Temozolomide + Radiation Therapy for Brain Cancer

(CATNON Trial)

Recruiting at 136 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: European Organisation for Research and Treatment of Cancer - EORTC

Must not be taking: Chemotherapy, Anticancer agents

Disqualifiers: HIV, Hepatitis B/C, Prior chemotherapy, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 36

751 Participants Needed

Trial Summary

What is the purpose of this trial?

RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving radiation therapy together with temozolomide may kill more tumor cells. It is not yet known whether giving temozolomide during and/or after radiation therapy is more effective than radiation therapy alone in treating anaplastic glioma. PURPOSE: This randomized phase III trial is studying giving temozolomide during and/or after radiation therapy to see how well it works compared to radiation therapy alone in treating patients with anaplastic glioma.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications, but you must not be on any other anticancer agents or investigational treatments. You also need to be on a stable or decreasing dose of steroids for at least two weeks before joining the trial.

What data supports the effectiveness of the drug Temozolomide combined with radiation therapy for brain cancer?

Research shows that combining Temozolomide with radiation therapy can improve survival in patients with glioblastoma, a type of brain cancer, compared to radiation therapy alone. Additionally, studies on brain metastases from lung cancer suggest that this combination may enhance treatment response. ^{1 2 3 4 5}

Is the combination of Temozolomide and Radiation Therapy safe for treating brain cancer?

The combination of Temozolomide and Radiation Therapy has been studied for safety, showing common side effects like fatigue, nausea, vomiting, and low blood cell counts, which are usually mild to moderate. Severe blood-related side effects are rare, but have been reported in some cases. ^{5 6 7 8 9}

What makes the treatment of Temozolomide and Radiation Therapy unique for brain cancer?

The combination of Temozolomide (TMZ) and radiation therapy is unique because it has been shown to improve survival in patients with high-grade gliomas compared to radiation therapy alone. Temozolomide is an oral drug that can penetrate the brain effectively, and when used with radiation, it enhances the treatment's ability to kill cancer cells, especially in aggressive brain tumors like glioblastoma. ^{2 7 10 11 12}

Research Team

Anna Nowak, MD

Principal Investigator

Sir Charles Gairdner Hospital - Nedlands

S. Erridge

Principal Investigator

Medical Research Council

Wolfgang Wick

Principal Investigator

Universitatsklinikum Heidelberg

Warren P. Mason, MD

Principal Investigator

Princess Margaret Hospital, Canada

Michael A. Vogelbaum, MD, PhD

Principal Investigator

The Cleveland Clinic

Eligibility Criteria

This trial is for adults with a specific type of brain tumor called anaplastic glioma without 1p/19q LOH. They should have normal liver function, not be pregnant or nursing, and able to use contraception. Patients must have stable health without serious conditions affecting medication intake or follow-up, no HIV/hepatitis infections, and acceptable blood counts.

Inclusion Criteria

My cancer does not have a specific genetic feature (1p/19q loss).

Fertile patients must use effective contraception

No psychological, familial, sociological, or geographical condition that would potentially hamper compliance

Exclusion Criteria

I have not had radiation treatment to my brain.

I have not had chemotherapy or used Gliadel wafers.

I am not using growth factors unless absolutely necessary.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radiation

Patients undergo radiotherapy once daily, 5 days a week, for 6.5 weeks

6.5 weeks

33 visits (in-person)

Concurrent Chemotherapy

Patients receive oral temozolomide once daily during radiotherapy

6.5 weeks

Adjuvant Chemotherapy

Patients receive adjuvant oral temozolomide once daily on days 1-5, repeating every 28 days for up to 12 courses

up to 12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Every 3 months

Treatment Details

Interventions

• Adjuvant Therapy
• Radiation Therapy
• Temozolomide

Trial Overview The study compares the effectiveness of radiation therapy alone versus in combination with temozolomide chemotherapy in treating anaplastic glioma. Participants are randomly assigned to receive either just radiation or both treatments to see which works better at killing tumor cells.

Participant Groups

Group I: Radiotherapy (RT) alone Active Control 4 Interventions

radiation therapy alone

Group II: RT & Concurrent CT Active Control 5 Interventions

Radiotherapy and concurrent temozolomide chemotherapy

Group III: RT + Adjuvant CT Active Control 6 Interventions

Radiotherapy plus adjuvant temozolomide chemotherapy

Group IV: RT & Concurrent CT + adjuvant CT Active Control 6 Interventions

Radiotherapy and concurrent chemotherapy plus adjuvant temozolomide chemotherapy

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?

European Organisation for Research and Treatment of Cancer - EORTC

Lead Sponsor

Trials

417

Recruited

166,000+

NCIC Clinical Trials Group

Collaborator

Trials

190

Recruited

145,000+

Cooperative Trials Group for Neuro-Oncology

Collaborator

Trials

2

Recruited

850+

Medical Research Council

Collaborator

Trials

327

Recruited

1,999,000+

Radiation Therapy Oncology Group

Collaborator

Trials

191

Recruited

64,900+

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Findings from Research

In a randomized trial involving 144 patients with anaplastic astrocytoma (AA) and glioblastoma (GBM), neoadjuvant temozolomide (NeoTMZ) did not show a survival advantage for the overall population or for GBM patients compared to radiotherapy alone.

However, patients with AA who received NeoTMZ had a significantly longer median survival of 95.1 months compared to 35.2 months for those receiving only radiotherapy, indicating a potential benefit of NeoTMZ specifically for AA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Postoperative neoadjuvant temozolomide before radiotherapy versus standard radiotherapy in patients 60 years or younger with anaplastic astrocytoma or glioblastoma: a randomized trial. Malmström, A., Poulsen, HS., Grønberg, BH., et al.[2018]

In a study of 128 patients with brain metastases from non-small cell lung cancer, synchronous stereotactic radiotherapy (SRT) combined with temozolomide (TMZ) and whole brain radiotherapy (WBRT) significantly improved overall survival (OS) and progression-free survival (PFS) compared to SRT with WBRT alone, with median OS of 13.1 months and PFS of 11.2 months in the TMZ group.

While the combination treatment led to a higher incidence of nausea and vomiting (67.2% vs. 43.8%), other adverse reactions were similar between the two groups, indicating that the treatment is generally tolerable despite some side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of synchronous stereotactic radiotherapy with temozolomide combined with whole brain radiotherapy in treating brain metastases originating from non-small cell lung cancer. Liu, P., Ren, R., You, D., et al.[2021]

Combining brain radiotherapy (RT) with temozolomide (TMZ) significantly improves the objective response rate (ORR) in patients with brain metastases, with an odds ratio of 2.27, indicating a better response to treatment compared to RT alone.

However, this combination treatment does not lead to a significant improvement in overall survival (OS) or progression-free survival (PFS), and it is associated with increased adverse effects, such as severe nausea and thrombocytopenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brain Radiotherapy plus Concurrent Temozolomide versus Radiotherapy Alone for Patients with Brain Metastases: A Meta-Analysis. Zhao, Q., Qin, Q., Sun, J., et al.[2018]

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]

Whole-brain radiotherapy (WBRT) combined with temozolomide (TMZ) significantly improves the objective response rate in patients with brain metastases from non-small-cell lung cancer (NSCLC), with a relative risk of 1.43 based on a meta-analysis of 25 clinical trials.

However, this combination treatment also increases the risk of severe hematological (grade III-IV) and gastrointestinal toxicities compared to WBRT alone, indicating a need for careful monitoring of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Response and safety of whole-brain radiotherapy plus temozolomide for patients with brain metastases of non-small-cell lung cancer: A meta-analysis. Han, J., Qiu, M., Su, L., et al.[2022]

In a study of 9 patients with brain metastases from lung adenocarcinoma, the combination of intensity-modulated radiation therapy (IMRT) and temozolomide (TMZ) resulted in a high objective response rate of 77.8%, with one complete response and six partial responses, confirming the efficacy of this treatment approach.

Patients receiving the combination treatment experienced fewer severe adverse effects compared to those who only received IMRT, with no grade ≥3 hematologic toxicities reported, and an improvement in quality of life was noted, indicating that the addition of TMZ is both effective and relatively safe.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intensity-modulated radiation therapy combined with concomitant temozolomide for brain metastases from lung adenocarcinoma. Li, J., Chai, X., Cao, Y., et al.[2020]

In a phase II study involving 30 patients with brain metastases from non-small cell lung cancer (NSCLC), temozolomide (TMZ) was found to be an active and safe treatment option, with 10% of patients achieving an objective response, including two complete remissions.

No severe (grade 3 or 4) toxicities were reported, and all treatment-related adverse events were mild to moderate, indicating that TMZ can be administered without significant safety concerns in this heavily pre-treated patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral temozolomide in heavily pre-treated brain metastases from non-small cell lung cancer: phase II study. Giorgio, CG., Giuffrida, D., Pappalardo, A., et al.[2018]

Temozolomide (TMZ) is generally safe with mild to moderate side effects, but this case report highlights a rare instance of severe aplastic anemia (AA) in a 68-year-old female patient following treatment for glioblastoma, indicating a potential serious risk associated with the drug.

The patient's AA was managed successfully with supportive care, including platelet transfusions and growth factor treatment, and her blood counts returned to normal within 38 days, emphasizing the importance of monitoring blood parameters during and after TMZ treatment to detect such rare toxicities early.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide-induced aplastic anaemia: Case report and review of the literature. Gilbar, PJ., Pokharel, K., Mangos, HM.[2022]

A study of 128 glioma patients over a period of more than 10 years showed that combining temozolomide (TMZ) with radiotherapy significantly improves long-term survival compared to radiotherapy alone.

The treatment with TMZ resulted in manageable side effects, with only 9% of patients experiencing grade 3 hematological toxicity, indicating that the combination therapy is both effective and relatively safe.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide and radiotherapy versus radiotherapy alone in high grade gliomas: a very long term comparative study and literature review. Parisi, S., Corsa, P., Raguso, A., et al.[2018]

Temozolomide (TMZ) is the only anticancer drug proven to improve survival in glioblastoma when used with radiotherapy, showing high concentrations in brain tumors and cerebrospinal fluid, which enhances its effectiveness.

Molecular markers like MGMT promoter methylation can predict better responses to TMZ treatment, but side effects such as myelosuppression and nausea are common, necessitating precautions like prophylaxis against Pneumocystis carinii pneumonia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Temozolomide: Temodal]. Shinoura, N., Yamada, R., Tabei, Y., 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]

References

1. England pubmed.ncbi.nlm.nih.gov

Postoperative neoadjuvant temozolomide before radiotherapy versus standard radiotherapy in patients 60 years or younger with anaplastic astrocytoma or glioblastoma: a randomized trial. [2018]

2. Cyprus pubmed.ncbi.nlm.nih.gov

Efficacy of synchronous stereotactic radiotherapy with temozolomide combined with whole brain radiotherapy in treating brain metastases originating from non-small cell lung cancer. [2021]

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

Brain Radiotherapy plus Concurrent Temozolomide versus Radiotherapy Alone for Patients with Brain Metastases: A Meta-Analysis. [2018]

4. England pubmed.ncbi.nlm.nih.gov

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

5. Singapore pubmed.ncbi.nlm.nih.gov

Response and safety of whole-brain radiotherapy plus temozolomide for patients with brain metastases of non-small-cell lung cancer: A meta-analysis. [2022]

6. Greece pubmed.ncbi.nlm.nih.gov

Intensity-modulated radiation therapy combined with concomitant temozolomide for brain metastases from lung adenocarcinoma. [2020]

7. Ireland pubmed.ncbi.nlm.nih.gov

Oral temozolomide in heavily pre-treated brain metastases from non-small cell lung cancer: phase II study. [2018]

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

Concomitant treatment of brain metastasis with whole brain radiotherapy [WBRT] and temozolomide [TMZ] is active and improves quality of life. [2022]

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

Temozolomide-induced aplastic anaemia: Case report and review of the literature. [2022]

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

Temozolomide and radiotherapy versus radiotherapy alone in high grade gliomas: a very long term comparative study and literature review. [2018]

11. Japan pubmed.ncbi.nlm.nih.gov

[Temozolomide: Temodal]. [2018]

12. Iran pubmed.ncbi.nlm.nih.gov

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