TSR-022 for Advanced Cancer
Recruiting in Palo Alto (17 mi)
+50 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: GlaxoSmithKline
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.
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, participants must not be on systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of the study treatment. It's best to discuss your current medications with the study team to ensure they align with the trial requirements.
What safety data exists for TSR-022 (Cobolimab) in humans?
How is the drug TSR-022 (Cobolimab) unique compared to other treatments for advanced cancer?
TSR-022 (Cobolimab) is unique because it targets TIM-3, a protein that can suppress the immune system's ability to fight cancer, making it a novel approach in cancer immunotherapy. This mechanism of action is different from other treatments that may target different pathways or proteins involved in cancer progression.678910
Eligibility Criteria
This trial is for individuals with advanced solid tumors. Participants must meet certain health criteria to join, but specific inclusion and exclusion details are not provided here.Inclusion Criteria
Negative human immunodeficiency virus (HIV) test at screening
Participant has measurable disease as per RECIST v1.1.
I am 18 years old or older.
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Exclusion Criteria
I finished palliative radiotherapy less than a week ago.
Participant is pregnant or breastfeeding or expecting to conceive children within the projected duration of the study, starting with the Screening Visit through 150 days after the last dose of study treatment.
Participant must not have a known hypersensitivity to TSR-042 and TSR-022 components or excipients.
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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
Up to 42 days
Dose Expansion
Part 2 of the study evaluates the antitumor activity of TSR-022 in combination with TSR-042 or docetaxel and as monotherapy
Up to 2 years
Follow-up
Participants are monitored for safety and effectiveness after treatment
Up to 2 years
Treatment Details
Interventions
- TSR-022 (Monoclonal Antibodies)
Trial OverviewThe study tests TSR-022, an antibody targeting TIM-3 in the immune system. It's a two-part study: first finding the right dose (dose escalation) and then testing its effectiveness alone or with other drugs like TSR-042 or docetaxel (dose expansion).
Participant Groups
17Treatment groups
Experimental Treatment
Group I: Part 2:Cohort C Colorectal cancer-TSR-022 with TSR-042Experimental Treatment2 Interventions
Group II: Part 2:Cohort C Colorectal cancer-TSR-022 as monotherapyExperimental Treatment1 Intervention
Group III: Part 2:Cohort B Non-small cell lung cancer-TSR-022-monotherapyExperimental Treatment1 Intervention
Group IV: Part 2:Cohort B Non-small cell lung cancer-TSR-022 with TSR-042Experimental Treatment2 Interventions
Group V: Part 2: Cohort F- Hepatocellular carcinoma (HCC)-TSR-022 with TSR-042Experimental Treatment2 Interventions
Group VI: Part 2: Cohort E-Non-small cell lung cancer-TSR-022 with docetaxelExperimental Treatment2 Interventions
Group VII: Part 2: Cohort D-TIM-3 selected non-small cell lung cancer (NSCLC)-TSR-022 with TSR-042Experimental Treatment2 Interventions
Group VIII: Part 2: Cohort A Melanoma-TSR-022 with TSR-042Experimental Treatment2 Interventions
Group IX: Part 2: Cohort A Melanoma-TSR-022 as monotherapyExperimental Treatment1 Intervention
Group X: Part 1h: TSR-022 in combination with TSR-042, pemetrexed, and carboplatinExperimental Treatment4 Interventions
Group XI: Part 1g: TSR-022 in combination with TSR-042, pemetrexed, and cisplatinExperimental Treatment4 Interventions
Group XII: Part 1f: TSR-022 in combination with TSR-042 and DocetaxelExperimental Treatment3 Interventions
Group XIII: Part 1e: TSR-022 with TSR-042 (not previously treated with anti-programmed death ligand [PD-{L}]1)Experimental Treatment2 Interventions
Group XIV: Part 1d: TSR-022 in combination with TSR-042 and TSR-033Experimental Treatment3 Interventions
Group XV: Part 1c: TSR-022 in combination with TSR-042Experimental Treatment2 Interventions
Group XVI: Part 1b: TSR-022 in combination with nivolumabExperimental Treatment2 Interventions
Group XVII: Part 1a: TSR-022 monotherapyExperimental Treatment1 Intervention
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
GSK Investigational SiteDenver, CO
GSK Investigational SiteNiles, IL
GSK Investigational SiteWashington, United States
GSK Investigational SiteIowa City, IA
More Trial Locations
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Who Is Running the Clinical Trial?
GlaxoSmithKlineLead Sponsor
References
Identification and characterization of M6903, an antagonistic anti-TIM-3 monoclonal antibody. [2021]T cell immunoglobulin and mucin domain-3 (TIM-3) is an immune checkpoint that regulates normal immune responses but can be exploited by tumor cells to evade immune surveillance. TIM-3 is primarily expressed on immune cells, particularly on dysfunctional and exhausted T cells, and engagement of TIM-3 with its ligands promotes TIM-3-mediated T cell inhibition. Antagonistic ligand-blocking anti-TIM-3 antibodies have the potential to abrogate T cell inhibition, activate antigen-specific T cells, and enhance anti-tumor immunity. Here we describe M6903, a fully human anti-TIM-3 antibody without effector function and with high affinity and selectivity to TIM-3. We demonstrate that M6903 blocks the binding of TIM-3 to three of its ligands, phosphatidylserine (PtdSer), carcinoembryonic antigen cell adhesion-related molecule 1 (CEACAM1), and galectin 9 (Gal-9). These results are supported by an atomic resolution crystal structure and functional assays, which demonstrate that M6903 monotherapy enhanced T cell activation. This activation was further enhanced by the combination of M6903 with bintrafusp alfa, a bifunctional fusion protein that simultaneously blocks the transforming growth factor-β (TGF-β) and programmed death ligand 1 (PD-L1) pathways. M6903 and bintrafusp alfa combination therapy also enhanced anti-tumor efficacy in huTIM-3 knock-in mice, relative to either monotherapy. These in vitro and in vivo data, along with favorable pharmacokinetics in marmoset monkeys, suggest that M6903 as a monotherapy warrants further pre-clinical assessment and that M6903 and bintrafusp alfa may be a promising combination therapy in the clinic.
Combined blockade of TIM-3 and TIM-4 augments cancer vaccine efficacy against established melanomas. [2016]Cancer vaccines have been developed to instruct the endogenous immune responses to autologous tumors and to generate durable clinical responses. However, the therapeutic benefits of cancer vaccines remain insufficient due to the multiple immunosuppressive signals delivered by tumors. Thus, to improve the clinical efficacy of cancer immunotherapy, it is important to develop new modalities to overcome immunosuppressive tumor microenvironments and elicit effective antitumor immune responses. In this study, we show that novel monoclonal antibodies (mAbs) specifically targeting either T cell immunoglobulin mucin protein-3 (TIM-3) or T cell immunoglobulin mucin protein-4 (TIM-4) enhance the therapeutic effects of vaccination against established B16 murine melanomas. This is true for vaccination with irradiated B16 melanoma cells engineered to express the flt3 ligand gene (FVAX). More importantly, combining anti-TIM-3 and anti-TIM-4 mAbs markedly increased vaccine-induced antitumor responses against established B16 melanoma. TIM-3 blockade mainly stimulated antitumor effector activities via natural killer cell-dependent mechanisms, while CD8(+) T cells served as the main effectors induced by anti-TIM-4 mAb. Our findings reveal that therapeutic manipulation of TIM-3 and TIM-4 may provide a novel strategy for improving the clinical efficacy of cancer immunotherapy.
Tim-3 finds its place in the cancer immunotherapy landscape. [2021]The blockade of immune checkpoint receptors has made great strides in the treatment of major cancers, including melanoma, Hodgkin's lymphoma, renal, and lung cancer. However, the success rate of immune checkpoint blockade is still low and some cancers, such as microsatellite-stable colorectal cancer, remain refractory to these treatments. This has prompted investigation into additional checkpoint receptors. T-cell immunoglobulin and mucin domain 3 (Tim-3) is a checkpoint receptor expressed by a wide variety of immune cells as well as leukemic stem cells. Coblockade of Tim-3 and PD-1 can result in reduced tumor progression in preclinical models and can improve antitumor T-cell responses in cancer patients. In this review, we will discuss the basic biology of Tim-3, its role in the tumor microenvironment, and the emerging clinical trial data that point to its future application in the field of immune-oncology.
Tim-3, a negative regulator of anti-tumor immunity. [2022]T cell immunoglobulin-3 (Tim-3) was identified nearly 10 years ago as a negative regulator of IFN-γ-secreting CD4(+) T helper 1 and CD8(+) T cytotoxic 1 cells. Tim-3 is now classed with other inhibitory receptors, such as cytotoxic lymphocyte antigen-4 and programmed death-1 that are commonly referred to as immune checkpoint molecules. Recent studies have highlighted Tim-3 as an important player in the CD8(+) T cell exhaustion that takes place in chronic immune conditions such as chronic viral infection and cancer in both humans and experimental models. In addition to its role in exhausted T cells, recent data suggest that Tim-3 can further influence cancer outcome through its action on myeloid cells and cancer stem cells.
Tim-3 and its role in regulating anti-tumor immunity. [2022]Immunotherapy is being increasingly recognized as a key therapeutic modality to treat cancer and represents one of the most exciting treatments for the disease. Fighting cancer with immunotherapy has revolutionized treatment for some patients and therapies targeting the immune checkpoint molecules such as CTLA-4 and PD-1 have achieved durable responses in melanoma, renal cancer, Hodgkin's diseases and lung cancer. However, the success rate of these treatments has been low and a large number of cancers, including colorectal cancer remain largely refractory to CTLA-4 and PD-1 blockade. This has provided impetus to identify other co-inhibitory receptors that could be exploited to enhance response rates of current immunotherapeutic agents and achieve responses to the cancers that are refectory to immunotherapy. Tim-3 is a co-inhibitory receptor that is expressed on IFN-g-producing T cells, FoxP3+ Treg cells and innate immune cells (macrophages and dendritic cells) where it has been shown to suppress their responses upon interaction with their ligand(s). Tim-3 has gained prominence as a potential candidate for cancer immunotherapy, where it has been shown that in vivo blockade of Tim-3 with other check-point inhibitors enhances anti-tumor immunity and suppresses tumor growth in several preclinical tumor models. This review discusses the recent findings on Tim-3, the role it plays in regulating immune responses in different cell types and the rationale for targeting Tim-3 for effective cancer immunotherapy.
Radioimmunoscintigraphy of intracranial glioma xenograft with a technetium-99m-labeled mouse monoclonal antibody specifically recognizing type III mutant epidermal growth factor receptor. [2019]The type III mutant epidermal growth factor receptor (EGFR) is expressed on the cell surface of a subset of glioma, but not of normal tissues. In this study, we investigated the in vivo kinetics of 3C10 mouse monoclonal antibody (mAb), specifically recognizing the type III mutant EGFR (EGFRvIII), using athymic nude mice bearing the intracranial glioma xenograft overexpressing the EGFRvIII. Human glioma cell line, U87MG, expressing the wild type EGFR and the transfectant, named U87MG x deltaEGFR, expressing the EGFRvIII, were transplanted subcutaneously or intracranially to nude mice. 3C10 mAb labeled with a technetium-99m (99mTc) was intravenously injected into these nude mice and then the mice were sacrificed at 24 h later, and the 99mTc-uptake by xenografts and major normal organs was measured to determine the biodistribution of mAb. Furthermore, at 3, 6 and 24 h after injection of 99mTc-labeled 3C10 mAb, whole-body scintigraphy was obtained with a gamma camera to localize the tumor site. 3C10 mAb significantly accumulated to U87MG x deltaEGFR xenografts transplanted subcutaneously or intracranially in nude mice, showing high tumor-to-blood ratio of 10.30 and 4.01, respectively. In contrast, uptake of control antibody in the intracranial tumor was as low as 0.43. In scintigrams, intracranially transplanted U87MG x deltaEGFR xenografts were detectable at 3 h after injection of 99mTc-labeled 3C10 mAb. These results suggest that intravenously injected 3C10 mAb specifically accumulated to the subcutaneous or intracranial glioma xenograft expressing the EGFRvIII and 3C10 mAb is a potential diagnostic and therapeutic agent for patients with gliomas expressing the EGFRvIII.
A new format of single chain tri-specific antibody with diminished molecular size efficiently induces ovarian tumor cell killing. [2006]A combination of bi-specific antibodies (BsAb), anti-tumorxanti-CD3 and anti-tumorxanti-CD28, is effective in vitro and in vivo, whereas production of two kinds of bi-specific antibodies is labor intensive and administration is complicated. Accordingly, we previously developed a new model of single chain tri-specific antibody (scTsAb), sTRI, which linked both the CD3 and CD28 signals for T-cell activation in one molecule, and demonstrated its capacity for triggering T-cells to kill ovary tumor cells. To improve the pharmacokinetics further and decrease the immunogenicity of scTsAb, we have now generated a new format of scTsAb, TR3H, whose molecular size is smaller than sTRI. Here we describe the construction, purification and characterization of TR3H. TR3H scTsAb bound to effector cells and tumor target cells specifically and induced redirected lyses of ovary tumor cells through freshly isolated, unstimulated human peripheral blood lymphocytes (PBLs). This new format of scTsAb possesses properties that support its potential as a new tumor immunotherapeutic agent.
Phase I Study of MK-4166, an Anti-human Glucocorticoid-Induced TNF Receptor Antibody, Alone or with Pembrolizumab in Advanced Solid Tumors. [2022]In this first-in-human phase I study (NCT02132754), we explored MK-4166 [humanized IgG1 agonist mAb targeting glucocorticoid-induced TNF receptor (GITR)] with and without pembrolizumab in advanced solid tumors.
Development of a fully human anti-GITR antibody with potent antitumor activity using H2L2 mice. [2022]Glucocorticoid-induced TNF receptor-related (GITR) can act as a co-stimulatory receptor, representing a potential target for safely enhancing immunotherapy efficacy. GITR is triggered by a GITR ligand or an agonist antibody and activates CD8+ and CD4+ effector T cells, reducing tumor-infiltrating Treg numbers and resulting in activation of immune responses and tumor cell destruction by effector T cells. GITR is an attractive target for immunotherapy, especially in combination therapy with immune checkpoint inhibitors, as is being explored in clinical trials. Using H2L2 transgenic mice encoding the human immunoglobulin variable region and hybridoma technology, we generated a panel of fully human antibodies that showed excellent specific affinity and strong activation of human T cells. After conversion to fully human antibodies and engineering modification, we obtained an anti-GITR antibody hab019e2 with enhanced antitumor activity in a B-hGITR MC38 mouse model compared to Tab9H6V3, an anti-GITR antibody that activates T cells and inhibits Treg suppression from XenoMouse. As a fully human antibody with its posttranslational modification hot spot removed, the hab019e2 antibody exerted more potent therapeutic effects, and may have potential as a novel and developable antibody targeting GITR for follow-up drug studies.
Therapeutic effect of ansamitocin targeted to tumor by a bispecific monoclonal antibody. [2019]We have constructed a murine hybrid hybridoma that secretes a bispecific monoclonal antibody (mAb) by fusing a hybridoma secreting an anti-ansamitocins mAb with a hybridoma secreting an anti-human transferrin receptor (TfR) mAb that binds to human A431 epidermoid carcinoma cells. The bispecific mAb, reactive to both ansamitocins and TfR, was purified by a combination of hydrophobic column chromatography and hydroxyapatite high-performance liquid chromatography, and evaluated in in vivo experiments using human tumor cell-implanted nude mice. Ansamitocin P-3 targeted through one of the antigen combining sites of the bispecific mAb was potentially more effective in suppressing the growth of established A431 tumor xenografts implanted on nude mice than unconjugated ansamitocin P-3 or the immunoconjugate of ansamitocin P-3 and monospecific anti-ansamitocins antibody, and the targeted ansamitocin P-3 finally eradicated the tumor mass. The bispecific mAb also played an important role in reducing such undesirable side-effects of ansamitocin P-3 as the loss of body weight, the damage to liver functions and the decrease in the number of white blood cells.