Atezolizumab + Cabozantinib for Glioblastoma

Overseen By Eva Gachimova

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Anti-PD-1, Anti-PD-L1, Anti-VEGF, Immunosuppressives

Disqualifiers: Autoimmune disease, Active infection, Hypertension, 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: 3

Duration: Up to 3 years

6 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I/II trial tests the safety and side effects of atezolizumab in combination with cabozantinib and whether they work to shrink tumors in patients with glioblastoma that has come back (recurrent). Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving atezolizumab and cabozantinib may help control the disease in patients with recurrent glioblastoma.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot take certain treatments like chemotherapy, hormonal therapy, immunotherapy, or radiotherapy while on the study. It's best to discuss your specific medications with the study team.

What data supports the effectiveness of the drug combination Atezolizumab and Cabozantinib for treating glioblastoma?

Cabozantinib has shown activity in patients with recurrent glioblastoma, and Atezolizumab, an immune checkpoint inhibitor, has demonstrated clinical activity in various cancers, including glioblastoma. These findings suggest potential effectiveness when used together for glioblastoma. ^{1 2 3 4 5}

Is the combination of Atezolizumab and Cabozantinib safe for humans?

Atezolizumab and Cabozantinib have been studied separately in patients with glioblastoma, showing some clinical activity. Atezolizumab has been tested for safety in various cancers, and Cabozantinib has been evaluated in glioblastoma patients, indicating it is generally safe, but specific safety data for their combination in glioblastoma is not provided. ^{1 2 3 4 6}

How is the drug combination of Atezolizumab and Cabozantinib unique for treating glioblastoma?

This drug combination is unique because it combines Atezolizumab, an immune checkpoint inhibitor that helps the immune system attack cancer cells, with Cabozantinib, which targets specific proteins (MET and VEGFR2) involved in tumor growth and blood supply. This dual approach may offer a novel way to treat glioblastoma, especially since there is no standard treatment for recurrent cases. ^{1 2 3 4 7}

Research Team

Shiao-Pei S. Weathers

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

Adults (18+) with recurrent glioblastoma previously treated with radiation and temozolomide, who have a Karnofsky performance status of >=60. Must not be pregnant or breastfeeding, agree to use contraception, and have adequate organ function as indicated by specific lab values. Cannot join if they've had certain other cancer treatments, serious medical conditions that interfere with the study, or known allergies to trial medications.

Inclusion Criteria

Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN

I am a woman able to have children and agree to use 2 birth control methods or abstain from sex during the study and for 5 months after.

I am mostly able to care for myself but may need occasional help.

Exclusion Criteria

Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator

History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies, fusion proteins or components of cabozantinib

I haven't had radiation for bone metastasis in 2 weeks or any radiation in 4 weeks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive atezolizumab intravenously on day 1 and cabozantinib orally on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Up to 3 years

Monthly visits for treatment administration

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up at 30 days and then every 3 months.

Up to 3 years

Follow-up visits every 3 months

Treatment Details

Interventions

• Atezolizumab
• Cabozantinib

Trial Overview The safety and effectiveness of combining Atezolizumab (an immunotherapy drug) with Cabozantinib (a drug that blocks tumor growth enzymes) in shrinking tumors for patients whose glioblastoma has returned after treatment.

Participant Groups

Group I: Treatment (atezolizumab, cabozantinib) Experimental Treatment 2 Interventions

Patients receive atezolizumab IV over 30-60 minutes on day 1 and cabozantinib PO on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Atezolizumab is already approved in United States, European Union for the following indications:

Approved in United States as Tecentriq for:

• Melanoma
• Hepatocellular carcinoma
• Small cell lung cancer
• Non-small cell lung cancer
• Urothelial carcinoma

Approved in European Union as Tecentriq for:

• Melanoma
• Hepatocellular carcinoma
• Small cell lung cancer
• Non-small cell lung cancer
• Urothelial carcinoma

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Findings from Research

Cabozantinib, when administered at a dose of 40 mg daily alongside radiotherapy and temozolomide, was generally well tolerated in patients with newly diagnosed high-grade glioma, with no significant drug interactions noted.

The study identified thrombocytopenia, leukopenia, and deep vein thrombosis/pulmonary embolism as the most common severe side effects, indicating the need for careful monitoring of these conditions in patients undergoing this treatment regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 dose escalation trial of the safety and pharmacokinetics of cabozantinib concurrent with temozolomide and radiotherapy or temozolomide after radiotherapy in newly diagnosed patients with high-grade gliomas. Schiff, D., Desjardins, A., Cloughesy, T., et al.[2018]

In a phase II trial involving 222 patients with recurrent glioblastoma, cabozantinib showed a modest objective response rate of 4.3% among those who had previously received antiangiogenic therapy, indicating limited efficacy in this population.

The treatment was associated with significant adverse events, with 74.3% of patients experiencing fatigue and 48.6% requiring dose reductions due to side effects, highlighting safety concerns that led to a dose adjustment from 140 mg/day to 100 mg/day.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of cabozantinib in patients with progressive glioblastoma: subset analysis of patients with prior antiangiogenic therapy. Cloughesy, TF., Drappatz, J., de Groot, J., et al.[2019]

Atezolizumab, an immune checkpoint inhibitor, was found to be safe and well tolerated in a phase 1a clinical trial involving 16 patients with recurrent glioblastoma, with no severe treatment-related side effects reported.

The treatment showed some efficacy, with one patient achieving a partial response and three others stabilizing their disease, while median overall survival was 4.2 months, suggesting that certain biomarkers like peripheral CD4+ T cells may help identify patients who could benefit most from this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical activity and safety of atezolizumab in patients with recurrent glioblastoma. Lukas, RV., Rodon, J., Becker, K., et al.[2020]

In a phase II trial involving 152 patients with recurrent glioblastoma, cabozantinib demonstrated an objective response rate of 17.6% at a higher dose and 14.5% at a lower dose, indicating some clinical activity but not meeting the predefined success criteria.

The treatment was associated with a high incidence of grade 3/4 adverse events (around 79-85%), leading to significant dose reductions in many patients, highlighting the need for careful management of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of cabozantinib in patients with progressive glioblastoma: subset analysis of patients naive to antiangiogenic therapy. Wen, PY., Drappatz, J., de Groot, J., et al.[2022]

A new treatment strategy using a p38MAPK inhibitor combined with a PD-L1 antibody has been shown to significantly prolong survival in mouse models of glioblastoma that are resistant to temozolomide (TMZ).

This combination therapy works by reducing harmful macrophages and microglia in the tumor environment, suggesting it could be a promising option for patients with recurrent or chronic TMZ-resistant glioblastoma, pending further clinical safety and efficacy studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of p38 MAPK inhibitor with PD-L1 antibody effectively prolongs survivals of temozolomide-resistant glioma-bearing mice via reduction of infiltrating glioma-associated macrophages and PD-L1 expression on resident glioma-associated microglia. Dang, W., Xiao, J., Ma, Q., et al.[2021]

In a phase II clinical trial involving 158 patients with newly diagnosed glioblastoma, cediranib combined with radiation and temozolomide significantly improved 6-month progression-free survival (PFS) to 46.6% compared to 24.5% for the placebo group (P = 0.005).

Although cediranib showed efficacy in prolonging PFS, it was associated with a higher incidence of grade ≥3 adverse events compared to placebo (P = 0.02), and there was no significant difference in overall survival between the two treatment groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NRG/RTOG 0837: Randomized, phase II, double-blind, placebo-controlled trial of chemoradiation with or without cediranib in newly diagnosed glioblastoma. Batchelor, TT., Won, M., Chakravarti, A., et al.[2023]

In a study of 33 adults with newly diagnosed glioblastoma, bavituximab combined with standard treatment (radiotherapy and temozolomide) achieved a 12-month overall survival rate of 73%, meeting the primary endpoint of the trial.

Bavituximab treatment led to a significant reduction in immunosuppressive myeloid-derived suppressor cells in tumor specimens, suggesting its potential to enhance anti-tumor immunity in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bavituximab Decreases Immunosuppressive Myeloid-Derived Suppressor Cells in Newly Diagnosed Glioblastoma Patients. Ly, KI., Richardson, LG., Liu, M., et al.[2023]

References

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

Phase 1 dose escalation trial of the safety and pharmacokinetics of cabozantinib concurrent with temozolomide and radiotherapy or temozolomide after radiotherapy in newly diagnosed patients with high-grade gliomas. [2018]

2. England pubmed.ncbi.nlm.nih.gov

Phase II study of cabozantinib in patients with progressive glioblastoma: subset analysis of patients with prior antiangiogenic therapy. [2019]

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

Clinical activity and safety of atezolizumab in patients with recurrent glioblastoma. [2020]

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

Phase II study of cabozantinib in patients with progressive glioblastoma: subset analysis of patients naive to antiangiogenic therapy. [2022]

5. Japan pubmed.ncbi.nlm.nih.gov

Combination of p38 MAPK inhibitor with PD-L1 antibody effectively prolongs survivals of temozolomide-resistant glioma-bearing mice via reduction of infiltrating glioma-associated macrophages and PD-L1 expression on resident glioma-associated microglia. [2021]

6. England pubmed.ncbi.nlm.nih.gov

NRG/RTOG 0837: Randomized, phase II, double-blind, placebo-controlled trial of chemoradiation with or without cediranib in newly diagnosed glioblastoma. [2023]

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

Bavituximab Decreases Immunosuppressive Myeloid-Derived Suppressor Cells in Newly Diagnosed Glioblastoma Patients. [2023]