TSR-022 for Cancer

Recruiting in Palo Alto (17 mi)

+52 other locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Tesaro, Inc.

Must be taking: Antivirals

Must not be taking: Immunosuppressants, Steroids

Disqualifiers: Uncontrolled CNS metastases, Active infection, Autoimmune disease, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial is testing TSR-022, a new medicine that helps the immune system fight cancer by blocking a protein called TIM-3. TIM-3 has gained prominence as a potential candidate for cancer immunotherapy, where it has been shown that blocking TIM-3 with other treatments enhances the body's ability to fight tumors and suppress their growth. It targets patients with tumors, especially those who may not respond to standard treatments. The goal is to see if this medicine can help the immune system better attack cancer cells.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on systemic steroid therapy or immunosuppressive therapy, you must stop these at least 7 days before starting the study treatment. It's best to discuss your specific medications with the study team.

What data supports the effectiveness of the drug TSR-022 (Cobolimab, GSK-4069889, WBP 296A, Anti-TIM-3-antibody-GSK) for cancer?

Research shows that blocking TIM-3, a molecule that can help cancer cells evade the immune system, may enhance the body's ability to fight cancer. Studies on similar anti-TIM-3 antibodies have demonstrated improved immune responses and reduced tumor growth in preclinical models, suggesting potential effectiveness in cancer treatment. ^{1 2 3 4 5}

Is TSR-022 (Cobolimab) safe for humans?

The research does not provide specific safety data for TSR-022 (Cobolimab) in humans, but similar treatments targeting TIM-3 have shown promising results in preclinical studies, suggesting potential for safe use in humans. ^{2 5 6 7 8}

What makes the drug TSR-022 unique for cancer treatment?

TSR-022, also known as Cobolimab, is unique because it targets TIM-3, a protein that can suppress immune responses, thereby enhancing the body's ability to fight cancer by activating T-cells (a type of immune cell). This mechanism is different from many traditional cancer treatments that directly target cancer cells, as TSR-022 works by boosting the immune system's natural ability to attack tumors. ^{9 10 11 12 13}

Research Team

GSK Clinical Trials

Principal Investigator

GlaxoSmithKline

Eligibility Criteria

This trial is for adults with advanced solid tumors who've had no more than two prior therapies, including a platinum-based chemo and an anti-PD-(L)1 antibody. They must have measurable disease progression, adequate organ function, ECOG performance status of 0 or 1, and a life expectancy of at least three months. Women of childbearing potential need a negative pregnancy test.

Inclusion Criteria

I've had up to 2 treatments for my advanced cancer, including platinum chemotherapy and anti-PD-1/L1 therapy.

My cancer has worsened after treatments including platinum chemotherapy and anti-PD-1 or PD-L1 therapy.

I agree to provide a tissue sample from my cancer that was not treated with radiation.

Exclusion Criteria

Participant is pregnant or breastfeeding, or expecting to conceive children within the projected duration of the study.

My cancer has a specific change in the EGFR, ALK, or ROS-1 gene.

My cancer progressed within 8 weeks after starting treatment with a PD-1 or PD-L1 inhibitor.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Part 1 of the study involves dose escalation to determine the recommended Phase 2 dose (RP2D) of TSR-022

8-12 weeks

Dose Expansion

Part 2 of the study evaluates the antitumor activity of TSR-022 in combination with TSR-042 or docetaxel and as monotherapy

16-24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

Treatment Details

Interventions

• TSR-022 (Monoclonal Antibodies)

Trial Overview The AMBER study tests TSR-022, an anti-TIM-3 antibody for treating tumors. It has two parts: dose escalation to find the safe dosage (Part 1), and dose expansion to assess antitumor activity in combination with other drugs like TSR-042 or docetaxel or as monotherapy (Part 2).

Participant Groups

Group I: Part 2:Cohort C Colorectal cancer-TSR-022 with TSR-042 Experimental Treatment 2 Interventions

Group II: Part 2:Cohort C Colorectal cancer-TSR-022 as monotherapy Experimental Treatment 1 Intervention

Group III: Part 2:Cohort B Non-small cell lung cancer-TSR-022-monotherapy Experimental Treatment 1 Intervention

Group IV: Part 2:Cohort B Non-small cell lung cancer-TSR-022 with TSR-042 Experimental Treatment 2 Interventions

Group V: Part 2: Cohort F- Hepatocellular carcinoma (HCC)-TSR-022 with TSR-042 Experimental Treatment 2 Interventions

Group VI: Part 2: Cohort E-Non-small cell lung cancer-TSR-022 with docetaxel Experimental Treatment 2 Interventions

Group VII: Part 2: Cohort D-TIM-3 selected non-small cell lung cancer (NSCLC)-TSR-022 with TSR-042 Experimental Treatment 2 Interventions

Group VIII: Part 2: Cohort A Melanoma-TSR-022 with TSR-042 Experimental Treatment 2 Interventions

Group IX: Part 2: Cohort A Melanoma-TSR-022 as monotherapy Experimental Treatment 1 Intervention

Group X: Part 1h: TSR-022 in combination with TSR-042, pemetrexed, and carboplatin Experimental Treatment 4 Interventions

Group XI: Part 1g: TSR-022 in combination with TSR-042, pemetrexed, and cisplatin Experimental Treatment 4 Interventions

Group XII: Part 1f: TSR-022 in combination with TSR-042 and Docetaxel Experimental Treatment 3 Interventions

Group XIII: Part 1e: TSR-022 with TSR-042 (not previously treated with anti-programmed death ligand [PD-{L}]1) Experimental Treatment 2 Interventions

Group XIV: Part 1d: TSR-022 in combination with TSR-042 and TSR-033 Experimental Treatment 3 Interventions

Group XV: Part 1c: TSR-022 in combination with TSR-042 Experimental Treatment 2 Interventions

Group XVI: Part 1b: TSR-022 in combination with nivolumab Experimental Treatment 2 Interventions

Group XVII: Part 1a: TSR-022 monotherapy Experimental Treatment 1 Intervention

Who Is Running the Clinical Trial?

Tesaro, Inc.

Lead Sponsor

Trials

57

Recruited

10,600+

Findings from Research

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]

TIM-3 is expressed in tumor infiltrating lymphocytes (TILs) in all 109 samples of triple-negative breast cancer (TNBC) studied, and higher levels of TIM-3 are associated with younger patients, higher tumor stages, and increased expression of PD-1 and PD-L1.

High TIM-3 expression is linked to significantly better disease-free survival and overall survival in TNBC patients, indicating it may serve as an independent positive prognostic factor despite being associated with more aggressive disease features.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T-Cell Immunoglobulin Mucin 3 Expression on Tumor Infiltrating Lymphocytes as a Positive Prognosticator in Triple-Negative Breast Cancer. Byun, KD., Hwang, HJ., Park, KJ., et al.[2022]

The blockade of immune checkpoint receptors, like Tim-3 and PD-1, shows promise in reducing tumor progression and enhancing T-cell responses in cancer treatment, particularly in preclinical models.

Tim-3 is expressed by various immune cells and leukemic stem cells, indicating its potential as a target for improving therapies in cancers that currently resist treatment, such as microsatellite-stable colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tim-3 finds its place in the cancer immunotherapy landscape. Acharya, N., Sabatos-Peyton, C., Anderson, AC.[2021]

Tim-3 is a promising new target for cancer immunotherapy, particularly in breast cancer, where its expression on both immune and tumor cells can influence treatment outcomes.

Genetic variations in the Tim-3 gene are linked to a higher risk of developing breast cancer, suggesting that targeting Tim-3 could enhance therapeutic strategies for patients who do not respond to current immune checkpoint inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Emerging Role of T-Cell Immunoglobulin Mucin-3 in Breast Cancer: A Promising Target For Immunotherapy. Cong, Y., Liu, J., Chen, G., et al.[2021]

The compound ML-T7 effectively targets Tim-3, enhancing the survival and antitumor activity of CD8+ T cells and CAR T cells, while also reducing T cell exhaustion in both laboratory and animal studies.

ML-T7 not only improves T cell function but also boosts the activity of natural killer (NK) cells and dendritic cells, showing comparable tumor inhibition to Tim-3 blocking antibodies and greater efficacy when combined with anti-PD-1 therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification of a small-molecule Tim-3 inhibitor to potentiate T cell-mediated antitumor immunotherapy in preclinical mouse models. Ma, S., Tian, Y., Peng, J., et al.[2023]

Novel monoclonal antibodies targeting TIM-3 and TIM-4 significantly enhance the effectiveness of cancer vaccines against established B16 murine melanomas, suggesting a new approach to improve cancer immunotherapy.

The combination of anti-TIM-3 and anti-TIM-4 mAbs not only boosts vaccine-induced antitumor responses but also reveals distinct mechanisms of action, with TIM-3 blockade enhancing natural killer cell activity and TIM-4 primarily activating CD8(+) T cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined blockade of TIM-3 and TIM-4 augments cancer vaccine efficacy against established melanomas. Baghdadi, M., Nagao, H., Yoshiyama, H., et al.[2016]

Tim-3 is recognized as a key negative regulator of immune responses, particularly affecting CD4(+) T helper 1 and CD8(+) T cytotoxic 1 cells, which are crucial for fighting infections and cancer.

Recent research indicates that Tim-3 contributes to T cell exhaustion in chronic conditions like viral infections and cancer, and it also impacts cancer outcomes by influencing myeloid cells and cancer stem cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tim-3, a negative regulator of anti-tumor immunity. Anderson, AC.[2022]

GFRA1 has been identified as a promising tumor-associated antigen in breast cancer, showing limited expression in normal tissues but overexpression in certain breast cancer subsets, making it a potential target for treatment.

The GFRA1-targeted antibody-drug conjugate (ADC) demonstrated effective cytotoxicity in GFRA1-positive cancer cell lines and patient-derived xenograft models, with a safety profile indicating no on-target toxicity, although some transient effects were noted in bone marrow and peripheral blood.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical evaluation of a GFRA1 targeted antibody-drug conjugate in breast cancer. Bosco, EE., Christie, RJ., Carrasco, R., et al.[2019]

The study highlights the potential of targeting the glucocorticoid-induced TNF receptor-related (GITR) as a co-stimulatory receptor to enhance immunotherapy efficacy by activating T cells and reducing tumor-infiltrating Treg cells.

A newly developed fully human anti-GITR antibody, hab019e2, demonstrated superior antitumor activity in a mouse model compared to existing antibodies, suggesting it could be a promising candidate for future cancer treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of a fully human anti-GITR antibody with potent antitumor activity using H2L2 mice. Tong, Q., Liu, H., Qi, Q., et al.[2022]

Glofitamab, a bispecific antibody targeting CD20 and CD3, demonstrated clinical activity in patients with relapsed/refractory B-cell non-Hodgkin lymphoma during a phase 1 trial, showing T-cell activation and tumor cell killing.

The study identified that tumor intrinsic factors, such as TP53 signaling, may contribute to resistance against glofitamab, indicating that these factors could serve as important biomarkers for predicting treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacodynamics and molecular correlates of response to glofitamab in relapsed/refractory non-Hodgkin lymphoma. Bröske, AE., Korfi, K., Belousov, A., et al.[2022]

The newly developed TR3H single chain tri-specific antibody (scTsAb) effectively activates T-cells to target and kill ovarian tumor cells, demonstrating its potential as a tumor immunotherapy.

TR3H has a smaller molecular size compared to the previous scTsAb format (sTRI), which may improve its pharmacokinetics and reduce immunogenicity, making it a promising candidate for cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A new format of single chain tri-specific antibody with diminished molecular size efficiently induces ovarian tumor cell killing. Liu, J., Zhao, Q., Zhao, B., et al.[2006]

Bispecific antibodies (bsAbs) targeting glioblastoma-associated antigens can effectively activate T cells to kill tumor cells, with the anti-CD28 bsFab2 showing superior co-stimulation when targeting the chondroitin-sulfate proteoglycan (CSPG) due to its higher expression on the tumor surface.

The effectiveness of anti-CD3 bsFab2 is enhanced when targeting the EGF receptor (EGFR), suggesting that factors beyond just antigen expression, like membrane mobility, influence T-cell activation; this has led to the use of EGFR-targeting bsFab2 in a clinical trial for glioma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of target antigen in bispecific-antibody-mediated killing of human glioblastoma cells: a pre-clinical study. Pfosser, A., Brandl, M., Salih, H., et al.[2019]

References

1. 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]

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

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

3. Korea (South) pubmed.ncbi.nlm.nih.gov

T-Cell Immunoglobulin Mucin 3 Expression on Tumor Infiltrating Lymphocytes as a Positive Prognosticator in Triple-Negative Breast Cancer. [2022]

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

Tim-3 finds its place in the cancer immunotherapy landscape. [2021]

5. Switzerland pubmed.ncbi.nlm.nih.gov

The Emerging Role of T-Cell Immunoglobulin Mucin-3 in Breast Cancer: A Promising Target For Immunotherapy. [2021]

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

Identification of a small-molecule Tim-3 inhibitor to potentiate T cell-mediated antitumor immunotherapy in preclinical mouse models. [2023]

7. Germany pubmed.ncbi.nlm.nih.gov

Combined blockade of TIM-3 and TIM-4 augments cancer vaccine efficacy against established melanomas. [2016]

8. England pubmed.ncbi.nlm.nih.gov

Tim-3, a negative regulator of anti-tumor immunity. [2022]

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

Preclinical evaluation of a GFRA1 targeted antibody-drug conjugate in breast cancer. [2019]

10. England pubmed.ncbi.nlm.nih.gov

Development of a fully human anti-GITR antibody with potent antitumor activity using H2L2 mice. [2022]

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

Pharmacodynamics and molecular correlates of response to glofitamab in relapsed/refractory non-Hodgkin lymphoma. [2022]

12. Netherlands pubmed.ncbi.nlm.nih.gov

A new format of single chain tri-specific antibody with diminished molecular size efficiently induces ovarian tumor cell killing. [2006]

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

Role of target antigen in bispecific-antibody-mediated killing of human glioblastoma cells: a pre-clinical study. [2019]