This is a Phase 1b/2a dose escalation and expansion, multi-center study to be conducted in 2 phases:
* Phase 1b
* Dose Escalation Part 1 (Doublet Therapy)
* Dose Escalation Part 2 (Triplet Therapy)
* Phase 2a
* Dose Expansion (Triplet Therapy)
Approximately 125 adult patients with histologically confirmed advanced solid tumors requiring therapy will be enrolled in the study. It is expected that approximately 24 patients will be enrolled in up to 4 cohorts, 2 cohorts in Dose Escalation Part 1 and 2 cohorts in Dose Escalation Part 2, of up to 6 patients per cohort. Up to 98 additional patients will be enrolled in the Dose Expansion phase of the study to achieve 88 evaluable patients (i.e., received at least 1 dose of study drug(s) and have 1 evaluable post-baseline modified RECIST v1.1 tumor response assessment; for mCRPC, assessment of soft tissue response will be per modified RECIST v1.1 and bone progression assessment will be per PCWG3 guidelines or discontinued treatment due to death, toxicity, or clinical progression) over 4 independent expansion groups.In either phase (1b or 2a), patients discontinuing for reasons unrelated to study treatment toxicity prior to completion of Cycle (C) 1 may be replaced to achieve the number of required evaluable patients per cancer type following consultation with the Sponsor. Data from each cohort in the Dose Escalation phase will be evaluated independently for safety and dose limiting toxicities (DLTs) prior to dose escalation and again prior to the Dose Expansion phase.

Start Date20 May 2019

Sponsor / Collaborator

Leap Therapeutics, Inc.

[+2]

NCT02628574

/ CompletedPhase 1

A Phase 1 Study of TRX518 Monotherapy and TRX518 in Combination With Gemcitabine, Pembrolizumab, or Nivolumab in Adults With Advanced Solid Tumors

This study will be conducted in 5 parts (Parts A, B, C, D and E).
Monotherapy Treatment:
Subjects ≥18 years with advanced solid tumors will be enrolled in the study. Monotherapy dose escalation will be performed in Part A. Cycle 1 data from each cohort will be evaluated for safety and dose-limiting toxicities (DLTs) prior to dose escalation. Subjects will be assigned to a cohort in the order screening is completed. Dose will depend upon the cohort in which a patient is enrolled and cohorts will be dosed consecutively by ascending dose. Once the maximum tolerated dose (MTD) or maximum administered dose (MAD) has been identified, an expanded cohort will be enrolled (Part B).
Combination Treatment:
Subjects ≥18 years with advanced solid tumors will be enrolled in the study. Subjects will receive TRX518 in combination with gemcitabine (Part C), pembrolizumab (Part D), or nivolumab (Part E). Dose escalation will be performed for each part (Part Cesc, Part Desc, Part Eesc) and Cycle 1 data from each cohort will be evaluated for safety and dose-limiting toxicities (DLTs) prior to dose escalation. Subjects will be assigned to a cohort in the order screening is completed. Dose will depend upon the cohort in which a patient is enrolled and cohorts will be dosed consecutively by ascending dose. Once the maximum tolerated dose (MTD) or maximum administered dose (MAD) has been identified, an expanded cohort will be enrolled (Part Cexp, Part Dexp, Part Eexp).

Start Date01 Jan 2016

Sponsor / Collaborator

Leap Therapeutics, Inc.

NCT01239134

/ CompletedPhase 1

Part A: A First-in-Human Single Ascending Dose Study of TRX518 in Subjects With Unresectable Stage III or Stage IV Malignant Melanoma or Other Solid Tumor Malignancies Part B: A Dose-Escalation Study of Multi-dose TRX518 Monotherapy Part C: An Expansion Cohort of Multi-dose TRX518 Monotherapy at the Maximum Tolerated Dose

TRX518-001 is an open label, non-randomized single group assignment, Phase 1 single dose escalation study in adults with biopsy proven unresectable Stage III or Stage IV melanoma or other solid tumor malignancies.
Part A: The study objectives are to determine the safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) profiles of TRX518 and to define the maximum tolerated dose at which there are tolerable side effects and/or maximum PK/PD parameter changes.
Subjects will be assigned to a cohort in the order screening is completed. Dose will depend upon the cohort in which a subject is enrolled and cohorts will be dosed consecutively by ascending dose. Part A has been completed.
Part B: A Dose-Escalation Study of Multi-dose TRX518 Monotherapy with objectives including characterization of the safety, tolerability, and pharmacokinetics, as well as, evaluate for evidence of anti-tumor activity and assess TRX518 immunogenicity.
Part C: An Expansion Cohort of Multi-dose TRX518 Monotherapy at the Maximum Tolerated Dose

Start Date01 Oct 2010

Sponsor / Collaborator

Leap Therapeutics, Inc.

[+1]

100 Clinical Results associated with TRX-518

100 Translational Medicine associated with TRX-518

100 Patents (Medical) associated with TRX-518

Literatures (Medical) associated with TRX-518

15 Sep 2022·Clinical cancer research : an official journal of the American Association for Cancer Research

GITR Antibodies in Cancer: Not Ready for Prime Time

Communications

Author: Moreno, Victor ; Hernandez-Guerrero, Tatiana

Summary:

Glucocorticoid-induced TNF receptor (TNFR)-related protein (GITR) agonistic antibodies are expected to increase the antitumor response mainly by reducing the effect of Foxp3+ T-regulatory cells. TRX-518 is a novel GITR agonist that has shown good pharmacodynamic activity by depleting regulatory T cells (Tregs) in preclinical models, with limited clinical activity demonstrated in patients with advanced solid tumors.See related article by Davar et al., p. 3990

15 Sep 2022·CLINICAL CANCER RESEARCHQ1 · MEDICINE

Phase IB Study of GITR Agonist Antibody TRX518 Singly and in Combination with Gemcitabine, Pembrolizumab, or Nivolumab in Patients with Advanced Solid Tumors

Q1 · MEDICINE

Article

Author: Davar, Diwakar ; Piper, Diane ; Bajor, David ; Naik, Girish S. ; Wong, Phillip ; Holland, Aliya ; Qi, Jingjing ; Bauer, Todd ; Luke, Jason J. ; Rixe, Olivier ; Zappasodi, Roberta ; Wolchok, Jedd D. ; Sifferlen, Lianna ; Sato, Takami ; Sirard, Cynthia A. ; Wang, Hong ; Merghoub, Taha ; Newman, Walter

Abstract:

Purpose::

TRX518 is a mAb engaging the glucocorticoid-induced TNF receptor−related protein (GITR). This open-label, phase I study (TRX518-003) evaluated the safety and efficacy of repeated dose TRX518 monotherapy and in combination with gemcitabine, pembrolizumab, or nivolumab in advanced solid tumors.

Patients and Methods::

TRX518 monotherapy was dose escalated (Part A) and expanded (Part B) up to 4 mg/kg loading, 1 mg/kg every 3 weeks. Parts C–E included dose-escalation (2 and 4 mg/kg loading followed by 1 mg/kg) and dose-expansion (4 mg/kg loading) phases with gemcitabine (Part C), pembrolizumab (Part D), or nivolumab (Part E). Primary endpoints included incidence of dose-limiting toxicities (DLT), serious adverse events (SAE), and pharmacokinetics. Secondary endpoints were efficacy and pharmacodynamics.

Results::

A total of 109 patients received TRX518: 43 (Parts A+B), 30 (Part C), 26 (Part D), and 10 (Part E), respectively. A total of 67% of patients in Parts D+E had received prior anti–PD(L)1 or anti–CTLA-4. No DLTs, treatment-related SAEs, and/or grade 4 or 5 AEs were observed with TRX518 monotherapy. In Parts C–E, no DLTs were observed, although TRX518-related SAEs were reported in 3.3% (Part C) and 10.0% (Part E), respectively. Objective response rate was 3.2%, 3.8%, 4%, and 12.5% in Parts A+B, C, D, and E, respectively. TRX518 affected peripheral and intratumoral regulatory T cells (Treg) with different kinetics depending on the combination regimen. Responses with TRX518 monotherapy+anti–PD1 combination were associated with intratumoral Treg reductions and CD8 increases and activation after treatment.

Conclusions::

TRX518 showed an acceptable safety profile with pharmacodynamic activity. Repeated dose TRX518 monotherapy and in combination resulted in limited clinical responses associated with immune activation.See related commentary by Hernandez-Guerrero and Moreno, p. 3905

25 Feb 2022·Science advancesQ1 · CROSS-FIELD

Therapeutic antibody activation of the glucocorticoid-induced TNF receptor by a clustering mechanism

Q1 · CROSS-FIELD

ArticleOA

Author: Zappasodi, Roberta ; He, Changhao ; Dahan, Rony ; Wolchok, Jedd D. ; Heath, Heidi ; Merghoub, Taha ; Newman, Walter ; Meyerson, Joel R. ; Rusinova, Radda ; Avraham, Yahel ; Maniyar, Rachana R.

GITR is a TNF receptor, and its activation promotes immune responses and drives antitumor activity. The receptor is activated by the GITR ligand (GITRL), which is believed to cluster receptors into a high-order array. Immunotherapeutic agonist antibodies also activate the receptor, but their mechanisms are not well characterized. We solved the structure of full-length mouse GITR bound to Fabs from the antibody DTA-1. The receptor is a dimer, and each subunit binds one Fab in an orientation suggesting that the antibody clusters receptors. Binding experiments with purified proteins show that DTA-1 IgG and GITRL both drive extensive clustering of GITR. Functional data reveal that DTA-1 and the anti-human GITR antibody TRX518 activate GITR in their IgG forms but not as Fabs. Thus, the divalent character of the IgG agonists confers an ability to mimic GITRL and cluster and activate GITR. These findings will inform the clinical development of this class of antibodies for immuno-oncology.

News (Medical) associated with TRX-518

04 Jun 2025

·pipelinereview.com

Kairos Pharma Ltd. Announces New Data on Small Molecule GITR Ligand Agonist KROS 101 as Promising Cancer Immunotherapy at the American Society of Clinical Oncology (ASCO) 2025 Annual Meeting

LOS ANGELES, CA, USA I June 03, 2025 I Kairos Pharma, Ltd. (NYSE American: KAPA), a clinical stage biopharmaceutical company, announces its presentation at the American Society of Clinical Oncology (ASCO) 2025 Annual Meeting highlighting data on its investigational small molecule GITR ligand agonist KROS101. ASCO is being held May 30-June 3, 2025 at McCormick Place in Chicago, Ill. In the presentation titled, “Effect of KROS 101, a small molecule GITR ligand agonist, on T effector cells, T reg cells and intratumoral CD8 T cell cytotoxicity,” the study authors presented their findings that demonstrated KROS 101’s capability to act as a potent glucocorticosteroid-induced tumor necrosis factor receptor (GITR) ligand agonist with dual mechanisms of action. The study authors also indicated their study showed KROS 101 enhanced T cell function by promoting proliferation and increasing cytotoxicity, enhancing the immune response by boosting cytokine production and tumor cancer cell killing. In addition, the study found that KROS101 reduced T reg-mediated suppression by reducing T reg populations, which reverses immune system suppression and enhances effector T cell activity. Further, the study showed KROS to be superior to anti-GITR antibody TRX518 in T cell tumor infiltration, T reg decrease, enhancing tumor cell cytotoxicity and preventing T cell exhaustion. TRX518 was previously in clinical trials. The presentation can be accessed here . John Yu, M.D., Kairos CEO commented, “These results strongly support continued study of KROS101 as a cancer immunotherapy, as they show strong activity in boosting the immune system while targeting and killing tumor cells. Its dual mechanism of action provides significant opportunity to a market that remains in desperate need of new solutions. We continue to believe that KROS 101 has the potential to help optimize cancer treatment and we look forward to discussing these findings with the medical and scientific communities while providing additional progress updates as appropriate.” About Kairos Pharma Ltd. Based in Los Angeles, California, Kairos Pharma Ltd. ( NYSE American: KAPA ) is at the forefront of oncology therapeutics, utilizing structural biology to overcome drug resistance and immune suppression in cancer. Our lead candidate, ENV105, is an antibody that targets CD105 – a protein identified as a key driver of resistance to various cancer treatments. Elevation of CD105 in response to standard therapy results in resistance and disease relapse. ENV105 aims to reverse drug resistance by targeting CD105 and restore the effectiveness of standard therapies across multiple cancer types. Currently, ENV105 is in a Phase 2 clinical trial for castrate-resistant prostate cancer and a Phase 1 trial for lung cancer, with the trials aimed at addressing significant unmet medical needs. For more information, visit kairospharma.com . SOURCE: Kairos Pharma

ImmunotherapyASCOPhase 2Phase 1

100 Deals associated with TRX-518

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Breast Cancer	Phase 2	-	Tolerx, Inc.	-
Breast Cancer	Phase 2	-	Leap Therapeutics, Inc.	-
Ovarian Cancer	Phase 2	-	Leap Therapeutics, Inc.	-
Ovarian Cancer	Phase 2	-	Tolerx, Inc.	-
Prostatic Cancer	Phase 2	-	Tolerx, Inc.	-
Prostatic Cancer	Phase 2	-	Leap Therapeutics, Inc.	-
Hormone Receptor Positive Breast Adenocarcinoma	Phase 1	United States	Leap Therapeutics, Inc.	20 May 2019
Metastatic castration-resistant prostate cancer	Phase 1	United States	Leap Therapeutics, Inc.	20 May 2019
Platinum-Resistant Ovarian Carcinoma	Phase 1	United States	Leap Therapeutics, Inc.	20 May 2019
Advanced Malignant Solid Neoplasm	Phase 1	United States	Leap Therapeutics, Inc.	01 Jan 2016

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02628574 (ESMO_IO2018) Manual	Phase 1	Advanced Malignant Solid Neoplasm	26	TRX518+Gemcitabine	domkyzvcpm(xmapswfojs) = none flaruuludk (makawsxpvo ) View more	Positive	14 Dec 2018

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