Delving into the Latest Updates on Triapine with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Triapine, 3-AP, NSC#663249

+ [5]

Target

RNR

Mechanism

RNR inhibitors(Ribonucleotide reductase inhibitors)

Therapeutic Areas

NeoplasmsUrogenital DiseasesOther Diseases+ [3]

Active Indication

Adenosquamous CarcinomaCervical Squamous Cell CarcinomaSquamous Cell Carcinoma+ [12]

Inactive Indication

Acinar Cell CarcinomaAcute Promyelocytic LeukemiaAdenocarcinoma of Esophagus+ [60]

Originator Organization

Nanotherapeutics, Inc.

Active Organization

Nanotherapeutics, Inc.

National Cancer Institute

Nanopharmaceutics, Inc.Startup

+ [1]

Inactive Organization

Vion Pharmaceuticals, Inc.

Drug Highest PhasePhase 3

First Approval Date-

Regulation-

Structure

Molecular FormulaC7H9N5S

InChIKeyXMYKNCNAZKMVQN-UHFFFAOYSA-N

CAS Registry143621-35-6

This phase I trial tests the safety, side effects, and best dose of triapine in combination with temozolomide in treating patients with glioblastoma that has come back after a period of improvement (recurrent). Triapine inhibits an enzyme responsible for producing molecules required for the production of deoxyribonucleic acid (DNA), which may inhibit tumor cell growth. Temozolomide is in a class of medications called alkylating agents. It works by damaging the cell's DNA and may kill tumor cells and slow down or stop tumor growth. Giving triapine in combination with temozolomide may be safe, tolerable, and/or effective in treating patients with recurrent glioblastoma.

Start Date12 Jul 2024

Sponsor / Collaborator

Northwestern University

[+2]

NCT05724108 / RecruitingPhase 2IIT

A Phase II Randomized Control Trial of Triapine Plus Lutetium Lu 177 Dotatate Versus Lutetium Lu 177 Dotatate Alone for Well-Differentiated Somatostatin Receptor-Positive Neuroendocrine Tumors

This phase II trial compares the effect of adding triapine to lutetium Lu 177 dotatate versus lutetium Lu 177 dotatate alone (standard therapy) in shrinking tumors or slowing tumor growth in patients with neuroendocrine tumors that have spread from where they first started (primary site) to other places in the body (metastatic). Triapine may stop the growth of tumor cells by blocking some of the enzymes needed for deoxyribonucleic acid synthesis and cell growth. Lutetium Lu 177 dotatate is a radioactive drug. It binds to a protein called somatostatin receptor, which is found on some neuroendocrine tumor cells. Lutetium Lu 177 dotatate builds up in these cells and gives off radiation that may kill them. It is a type of radioconjugate and a type of somatostatin analog. Giving triapine in combination with lutetium Lu 177 dotatate may be more effective at shrinking tumors or slowing tumor growth in patients with metastatic neuroendocrine tumors than the standard therapy of lutetium Lu 177 dotatate alone.

Start Date30 Aug 2023

Sponsor / Collaborator

National Cancer Institute

NCT04494113 / RecruitingEarly Phase 1IIT

A Phase 0 Window-of-Opportunity Pharmacodynamic Trial of Triapine (NSC# 663249) in Uterine Corpus Serous Adenocarcinoma

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.

Start Date08 Feb 2022

Sponsor / Collaborator

National Cancer Institute

100 Clinical Results associated with Triapine

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100 Translational Medicine associated with Triapine

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100 Patents (Medical) associated with Triapine

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297

Literatures (Medical) associated with Triapine

01 Feb 2024·Annals of anatomy = Anatomischer Anzeiger : official organ of the Anatomische Gesellschaft

3-acetylpyridine induced behavioral dysfunction and neuronal loss in the striatum and hippocampus of adult male rats

Article

Author: Shenasandeh, Zahra ; Bayat, Amir-Hossein ; Sani, Mojtaba ; Meftahi, Gholam Hossein ; Moghaddam, Meysam Hassani ; Ghorbani, Zeynab ; Rasoolijazi, Homa ; Abdollahifar, Mohammad-Amin ; Aghighi, Zahra ; Mohammadbagheri, Esmaeil ; Aliaghaei, Abbas ; Fathi, Mobina ; Salehi, Mina ; Eskandari, Neda ; Fotouhi, Farid

3-acetylpyridine (3-AP) is a neurotoxin that is known to mainly affect the inferior olivary nucleus (ION) in the brain stem. Although several studies have explored the effect of this neurotoxin, still further investigation is required to understand the impact of this toxin on different parts of the brain. In this research, two groups of rats were studied, the 3-AP-treated and the control groups. Behavioral, stereological, and immunohistochemical analyses were performed. The locomotor activity of the 3-AP-treated rats decreased whereas their anxiety levels were higher than in normal controls. Also, memory performance was impaired in animals in the 3-AP group. Microscopic observations showed a decline in the numerical density of neurons in the hippocampus and striatum along with gliosis. Although this toxin is used to affect the ION, it exerts a neurotoxic effect on different brain regions.

23 Nov 2023·Journal of medicinal chemistryQ1 · MEDICINE

Steric Blockade of Oxy-Myoglobin Oxidation by Thiosemicarbazones: Structure–Activity Relationships of the Novel PPP4pT Series

Q1 · MEDICINE

Article

Author: Gholam Azad, Mahan ; Wijesinghe, Tharushi P ; Bernhardt, Paul V ; Gonzálvez, Miguel A ; Harmer, Jeffrey R ; Kaya, Busra ; Richardson, Des R ; Dharmasivam, Mahendiran

The di-2-pyridylketone thiosemicarbazones demonstrated marked anticancer efficacy, prompting progression of DpC to clinical trials. However, DpC induced deleterious oxy-myoglobin oxidation, stifling development. To address this, novel substituted phenyl thiosemicarbazone (PPP4pT) analogues and their Fe(III), Cu(II), and Zn(II) complexes were prepared. The PPP4pT analogues demonstrated potent antiproliferative activity (IC₅₀: 0.009-0.066 μM), with the 1:1 Cu:L complexes showing the greatest efficacy. Substitutions leading to decreased redox potential of the PPP4pT:Cu(II) complexes were associated with higher antiproliferative activity, while increasing potential correlated with increased redox activity. Surprisingly, there was no correlation between redox activity and antiproliferative efficacy. The PPP4pT:Fe(III) complexes attenuated oxy-myoglobin oxidation significantly more than the clinically trialed thiosemicarbazones, Triapine, COTI-2, and DpC, or earlier thiosemicarbazone series. Incorporation of phenyl- and styryl-substituents led to steric blockade, preventing approach of the PPP4pT:Fe(III) complexes to the heme plane and its oxidation. The 1:1 Cu(II):PPP4pT complexes were inert to transmetalation and did not induce oxy-myoglobin oxidation.

01 Sep 2023·Journal of cancer research and clinical oncology

Synergistic anticancer activity of combined ATR and ribonucleotide reductase inhibition in Ewing's sarcoma cells.

Article

Author: Sonnemann, Jürgen ; Proquitté, Hans ; Beck, James F ; Sturm, Max-Johann ; Becker, Sabine ; Henao-Restrepo, Julián Andrés

PURPOSE:

Ewing's sarcoma is a highly malignant childhood tumour whose outcome has hardly changed over the past two decades despite numerous attempts at chemotherapy intensification. It is therefore essential to identify new treatment options. The present study was conducted to explore the effectiveness of combined inhibition of two promising targets, ATR and ribonucleotide reductase (RNR), in Ewing's sarcoma cells.

METHODS:

Effects of the ATR inhibitor VE821 in combination with the RNR inhibitors triapine and didox were assessed in three Ewing's sarcoma cell lines with different TP53 status (WE-68, SK-ES-1, A673) by flow cytometric analysis of cell death, mitochondrial depolarisation and cell cycle distribution as well as by caspase 3/7 activity determination, by immunoblotting and by real-time RT-PCR. Interactions between inhibitors were evaluated by combination index analysis.

RESULTS:

Single ATR or RNR inhibitor treatment produced small to moderate effects, while their combined treatment produced strong synergistic ones. ATR and RNR inhibitors elicited synergistic cell death and cooperated in inducing mitochondrial depolarisation, caspase 3/7 activity and DNA fragmentation, evidencing an apoptotic form of cell death. All effects were independent of functional p53. In addition, VE821 in combination with triapine increased p53 level and induced p53 target gene expression (CDKN1A, BBC3) in p53 wild-type Ewing's sarcoma cells.

CONCLUSION:

Our study reveals that combined targeting of ATR and RNR was effective against Ewing's sarcoma in vitro and thus rationalises an in vivo exploration into the potential of combining ATR and RNR inhibitors as a new strategy for the treatment of this challenging disease.

4

News (Medical) associated with Triapine

14 May 2024

·www.prnewswire.com

Nanopharmaceutics and Northwestern University Announce Initiation of Phase I Adaptive Dose Escalation Clinical Study with Dose Expansion of Oral Triapine® in Combination with Temozolomide (TMZ) for Patients with Recurrent Glioblastoma

ALACHUA, Fla. and CHICAGO, May 14, 2024 /PRNewswire/ -- Nanopharmaceutics, Inc. (OTC:TGRP), a clinical-stage pharmaceutical development company, announced the initiation of a Phase I clinical study with the Robert H. Lurie Comprehensive Cancer Center of Northwestern University "A Phase 1 Adaptive Dose Escalation With Dose Expansion Study of Triapine in Combination With Temozolomide (TMZ) for Patients With Recurrent Glioblastoma" (ClinicalTrials.gov Identifier: NCT06410248). The primary objective of this phase 1 study will be to determine the recommended phase 2 dose (RP2D) for Triapine® in combination with temozolomide (TMZ). Secondary objectives include evaluation of the safety profile of Triapine® in combination with temozolomide (TMZ), progression-free survival (PFS), overall survival (OS), overall response rate (ORR) per RANO criteria, and quality of life per FACT-Br. The study will recruit 40-45 patients with an established diagnosis of recurrent glioblastoma, and there will be an exploratory arm to investigate drug delivery into brain tumor tissue and target engagement in a cohort who are surgical candidates for re-resection of recurrent glioblastoma. Funding for the study is provided by BrainUp. Oral Triapine® has been shown to be safe, tolerable, and convenient in multiple clinical studies. Ribonucleotide Reductase (RNR) Regulatory Subunit 2 (RRM2) targeting with Triapine® may overcome chemoresistance and improve the clinical efficacy of TMZ therapy. Preliminary research from Dr. Atique Ahmed's lab at Northwestern University has uncovered a critical factor that helps glioblastoma, an aggressive brain cancer, resist chemotherapy treatment. About the Robert H. Lurie Comprehensive Cancer Center of Northwestern University The Robert H. Lurie Comprehensive Cancer Center of Northwestern University is a National Cancer Institute-designated Comprehensive Cancer Center located on Northwestern Memorial Hospital's downtown medical campus in the Streeterville neighborhood of Chicago, Illinois, United States. About BrainUp BrainUp is a nonprofit founded by Dan & Meg Kresach of Frankfort, Illinois. They founded BrainUp after their only child Olivia, was diagnosed 10 years ago with a Glioblastoma at the age of 22 years old. She died on April 19, 2014. The Kresachs formed BrainUp to fund brain cancer research. They have an annual run/walk to raise money for brain cancer research. They have funded over 1.2 million dollars supporting brain cancer research and trials at Chicago healthcare institutions. BrainUp is the financial supporter of Karan Dixit, M.D. (PI) and Atique Ahmed, Ph.D of Northwestern University Chicago, Illinois. To learn more about BrainUp, visit brainup.ngo About Nanopharmaceutics, Inc. Nanopharmaceutics, Inc. is a clinical-stage specialty pharmaceutical company developing oral, topical, and injectable products for cancer, central nervous system (CNS) disorders, and infectious diseases. Leveraging its expertise in nanoparticle and fine-particle formulations, which can specifically be used to improve hard-to-deliver BCS category II and IV drugs, Nanopharmaceutics is focused on formulation development aimed at improving drug absorption and stability. Contact: Nanopharmaceutics, Inc. (OTC: TGRP) James D. Talton, Ph.D. President and Chief Executive Officer 386-401-6304 SOURCE Nanopharmaceutics, Inc.

Phase 1Oligonucleotide

02 Nov 2022

·www.prnewswire.com

Nanopharmaceutics, Inc. Announces the End of Patient Recruitment for the National Cancer Institute (NCI) Sponsored Phase 3 Clinical Study in Advanced-Stage Cervical and Vaginal Cancers with Cisplatin During Radiation Therapy with and without Triapine®

ALACHUA, Fla., Nov. 2, 2022 /PRNewswire/ -- Nanopharmaceutics, Inc., a clinical-stage pharmaceutical development company, today announced completion of patient enrollment in the 450 patient Phase 3 clinical study sponsored by the NCI, part of the National Institutes of Health, and led by NCI funded network group, NRG Oncology, with participation of the NCI National Clinical Trials Network (NCTN), "A Randomized Phase III Trial of Radiation Therapy and Cisplatin Alone or in Combination with Intravenous Triapine in Women with Newly Diagnosed Bulky Stage IB2, Stage II, IIIB, or IVA Cancer of the Uterine Cervix or Stage II-IVA Vaginal," (NRG-GY006, ClinicalTrials.gov Identifier: NCT02466971). The randomized phase 3 trial is evaluating radiation therapy and cisplatin with Nanopharmaceutics' proprietary formulation of Triapine® compared to the standard radiation therapy and cisplatin, alone, in treating patients with newly diagnosed stage IB2, II, or IIIB-IVA cervical cancer or stage II-IVA vaginal cancer. Radiation therapy uses high energy protons to kill tumor cells and shrink tumors. Drugs used in chemotherapy, such as cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, stopping them from dividing, or by stopping them from spreading. Triapine® may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether radiation therapy and cisplatin are more effective with Triapine® Injection in treating cervical or vaginal cancer. 450 patients were enrolled in the study, which was performed under a Cooperative Research and Development Agreement (CRADA) between NCI and Nanopharmaceutics. About Triapine® Triapine® is a synthetic heterocyclic carboxaldehyde thiosemicarbazone with potential antineoplastic activity being studied in the treatment of cancer. It is a type of ribonucleotide reductase inhibitor. Also called 3-aminopyridine-2-carboxaldehyde thiosemicarbazone and 3-AP, Triapine® inhibits the enzyme ribonucleotide reductase, resulting in the inhibition of the conversion of ribonucleoside diphosphates to deoxyribonucleotides necessary for DNA synthesis. About Nanopharmaceutics, Inc. Nanopharmaceutics, Inc. is a clinical-stage specialty pharmaceutical company developing oral, topical, and injectable products for cancer, central nervous system (CNS) disorders, and infectious diseases. Leveraging its expertise in nanoparticle and fine-particle formulations, which can specifically be used to improve hard-to-deliver Biopharmaceutics Classification System (BCS) category II and IV drugs, Nanopharmaceutics is focused on formulation development aimed at improving drug absorption and stability. Contact: Nanopharmaceutics, Inc. James D. Talton, Ph.D. President and Chief Executive Officer 352-401-6304 [email protected] SOURCE Nanopharmaceutics, Inc.

Radiation Therapy

02 Nov 2022

·www.biospace.com

Nanopharmaceutics, Inc. Announces the End of Patient Recruitment for the NCI Sponsored Phase 3 Clinical Study in Advanced-Stage Cervical and Vaginal Cancers with Cisplatin During Radiation Therapy with and without Triapine®

ALACHUA, Fla., Nov. 2, 2022 /PRNewswire/ -- Nanopharmaceutics, Inc., a clinical-stage pharmaceutical development company, today announced completion of patient enrollment in the 450 patient Phase 3 clinical study sponsored by the NCI, part of the National Institutes of Health, and led by NCI funded network group, NRG Oncology, with participation of the NCI National Clinical Trials Network (NCTN), "A Randomized Phase III Trial of Radiation Therapy and Cisplatin Alone or in Combination with Intravenous Triapine in Women with Newly Diagnosed Bulky Stage IB2, Stage II, IIIB, or IVA Cancer of the Uterine Cervix or Stage II-IVA Vaginal," (NRG-GY006, ClinicalTrials.gov Identifier: NCT02466971). The randomized phase 3 trial is evaluating radiation therapy and cisplatin with Nanopharmaceutics' proprietary formulation of Triapine® compared to the standard radiation therapy and cisplatin, alone, in treating patients with newly diagnosed stage IB2, II, or IIIB-IVA cervical cancer or stage II-IVA vaginal cancer. Radiation therapy uses high energy protons to kill tumor cells and shrink tumors. Drugs used in chemotherapy, such as cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, stopping them from dividing, or by stopping them from spreading. Triapine® may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether radiation therapy and cisplatin are more effective with Triapine® Injection in treating cervical or vaginal cancer. 450 patients were enrolled in the study, which was performed under a Cooperative Research and Development Agreement (CRADA) between NCI and Nanopharmaceutics. About Triapine® Triapine® is a synthetic heterocyclic carboxaldehyde thiosemicarbazone with potential antineoplastic activity being studied in the treatment of cancer. It is a type of ribonucleotide reductase inhibitor. Also called 3-aminopyridine-2-carboxaldehyde thiosemicarbazone and 3-AP, Triapine® inhibits the enzyme ribonucleotide reductase, resulting in the inhibition of the conversion of ribonucleoside diphosphates to deoxyribonucleotides necessary for DNA synthesis. About Nanopharmaceutics, Inc. Nanopharmaceutics, Inc. is a clinical-stage specialty pharmaceutical company developing oral, topical, and injectable products for cancer, central nervous system (CNS) disorders, and infectious diseases. Leveraging its expertise in nanoparticle and fine-particle formulations, which can specifically be used to improve hard-to-deliver Biopharmaceutics Classification System (BCS) category II and IV drugs, Nanopharmaceutics is focused on formulation development aimed at improving drug absorption and stability. Contact: Nanopharmaceutics, Inc. James D. Talton, Ph.D. President and Chief Executive Officer 352-401-6304 jtalton@nanopharmaceutics.com View original content: SOURCE Nanopharmaceutics, Inc.

Radiation Therapy

100 Deals associated with Triapine

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External Link

KEGG	Wiki	ATC	Drug Bank
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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Adenosquamous Carcinoma	Phase 3	US	National Cancer Institute	10 May 2016
Adenosquamous Carcinoma	Phase 3	CA	National Cancer Institute	10 May 2016
Adenosquamous Carcinoma	Phase 3	PR	National Cancer Institute	10 May 2016
Cervical Squamous Cell Carcinoma	Phase 3	US	National Cancer Institute	10 May 2016
Cervical Squamous Cell Carcinoma	Phase 3	CA	National Cancer Institute	10 May 2016
Cervical Squamous Cell Carcinoma	Phase 3	PR	National Cancer Institute	10 May 2016
Squamous Cell Carcinoma	Phase 3	US	National Cancer Institute	10 May 2016
Squamous Cell Carcinoma	Phase 3	CA	National Cancer Institute	10 May 2016
Squamous Cell Carcinoma	Phase 3	PR	National Cancer Institute	10 May 2016
Uterine Cervix Adenocarcinoma	Phase 3	US	National Cancer Institute	10 May 2016

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02466971 (NRG-GY006, CTgov)	Phase 3	Adenosquamous Carcinoma \| Vagina Carcinoma \| Cervical Squamous Cell Carcinoma ... View more	450	Intensity-Modulated Radiation Therapy+cisplatin (Arm I (Cisplatin, IMRT or RT, Brachytherapy))	fbmaaqlqee(mkemdurzyt) = wkpphplrjy ecmbfkuzox (vliofgbset, vawncaaomn - oaeqfdtcuy) View more	-	05 Jan 2024
				Intensity-Modulated Radiation Therapy+Triapine+cisplatin (Arm II (Cisplatin, IMRT or RT, Brachytherapy, Triapine))	fbmaaqlqee(mkemdurzyt) = qrdcszukuv ecmbfkuzox (vliofgbset, intdkfvxla - fxekzbxcim) View more
NCT02466971 (NRG-GY006, ASCO2023)	Phase 3	Vaginal Neoplasms \| Locally Advanced Cervical Carcinoma	448	Cisplatin + RT	gpkwdmwdhi(hppzmdywrc): HR = 1.018 (95% CI, 0.634 - 1.635) View more	Negative	31 May 2023
				Cisplatin + RT + Triapine
NCT04234568 (AACR2023) Manual	Phase 1	Gastro-Enteropancreatic Neuroendocrine Tumor SSTR Expression	31	triapine+Lutetium Dotatate LU-177	clawreyanl(xyjnswrafo) = One DLT in dose level 1, seven DLTs in dose level 2, and one grade 5 DLT in dose level 3 were observed. hiwxygpesh (qhsmxoitwo ) View more	Positive	14 Apr 2023
NCT04234568 (ASCO_GI2023) Manual	Phase 1	SSTR positive Gastro-Enteropancreatic Neuroendocrine Tumor SSTR1 Expression	31	triapine+lutetium Lu-177 dotatate	kdkxuxiqsa(rrsukezadv) = gxskdvbxpc kucbbdbdbw (etrnmrlveh ) View more	Positive	24 Jan 2023
Etctn 10388 (ASCO2020)	Phase 1	Neuroendocrine Tumors First line	29	Triapine and Lutetium Lu 177 Dotatate	giwuwbeomy(yxxbvxkeup) = fhjyummfyk oiejnlhgkp (pregpyvdou )	-	25 May 2020
NCT02466971 (Pubmed \| Front Oncol) Manual	Phase 2	Vaginal Neoplasms \| Uterine Cervical Diseases	26	cisplatin+Radiotherapy+triapine	vfhnbycigu(radrpxtuzl) = shnadwfxyr lihsfbvxsn (wycdygvgms ) View more	Positive	15 Oct 2019
				cisplatin+Radiotherapy	vfhnbycigu(radrpxtuzl) = msjfwmenls lihsfbvxsn (wycdygvgms ) View more
NCT00016874 (Pubmed \| Front Oncol) Manual	Phase 1	Solid tumor	13	cisplatin+paclitaxel+triapine	itrhdxgjog(wtwxqykpdv) = triapine (80 mg/m2), cisplatin (50 mg/m2), paclitaxel (80 mg/m2) bcczwylkfs (cbytkgvcsu ) View more	Positive	04 Apr 2017
NCT00024323 (Pubmed \| Cancer Chemother Pharmacol)	Phase 1	Neoplasms	-	Triapine	ljqbknewjz(vioefbrpti) = bjlzbmmvvm skxoepwcvk (jafvehoxxz )	-	01 Jan 2017
				Cisplatin	ljqbknewjz(vioefbrpti) = fuypnzdzmm skxoepwcvk (jafvehoxxz )
NCT00075504 (CTgov)	Phase 2	Gallbladder Neoplasms \| Gallbladder Carcinoma	33	Gemcitabine+Triapine (Stratum A Normal Liver Function Triapine, Gemcitabine)	agbpnabtkq(bqhwmsvlnn) = wjvjfqxump dlubrmxaiw (ncjsrzhbhx, ijtuaaapkz - bbaalbomfp) View more	-	28 Sep 2015
				Gemcitabine+Triapine (Stratum B Abnormal Liver Function Triapine, Gemcitabine)	agbpnabtkq(bqhwmsvlnn) = kqrunhrktp dlubrmxaiw (ncjsrzhbhx, rsfoyxsdpv - jiiohfznjd) View more
NCT00381550 (CTgov)	Phase 2	Polycythemia Vera \| Philadelphia chromosome positive chronic myelogenous leukemia \| Chronic Myelomonocytic Leukemia ... View more	35	laboratory biomarker analysis+fludarabine phosphate+triapine	uyqjxobxwv(mebvuvfvmb) = ctunljuahd jetqsjqzcv (dgdfdsjggt, wzqqfzlqnn - fgrwmgukqb) View more	-	21 May 2014