Triapine for Uterine Cancer
Palo Alto (17 mi)Overseen byRebecca L Stone
Age: 18+
Sex: Female
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase < 1
Recruiting
Sponsor: National Cancer Institute (NCI)
No Placebo Group
Trial Summary
What is the purpose of this trial?This early phase I trial investigates the response to the anti-cancer drug, triapine, in uterine cancers by using markers from tissue samples at the time of removal of the uterus, ovaries, and fallopian tubes (hysterectomy and bilateral salpingo-oophorectomy). Triapine may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Adding triapine to the usual approach of surgery followed by chemotherapy alone or in combination with radiation therapy may help to slow the growth of uterine cancer.
Is the drug Triapine a promising treatment for uterine cancer?Triapine is a promising drug because it helps make cancer treatments more effective by slowing down the repair of cancer cells' DNA. This can lead to better control of the disease and improve survival rates in patients with certain types of cancer.13456
What safety data is available for Triapine in treating cancer?Triapine, also known as 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, has been evaluated in several clinical trials for its safety and efficacy. A Phase I trial identified dose-limiting toxicities and the maximum-tolerated dose for a 96-hour intravenous infusion in patients with advanced cancer. Additionally, Triapine has been studied in combination with cisplatin radiochemotherapy for cervical cancer, showing long-term disease control. However, challenges such as short plasma half-life and fast metabolism have been noted, leading to research into liposomal formulations to improve its pharmacokinetic properties. Overall, Triapine has been shown to enhance radiochemosensitivity and induce apoptosis in cancer cells, but further studies are needed to optimize its delivery and efficacy.12346
What data supports the idea that Triapine for Uterine Cancer is an effective treatment?The available research shows that Triapine has been studied for its effectiveness in treating cervical cancer, which is similar to uterine cancer. In clinical trials, Triapine was combined with another drug, cisplatin, and radiation therapy, and it helped control the disease over a long period. However, some studies suggest that Triapine alone may not be very effective against solid tumors due to its short time in the body and quick breakdown. Researchers are exploring ways to improve its effectiveness, such as using special carriers to deliver the drug more efficiently. While there is promising data for cervical cancer, specific data for uterine cancer is not provided in the available research.13456
Do I have to stop taking my current medications for the trial?The trial protocol does not specify if you must stop taking your current medications. However, you cannot take medications that are inhibitors or inducers of triapine, or those associated with methemoglobinemia. You will be counseled on potential drug interactions during the enrollment process.
Eligibility Criteria
This trial is for adults with specific types of uterine cancer who are planning to have a hysterectomy and haven't had previous cancer treatment. They must be in good health overall, with proper kidney, liver, and blood cell function. People with certain heart conditions or infections like hepatitis B or C need to have them under control. Pregnant women can't join, and participants should understand the study well enough to consent.Inclusion Criteria
I have not had any previous cancer treatment for endometrial cancer.
My cancer is a specific type of uterine cancer called serous adenocarcinoma.
I can take care of myself but might not be able to do heavy physical work.
I can understand and am willing to sign the consent form.
I am 18 years old or older.
I had hepatitis C but am cured, or I'm being treated with no detectable virus.
I am scheduled for a surgical removal of the uterus and staging.
My hepatitis B is under control with treatment.
My tumor is large enough for both research and clinical tests.
Exclusion Criteria
I do not have G6PD deficiency.
I have brain metastases and cannot undergo surgery.
Treatment Details
The trial is testing Triapine's effectiveness when added to standard surgery followed by chemotherapy or radiation therapy for uterine cancers. Researchers will look at tissue markers from samples collected during surgery to see how the tumor cells respond.
1Treatment groups
Experimental Treatment
Group I: Treatment (triapine, surgical resection)Experimental Treatment4 Interventions
Patients receive triapine IV over 2 hours on day 1. Patients then undergo surgical resection and tissue collection 6-8 hours after the initiation of the triapine infusion. Patients also undergo biopsy and collection of blood samples on study.
Find a clinic near you
Research locations nearbySelect from list below to view details:
Thomas Jefferson University HospitalPhiladelphia, PA
UM Sylvester Comprehensive Cancer Center at Coral GablesCoral Gables, FL
Johns Hopkins University/Sidney Kimmel Cancer CenterBaltimore, MD
UM Sylvester Comprehensive Cancer Center at Deerfield BeachDeerfield Beach, FL
More Trial Locations
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Who is running the clinical trial?
National Cancer Institute (NCI)Lead Sponsor
References
Phase I and pharmacokinetic study of the ribonucleotide reductase inhibitor, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, administered by 96-hour intravenous continuous infusion. [2007]3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP; Triapine; Vion Pharmaceuticals Inc, New Haven, CT) is a potent inhibitor of ribonucleotide reductase, with activity in preclinical tumor model systems. A phase I trial was initiated to determine the dose-limiting toxicities, maximum-tolerated dose, and pharmacokinetics of a 96-hour intravenous (IV) continuous infusion in patients with advanced cancer.
Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone) induces apoptosis in ovarian cancer cells. [2015]Triapine (Vion Pharmaceuticals, New Haven, CT) is a potent ribonucleotide reductase inhibitor which exerts its antineoplastic activity by inhibiting DNA synthesis and repair. The objectives of this study were: (1) to determine whether Triapine has cytotoxic effects on epithelial ovarian cancer (EOC) cells; (2) to characterize the apoptotic cascade induced in response to this agent; and (3) to determine its utility in combination treatment with carboplatin and paclitaxel.
Long-Term Disease Control with Triapine-Based Radiochemotherapy for Patients with Stage IB2-IIIB Cervical Cancer. [2021]National Cancer Institute phase I #7336 and phase II #8327 clinical trials explored the safety and efficacy of triapine (NSC #663249) added to cisplatin radiochemotherapy in untreated patients with advanced-stage cervical cancer. Triapine inhibits ribonucleotide reductase, the rate-limiting enzyme responsible for DNA-building deoxyribonucleotides, and thereby, enhances radiochemosensitivity by prolonging DNA repair time. Here, we report 3-year efficacy endpoints of pelvic locoregional relapse rate, disease-free, and overall survivals.
LC-MS/MS assay for the quantitation of the ribonucleotide reductase inhibitor triapine in human plasma. [2018]The ribonucleotide reductase inhibitor and radiosensitizer triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP), NSC 663249) is clinically being evaluated via the intravenous (IV) route for the treatment of cervical and vulvar cancer in combination with primary cisplatin chemoradiation. The need for a 2-h infusion and frequent administration of triapine is logistically challenging, prompting us to pursue oral (PO) administration. In support of the clinical trial investigating oral triapine in combination with chemoradiation, we developed and validated a novel LC-MS/MS assay for the quantification of triapine in 50μL human plasma. After protein precipitation, chromatographic separation of the supernatant was achieved with a Shodex ODP2 column and an isocratic acetonitrile-water mobile phase with 10% ammonium acetate. Detection with an ABI 4000 mass spectrometer utilized electrospray positive mode ionization. The assay was linear from 3 to 3,000ng/mL and proved to be accurate (97.1-103.1%) and precise (
Triapine Analogues and Their Copper(II) Complexes: Synthesis, Characterization, Solution Speciation, Redox Activity, Cytotoxicity, and mR2 RNR Inhibition. [2021]Three new thiosemicarbazones (TSCs) HL1-HL3 as triapine analogues bearing a redox-active phenolic moiety at the terminal nitrogen atom were prepared. Reactions of HL1-HL3 with CuCl2·2H2O in anoxic methanol afforded three copper(II) complexes, namely, Cu(HL1)Cl2 (1), [Cu(L2)Cl] (2'), and Cu(HL3)Cl2 (3), in good yields. Solution speciation studies revealed that the metal-free ligands are stable as HL1-HL3 at pH 7.4, while being air-sensitive in the basic pH range. In dimethyl sulfoxide they exist as a mixture of E and Z isomers. A mechanism of the E/Z isomerization with an inversion at the nitrogen atom of the Schiff base imine bond is proposed. The monocationic complexes [Cu(L1-3)]+ are the most abundant species in aqueous solutions at pH 7.4. Electrochemical and spectroelectrochemical studies of 1, 2', and 3 confirmed their redox activity in both the cathodic and the anodic region of potentials. The one-electron reduction was identified as metal-centered by electron paramagnetic resonance spectroelectrochemistry. An electrochemical oxidation pointed out the ligand-centered oxidation, while chemical oxidations of HL1 and HL2 as well as 1 and 2' afforded several two-electron and four-electron oxidation products, which were isolated and comprehensively characterized. Complexes 1 and 2' showed an antiproliferative activity in Colo205 and Colo320 cancer cell lines with half-maximal inhibitory concentration values in the low micromolar concentration range, while 3 with the most closely related ligand to triapine displayed the best selectivity for cancer cells versus normal fibroblast cells (MRC-5). HL1 and 1 in the presence of 1,4-dithiothreitol are as potent inhibitors of mR2 ribonucleotide reductase as triapine.
Liposomal formulations of anticancer copper(II) thiosemicarbazone complexes. [2022]α-N-Heterocyclic thiosemicarbazones such as triapine and COTI-2 are currently investigated as anticancer therapeutics in clinical trials. However, triapine was widely inactive against solid tumor types. A likely explanation is the short plasma half-life time and fast metabolism. One promising approach to overcome these drawbacks is the encapsulation of the drug into nanoparticles (passive drug-targeting). In a previous work we showed that it was not possible to stably encapsulate free triapine into liposomes. Hence, in this manuscript we present the successful preparation of liposomal formulations of the copper(II) complexes of triapine and COTI-2. To this end, various drug-loading strategies were examined and the resulting liposomes were physico-chemically characterized. Especially for liposomal Cu-triapine, a decent encapsulation efficacy and a slow drug release behavior could be observed. In contrast, for COTI-2 and its copper(II) complex no stable loading could be achieved. Subsequent in vitro studies in different cell lines with liposomal Cu-triapine showed the expected strongly reduced cytotoxicity and DNA damage induction. Also in vivo distinctly higher copper plasma levels and a continuous release could be observed for the liposomal formulation compared to free Cu-triapine. Taken together, the here presented nanoformulation of Cu-triapine is an important step further to increase the plasma half-life time and tumor targeting properties of anticancer thiosemicarbazones.