Anti-Tim-3 + Anti-PD-1 + SRS for Glioblastoma

Not currently recruiting at 2 trial locations

Overseen By Kelly Szajna Szajna, RN, BSN

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Must not be taking: Corticosteroids, Immunosuppressives

Disqualifiers: Other malignancy, Metastatic disease, Hemorrhage, Transplant, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 28 days per cycle

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new approach to treat glioblastoma, a type of brain cancer that has returned after treatment. It combines precise radiation therapy with two experimental drugs, MBG453 (an anti-Tim-3 monoclonal antibody) and spartalizumab, designed to help the immune system fight cancer. The main goal is to determine if this combination is safe and potentially more effective than current treatments. Candidates for this trial include those previously treated for glioblastoma, with specific tumor characteristics, and who can undergo MRI scans. As a Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the chance to be among the first to receive this innovative therapy.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are taking more than 4 mg of dexamethasone per day or other immunosuppressive medications, you may need to adjust your dosage before joining the trial.

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

Research has shown that the combination of two drugs, MBG453 and spartalizumab, has been tested in patients with advanced solid tumors. These studies have not identified any major safety issues, indicating that the treatment is generally well-tolerated. However, like many new treatments, some patients have experienced mild to moderate side effects, such as tiredness, nausea, or skin reactions.

This trial is in an early stage, and its main goal is to study the side effects and safety of this drug combination when used with a type of precise radiation therapy called stereotactic radiosurgery. The aim is to ensure safety before progressing to larger trials. While this phase focuses on safety, it's important to remember that treatments can affect people differently. Prospective participants should discuss potential risks and benefits with their healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments for glioblastoma?

Researchers are excited about the treatment combining MBG453, spartalizumab, and stereotactic radiosurgery (SRS) for glioblastoma because it targets the cancer in a unique way. Unlike the standard chemotherapy and radiation options, this approach uses immune checkpoint inhibitors—MBG453 and spartalizumab—that work by revving up the body's immune system to attack cancer cells. Additionally, the use of stereotactic radiosurgery allows for precise targeting of the tumor with high doses of radiation, potentially reducing damage to surrounding healthy tissue. This combination aims to enhance treatment effectiveness and could offer a new hope for patients with this aggressive brain cancer.

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

In this trial, participants will receive a combination of MBG453 and spartalizumab with targeted radiation therapy to treat glioblastoma. MBG453 blocks TIM-3, a protein that helps cancer cells evade the immune system, while spartalizumab inhibits PD-1, another protein that allows tumors to escape immune attacks. Research has shown that these drugs together have potential in stopping tumor growth in various solid cancers. Although this combination has been generally well-tolerated, glioblastoma remains a challenging cancer, and results can vary. By strengthening the immune system and accurately targeting the tumor with radiation, this method aims to improve patient outcomes. ^{2 3 5 6 7}

Who Is on the Research Team?

Lawrence Kleinberg, MD

Principal Investigator

Johns Hopkins University/Sidney Kimmel Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults over 18 with recurrent GBM who've had first-line therapy including surgery, radiation, and Temozolomide. They must have a Karnofsky Performance Status ≥ 70, no more than two recurrences of GBM or gliosarcoma confirmed by biopsy or MRI, normal organ/marrow function, and be able to undergo MRIs. Women must not be pregnant/breastfeeding and use contraception.

Inclusion Criteria

WBC ≥ 2,000/mcL absolute neutrophil count ≥ 1,500/mcL platelets ≥ 100,000/mcL hemoglobin ≥ 9.0 g/dL lymphocytes ≥ 500/mcL total bilirubin ≤ 1.5X institutional upper limit of normal AST/ALT ≤ 3.0 X institutional upper limit of normal creatinine ≤ 1.5X institutional upper limit of normal OR Creatinine clearance (CrCl) ≥ 50 mL/min (using the Cockcroft-Gault formula)

I am not pregnant or breastfeeding and have a recent negative pregnancy test.

I am able to care for myself but may not be able to do active work.

Exclusion Criteria

I have been treated with immune therapy, not including steroids.

I have lung disease that causes symptoms or could affect lung-related side effect management.

I have a known positive history of HIV or active Hepatitis B/C.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive MBG453 and spartalizumab intravenously on Day 1 and undergo stereotactic radiosurgery on Day 8. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

28 days per cycle

Follow-up

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

Up to 24 months

What Are the Treatments Tested in This Trial?

Interventions

• MBG453

Trial Overview The trial tests the safety of stereotactic radiosurgery combined with MBG453 and spartalizumab in treating recurrent GBM. It aims to see if this combination can better target cancer cells while sparing healthy tissue compared to current treatments.

How Is the Trial Designed?

Group I: Treatment (MBG453, spartalizumab, stereotactic radiosurgery) Experimental Treatment 1 Intervention

Patients receive MBG453 and spartalizumab IV over 30 minutes on Day 1. Patients then undergo stereotactic radiosurgery on Day 8. Courses with MBG453 and spartalizumab repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Who Is Running the Clinical Trial?

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Lead Sponsor

Trials

578

Recruited

33,600+

Novartis Pharmaceuticals

Industry Sponsor

Trials

2,963

Recruited

4,275,000+

Founded

1996

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Gleevec, Cosentyx, Entresto, Kisqali

Dr. Vas Narasimhan

Novartis Pharmaceuticals

Chief Executive Officer since 2018

MD from Harvard Medical School

Dr. Shreeram Aradhye

Novartis Pharmaceuticals

Chief Medical Officer since 2021

MD

Published Research Related to This Trial

M6903 is a fully human anti-TIM-3 antibody that effectively blocks TIM-3's interaction with its ligands, leading to enhanced T cell activation, which is crucial for improving anti-tumor immunity.

The combination of M6903 with bintrafusp alfa showed superior anti-tumor efficacy in preclinical models compared to either treatment alone, suggesting a promising avenue for cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification and characterization of M6903, an antagonistic anti-TIM-3 monoclonal antibody. Zhang, D., Jiang, F., Zaynagetdinov, R., et al.[2021]

Sabatolimab is a novel immunotherapy targeting TIM-3, designed to reactivate the immune system and directly attack TIM-3+ leukemic cells, which could improve outcomes for patients with higher-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML).

The phase III STIMULUS-MDS2 trial is investigating the combination of sabatolimab and azacitidine to assess its effectiveness in enhancing survival rates for patients who are unfit for hematopoietic stem cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

STIMULUS-MDS2 design and rationale: a phase III trial with the anti-TIM-3 sabatolimab (MBG453) + azacitidine in higher risk MDS and CMML-2. Zeidan, AM., Giagounidis, A., Sekeres, MA., et al.[2023]

Sabatolimab, a humanized anti-TIM-3 monoclonal antibody, is being developed for treating myeloproliferative disorders like acute myeloid leukemia, showcasing its potential as a novel immunotherapy.

This therapy works through multiple mechanisms, including blocking TIM-3 and its ligands, modulating leukemic cell self-renewal, and promoting antibody-dependent phagocytosis of TIM-3-expressing leukemic cells, which may enhance the overall antitumor immune response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TIM-3: a tumor-associated antigen beyond checkpoint inhibition? Barth, S., Naran, K.[2023]

In a phase I/II study involving 219 patients with advanced solid tumors, the combination of sabatolimab and spartalizumab was well tolerated, with fatigue being the most common treatment-related side effect.

While no responses were observed with sabatolimab alone, the combination treatment showed preliminary antitumor activity, with 5 patients achieving partial responses in various cancers, suggesting potential efficacy in specific populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/Ib Clinical Trial of Sabatolimab, an Anti-TIM-3 Antibody, Alone and in Combination with Spartalizumab, an Anti-PD-1 Antibody, in Advanced Solid Tumors. Curigliano, G., Gelderblom, H., Mach, N., et al.[2023]

The TIM-3 monoclonal antibody, LY3321367, demonstrated an acceptable safety profile in a phase Ia/b study with no dose-limiting toxicities observed in 30 patients receiving monotherapy and 28 patients receiving combination therapy.

While LY3321367 showed favorable pharmacokinetics and pharmacodynamics, its antitumor activity was modest, with only 4% objective response rate in combination therapy and 7% in monotherapy for patients previously treated with anti-PD-1 therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Blocking TIM-3 in Treatment-refractory Advanced Solid Tumors: A Phase Ia/b Study of LY3321367 with or without an Anti-PD-L1 Antibody. Harding, JJ., Moreno, V., Bang, YJ., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10849935/

Immunotherapy: Advancing glioblastoma treatment—A ... Immune checkpoint Inhibitors, specifically anti‐PD‐1 and anti‐PD‐L1 antibodies, have shown improvement in patient outcomes for cancers such as ...

2. withpower.com withpower.com/trial/anti-tim-3-anti-pd-1-srs-for-glioblastoma-bee4c

Anti-Tim-3 + Anti-PD-1 + SRS for Glioblastoma This trial studies a combination of precise radiation therapy and immune-boosting drugs to treat patients with recurring brain cancer.

3. aacrjournals.org aacrjournals.org/clincancerres/article/27/13/3620/671520/Phase-I-Ib-Clinical-Trial-of-Sabatolimab-an-Anti

Phase I/Ib Clinical Trial of Sabatolimab, an Anti–TIM-3 ... This phase I/II study evaluated the safety and efficacy of sabatolimab, with or without spartalizumab, in patients with advanced solid tumors.

4. sciencedirect.com sciencedirect.com/science/article/pii/S2950329924000158

Promising immunotherapy targets: TIM3, LAG3, and TIGIT ... Also, MBG453 combined with spartalizumab (anti-PD-1 antibody) was well tolerated with preliminary signs of anti-tumor activity in multiple solid ...

5. stanfordhealthcare.org stanfordhealthcare.org/trials/t/NCT03961971.html

Trial of Anti-Tim-3 in Combination With Anti-PD-1 and SRS ... This phase I trial studies the side effects of stereotactic radiosurgery with MBG453 and spartalizumab in treating patients with recurrent glioblastoma ...

6. clinicaltrials.gov clinicaltrials.gov/show/NCT03961971

Trial of Anti-Tim-3 in Combination With Anti-PD-1 and SRS ... This phase I trial studies the side effects of stereotactic radiosurgery with MBG453 and spartalizumab in treating patients with recurrent glioblastoma ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/33883177/

Phase I/Ib Clinical Trial of Sabatolimab, an Anti-TIM ... - PubMed This phase I/II study evaluated the safety and efficacy of sabatolimab, with or without spartalizumab, in patients with advanced solid tumors.