TRX-518 / Cypherpunk Technologies - LARVOL DELTA

Effect of KROS 101, a small molecule GITR ligand agonist, on T effector cells, T reg cells and intratumoral CD8 T cell cytotoxicity. (ASCO 2025) - "KROS 101 is a GITR ligand agonist that increases T cell proliferation and increased cytotoxicity and reduces the T reg population more effectively than TRX 518 which is a therapeutic GITR antibody that was in clinical trial."

Brain Cancer • Glioblastoma • Oncology • Solid Tumor • CD4 • CD8 • HAVCR2 • IFNG • TIGIT • TNFA

A Dose Escalation and Expansion Study of TRX518 in Combination With Cyclophosphamide Plus Avelumab in Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=10 | Terminated | Sponsor: Leap Therapeutics, Inc. | Phase classification: P1/2 ➔ P1

Phase classification • Breast Cancer • Genito-urinary Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Metastatic Castration-Resistant Prostate Cancer • Oncology • Ovarian Cancer • Prostate Cancer • Refractory Ovarian Cancer • Solid Tumor • Triple Negative Breast Cancer • ER • HER-2

"It’s a shame TRX518 has fallen to the wayside during this difficult financing environment." (@Slambucket)

Financing

Rational combination of GITR agonism with PD-1 blockade in cancer patients (SITC 2018) - P1; "...Based on this rationale, we initiated the first in-human phase-I trial of GITR stimulation with the agonist antibody TRX518 in advanced solid cancer patients (NCT01239134)...Conclusions These findings indicate that Treg elimination from advanced tumors is not sufficient to activate cytotoxic CD8+ T-cell responses unless the T-cell exhaustion process is concurrently blocked, underscoring the need to combine Treginhibiting/ depleting immunotherapies with strategies that counteract exhaustion to regress advanced tumors. This study highlights the importance of developing rational, evidence-based combination immunotherapies."

Clinical • IO Biomarker • PD(L)-1 Biomarker • Melanoma • Oncology • Solid Tumor

Rational combination of GITR agonism with PD-1 blockade (AACR 2019) - P1; "This provides the rationale to combine immunotherapies targeting Tregs with strategies able to counteract exhaustion, such as anti-PD-1, to regress advanced tumors. Based on these observations, we have started to investigate TRX518 in combination with PD-1 pathway blockade in patients with advanced solid tumors (NCT02628574)."

IO Biomarker • PD(L)-1 Biomarker

Intratumor and peripheral Treg modulation as a pharmacodynamic biomarker of the GITR agonist antibody TRX-518 in the first in-human trial (AACR 2017) - P1; "Circulating Treg reduction is a potential pharmacodynamic biomarker of TRX518 biological activity. This parameter may allow predictive correlation with changes in intratumoral Treg infiltration. We plan to further investigate this effect and its relevance for the association with clinical responses in our recently opened TRX518 multi-dose study."

Biosimilar • Bladder Cancer • Colorectal Cancer • Genito-urinary Cancer • Melanoma • Oncology • Urothelial Cancer

GITR antibodies in cancer: not ready for prime time. (PubMed, Clin Cancer Res) - "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 T regs in preclinical models, with limited clinical activity demonstrated in patients with advanced solid tumors."

Journal • Oncology • Solid Tumor • FOXP3

Phase IB Study of GITR Agonist Antibody TRX518 Singly and in Combination with Gemcitabine, Pembrolizumab or Nivolumab in Patients with Advanced Solid Tumors. (PubMed, Clin Cancer Res) - "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."

Combination therapy • Journal • P1 data • Oncology • Solid Tumor • CD8 • TNFA

Therapeutic antibody activation of the glucocorticoid-induced TNF receptor by a clustering mechanism. (PubMed, Sci Adv) - "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."

Journal • Oncology

Anti-GITR agonist TRX518 in combination with gemcitabine in advanced solid cancers: Preliminary safety and efficacy from a multi-center phase Ib trial (ESMO-IO 2018) - "Preliminary evidence of clinical benefit was observed including in pts with PBC previously treated with gem. This study is ongoing."

Clinical • Combination therapy • P1 data

A Dose Escalation and Expansion Study of TRX518 in Combination With Cyclophosphamide Plus Avelumab in Advanced Solid Tumors (clinicaltrials.gov) - P1/2; N=125; Not yet recruiting; Sponsor: Leap Therapeutics, Inc.

Combination therapy • New P1/2 trial • Breast Cancer • Genito-urinary Cancer • Gynecologic Cancers • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Ovarian Cancer • Prostate Cancer • Solid Tumor • Triple Negative Breast Cancer • ER • HER-2

A Dose Escalation and Expansion Study of TRX518 in Combination With Cyclophosphamide Plus Avelumab in Advanced Solid Tumors (clinicaltrials.gov) - P1/2; N=125; Recruiting; Sponsor: Leap Therapeutics, Inc.; Not yet recruiting ➔ Recruiting

Combination therapy • Enrollment open • Breast Cancer • Genito-urinary Cancer • Gynecologic Cancers • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Ovarian Cancer • Prostate Cancer • Solid Tumor • Triple Negative Breast Cancer • ER • HER-2

A Dose Escalation and Expansion Study of TRX518 in Combination With Cyclophosphamide Plus Avelumab in Advanced Solid Tumors (clinicaltrials.gov) - P1/2; N=125; Active, not recruiting; Sponsor: Leap Therapeutics, Inc.; Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Breast Cancer • Genito-urinary Cancer • Gynecologic Cancers • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Ovarian Cancer • Prostate Cancer • Solid Tumor • Triple Negative Breast Cancer • ER • HER-2

A Dose Escalation and Expansion Study of TRX518 in Combination With Cyclophosphamide Plus Avelumab in Advanced Solid Tumors (clinicaltrials.gov) - P1/2; N=10; Terminated; Sponsor: Leap Therapeutics, Inc.; N=125 ➔ 10; Trial completion date: Sep 2021 ➔ Jul 2020; Active, not recruiting ➔ Terminated; Trial primary completion date: Jun 2021 ➔ Jul 2020; Product development discontinued unrelated to safety.

Combination therapy • Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Breast Cancer • Genito-urinary Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Ovarian Cancer • Prostate Cancer • Solid Tumor • Triple Negative Breast Cancer • ER • HER-2

"I wish TRX518 was still in the game." (@Slambucket)

Phase 1 Open-label Study of TRX518 Monotherapy and TRX518 in Combination With Gemcitabine, Pembrolizumab, or Nivolumab (clinicaltrials.gov) - P1; N=109; Completed; Sponsor: Leap Therapeutics, Inc.; Active, not recruiting ➔ Completed; Trial primary completion date: Mar 2020 ➔ Jul 2020

Clinical • Combination therapy • Monotherapy • Trial completion • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

TRX-518: Data from P1 trial (NCT02628574) in combination with Keytruda or Opdivo at SITC (November 7-11, 2018) (Ladenburg Thalman Healthcare Conference 2018, Leap Therapeutics) - Data from P1 trial in combination with gemcitabine for advanced solid tumors in Q4 2018

P1 data • Oncology • Solid Tumor

TRX-518: Data from P1 trial (NCT02628574) in combination with Keytruda or Opdivo at SITC (November 7-11, 2018) (Ladenburg Thalman Healthcare Conference 2018, Leap Therapeutics) - Data from P1 trial in combination with gemcitabine for advanced solid tumors in Q4 2018

P1 data • Oncology • Solid Tumor

Leap Therapeutics presents TRX518 data at ESMO Immuno-Oncology Congress 2018 and updated data from DKN-01 study in biliary tract cancer (PRNewswire) - P1/2, N=146; NCT02628574; Sponsor: Leap Therapeutics, Inc."TRX518 in combination with Keytruda or Opdivo achieved durable complete and partial responses in patients not expected to respond to anti-PD-1 therapy alone, including a confirmed complete response in an esophageal squamous cell cancer patient and a confirmed partial response in an anti-PD-1 refractory urothelial cancer patient...TRX518 in combination with gemcitabine achieved meaningful clinical benefit and objective tumor reduction for heavily pretreated patients suffering from pancreatic, biliary tract, mesothelioma, appendiceal, and ovarian cancer....Enrollment is now complete in the dose escalation cohort for TRX518 and Keytruda and continues in the high dose escalation cohort of TRX518 and Opdivo. Leap anticipates that dose expansion cohorts for both combinations will initiate in the first quarter 2019."

Enrollment status • P1/2 data • Trial status • Biliary Cancer • Esophageal Cancer • Mesothelioma • Oncology • Ovarian Cancer • Pancreatic Cancer • Solid Tumor

Mechanistic rationale to combine GITR agonism with PD-1 blockade in cancer patients. (CRI-CIMT-EATI-AACR 2018) - P1; "This underscores the need to combine Treg-inhibiting/depleting immunotherapies with strategies able to counteract exhaustion, such as PD-1 blockade, to regress advanced tumors. Based on these observations, we have initiated a clinical trial exploring TRX518 in combination with PD-1 pathway blockade in patients with advanced solid tumor malignancies (NCT02628574). "

Clinical • IO Biomarker • PD(L)-1 Biomarker • Melanoma • Oncology • Solid Tumor

TRX-518: Completion of enrollment of P1 trial (NCT02628574) in combination with gemcitabine for solid tumors in Q4 2018 (Leap Therapeutics) - H.C Wainwright 20th Annual Global Investment Conference

Enrollment status • Oncology • Solid Tumor

TRX518: “Modulates peripheral and intratumoral tregs in single dose phase 1 study” (Jefferies 2017 Global Healthcare Conference, Leap Therapeutics)

P1 data • Oncology

TRX518: “Modulates peripheral and intratumoral tregs in single dose phase 1 study” (Jefferies 2017 Global Healthcare Conference, Leap Therapeutics)

P1 data • Oncology

TRX-518: Expiry of patents in US in 2026 (Leap Therapeutics) - Annual Report 2019: Expiry of patents related to use in US in 2028

Patent

Leap Therapeutics reports third quarter 2019 financial results (PRNewswire) - "Leap has completed enrollment in dose escalation phase of the clinical trial evaluating TRX518 in combination with cyclophosphamide chemotherapy and BAVENCIO® (avelumab). However, instead of pursuing additional enrollment through the expansion cohorts in this study as initially planned, the Company has decided to reprioritize resources on the further development of the DKN-01 program. There were no safety or efficacy concerns leading to this decision, and patients who are benefitting from the combination therapy will continue to be treated in the study."

Trial status