Mycophenolate Mofetil + Standard Care for Glioblastoma

Overseen by Priya U. Kumthekar

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Northwestern University

Must not be taking: Investigational agents, Viral-vector therapy

Disqualifiers: Uncontrolled epilepsy, Concurrent malignancy, HIV, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial tests if combining mycophenolate mofetil with temozolomide and radiation can better treat glioblastoma, an aggressive brain cancer. Mycophenolate mofetil may help chemotherapy work better by making cancer cells easier to kill. Temozolomide is a standard chemotherapeutic drug for glioblastoma, often combined with radiotherapy to improve patient survival.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, you cannot participate if you are on other investigational drugs or require live vaccinations within two weeks of starting the trial medications.

What data supports the effectiveness of the drug combination of Mycophenolate Mofetil and Temozolomide with radiation therapy for glioblastoma?

Research shows that Temozolomide, when used with radiation therapy, improves survival rates in patients with glioblastoma. This combination has become a standard treatment, demonstrating benefits in both median and 2-year survival rates. ^{1 2 3 4 5}

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

Temozolomide, when used with radiation therapy, has been shown to have a lower toxicity profile compared to older chemotherapy drugs and is generally well-tolerated in patients with glioblastoma. However, patients may need preventive treatment for certain infections during therapy. ^{1 6 7 8 9}

How is the drug Mycophenolate Mofetil combined with standard care different from other treatments for glioblastoma?

The combination of Mycophenolate Mofetil with standard care for glioblastoma is unique because it adds an immunosuppressive drug (Mycophenolate Mofetil) to the existing standard treatment of temozolomide and radiation therapy, potentially offering a novel approach to enhance treatment effectiveness by targeting the immune system. ^{1 2 3 10 11}

Research Team

Priya U. Kumthekar

Principal Investigator

Northwestern University

Eligibility Criteria

Adults diagnosed with glioblastoma, who've had surgery or biopsy and are stable on low-dose corticosteroids. They must be able to perform daily activities (Karnofsky score >=70), have adequate organ function, and agree to use contraception. Excluded are those with other cancers, certain infections, uncontrolled illnesses, pregnant/nursing women, inability to take oral meds, or known HIV/HBV/HCV.

Inclusion Criteria

Patients with specific laboratory values within 14 days prior to study registration

My brain tumor is confirmed as glioblastoma or has similar features.

My dose of corticosteroids is stable or decreasing.

Exclusion Criteria

I do not have uncontrolled epilepsy, another cancer needing treatment, severe infections, immune issues, major psychiatric illness, and I'm not pregnant or nursing. I also don't have trouble swallowing or a history of HIV, HBV, or HCV.

I do not have another cancer that could affect this study's treatment or safety.

Patients with history of allergic reactions to compounds similar to temozolomide or mycophenolate mofetil

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive mycophenolate mofetil (MMF) in combination with temozolomide (TMZ) and/or radiation therapy. Treatment repeats every 28 days for up to 6 cycles.

24 weeks

Daily visits for radiation therapy during the first 6 weeks, followed by regular visits every 28 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

18 months

Follow-up at 30 days post-treatment, then every 3 months

Treatment Details

Interventions

• Mycophenolate Mofetil (Immunosuppressant)
• Radiation Therapy (Radiation)
• Temozolomide (Alkylating agents)

Trial Overview The trial is testing the safety and optimal dose of Mycophenolate Mofetil when combined with standard treatments for glioblastoma: Temozolomide and Radiation Therapy. The goal is to see if this drug makes cancer cells more sensitive to treatment.

Participant Groups

Group I: Group S (pre-surgical MMF, TMZ) Experimental Treatment 3 Interventions

Patients planning to undergo surgery receive MMF PO BID and TMZ PO QD for 5 days prior to surgery in the absence of disease progression or unacceptable toxicity.

Group II: Group 3 (TMZ, MMF, radiation therapy) Experimental Treatment 4 Interventions

Patients who have already undergone surgery or biopsy receive TMZ PO QD on days 1-5 of each cycle and MMF PO BID. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Starting at the same time as TMZ and MMF administration, patients also receive radiation therapy daily, 5 days per week, for 6 weeks.

Group III: Group 2 (TMZ, MMF, radiation therapy) Experimental Treatment 4 Interventions

Patients with unmethylated glioblastoma who have already undergone surgery or biopsy receive TMZ PO QD on days 1-5 of each cycle and MMF PO BID. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Starting at the same time as TMZ and MMF administration, patients also receive radiation therapy daily, 5 days per week, for 6 weeks.

Group IV: Group 1 (TMZ, MMF) Experimental Treatment 3 Interventions

Patients who have already undergone surgery or biopsy followed by chemoradiation receive TMZ PO QD on days 1-5 of each cycle and MMF PO BID. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

Mycophenolate Mofetil is already approved in Canada, Japan for the following indications:

Approved in Canada as Cellcept for:

• Prevention of acute organ rejection in kidney, liver, and heart transplant patients
• Treatment of autoimmune diseases such as lupus nephritis and rheumatoid arthritis

Approved in Japan as Cellcept for:

• Prevention of acute organ rejection in kidney, liver, and heart transplant patients
• Treatment of autoimmune diseases such as lupus nephritis and rheumatoid arthritis

Who Is Running the Clinical Trial?

Northwestern University

Lead Sponsor

Trials

1,674

Recruited

989,000+

Dr. Jeffrey Sherman

Northwestern University

Chief Medical Officer

MD from Northwestern University

Dr. Alicia Löffler

Northwestern University

Chief Executive Officer since 2010

PhD from the University of Massachusetts at Amherst, post-doctoral training at Caltech

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Dr. Douglas R. Lowy

National Cancer Institute (NCI)

Chief Executive Officer since 2023

MD from New York University School of Medicine

Dr. Monica Bertagnolli

National Cancer Institute (NCI)

Chief Medical Officer since 2022

MD from Harvard Medical School

Findings from Research

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 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]

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]

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 study of 51 patients with newly diagnosed glioblastoma, concurrent treatment with temozolomide (TMZ) and radiotherapy was found to be the new standard of care.

The occurrence of early necrosis in 14% of patients, without signs of tumor recurrence, suggests that TMZ may enhance the effectiveness of radiotherapy by acting as a radiosensitizer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early necrosis following concurrent Temodar and radiotherapy in patients with glioblastoma. Chamberlain, MC., Glantz, MJ., Chalmers, L., 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]

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 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 573 glioblastoma multiforme patients, those treated with temozolomide alongside radiotherapy experienced significantly improved overall survival, with a median survival of 14.6 months compared to 12.1 months for those receiving radiotherapy alone.

The combination treatment was associated with some adverse effects, including thrombocytopenia and nausea, but overall, the benefits in survival rates suggest that temozolomide is an effective option for newly diagnosed glioblastoma multiforme patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Food and Drug Administration Drug approval summary: temozolomide plus radiation therapy for the treatment of newly diagnosed glioblastoma multiforme. Cohen, MH., Johnson, JR., Pazdur, R.[2018]

Temozolomide, a key chemotherapy drug for glioblastoma, faces significant resistance primarily due to the activation of the O-6-methylguanine-DNA methyltransferase enzyme, which repairs the DNA damage caused by the drug, thus restoring genomic integrity.

Recent research has identified various mechanisms contributing to temozolomide resistance, including indirect DNA repair systems, drug efflux mechanisms, epigenetic changes, and influences from the tumor microenvironment, highlighting the complexity of overcoming this resistance in treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide Resistance: A Multifarious Review on Mechanisms Beyond O-6-Methylguanine-DNA Methyltransferase. Rao, V., Kumar, G., Vibhavari, RJA., et al.[2023]

In a study of 116 patients with glioblastoma multiforme (GBM), treatment with radiotherapy combined with concomitant and adjuvant temozolomide resulted in a median overall survival of 9 months, with 1- and 2-year survival rates of 41.9% and 9.6%, respectively.

Key prognostic factors influencing survival included age, Karnofsky performance scale (KPS) score, presence of seizures, and total radiation doses, all of which were confirmed as significant in both univariate and multivariate analyses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prognostic significance of concomitant radiotherapy in newly diagnosed glioblastoma multiforme: a multivariate analysis of 116 patients. Okumus, NO., Gursel, B., Meydan, D., et al.[2021]

References

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

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

2. Netherlands pubmed.ncbi.nlm.nih.gov

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

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. England pubmed.ncbi.nlm.nih.gov

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

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

Early necrosis following concurrent Temodar and radiotherapy in patients with glioblastoma. [2022]

6. 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]

7. 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]

8. Greece pubmed.ncbi.nlm.nih.gov

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

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

Food and Drug Administration Drug approval summary: temozolomide plus radiation therapy for the treatment of newly diagnosed glioblastoma multiforme. [2018]

10. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Temozolomide Resistance: A Multifarious Review on Mechanisms Beyond O-6-Methylguanine-DNA Methyltransferase. [2023]

11. Saudi Arabia pubmed.ncbi.nlm.nih.gov

Prognostic significance of concomitant radiotherapy in newly diagnosed glioblastoma multiforme: a multivariate analysis of 116 patients. [2021]