pteridines and Cancer of Ovary studies

Research Excerpts

Excerpt	Relevance	Reference
"BI 2536 is a selective and potent small-molecule inhibitor of polo-like kinase 1."	6.75	Multicentric parallel phase II trial of the polo-like kinase 1 inhibitor BI 2536 in patients with advanced head and neck cancer, breast cancer, ovarian cancer, soft tissue sarcoma and melanoma. The first protocol of the European Organization for Research ( Aerts, C; Allgeier, A; Blay, JY; Bogaerts, J; Brain, E; De Greve, J; Fontaine, C; Fritsch, H; Hanft, G; Lacombe, D; Machiels, JP; Munzert, G; Rapion, J; Ray-Coquard, I; Schöffski, P; Sleijfer, S; Soria, JC; Wolter, P, 2010)
"Volasertib is a potent and selective cell-cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinase."	2.82	Volasertib Versus Chemotherapy in Platinum-Resistant or -Refractory Ovarian Cancer: A Randomized Phase II Groupe des Investigateurs Nationaux pour l'Etude des Cancers de l'Ovaire Study. ( Del Campo, JM; Follana, P; Freyer, G; Garin-Chesa, P; Gladieff, L; Joly, F; Lesoin, A; Lortholary, A; Marzin, K; Nazabadioko, S; Pardo, B; Pilz, K; Pujade-Lauraine, E; Ray-Coquard, IL; Sassi, M; Selle, F; Sufliarsky, J; Tholander, B; Vergote, I; Vidal, L; Weber, B, 2016)
"BI 2536 is a selective and potent small-molecule inhibitor of polo-like kinase 1."	2.75	Multicentric parallel phase II trial of the polo-like kinase 1 inhibitor BI 2536 in patients with advanced head and neck cancer, breast cancer, ovarian cancer, soft tissue sarcoma and melanoma. The first protocol of the European Organization for Research ( Aerts, C; Allgeier, A; Blay, JY; Bogaerts, J; Brain, E; De Greve, J; Fontaine, C; Fritsch, H; Hanft, G; Lacombe, D; Machiels, JP; Munzert, G; Rapion, J; Ray-Coquard, I; Schöffski, P; Sleijfer, S; Soria, JC; Wolter, P, 2010)
"Ovarian cancer is responsible for the highest mortality among all gynecologic malignancies, and novel therapies are urgently needed to improve patient outcome."	1.43	BET Bromodomain Inhibition as a Therapeutic Strategy in Ovarian Cancer by Downregulating FoxM1. ( Cai, MC; Di, W; Gao, WQ; Gu, Z; Ji, ZL; Jing, Y; Ma, P; Peng, H; Yan, Y; Zhang, M; Zhang, S; Zhang, Z; Zhuang, G, 2016)
"Early diagnostics of ovarian cancer is difficult, because there are no symptoms until the disease has progressed to an advanced stage."	1.39	Fluorescence characteristics of human urine from normal individuals and ovarian cancer patients. ( Hunakova, L; Lajdova, I; Martinicky, D; Sikurova, L; Zvarik, M, 2013)
"Nine patients with ovarian cancer (stages IIb-IV) were followed for a period of 16 months to date."	1.27	Significance of urinary neopterine in gynecological oncology: follow-up of patients with ovarian cancer. ( Bichler, A; Fuchs, D; Hausen, A; Hetzel, H; Reibnegger, G; Wachter, H, 1983)

Research

Studies (9)

Authors

Clinical Trials (2)

Trial Overview

Trial Outcomes

AUC (0-24); Area Under the Concentration-time Curve in Plasma Over the Time Interval From 0 to 24 Hours for BI 6727 BS

Timeframe	Studies, this research(%)	All Research%
pre-1990	1 (11.11)	18.7374
1990's	0 (0.00)	18.2507
2000's	0 (0.00)	29.6817
2010's	5 (55.56)	24.3611
2020's	3 (33.33)	2.80

Authors	Studies
Pautier, P	1
Motte-Rouge, T	1
Lécuru, F	1
Classe, JM	1
Ferron, G	1
Floquet, A	1
Kurtz, JE	1
Freyer, G	2
Hardy-Bessard, AC	1
Wang, Z	1
Zhao, S	1
Gu, W	1
Dong, Y	1
Meng, F	1
Yuan, J	1
Zhong, Z	1
Díaz-Carballo, D	1
Saka, S	1
Acikelli, AH	1
Homp, E	1
Erwes, J	1
Demmig, R	1
Klein, J	1
Schröer, K	1
Malak, S	1
D'Souza, F	1
Noa-Bolaño, A	1
Menze, S	1
Pano, E	1
Andrioff, S	1
Teipel, M	1
Dammann, P	1
Klein, D	1
Nasreen, A	1
Tannapfel, A	1
Grandi, N	1
Tramontano, E	1
Ochsenfarth, C	1
Strumberg, D	1
Zvarik, M	2
Martinicky, D	2
Hunakova, L	2
Lajdova, I	1
Sikurova, L	2
Pujade-Lauraine, E	1
Selle, F	1
Weber, B	1
Ray-Coquard, IL	1
Vergote, I	1
Sufliarsky, J	1
Del Campo, JM	1
Lortholary, A	1
Lesoin, A	1
Follana, P	1
Pardo, B	1
Vidal, L	1
Tholander, B	1
Gladieff, L	1
Sassi, M	1
Garin-Chesa, P	1
Nazabadioko, S	1
Marzin, K	1
Pilz, K	1
Joly, F	1
Zhang, Z	1
Ma, P	1
Jing, Y	1
Yan, Y	1
Cai, MC	1
Zhang, M	1
Zhang, S	1
Peng, H	1
Ji, ZL	1
Di, W	1
Gu, Z	1
Gao, WQ	1
Zhuang, G	1
Schöffski, P	1
Blay, JY	1
De Greve, J	1
Brain, E	1
Machiels, JP	1
Soria, JC	1
Sleijfer, S	1
Wolter, P	1
Ray-Coquard, I	1
Fontaine, C	1
Munzert, G	1
Fritsch, H	1
Hanft, G	1
Aerts, C	1
Rapion, J	1
Allgeier, A	1
Bogaerts, J	1
Lacombe, D	1
Hetzel, H	1
Bichler, A	1
Fuchs, D	1
Hausen, A	1
Reibnegger, G	1
Wachter, H	1

Trial	Phase	Enrollment	Study Type	Start Date	Status
Phase II Randomized Trial of the Polo-like Kinase 1 Inhibitor BI 6727 Monotherapy Versus Investigator´s Choice Chemotherapy in Ovarian Cancer Patients Resistant or Refractory to Platinum-based Cytotoxic Therapy[NCT01121406]	Phase 2	110 participants (Actual)	Interventional	2010-04-30	Completed
Multicenter Parallel Phase II Trial of BI 2536 Administered as One Hour IV Infusion Every 3 Weeks in Defined Cohorts of Patients With Various Solid Tumors. A New Drug Screening Program of the EORTC Network of Core Institutions (NOCI)[NCT00526149]	Phase 2	76 participants (Actual)	Interventional	2007-07-31	Completed
[information is prepared from clinicaltrials.gov, extracted Sep-2024]

AUC (0-24); area under the concentration-time curve in plasma over the time interval from 0 to 24 hours for BI 6727 BS (NCT01121406)
Timeframe: -0.083 hours (h), 2h, 4h, 6h, 24h, 168h and 336 h after first drug administration

AUC (0-24); Area Under the Concentration-time Curve in Plasma Over the Time Interval From 0 to 24 Hours for CD 10899 BS

Intervention	ng*h/mL (Geometric Mean)
Volasertib	2140

AUC (0-24); area under the concentration-time curve in plasma over the time interval from 0 to 24 hours for CD 10899 BS (metabolite of Volasertib BI 6727) (NCT01121406)
Timeframe: -0.083 hours (h), 2h, 4h, 6h, 24h, 168h and 336 h after first drug administration

AUC (0-inf); Area Under the Concentration-time Curve in Plasma Over the Time Interval From 0 Extrapolated to Infinity for BI 6727 BS

Intervention	ng*h/mL (Geometric Mean)
Volasertib	204

AUC (0-inf); area under the concentration-time curve in plasma over the time interval from 0 extrapolated to infinity for BI 6727 BS (NCT01121406)
Timeframe: -0.083 hours (h), 2h, 4h, 6h, 24h, 168h and 336 h after first drug administration

AUC (0-inf); Area Under the Concentration-time Curve in Plasma Over the Time Interval From 0 Extrapolated to Infinity for CD 10899 BS

Intervention	ng*h/mL (Geometric Mean)
Volasertib	6240

AUC (0-inf); area under the concentration-time curve in plasma over the time interval from 0 extrapolated to infinity for CD 10899 BS (metabolite of Volasertib BI 6727) (NCT01121406)
Timeframe: -0.083 hours (h), 2h, 4h, 6h, 24h, 168h and 336 h after first drug administration

Biological Progression-free Survival Based on Serum Cancer Antigen 125 (CA-125) According to the Gynaecologic Cancer Intergroup (GCIG) Criteria

Intervention	ng*h/mL (Geometric Mean)
Volasertib	1400

"Biological PFS including assessment of CA-125 levels was defined as the time from randomisation until the first occurrence of progressive disease according to CA-125, progressive disease according to radiological evidence, or death.~Also according to the below criterias,~In patients with radiological measurable disease, disease progression during study treatment could not be declared on the basis of CA-125 alone.~Patients with elevated CA-125 pre-treatment and normalization of CA-125 had to show evidence of CA-125 ≥ to two times the upper normal limit on two occasions at least one week apart or~Patients with elevated CA-125 pre-treatment, which never normalized, had to show evidence of CA-125 ≥ to two times the nadir value on two occasions at least one week apart or~Patients with CA-125 in the normal range pre-treatment had to show evidence of CA-125 ≥ to two times the upper normal limit on two occasions at least one week apart." (NCT01121406)
Timeframe: At screening and every 6 weeks thereafter (Up to 213 weeks )

CL; Total Clearance of BI 6727 BS in Plasma After Intravenous Administration

Intervention	weeks (Median)
Volasertib (BI 6727)	13.1
Cytotoxic	20.6

CL; total clearance of BI 6727 BS in plasma after intravenous administration (NCT01121406)
Timeframe: -0.083 hours (h), 2h, 4h, 6h, 24h, 168h and 336 h after first drug administration

Cmax; Maximum Measured Concentration of BI 6727 BS in Plasma

Intervention	mL/min (Geometric Mean)
Volasertib	801

Cmax; maximum measured concentration of BI 6727 BS in plasma (NCT01121406)
Timeframe: -0.083 hours (h), 2h, 4h, 6h, 24h, 168h and 336 h after first drug administration

Cmax; Maximum Measured Concentration of CD 10899 BS in Plasma

Intervention	ng/mL (Geometric Mean)
Volasertib	341

Cmax; maximum measured concentration of CD 10899 BS (metabolite of Volasertib BI 6727) in plasma (NCT01121406)
Timeframe: -0.083 hours (h), 2h, 4h, 6h, 24h, 168h and 336 h after first drug administration

Disease Control Rate (DCR) at Week 24 According to Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1

Intervention	ng/mL (Geometric Mean)
Volasertib	10.8

DCR was defined as the proportion of patients who had an overall response of complete response (CR), partial response (PR), or stable disease (SD). (NCT01121406)
Timeframe: Week 24

MRT; Mean Residence Time of BI 6727 BS in the Body

Intervention	percentage of participants (Number)
Volasertib (BI 6727)	30.6
Cytotoxic	43.1

MRT; Mean residence time of BI 6727 BS in the body (NCT01121406)
Timeframe: -0.083 hours (h), 2h, 4h, 6h, 24h, 168h and 336 h after first drug administration

Overall Survival (OS)

Intervention	hours (Geometric Mean)
Volasertib	118

OS is defined as time from randomisation to death irrespective of the cause of the death. (NCT01121406)
Timeframe: From randomization until death or study discontinuation; Up to 213 weeks

Progression Free Survival (PFS)

Intervention	weeks (Median)
Volasertib (BI 6727)	60.1
Cytotoxic	68.6

"Progression-free survival of a patient was based on the investigator's assessment; it was defined as the number of days from the date of randomisation until the date of either disease progression or death from any cause, whichever occurred first.~Definition of disease progression according to RECIST version 1.1; Patients with measurable tumour lesions at baseline, Target-lesions: at least a 20% increase in the sum of diameters of target lesions, the sum of diameters must also demonstrate an absolute increase of at least 5 mm,taking as reference the smallest sum on study, or appearance of 1 or more new lesions.~Non-target lesions: unequivocal progression of existing non-target lesions or appearance of 1 or more new lesions Patients with non-measurable tumour lesions at baseline, Non-target lesions: requires unequivocal progression of existing non-target lesions or appearance of 1 or more new lesions" (NCT01121406)
Timeframe: From randomization until disease progression, death or study discontinuation; Up to 213 weeks

t1/2; Terminal Half-life of BI 6727 BS in Plasma

Intervention	weeks (Median)
Volasertib (BI 6727)	13.1
Cytotoxic	20.6

t1/2; Terminal half-life of BI 6727 BS in plasma (NCT01121406)
Timeframe: -0.083 hours (h), 2h, 4h, 6h, 24h, 168h and 336 h after first drug administration

t1/2; Terminal Half-life of CD 10899 BS in Plasma

Intervention	hours (Geometric Mean)
Volasertib	143

t1/2; Terminal half-life of CD 10899 BS in plasma (NCT01121406)
Timeframe: -0.083 hours (h), 2h, 4h, 6h, 24h, 168h and 336 h after first drug administration

Time to Deterioration in Abdominal Bloating/ Quality of Life (QOL)

Intervention	hours (Geometric Mean)
Volasertib	146

"Time to deterioration in abdominal bloating/ Quality of life (QOL) and symptom control assessed by the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30, QLQ-OV28, and individual symptom questionnaires.~The time to deterioration was defined as the time from randomisation to a score increased (i.e. worsened) by at least 10 points from baseline (0-100 point scale). If score is missing, and patient died within 28 days after scheduled time for completion, the patient was considered deteriorated. In this case, time to deterioration is time to death." (NCT01121406)
Timeframe: Every 6 weeks (Up to 213 weeks )

Time to Deterioration in Fatigue/Quality of Life (QOL)

Intervention	weeks (Median)
Volasertib (BI 6727)	NA
Cytotoxic	47.2

"Time to deterioration in fatigue/Quality of life (QOL) and symptom control assessed by the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30, QLQ-OV28, and individual symptom questionnaires.~The time to deterioration was defined as the time from randomisation to a score increased (i.e. worsened) by at least 10 points from baseline (0-100 point scale). If score is missing, and patient died within 28 days after scheduled time for completion, the patient was considered deteriorated. In this case, time to deterioration is time to death." (NCT01121406)
Timeframe: Every 6 weeks (Up to 213 weeks )

Time to Deterioration in Global Health Status/Quality of Life (QOL)

Intervention	weeks (Median)
Volasertib (BI 6727)	NA
Cytotoxic	67.1

"Time to deterioration in global health status/Quality of life (QOL) and symptom control assessed by the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30, QLQ-OV28, and individual symptom questionnaires.~The time to deterioration was defined as the time from randomisation to a score increased (i.e. worsened) by at least 10 points from baseline (0-100 point scale). If score is missing, and patient died within 28 days after scheduled time for completion, the patient was considered deteriorated. In this case, time to deterioration is time to death." (NCT01121406)
Timeframe: Every 6 weeks (Up to 213 weeks )

Time to Deterioration in Pain/ Quality of Life (QOL)

Intervention	weeks (Median)
Volasertib (BI 6727)	NA
Cytotoxic	39.6

"Time to deterioration in pain/ Quality of life (QOL) and symptom control assessed by the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30, QLQ-OV28, and individual symptom questionnaires.~The time to deterioration was defined as the time from randomisation to a score increased (i.e. worsened) by at least 10 points from baseline (0-100 point scale). If score is missing, and patient died within 28 days after scheduled time for completion, the patient was considered deteriorated. In this case, time to deterioration is time to death." (NCT01121406)
Timeframe: Every 6 weeks (Up to 213 weeks )

Time to Deterioration in the Three Most Troublesome Disease Specific Symptoms/ Quality of Life (QOL)

Intervention	weeks (Median)
Volasertib (BI 6727)	NA
Cytotoxic	54.1

"Three most troublesome disease specific symptoms, defined by the patient at baseline.~Patients that have defined more than 3 most troublesome symptoms have not been taken into account in the analysis.~Quality of life (QOL) and symptom control assessed by the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30, QLQ-OV28, and individual symptom questionnaires.~The time to deterioration was defined as the time from randomisation to a score increased (i.e. worsened) by at least 10 points from baseline (0-100 point scale). If score is missing, and patient died within 28 days after scheduled time for completion, the patient was considered deteriorated. In this case, time to deterioration is time to death." (NCT01121406)
Timeframe: Every 6 weeks (Up to 213 weeks)

Tmax; Time From Dosing to Maximum Measured Concentration of BI 6727 BS in Plasma

Intervention	weeks (Median)
Volasertib (BI 6727)	NA
Cytotoxic	18.9

tmax; time from dosing to maximum measured concentration of BI 6727 BS in plasma (NCT01121406)
Timeframe: -0.083 hours (h), 2h, 4h, 6h, 24h, 168h and 336 h after first drug administration

Tmax; Time From Dosing to Maximum Measured Concentration of CD 10899 BS in Plasma

Intervention	hours (Median)
Volasertib	2.00

tmax; time from dosing to maximum measured concentration of CD 10899 BS (metabolite of Volasertib BI 6727) in plasma (NCT01121406)
Timeframe: -0.083 hours (h), 2h, 4h, 6h, 24h, 168h and 336 h after first drug administration

Vss;Apparent Volume of Distribution at Steady State Following Intravenous Administration for BI 6727 BS

Intervention	hours (Median)
Volasertib	6.07

Vss;apparent volume of distribution at steady state following intravenous administration for BI 6727 BS (NCT01121406)
Timeframe: -0.083 hours (h), 2h, 4h, 6h, 24h, 168h and 336 h after first drug administration

Best Overall Response

Intervention	Litres (Geometric Mean)
Volasertib	5690

"Best overall response (BOR) is defined as the best response recorded at any time from the date of randomisation until the end of treatment.~Missing categories signify that no tumour imaging has been performed post baseline, and therefore the response status could not be assessed." (NCT01121406)
Timeframe: time from the date of randomisation until study completion/discontinuation; Up to 213 weeks

Biological Tumour Response Based on Serum Cancer Antigen 125 (CA-125) According to the Gynaecologic Cancer Intergroup (GCIG) Criteria

Intervention	participants (Number)
	CR- Measurable disease	PR- Measurable disease	SD- Measurable disease	PD- Measurable disease	Missing- Measurable disease	CR- Non-measurable disease	Non-CR/Non-PD- Non-measurable disease	PD- Non-measurable disease	Missing- Non-measurable disease
Cytotoxic	0	8	24	10	2	1	9	0	1
Volasertib (BI 6727)	0	7	24	14	0	0	6	3	0

"Patients were to have a pre-treatment CA-125 of at least twice the upper limit of normal to be considered for CA-125 response. Patients were not evaluable by CA-125 if they had received mouse antibodies or if they had undergone medical and/or surgical interference with their peritoneum or pleura during the previous 28 days. In eligible patients, a CA-125 response was defined as the moment the CA- 25 was reduced by 50%, with this being confirmed with a consecutive CA-125 assessment not earlier than 28 days after the previous one.~Biological response rate based on serum CA-125 levels was assessed according to the guidelines by the Gynaecologic Cancer Intergroup. Monitoring of blood levels of the tumour marker CA-125 was performed at screening and every 6 weeks thereafter." (NCT01121406)
Timeframe: At screening and every 6 weeks thereafter (Up to 213 weeks)

Clinically Relevant Changes in Laboratory and ECG Data

Intervention	participants (Number)
	Yes	No	Not evaluable	Missing
Cytotoxic	12	23	11	9
Volasertib (BI 6727)	10	33	4	7

Clinically relevant changes in laboratory and ECG data (NCT01121406)
Timeframe: From first treatment administration to 21 days after the last drug administration (Up to 1403 days)

Incidence and Intensity of Adverse Events According to the United States National Cancer Institute (US NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0

Intervention	percentage of participants (Number)
	Blood alkaline phosphatase increased	Blood creatinine increased	Platelet count decreased	Alanine aminotransferase increased	Aspartate aminotransferase increased	Blood uric acid increased	Gamma-glutamyltransferase increased	Alanine aminotransferase abnormal	Electrocardiogram QT prolonged	Haemoglobin decreased	Neutrophil count decreased	Troponin I increased	Blood lactate dehydrogenase increased	Blood magnesium decreased	White blood cell count decreased	Blood urea increased	Alanine aminotransferase decreased	Blood bilirubin increased	Blood creatine phosphokinase decreased	Blood potassium decreased	Hepatic enzyme increased	Aspartate aminotransferase abnormal	Transaminases increased
Cytotoxic	12.7	3.6	0.0	9.1	5.5	5.5	5.5	0.0	0.0	3.6	0.0	0.0	0.0	0.0	0.0	3.6	0.0	0.0	0.0	0.0	0.0	1.8	1.8
Cytotoxic to Volasertib Switch	8.3	0.0	8.3	4.2	4.2	0.0	4.2	4.2	4.2	4.2	4.2	4.2	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0
Volasertib (BI 6727)	3.7	9.3	9.3	1.9	3.7	1.9	3.7	0.0	0.0	3.7	1.9	0.0	3.7	3.7	3.7	1.9	1.9	1.9	1.9	1.9	1.9	0.0	0.0

Incidence and intensity of adverse events according to the United States National Cancer Institute (US NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 (NCT01121406)
Timeframe: From first treatment administration to 21 days after the last drug administration (Up to 1403 days)

Article	Year
α Acta biomaterialia, 2021, 04-01, Volume: 124 Topics: Animals; Cell Line, Tumor; Female; Humans; Integrin alpha3; Mice; Molecular Targeted Therapy; Ovaria	2021
Enhanced antitumoral activity of TLR7 agonists via activation of human endogenous retroviruses by HDAC inhibitors. Communications biology, 2021, 03-03, Volume: 4, Issue:1 Topics: Adjuvants, Immunologic; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Lin	2021
Fluorescence characteristics of human urine from normal individuals and ovarian cancer patients. Neoplasma, 2013, Volume: 60, Issue:5 Topics: Adult; Aged; Early Detection of Cancer; Female; Humans; Middle Aged; Optical Imaging; Ovarian Neopla	2013
Differences in pteridine urinary levels in patients with malignant and benign ovarian tumors in comparison with healthy individuals. Journal of photochemistry and photobiology. B, Biology, 2015, Volume: 153 Topics: Adult; Aged; Biopterins; Chromatography, High Pressure Liquid; Female; Humans; Manganese Compounds;	2015
BET Bromodomain Inhibition as a Therapeutic Strategy in Ovarian Cancer by Downregulating FoxM1. Theranostics, 2016, Volume: 6, Issue:2 Topics: Animals; Antineoplastic Agents; Azepines; Carcinoma; Cell Line, Tumor; Down-Regulation; Female; Fork	2016
Significance of urinary neopterine in gynecological oncology: follow-up of patients with ovarian cancer. Cancer detection and prevention, 1983, Volume: 6, Issue:1-2 Topics: Adult; Aged; Biopterins; Female; Follow-Up Studies; Humans; Middle Aged; Neopterin; Ovarian Neoplasm	1983

pteridines and Cancer of Ovary