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

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

16 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the drug combination of Anti-Tim-3, Anti-PD-1, and SRS for glioblastoma?

Research shows that combining Anti-PD-1 and stereotactic radiosurgery (SRS) improves immune response against tumors in a mouse model of glioma. Additionally, TIM-3, a target of the drug sabatolimab, is linked to immune responses in glioma, suggesting it could be a promising target for treatment when glioma becomes resistant to other therapies. ^{1 2 3 4 5}

Is the combination of Anti-Tim-3, Anti-PD-1, and SRS safe for humans?

Sabatolimab (also known as MBG453), an Anti-Tim-3 antibody, has been studied for safety in combination with spartalizumab, an Anti-PD-1 antibody, in patients with advanced solid tumors. These studies are part of early-phase clinical trials, which are designed to evaluate safety and tolerability in humans. ^{1 5 6 7 8}

What makes the Anti-Tim-3 + Anti-PD-1 + SRS treatment unique for glioblastoma?

This treatment is unique because it combines two immune checkpoint inhibitors, Anti-Tim-3 and Anti-PD-1, with stereotactic radiosurgery (SRS) to enhance the immune system's ability to fight glioblastoma, a type of brain cancer. By targeting both TIM-3 and PD-1, it aims to overcome immune resistance and improve the effectiveness of the immune response against the tumor. ^{1 2 4 9 10}

What is the purpose of this trial?

This trial studies a combination of precise radiation therapy and immune-boosting drugs to treat patients with recurring brain cancer. The goal is to directly target the tumor and enhance the body's immune response against cancer cells.

Research Team

Lawrence Kleinberg, MD

Principal Investigator

Johns Hopkins University/Sidney Kimmel Cancer Center

Eligibility Criteria

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.

My tumor is 5 cm or smaller.

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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]

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]

References

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

Combination Therapy with Anti-PD-1, Anti-TIM-3, and Focal Radiation Results in Regression of Murine Gliomas. [2022]

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

Molecular and clinical characterization of TIM-3 in glioma through 1,024 samples. [2022]

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

Expression of LAG-3 and efficacy of combination treatment with anti-LAG-3 and anti-PD-1 monoclonal antibodies in glioblastoma. [2022]

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

In Vivo Evaluation of Near-Infrared Fluorescent Probe for TIM3 Targeting in Mouse Glioma. [2023]

5. United States 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. [2023]

6. England 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. [2023]

7. England pubmed.ncbi.nlm.nih.gov

TIM-3: a tumor-associated antigen beyond checkpoint inhibition? [2023]

8. India pubmed.ncbi.nlm.nih.gov

Tim-3 expression in glioma cells is associated with drug resistance. [2022]

9. United States 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. [2023]

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

Identification and characterization of M6903, an antagonistic anti-TIM-3 monoclonal antibody. [2021]