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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial investigates whether combining atezolizumab and cabozantinib can shrink tumors in individuals with recurrent glioblastoma. Atezolizumab, an immunotherapy drug, aids the immune system in targeting cancer, while cabozantinib inhibits enzymes that promote tumor growth. The trial focuses on the safety and effectiveness of these treatments together. Individuals whose glioblastoma has returned after radiation and temozolomide treatment might be suitable candidates for this study. As a Phase 1 trial, the research aims to understand how the treatment works in people, providing participants an opportunity to contribute to groundbreaking cancer research.

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.

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

Research has shown that the combination of atezolizumab and cabozantinib is generally well-tolerated. In studies with patients who have recurrent glioblastoma, this treatment did not reveal any new safety concerns. The side effects were similar to those seen with other treatments using these drugs. While some side effects may occur, they are neither unexpected nor more severe than usual. This combination appears to be a manageable option for those considering joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about atezolizumab and cabozantinib for glioblastoma because they offer a novel approach compared to the traditional treatments like surgery, radiation, and chemotherapy. Atezolizumab is an immunotherapy drug that boosts the body's immune response to target cancer cells, while cabozantinib inhibits specific proteins that promote cancer cell growth and spread. This combination targets glioblastoma in a way that could enhance effectiveness and potentially improve outcomes for patients who have limited options with conventional therapies.

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

Research has shown that combining atezolizumab and cabozantinib may help treat recurring glioblastoma, a type of brain cancer. In this trial, participants will receive atezolizumab, which boosts the immune system to fight cancer cells, and cabozantinib, which inhibits enzymes that promote tumor growth. Studies have found this combination to be safe, with no new safety issues. Early results suggest it might help control tumor growth in glioblastoma patients. ^{1 3 4 5 6}

Who Is on the Research Team?

Shiao-Pei S. Weathers

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10639569/

CTIM-23. SAFETY RUN-IN RESULTS OF A PHASE I/II ... CONCLUSIONS. The combination of atezolizumab with cabozantinib was tolerable, and no new safety signals were noted. In this small cohort of recurrent GBM ...

2. academic.oup.com academic.oup.com/neuro-oncology/article/25/Supplement_5/v67/7405853

CTIM-23. SAFETY RUN-IN RESULTS OF A PHASE I/II STUDY ... The combination of atezolizumab with cabozantinib was tolerable, and no new safety signals were noted. In this small cohort of recurrent GBM ...

3. trialfinder.panfoundation.org trialfinder.panfoundation.org/en-US/trial/listing/303444

Atezolizumab and Cabozantinib for the Treatment of ... Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving atezolizumab and cabozantinib may ...

4. cancernetwork.com cancernetwork.com/view/second-line-cabozantinib-regimens-exhibit-efficacy-in-advanced-rcc

Second-Line Cabozantinib Regimens Exhibit Efficacy in ... The addition of atezolizumab (Tecentriq) to cabozantinib (Cabometyx) or cabozantinib alone exhibited efficacy and manageable safety as a second-line treatment ...

5. mdanderson.org mdanderson.org/patients-family/diagnosis-treatment/clinical-trials/clinical-trials-index/clinical-trials-detail.ID2021-0041.html

Phase I/II Study to Evaluate the Safety and Clinical Efficacy ... 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 ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05039281

NCT05039281 | Atezolizumab and Cabozantinib for the ... 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 ...