Ruxolitinib + Temozolomide + Radiation for Glioblastoma

Overseen By David Peereboom, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Case Comprehensive Cancer Center

Must not be taking: Blood thinners

Disqualifiers: Other cancers, Heart diseases, HIV, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 6 weeks

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

The purpose of this study is to test how well the drug works, safety and tolerability of an investigational drug called Ruxolitinib in gliomas and glioblastomas, when combined with standard treatment for brain cancer, temozolomide and radiation. Ruxolitinib is an experimental drug that works by targeting proteins in cells and stops them from growing. Ruxolitinib is experimental because it is not approved by the Food and Drug Administration (FDA) for the treatment of gliomas or glioblastomas Temozolomide works by damaging the DNA of tumor cells so that they cannot divide properly. Some tumor cells can repair that damage and therefore be resistant to temozolomide.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it excludes those using blood thinners and those receiving other cancer treatments. It's best to discuss your specific medications with the trial team.

Is the combination of temozolomide and radiation therapy safe for glioblastoma patients?

Temozolomide, when used with radiation therapy, is generally considered safe but can cause severe myelotoxicity (damage to the bone marrow, which can affect blood cell production) in some patients. Safety data from studies involving temozolomide and radiation therapy indicate that while effective, there is a risk of increased adverse events, particularly related to blood cell production. ^{1 2 3 4 5}

How is the Ruxolitinib + Temozolomide + Radiation treatment for glioblastoma different from other treatments?

This treatment is unique because it combines Ruxolitinib, a drug that targets specific pathways involved in cancer cell growth, with Temozolomide and radiation therapy, which are standard treatments for glioblastoma. The addition of Ruxolitinib may offer a novel approach by potentially enhancing the effectiveness of the existing treatment regimen. ^{5 6 7 8 9}

What data supports the effectiveness of the drug temozolomide when used with radiation therapy for glioblastoma?

Research shows that temozolomide, when used with radiation therapy, has demonstrated antitumor activity and improved survival in patients with glioblastoma. It is considered a standard treatment for newly diagnosed cases, offering benefits in both survival and quality of life. ^{5 7 8 10 11}

Who Is on the Research Team?

David Peereboom, MD

Principal Investigator

Cleveland Clinic Taussig Cancer institute, Case Comprehensive Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with certain high-grade brain tumors (gliomas or glioblastoma) that haven't spread beyond a specific area and have not been treated before. Participants need to be fairly independent, able to consent, and willing to use birth control. They can't join if they have other serious illnesses, HIV, hepatitis B/C, heart issues, are pregnant or on blood thinners.

Inclusion Criteria

I have no other cancers except possibly cured skin, bladder, prostate, cervical, or breast cancer over 3 years ago.

I have a specific type of brain tumor with a certain genetic feature.

My brain tumor is a high-grade type and tests show it is unmethylated.

Exclusion Criteria

Active hepatitis B or C infection

Patients with other serious diseases

I have heart issues or an abnormal EKG result.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ruxolitinib with radiation and temozolomide for 6 weeks

6 weeks

Weekly visits for monitoring and treatment administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

8 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Radiation
• Ruxolitinib
• Temozolomide

Trial Overview The study tests Ruxolitinib's effectiveness when combined with standard brain cancer treatments: radiation and Temozolomide. Ruxolitinib targets cell proteins to stop tumor growth but isn't FDA-approved yet for these cancers. Temozolomide damages tumor DNA.

How Is the Trial Designed?

Group I: ruxolitinib + radiation x 60 Gy for 6 weeks Experimental Treatment 2 Interventions

Unmethylated O6-methylguanine DNA methyltransferase (MGMT) Glioblastoma and grade III glioma Every patient gets ruxolitinib + radiation x 60 Gy for 6 weeks over 6 weeks. The dose of radiation therapy is fixed at 60 Gy over 6 weeks

Group II: ruxolitinib + radiation x 60 Gy + temozolomide 75 mg/m Experimental Treatment 3 Interventions

Methylated MGMT Glioblastoma and grade III glioma. Arm 2 will start once the safe dose has been established for Arm 1 for every dose level. Every patient gets ruxolitinib + radiation x 60 Gy + daily temozolomide at 75 mg/m2 for 6 weeks over 6 weeks. The dose of radiation therapy is fixed at 60 Gy over 6 weeks (2 Gy x 30). The dose of temozolomide is 75 mg/m2 daily for 6 weeks

Radiation 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
• HPV-positive throat cancer
• Various types of tumors

Approved in United States as Radiation Therapy for:

• Cancer treatment
• HPV-positive throat cancer
• Various types of tumors

Approved in Canada as Radiation Therapy for:

• Cancer treatment
• HPV-positive throat cancer
• Various types of tumors

Approved in Japan as Radiation Therapy for:

• Cancer treatment
• HPV-positive throat cancer
• Various types of tumors

Approved in China as Radiation Therapy for:

• Cancer treatment
• HPV-positive throat cancer
• Various types of tumors

Approved in Switzerland as Radiation Therapy for:

• Cancer treatment
• HPV-positive throat cancer
• Various types of tumors

Who Is Running the Clinical Trial?

Case Comprehensive Cancer Center

Lead Sponsor

Trials

472

Recruited

33,400+

Published Research Related to This Trial

The combination of Gliadel wafers with concurrent radio-chemotherapy using temozolomide (TMZ) in 24 patients with glioblastoma multiforme resulted in a median overall survival of 19.2 months and a median progression-free survival of 12.3 months, indicating a potential benefit of this treatment approach.

While the treatment was generally well tolerated, 10 patients experienced significant toxicity leading to premature discontinuation of TMZ, highlighting the need for careful monitoring of hematological and digestive side effects during this multimodal therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of the per-operatory application of GLIADEL wafers (BCNU, carmustine) in combination with temozolomide and radiotherapy in patients with glioblastoma multiforme: efficacy and toxicity. Miglierini, P., Bouchekoua, M., Rousseau, B., et al.[2018]

Temozolomide is primarily used for treating refractory central nervous system cancers like anaplastic astrocytoma and glioblastoma, but ongoing clinical trials are exploring its efficacy and safety in newly diagnosed gliomas and other types of tumors.

Research is also investigating different dosing schedules and combinations with other treatments, suggesting that temozolomide could be a versatile option in cancer therapy beyond its current approved uses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Future directions for temozolomide therapy. Yung, WK.[2019]

In a study of 103 glioblastoma patients treated with standard temozolomide and radiotherapy, the median overall survival was found to be 13.7 months, highlighting the effectiveness of this treatment regimen.

Three key prognostic factors were identified that negatively impacted overall survival: age over 65 years, a Medical Research Council (MRC) scale score of 3-4, and the occurrence of postoperative complications, suggesting that these factors can help predict patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Age, Neurological Status MRC Scale, and Postoperative Morbidity are Prognostic Factors in Patients with Glioblastoma Treated by Chemoradiotherapy. Verlut, C., Mouillet, G., Magnin, E., et al.[2020]

Temozolomide is an effective oral treatment for high-grade glioma and anaplastic astrocytoma, showing not only antitumor effects but also improvements in patients' quality of life.

It has potential advantages for treating neoplastic meningitis due to its ability to penetrate the blood-brain barrier and its demonstrated efficacy in increasing survival in preclinical models, making it a promising candidate for further research in central nervous system cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide in early stages of newly diagnosed malignant glioma and neoplastic meningitis. Friedman, HS.[2018]

In a study of 67 patients with newly diagnosed glioblastoma multiforme, the combination of temozolomide, thalidomide, and radiation therapy resulted in a median survival of 73 weeks, indicating a favorable outcome compared to those not receiving adjuvant chemotherapy.

The treatment was generally well tolerated, but the specific benefit of adding thalidomide to temozolomide remains uncertain, as the survival outcomes were similar to those seen with other chemotherapy regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of temozolomide and thalidomide with radiation therapy for newly diagnosed glioblastoma multiforme. Chang, SM., Lamborn, KR., Malec, M., et al.[2018]

In a study of 87 newly diagnosed glioblastoma patients, only 5% experienced severe myelotoxicity during treatment with temozolomide (TMZ) and radiation therapy, indicating that while the risk exists, it is relatively low.

Factors such as female sex, low pretreatment platelet counts, and specific genetic markers were identified as potential predictors of severe myelotoxicity, suggesting that personalized treatment approaches could help mitigate risks in vulnerable patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical and Genetic Factors Associated With Severe Hematological Toxicity in Glioblastoma Patients During Radiation Plus Temozolomide Treatment: A Prospective Study. Lombardi, G., Rumiato, E., Bertorelle, R., et al.[2018]

In a study of 165 glioblastoma patients, the extent of tumor resection was the only factor associated with longer survival, indicating that surgical removal of the tumor is crucial for improving outcomes.

The use of Gliadel wafers significantly increased the risk of adverse events, especially in patients with recurrent tumors, with those receiving eight wafers facing a 3-fold higher risk of adverse events and a 5.6-fold higher risk of site-related complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of Gliadel wafers for newly diagnosed and recurrent glioblastoma. De Bonis, P., Anile, C., Pompucci, A., et al.[2018]

Temozolomide (TZM) combined with X-ray irradiation significantly inhibits the proliferation and migration of human glioma spheroids, with the most effective results seen at higher concentrations of TZM.

The study found that while the combination of TZM and radiation enhances the effects on glioma cells, the overall impact is less than what would be expected from simply adding the effects of each treatment alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The inhibition of proliferation and migration of glioma spheroids exposed to temozolomide is less than additive if combined with irradiation. Fehlauer, F., Muench, M., Richter, E., et al.[2018]

Citations

1. Netherlands pubmed.ncbi.nlm.nih.gov

Impact of the per-operatory application of GLIADEL wafers (BCNU, carmustine) in combination with temozolomide and radiotherapy in patients with glioblastoma multiforme: efficacy and toxicity. [2018]

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

Future directions for temozolomide therapy. [2019]

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

Age, Neurological Status MRC Scale, and Postoperative Morbidity are Prognostic Factors in Patients with Glioblastoma Treated by Chemoradiotherapy. [2020]

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

Temozolomide in early stages of newly diagnosed malignant glioma and neoplastic meningitis. [2018]

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

Phase II study of temozolomide and thalidomide with radiation therapy for newly diagnosed glioblastoma multiforme. [2018]

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

North Central Cancer Treatment Group Phase I trial N057K of everolimus (RAD001) and temozolomide in combination with radiation therapy in patients with newly diagnosed glioblastoma multiforme. [2021]

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

Clinical and Genetic Factors Associated With Severe Hematological Toxicity in Glioblastoma Patients During Radiation Plus Temozolomide Treatment: A Prospective Study. [2018]

8. Austria pubmed.ncbi.nlm.nih.gov

Safety and efficacy of Gliadel wafers for newly diagnosed and recurrent glioblastoma. [2018]

9. Greece pubmed.ncbi.nlm.nih.gov

The inhibition of proliferation and migration of glioma spheroids exposed to temozolomide is less than additive if combined with irradiation. [2018]

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

Radiotherapy followed by adjuvant temozolomide treatment of malignant glioma. [2018]

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

Standard (60 Gy) or short-course (40 Gy) irradiation plus concomitant and adjuvant temozolomide for elderly patients with glioblastoma: a propensity-matched analysis. [2022]