cell lung cancer, renal cell carcinoma, or melanoma treated with immune checkpoint inhibitors (ICI) and stereotactic radiosurgery (SRS), the combination showed a low local failure rate of 5.8%, suggesting effective intracranial control when these treatments are used together.

Higher PD-L1 expression (≥50%) was linked to increased rates of grade 2+ radiation necrosis (17% vs. 3%), indicating that while the combination therapy is generally safe, patients with high PD-L1 levels may need closer monitoring for potential side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Factors associated with radiation necrosis and intracranial control in patients treated with immune checkpoint inhibitors and stereotactic radiotherapy. Hall, J., Lui, K., Tan, X., et al.[2023]

Adjuvant locoregional radio-immunotherapy (RIT) was well tolerated in 12 patients with malignant glioma, showing promising results with a median survival of 18.5 months, compared to 9.7 months for historical controls receiving conventional treatments.

RIT allows for targeted delivery of treatment directly to the tumor site, effectively bypassing the blood-brain barrier and minimizing systemic toxicity, which could enhance therapeutic outcomes for glioma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Initial experiences with adjuvant locoregional radioimmunotherapy using 131I-labeled monoclonal antibodies against tenascin (BC-4) for treatment of glioma (WHO III and IV)]. Pöpperl, G., Götz, C., Gildehaus, FJ., et al.[2016]

Radioimmunotherapy (RIT) uses radionuclides attached to tumor-targeting antibodies to deliver targeted radiation therapy, with successful examples like (90)Y-ibritumomab tiuxetan and (131)I-tositumomab approved for treating non-Hodgkin lymphoma.

Research is ongoing to improve RIT by minimizing unnecessary radiation exposure while enhancing its effectiveness, with promising results seen in preclinical studies for solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radioimmunotherapy: a specific treatment protocol for cancer by cytotoxic radioisotopes conjugated to antibodies. Kawashima, H.[2019]

In a study of 778 malignant glioma patients treated with hyperfractionated radiotherapy and carmustine, 89 patients (11.9%) were identified as potentially eligible for stereotactic radiosurgery (SRS), showing a median survival time of 14.4 months compared to 11.7 months for ineligible patients.

Patients eligible for SRS had a significantly better 18-month survival rate of 40% versus 27% for ineligible patients, indicating that SRS eligibility is a strong predictor of survival, particularly in patients with a Karnofsky performance status greater than 60.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Survival comparison of radiosurgery-eligible and -ineligible malignant glioma patients treated with hyperfractionated radiation therapy and carmustine: a report of Radiation Therapy Oncology Group 83-02. Curran, WJ., Scott, CB., Weinstein, AS., et al.[2017]

The combination of anti-GITR monoclonal antibody (mAb) and stereotactic radiosurgery (SRS) significantly improved survival rates in a mouse model of glioblastoma, with a cure rate of 24% compared to 0% for either treatment alone, indicating a strong immune-mediated effect.

The treatment with anti-GITR (1) and SRS led to increased infiltration of CD4+ effector T-cells and enhanced production of immune signaling molecules like IFNγ and IL-2, suggesting that this combination effectively shifts the immune response against the tumor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Agonist anti-GITR monoclonal antibody and stereotactic radiation induce immune-mediated survival advantage in murine intracranial glioma. Patel, MA., Kim, JE., Theodros, D., et al.[2022]

Intensity-modulated radiotherapy (IMRT) effectively reduces radiation exposure to healthy tissues, minimizing side effects and enhancing treatment efficiency by allowing for smaller or more frequent doses.

Chemoradiotherapy, particularly using cisplatin and cetuximab, has become a standard treatment for tumors, especially in cases beyond early-stage disease, highlighting its role in improving cancer care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Oncological treatment modalities in head and neck cancer]. Saarilahti, K., Lindholm, P.[2018]

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