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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of treatments for glioblastoma, a type of brain cancer. It includes an experimental drug, Ruxolitinib, alongside standard treatments like radiation (radiotherapy) and Temozolomide (a chemotherapy drug). Researchers aim to determine if adding Ruxolitinib enhances the effectiveness of these treatments. Suitable participants are those diagnosed with specific forms of high-grade glioma or glioblastoma who can care for themselves with only occasional help. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

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

Research has shown that using ruxolitinib with radiation and temozolomide is generally safe for patients. In previous studies, taking 20 mg of ruxolitinib twice a day did not cause major safety problems when combined with radiation and temozolomide. Patients tolerated the treatment well, experiencing no severe unexpected reactions.

Ruxolitinib remains experimental for brain cancers like gliomas and glioblastomas, but it is considered safe enough to test with these other treatments. This combination is under study because it attacks cancer cells in a new way, and early results appear promising compared to past treatments. Ruxolitinib works by blocking certain proteins in cells, which helps stop tumors from growing. Temozolomide damages the DNA of tumor cells, making it harder for them to multiply.

Overall, the safety data so far are reassuring, but more studies are needed to confirm these findings. Joining a clinical trial can help researchers learn more about how this treatment works and who it can benefit. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Ruxolitinib, Temozolomide, and radiation for treating glioblastoma because it brings a fresh approach to tackling this aggressive brain cancer. Unlike the standard treatment that primarily involves radiation and Temozolomide, this therapy adds Ruxolitinib, which targets a different pathway known as the JAK/STAT pathway, potentially enhancing the effectiveness of the treatment. For patients with methylated MGMT glioblastoma, the addition of daily Temozolomide aims to improve outcomes by sensitizing tumor cells to radiation. Meanwhile, in patients with unmethylated MGMT glioblastoma, the combination of Ruxolitinib with radiation alone seeks to improve outcomes where Temozolomide alone has limited effectiveness. This multi-pronged strategy offers hope for better control of the disease and potentially extended survival.

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

Research shows that combining ruxolitinib with radiation and temozolomide might help patients with glioblastoma live longer and slow cancer progression. In this trial, one treatment arm will receive this combination. Studies found that patients receiving it had better outcomes compared to standard treatments. Ruxolitinib targets specific proteins in cells, potentially stopping tumor growth. Temozolomide damages tumor cell DNA, hindering their ability to multiply. Early results suggest this treatment combination could be promising for those with aggressive brain tumors. ^{2 4 6 7 8}

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.

Patients and their sexual partners must agree to avoid conception while on the study due to possible risks from experimental drugs. Women will need a negative pregnancy test to be on the study

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]

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]

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]

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 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 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]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2021.39.15_suppl.2060

Phase I study of ruxolitinib with radiation and ... Patients that received ruxolitinib + radiation x 60 Gy + daily temozolomide at 75 mg/m2 for 6 weeks over 6 weeks (Arm 2) had significantly better PFS and OS.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7650934/

CTNI-41. PHASE I STUDY OF RUXOLITINIB WITH ... Patients with methylated MGMT glioblastoma or grade III glioma were eligible for Arm 2. Every patient received ruxolitinib + radiation x 60 Gy + daily ...

3. targetedonc.com targetedonc.com/view/ruxolitinib-is-well-tolerated-and-shows-promise-in-high-grade-gliomas

Ruxolitinib is Well-Tolerated and Shows Promise in High- ... Ruxolitinib is Well-Tolerated and Shows Promise in High-Grade Gliomas. Manmeet Ahluwalia, MD, discusses what early results from the CRUX trial ...

4. asco.org asco.org/abstracts-presentations/ABSTRACT345407

Phase I study of ruxolitinib with radiation and ... Phase I study of ruxolitinib with radiation and temozolomide in patients with newly diagnosed grade III gliomas and glioblastoma.

5. clinicaltrials.gov clinicaltrials.gov/study/NCT03514069

Study Details | NCT03514069 | Ruxolitinib With Radiation ... Every patient gets ruxolitinib + radiation x 60 Gy + daily temozolomide at 75 mg/m2 for 6 weeks over 6 weeks.

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.2060

Safety and feasibility of JAK inhibitor ruxolitinib in newly- ... Ruxolitinib therapy is safe and feasible in combination with TMZ and radiation. Efficacy of ruxolitinib plus SOC appears promising compared to historical ...

7. targetedonc.com targetedonc.com/view/ruxolitinib-plus-radiation-and-temozolomide-is-safe-and-feasible-for-high-grade-glioma

Ruxolitinib Plus Radiation and Temozolomide is Safe and ... The use of ruxolitinib (Jakafi) in combination with temozolomide and radiation therapy appears to be a safe and feasible option.

8. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.2061

Phase 1 trial of ruxolitinib, temozolomide, and radiation in ... Dose of 20 mg twice daily of ruxolitinib is safe with radiation and temozolomide. Preliminary survival data appears promising compared to the historical ...