Ibrutinib + Radiation + Temozolomide for Glioblastoma

Overseen By David Peereboom, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Case Comprehensive Cancer Center

Must not be taking: Anticoagulants, P450/CYP3A inhibitors

Disqualifiers: Infection, Pregnancy, Cardiovascular disease, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 6 weeks

36 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires participants to stop using certain medications, including anticoagulants (blood thinners) and drugs that affect the P450/CYP3A enzyme, at least a week before starting the study. Additionally, participants must stop using immunosuppressant therapy at least 21 days before the first dose of the study drug.

What data supports the effectiveness of this treatment for glioblastoma?

Research shows that combining temozolomide (a chemotherapy drug) with radiation therapy can improve survival rates for glioblastoma patients. Temozolomide helps kill cancer cells and has been shown to work well with radiation, making the treatment more effective. ^{1 2 3 4 5}

Is the combination of Ibrutinib, Radiation, and Temozolomide safe for humans?

Temozolomide, when used with radiation therapy, has been studied for safety in patients with glioblastoma and is generally considered to have a lower toxicity compared to some other chemotherapy drugs. It is often used because of its favorable safety profile and tolerability in combination with radiotherapy. ^{4 6 7 8 9}

What makes the Ibrutinib + Radiation + Temozolomide treatment unique for glioblastoma?

This treatment combines Ibrutinib, a drug that may enhance the effects of radiation, with Temozolomide, a chemotherapy drug known to improve survival when used with radiation in glioblastoma patients, potentially offering a more effective approach than standard treatments. ^{2 7 10 11 12}

What is the purpose of this trial?

Safety of combination of ibrutinib and radiation at various dose levels in unmethylated o6-methylguanine-DNA-methyltransferase (MGMT) glioblastoma and study of ibrutinib, temozolomide, and radiation combination therapy in methylated MGMT glioblastoma.

Research Team

David Peereboom, MD

Principal Investigator

Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center

Eligibility Criteria

This trial is for adults with newly diagnosed glioblastoma, specifically those with unmethylated MGMT tumors or methylated MGMT tumors. Participants must be in good physical condition (Karnofsky performance ≥ 70%), not pregnant, and willing to use birth control. They should have no serious concurrent illnesses, bleeding disorders, or recent surgeries and cannot be on certain medications that affect the immune system.

Inclusion Criteria

Arm 1: Prothrombin time (PT) / international normalized ratio (INR) and partial thromboplastin time (PTT) within normal limits

Arm 1: Must be able to provide written informed consent

Arm 1: Patients of reproductive potential must use acceptable birth control

Exclusion Criteria

I am taking certain blood thinners.

I do not have any serious infections or illnesses.

I have no other cancers, except for allowed exceptions.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ibrutinib and radiation for 6 weeks. Methylated MGMT patients also receive daily Temozolomide.

6 weeks

Break

Participants undergo a 4-week break after initial treatment phase.

4 weeks

Adjuvant Treatment

Methylated MGMT patients receive daily ibrutinib and Temozolomide for Days 1-5 of a 28-day cycle for up to 6 cycles.

6 cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment.

10 weeks

Treatment Details

Interventions

• Ibrutinib
• Radiation
• Temozolomide

Trial Overview The trial tests the safety of combining a drug called Ibrutinib with radiation therapy at different doses for patients with unmethylated MGMT glioblastoma. It also examines how well Ibrutinib works alongside Temozolomide (TMZ) and radiation in patients with methylated MGMT glioblastoma.

Participant Groups

Group I: Unmethylated MGMT Glioblastoma Experimental Treatment 2 Interventions

Every patient gets ibrutinib + radiation over 6 weeks. Patients will undergo a 4-week break and then Ibrutinib treatment will continue until disease progression, intolerable toxicity, or death.

Group II: Methylated MGMT Glioblastoma Experimental Treatment 3 Interventions

Every patient gets ibrutinib + radiation + daily Temozolomide (TMZ) (75mg/m2) for 6 weeks. Patients will undergo a 4-week break and patients will then receive daily ibrutinib and adjuvant Temozolomide for Days 1-5 of a 28-day cycle of temozolomide for 6 cycles. The temozolomide will continue until disease progression, intolerable toxicity, or death or maximum of 6 cycles. Ibrutinib treatment will continue until disease progression, intolerable toxicity, or death.

Ibrutinib is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Imbruvica for:

• Chronic lymphocytic leukemia
• Mantle cell lymphoma
• Waldenström's macroglobulinemia
• Marginal zone lymphoma
• Graft-versus-host disease

Approved in United States as Imbruvica for:

• Chronic lymphocytic leukemia/small lymphocytic lymphoma
• Mantle cell lymphoma
• Waldenström's macroglobulinemia
• Marginal zone lymphoma
• Graft-versus-host disease

Approved in Canada as Imbruvica for:

• Chronic lymphocytic leukemia
• Mantle cell lymphoma
• Waldenström's macroglobulinemia
• Marginal zone lymphoma

Approved in Japan as Imbruvica for:

• Chronic lymphocytic leukemia
• Mantle cell lymphoma
• Waldenström's macroglobulinemia

Who Is Running the Clinical Trial?

Case Comprehensive Cancer Center

Lead Sponsor

Trials

472

Recruited

33,400+

Findings from Research

In a study of 79 patients with glioblastoma, the combination of radiotherapy and temozolomide resulted in a median overall survival of 18.3 months and 2-year survival rate of 37.1%, which aligns with previous international studies.

The main side effect observed was hematologic toxicity in 8.8% of patients, indicating that while the treatment is effective, monitoring for blood-related side effects is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical outcome of concomitant chemoradiotherapy followed by adjuvant temozolomide therapy for glioblastaomas: single-center experience. Jeon, HJ., Kong, DS., Park, KB., et al.[2018]

Temozolomide (TMZ) enhances the effectiveness of radiation therapy in treating glioblastoma cells, leading to a significant reduction in colony formation when combined with irradiation, compared to either treatment alone.

While irradiation was more toxic to glioma cells than TMZ, the combination of both treatments increased the sensitivity of glioma cells to radiation, suggesting a potential strategy for improving glioblastoma treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiosensitization of Glioma Cells by Temozolomide (TMZ): A Colony Formation Assay. Babaloui, S., Najafi, M., Mozdarani, H., et al.[2022]

In a phase III study involving 716 patients with newly diagnosed glioblastoma, the addition of the immune checkpoint inhibitor nivolumab (NIVO) to standard radiotherapy (RT) and temozolomide (TMZ) did not significantly improve progression-free survival (PFS) or overall survival (OS) compared to placebo, with median OS of 28.9 months for NIVO versus 32.1 months for placebo.

The study found a higher rate of grade 3/4 treatment-related adverse events in the NIVO group (52.4%) compared to the placebo group (33.6%), indicating that while NIVO did not enhance efficacy, it was associated with increased toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase III trial of chemoradiotherapy with temozolomide plus nivolumab or placebo for newly diagnosed glioblastoma with methylated MGMT promoter. Lim, M., Weller, M., Idbaih, A., et al.[2023]

In a phase I clinical trial involving nine patients with glioblastoma, simultaneous integrated-boost intensity-modulated radiotherapy (SIB-IMRT) combined with temozolomide was found to be feasible and well tolerated up to a maximum dose of 80Gy.

No dose-limiting toxicities were observed at the highest dose level, indicating that this treatment combination may be safe for patients with malignant glioma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I dose escalation study using simultaneous integrated-boost IMRT with temozolomide in patients with unifocal glioblastoma. Truc, G., Bernier, V., Mirjolet, C., et al.[2018]

Adding nitrosourea-based chemotherapy to radiotherapy has been shown to increase progression-free survival in patients with grade II and III gliomas, although it does not improve overall survival.

Upcoming phase III trials will investigate whether adding temozolomide to radiotherapy can enhance overall survival in grade II/III gliomas, while also assessing cognitive function and quality of life for better patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide and radiation in low-grade and anaplastic gliomas: temoradiation. Schiff, D.[2018]

In a phase II clinical trial involving 21 patients with newly diagnosed glioblastoma multiforme (GBM), the combination of temozolomide (TMZ) with radiotherapy resulted in a one-year survival rate of 58% and a median survival time of 15.7 months, indicating its efficacy in extending survival.

The treatment regimen was well-tolerated, with only mild to moderate non-hematological side effects and minimal severe hematological toxicity, suggesting that TMZ has a favorable safety profile compared to traditional chemotherapy agents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide in radio-chemotherapy combined treatment for newly-diagnosed glioblastoma multiforme: phase II clinical trial. Lanzetta, G., Campanella, C., Rozzi, A., et al.[2018]

In a study of 46 patients with newly diagnosed glioblastoma multiforme, hypofractionated high-dose intensity modulated radiation therapy (IMRT) combined with temozolomide (TMZ) resulted in a median overall survival of 20 months, indicating its efficacy in prolonging life for these patients.

No acute toxicity from the IMRT was observed, but radiation necrosis occurred in 20 patients, particularly in the subventricular zone, which was linked to longer survival, although it also negatively impacted the quality of life for some long-term survivors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 trial of hypofractionated high-dose intensity modulated radiation therapy with concurrent and adjuvant temozolomide for newly diagnosed glioblastoma. Iuchi, T., Hatano, K., Kodama, T., et al.[2018]

Nivolumab combined with radiotherapy and temozolomide (NIVO+RT+TMZ) is tolerable for patients with newly diagnosed glioblastoma, with no new safety concerns identified; however, higher rates of grade 3/4 treatment-related adverse events were observed compared to Nivolumab with radiotherapy alone (NIVO+RT).

The study found that overall survival (OS) was similar for patients with unmethylated MGMT promoter whether they received NIVO+RT+TMZ or NIVO+RT, indicating that the addition of temozolomide may not significantly improve outcomes in this subgroup.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus radiotherapy with or without temozolomide in newly diagnosed glioblastoma: Results from exploratory phase I cohorts of CheckMate 143. Omuro, A., Reardon, DA., Sampson, JH., et al.[2023]

In a study of 1157 glioblastoma multiforme patients, the addition of temozolomide (TMZ) to radiotherapy (RT) significantly improved median overall survival from 9.0 months with RT alone to 16.2 months with RT + TMZ (P < .001).

The two-year survival rate increased from 4% with RT alone to 25% with the combination of RT and TMZ, confirming the efficacy of TMZ in enhancing survival outcomes in GBM patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A population-based study on the effect of temozolomide in the treatment of glioblastoma multiforme. Rønning, PA., Helseth, E., Meling, TR., et al.[2022]

The study determined that the maximum tolerated dose (MTD) of hypofractionated SIB-IMRT combined with temozolomide (TMZ) for treating high-grade gliomas is 3.6 Gy per fraction, with tolerable adverse reactions observed in 16 patients.

Patients treated with this regimen showed promising survival outcomes, with a median overall survival of 19 months and a 1-year overall survival rate of 86.7%, suggesting potential benefits of this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of high-grade gliomas using escalating doses of hypofractionated simultaneous integrated boost-intensity-modulated radiation therapy in combination with temozolomide: A modified Phase I clinical trial. Ge, X., Xue, X., Liu, H., et al.[2022]

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]

References

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

Clinical outcome of concomitant chemoradiotherapy followed by adjuvant temozolomide therapy for glioblastaomas: single-center experience. [2018]

2. Iran pubmed.ncbi.nlm.nih.gov

Radiosensitization of Glioma Cells by Temozolomide (TMZ): A Colony Formation Assay. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Phase III trial of chemoradiotherapy with temozolomide plus nivolumab or placebo for newly diagnosed glioblastoma with methylated MGMT promoter. [2023]

4. France pubmed.ncbi.nlm.nih.gov

A phase I dose escalation study using simultaneous integrated-boost IMRT with temozolomide in patients with unifocal glioblastoma. [2018]

5. England pubmed.ncbi.nlm.nih.gov

Temozolomide and radiation in low-grade and anaplastic gliomas: temoradiation. [2018]

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

Brain metastases from melanoma: is there a role for concurrent temozolomide in addition to whole brain radiation therapy? [2021]

7. Greece pubmed.ncbi.nlm.nih.gov

Temozolomide in radio-chemotherapy combined treatment for newly-diagnosed glioblastoma multiforme: phase II clinical trial. [2018]

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

Phase 2 trial of hypofractionated high-dose intensity modulated radiation therapy with concurrent and adjuvant temozolomide for newly diagnosed glioblastoma. [2018]

9. England pubmed.ncbi.nlm.nih.gov

Nivolumab plus radiotherapy with or without temozolomide in newly diagnosed glioblastoma: Results from exploratory phase I cohorts of CheckMate 143. [2023]

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

A population-based study on the effect of temozolomide in the treatment of glioblastoma multiforme. [2022]

11. India pubmed.ncbi.nlm.nih.gov

Treatment of high-grade gliomas using escalating doses of hypofractionated simultaneous integrated boost-intensity-modulated radiation therapy in combination with temozolomide: A modified Phase I clinical trial. [2022]

12. 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]