Carmustine + Retifanlimab + Radiation for Glioblastoma

Recruiting in Palo Alto (17 mi)

Overseen by Lawrence Kleinberg, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

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

Trial Summary

What is the purpose of this trial?

This trial is testing a combination of treatments including carmustine wafers, radiation, retifanlimab, and possibly temozolomide in adults newly diagnosed with glioblastoma multiforme. The goal is to see if these treatments are safe and help patients live longer. The treatments work by directly targeting the tumor, damaging cancer cells' DNA, and boosting the immune system to fight the cancer. Carmustine wafers have been shown to be an effective addition to standard treatment in glioblastoma, with a significant survival benefit.

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.

What data supports the effectiveness of the treatment Carmustine + Retifanlimab + Radiation for Glioblastoma?

Emerging data suggest that immune checkpoint inhibitors (like Retifanlimab) and stereotactic radiotherapy (a type of focused radiation) may work together to improve treatment outcomes, potentially increasing both effectiveness and side effects. Additionally, immunotherapy has shown synergistic survival benefits with focused radiation in glioblastoma models, indicating a potential advantage of combining these treatments. ^{1 2 3 4 5}

Is the combination of immune checkpoint inhibitors and stereotactic radiotherapy safe for humans?

Combining immune checkpoint inhibitors with stereotactic radiotherapy may increase the risk of radiation necrosis (damage to brain tissue from radiation) and symptomatic pneumonitis (lung inflammation), suggesting potential safety concerns. ^{4 6 7 8 9}

What makes the treatment with Carmustine, Retifanlimab, and Radiation Therapy unique for glioblastoma?

This treatment combines carmustine, a chemotherapy drug, with retifanlimab, an immune therapy that helps the body's immune system fight cancer, and radiation therapy, which uses high-energy rays to kill cancer cells. This combination aims to enhance the effectiveness of each component, potentially offering a more comprehensive approach to treating glioblastoma compared to using these treatments individually. ^{10 11 12 13 14}

Research Team

Lawrence Kleinberg, MD

Principal Investigator

Johns Hopkins University

Eligibility Criteria

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

Trial Timeline

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

Treatment Details

Interventions

• Carmustine Wafer (Anti-tumor antibiotic)
• Radiation Therapy (Radiation)
• Retifanlimab (Monoclonal Antibodies)
• Temozolomide (Alkylating agents)

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.

Participant Groups

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 Canada, Japan, China, Switzerland for the following indications:

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+

Dr. William G. Nelson

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Director since 1992

MD, PhD

Dr. Elizabeth Jaffee

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Chief Medical Officer since 2023

MD

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

Findings from Research

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]

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]

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]

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 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 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]

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 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]

References

1. Germany 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)]. [2016]

2. England pubmed.ncbi.nlm.nih.gov

Agonist anti-GITR monoclonal antibody and stereotactic radiation induce immune-mediated survival advantage in murine intracranial glioma. [2022]

3. Finland pubmed.ncbi.nlm.nih.gov

[Oncological treatment modalities in head and neck cancer]. [2018]

4. Ireland pubmed.ncbi.nlm.nih.gov

Factors associated with radiation necrosis and intracranial control in patients treated with immune checkpoint inhibitors and stereotactic radiotherapy. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

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

6. England pubmed.ncbi.nlm.nih.gov

Immune checkpoint inhibition in patients treated with stereotactic radiation for brain metastases. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Phase I Trial of Pembrolizumab and Radiation Therapy after Induction Chemotherapy for Extensive-Stage Small Cell Lung Cancer. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Incorporating Radiation Oncology into Immunotherapy: proceedings from the ASTRO-SITC-NCI immunotherapy workshop. [2019]

9. United States pubmed.ncbi.nlm.nih.gov

Safety of thoracic radiotherapy after PD-(L)1 inhibitor treatment in patients with lung cancer. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Temozolomide in combination with BCNU before and after radiotherapy in patients with inoperable newly diagnosed glioblastoma multiforme. [2022]

11. United States 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. [2017]

12. United States pubmed.ncbi.nlm.nih.gov

Phase I evaluation of radiation combined with recombinant interferon alpha-2a and BCNU for patients with high-grade glioma. [2019]

13. France pubmed.ncbi.nlm.nih.gov

[What type of adjuvant chemotherapy should be proposed for the initial treatment of glioblastoma?]. [2018]

14. United States pubmed.ncbi.nlm.nih.gov

Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery. [2022]