Triapine (3-AP) / Vion, Northwestern University - LARVOL DELTA

RRM2-driven dNTP biosynthesis: a therapeutic vulnerability in temozolomide-resistant glioblastoma (AACR 2025) - "Recognizing the limitations of first-generation RNR inhibitors, we explored the second-generation inhibitor Triapine (3-AP). These findings underscore the potential of targeting RRM2-mediated dNTP biosynthesis to overcome chemoresistance in GBM. We are conducting a Phase 1/1b clinical trial to assess the safety, toxicity, and maximum tolerated dose (MTD) of combining 3-AP with TMZ in recurrent GBM patients."

Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • RRM1 • RRM2 • RRM2B

Incorporation of triapine (T) to cisplatin chemoradiation (CRT) for locally advanced cervical and vaginal cancer: Results from NRG-GY006, a phase III randomized trial. (PubMed, Gynecol Oncol) - P3 | "Triapine added to CRT did not improve OS."

Journal • P3 data • Cardiovascular • Cervical Cancer • Metabolic Disorders • Oncology • Solid Tumor • Vaginal Cancer

Testing the Effectiveness of an Anti-cancer Drug, Triapine, When Used With Targeted Radiation-based Treatment (Lutetium Lu 177 Dotatate), Compared to Lutetium Lu 177 Dotatate Alone for Metastatic Neuroendocrine Tumors (clinicaltrials.gov) - P2 | N=94 | Recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Mar 2025 ➔ Sep 2025 | Trial primary completion date: Mar 2025 ➔ Sep 2025

Trial completion date • Trial primary completion date • Endocrine Cancer • Neuroendocrine Tumor • Oncology • Solid Tumor

ETCTN 10388: Testing the Addition of an Anti-cancer Drug, Triapine, to the Usual Radiation-Based Treatment (Lutetium Lu 177 Dotatate) for Neuroendocrine Tumors (clinicaltrials.gov) - P1 | N=33 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Mar 2025 ➔ Mar 2026 | Trial primary completion date: Mar 2025 ➔ Sep 2024

Trial completion date • Trial primary completion date • Endocrine Cancer • Neuroendocrine Tumor • Oncology • Solid Tumor

Testing the Response to the Anti-cancer Drug, Triapine, in Uterine Cancers Using Markers From the Tissue at the Time of Hysterectomy (clinicaltrials.gov) - P1 | N=12 | Suspended | Sponsor: National Cancer Institute (NCI) | Trial completion date: Feb 2025 ➔ Jun 2025 | Trial primary completion date: Feb 2025 ➔ Jun 2025

Trial completion date • Trial primary completion date • Endometrial Adenocarcinoma • Endometrial Cancer • Endometrial Serous Adenocarcinoma • Gynecology • Oncology • Solid Tumor • Uterine Cancer

Testing the Addition of an Anti-Cancer Drug, Triapine, to the Usual Radiation Therapy for Recurrent Glioblastoma or Astrocytoma (clinicaltrials.gov) - P1 | N=30 | Not yet recruiting | Sponsor: National Cancer Institute (NCI)

New P1 trial • Astrocytoma • Brain Cancer • CNS Tumor • Diffuse Midline Glioma • Glioblastoma • Glioma • Oncology • Solid Tumor

Study on the effects and mechanism of RRM2 on three gynecological malignancies. (PubMed, Cell Signal) - "The potential oncogenic effects of RRM2 in gynecologic tumor cell lines were further demonstrated using the RRM2 inhibitor Triapine (3-AP). These pro-tumorigenic effects may then be mediated through the involvement of RRM2 in the p53 and Akt/mTOR signaling pathways, altering the expression of p53 and Akt/mTOR. Thus, RRM2 is potentially a candidate gene for the unified diagnosis of cervical, endometrial, and ovarian cancers."

Journal • Cervical Cancer • Endometrial Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor • Women's Health • AKT1 • RRM2

Combined inhibition of ribonucleotide reductase and WEE1 induces synergistic anticancer activity in Ewing's sarcoma cells. (PubMed, BMC Cancer) - "Our findings show that combined inhibition of RNR and WEE1 was effective against Ewing's sarcoma in vitro. They thus provide a rationale for the evaluation of the potential of combined targeting of RNR and WEE1 in Ewing's sarcoma in vivo."

Journal • Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor • CASP3 • CASP7 • CHEK1

DefNEtTrp: An Iron Dual Chelator Approach for Anticancer Application. (PubMed, JACS Au) - "Two important chelators, deferasirox (Def) and triapine (Trp), attack the intracellular supply of iron (Fe) and inhibit Fe-dependent pathways responsible for cellular proliferation and metastasis...Its cytotoxicity (IC50 0.77 ± 0.06 μM) is superior to that of unconjugated Def and Trp ligands (IC50 2.6 ± 0.15 μM and 1.1 ± 0.04 μM, respectively) in single-compound and combination treatments and is selective toward cancer cells. The cell death mechanism of the dual chelator is assessed in the context of intracellular labile Fe binding and was found to induce both apoptosis and ferroptosis."

Journal • Oncology

Opposing effects of mycotoxins alternariol and deoxynivalenol on the immunomodulatory effects of oxaliplatin and triapine. (PubMed, Toxicology) - "While AOH generally suppressed a drug-induced activation and increased anti-inflammatory IL10 levels, DON potentiated activation and pro-inflammatory markers, such as CXCL8 and TNF in immune cells. In conclusion, AOH and DON have the potential to alter the immunological effects of anticancer therapies, which should be considered during therapy as well as in their future risk assessment."

IO biomarker • Journal • Oncology • CD14 • CXCL8 • IL10 • PTGS2 • TFRC • TNFA

Testing the Response to the Anti-cancer Drug, Triapine, in Uterine Cancers Using Markers From the Tissue at the Time of Hysterectomy (clinicaltrials.gov) - P1 | N=12 | Suspended | Sponsor: National Cancer Institute (NCI) | Recruiting ➔ Suspended

Trial suspension • Endometrial Adenocarcinoma • Endometrial Cancer • Endometrial Serous Adenocarcinoma • Gynecology • Oncology • Solid Tumor • Uterine Cancer

Dose finding, bioavailability, and PK-PD of oral triapine with concurrent chemoradiation for locally advanced cervical cancer and vaginal cancer (ETCTN 9892). (PubMed, Cancer Chemother Pharmacol) - P1 | "Oral triapine is safe when given with cisplatin chemoradiation, convenient, bioavailable. Exposure is negatively impacted by smoking, and methemoglobin is a biomarker of exposure."

Journal • Metastases • PK/PD data • Cardiovascular • Cervical Cancer • Heart Failure • Hematological Disorders • Hypertension • Leukopenia • Neutropenia • Oncology • Solid Tumor • Vaginal Cancer • CYP1A2

NRG-GY006: Testing the Addition of a New Anti-Cancer Drug, Triapine, to the Usual Chemotherapy Treatment (Cisplatin) During Radiation Therapy for Advanced-stage Cervical and Vaginal Cancers (clinicaltrials.gov) - P3 | N=450 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Sep 2024 ➔ Oct 2025

Combination therapy • Metastases • Trial completion date • Cervical Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Uterine Cancer • Vaginal Cancer

Triapine in Combination with Temozolomide for the Treatment of Patients with Recurrent Glioblastoma (clinicaltrials.gov) - P1 | N=30 | Recruiting | Sponsor: Northwestern University | Active, not recruiting ➔ Recruiting

Combination therapy • Enrollment open • Anaplastic Astrocytoma • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor

Synthesis of 5-hydroxyisatin thiosemicarbazones, spectroscopic investigation, protein-ligand docking, and in vitro anticancer activity. (PubMed, Bioorg Chem) - "L6 exhibited the highest potency against skin cancer A431 cell line, with an IC50 of 0.19 μM compared to 1.8 μM with triapine and showed low toxicity against PNT-2 cells with an SI index of >100 μM. Also, it lowered the ERK1/2 expression, which affected the caspase 3 activity and showed higher binding affinity compared to the FDA-approved drug Lenalidomide in molecular docking studies. Our findings demonstrated the possible future anticancer drug potency of L6 in the skin cancer A431 cells."

Journal • Preclinical • Breast Cancer • Genetic Disorders • Genito-urinary Cancer • Lung Cancer • Oncology • Prostate Cancer • Skin Cancer • Solid Tumor • CASP3

Triapine With Chemotherapy and Radiation Therapy in Treating Patients With IB2-IVA Cervical or Vaginal Cancer (clinicaltrials.gov) - P1 | N=21 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Nov 2024 ➔ Apr 2025

Combination therapy • Metastases • Trial completion date • Cervical Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Vaginal Cancer

Triapine in Combination With Temozolomide for the Treatment of Patients With Recurrent Glioblastoma (clinicaltrials.gov) - P1 | N=30 | Active, not recruiting | Sponsor: Northwestern University | Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Anaplastic Astrocytoma • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor

Comparison of Image-Guided Intensity Modulated Radiotherapy (IG-IMRT) vs. Conventional Radiotherapy (4FRT) for Locoregionally Advanced Cervical Cancer on the NRG GY006 Trial (ASTRO 2024) - "Materials/ We included patients with stage IB2-IVA cervical or vaginal carcinoma enrolled on NRG-GY006 randomized to RT + cisplatin +/- concurrent triapine. Despite reducing dose to organs at risk, IG-IMRT did not reduce GI or overall hematologic toxicity compared to 4FRT, possibly due to increased cisplatin delivery and different field sizes. IG-IMRT had no impact on long-term outcomes. Abstract 297 – Table 1 *Breslow-Day test suggested unequal odds ratio across stratum Endpoint 4FRT IG-IMRT p (4F vs."

Metastases • Cervical Cancer • Hematological Disorders • Oncology • Solid Tumor • Uterine Cancer • Vaginal Cancer

Identification of Triapine as a Novel Radiosensitizer in Glioblastoma (ASTRO 2024) - "Our preclinical study suggests that RRM2 is a promising therapeutic target for GBM, and triapine inhibition of RRM2 sensitizes GBM cells to radiation treatment in vitro and in vivo. Our findings suggest that combining triapine with radiation may improve therapeutic outcomes in GBM, warranting additional preclinical studies and providing a justification for a phase I clinical trial potentially in the recurrent setting."

Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • CHEK1 • RRM2

Enhancing [177Lu]Lu-DOTA-TATE therapeutic efficacy in vitro by combining it with chemotherapy (EANM 2024) - "Hydroxyurea, gemcitabine and triapine all increased cell size, SSTR2A expression, and [177Lu]Lu-DOTA-TATE uptake, whilst further reducing cell metabolic viability in U2OS+SSTR2A cells when compared to [177Lu]Lu-DOTA-TATE monotherapy. Further investigations could transform patient care and positively increase outcomes for patients treated with [177Lu] Lu-DOTA-TATE."

Preclinical • Endocrine Cancer • Neuroendocrine Tumor • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • SSTR • SSTR2

Enhancing [177Lu]Lu-DOTA-TATE therapeutic efficacy in vitro by combining it with metronomic chemotherapeutics. (PubMed, EJNMMI Res) - "Hydroxyurea, gemcitabine and triapine all increased cell size, SSTR2A expression, and [177Lu]Lu-DOTA-TATE uptake, whilst reducing cell metabolic viability in U2OS + SSTR2A cells when compared to [177Lu]Lu-DOTA-TATE monotherapy. Further investigations could transform patient care and positively increase outcomes for patients treated with [177Lu]Lu-DOTA-TATE."

Journal • Preclinical • Endocrine Cancer • Neuroendocrine Tumor • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • SSTR • SSTR2

Triapine in Combination With Temozolomide for the Treatment of Patients With Recurrent Glioblastoma (clinicaltrials.gov) - P1 | N=30 | Recruiting | Sponsor: Northwestern University | Not yet recruiting ➔ Recruiting

Combination therapy • Enrollment open • Anaplastic Astrocytoma • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor

Isosteric Replacement of Sulfur to Selenium in a Thiosemicarbazone: Promotion of Zn(II) Complex Dissociation and Transmetalation to Augment Anticancer Efficacy. (PubMed, J Med Chem) - "Importantly, in contrast to the Fe(III) complexes of the clinically trialed thiosemicarbazones Triapine, COTI-2, and DpC, the Fe(III) complexes of PPTP4c4mT and PPTP4c4mSe did not induce detrimental oxy-myoglobin oxidation. This latter effect probably promoted their antiproliferative activity. Both ligands down-regulated multiple key receptors that display inter-receptor cooperation that leads to aggressive and resistant breast cancer."

Journal • Breast Cancer • Oncology • Solid Tumor • MB

ETCTN 10388: Testing the Addition of an Anti-cancer Drug, Triapine, to the Usual Radiation-Based Treatment (Lutetium Lu 177 Dotatate) for Neuroendocrine Tumors (clinicaltrials.gov) - P1 | N=29 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Jun 2024 ➔ Dec 2024 | Trial primary completion date: Jun 2024 ➔ Dec 2024

Trial completion date • Trial primary completion date • Endocrine Cancer • Neuroendocrine Tumor • Oncology • Solid Tumor • SSTR

A phase II randomized control trial of triapine plus lutetium 177 DOTATATE versus lutetium 177 DOTATATE alone for well-differentiated somatostatin receptor-positive neuroendocrine tumors. (ASCO 2024) - P1 | "Secondary endpoint is to evaluate median PFS. We are also evaluating triapine PK, plasma deoxyribonucleosides, circulating DNA and plasma hPG80, a novel blood based diagnostic biomarker."

Clinical • P2 data • Endocrine Cancer • Neuroendocrine Tumor • Oncology • Pancreatic Cancer • Solid Tumor • SSTR