The DOI matches its Crossref record; 4 of the 4 references it cites were found in a registry or an index.
Phase I Study of PARP Inhibitor ABT-888 in Combination with Topotecan in Adults with Refractory Solid Tumors and Lymphomas
Open accessPublished version of a preprint
Abstract
A phase I trial of ABT-888 (veliparib), a PARP inhibitor, in combination with topotecan, a topoisomerase I-targeted agent, was carried out to determine maximum tolerated dose (MTD), safety, pharmacokinetics, and pharmacodynamics of the combination in patients with refractory solid tumors and lymphomas. Varying schedules and doses of intravenous topotecan in combination with ABT-888 (10 mg) administered orally twice a day (BID) were evaluated. Plasma and urine pharmacokinetics were assessed and levels of poly(ADP-ribose) (PAR) and the DNA damage marker γH2AX were measured in tumor and peripheral blood mononuclear cells (PBMC). Twenty-four patients were enrolled. Significant myelosuppression limited the ability to coadminister ABT-888 with standard doses of topotecan, necessitating dose reductions. Preclinical studies using athymic mice carrying human tumor xenografts also informed schedule changes. The MTD was established as topotecan 0.6 mg/m²/d and ABT-888 10 mg BID on days one to five of 21-day cycles. Topotecan did not alter the pharmacokinetics of ABT-888. A more than 75% reduction in PAR levels was observed in 3 paired tumor biopsy samples; a greater than 50% reduction was observed in PBMCs from 19 of 23 patients with measurable levels. Increases in γH2AX response in circulating tumor cells (CTC) and PBMCs were observed in patients receiving ABT-888 with topotecan. We show a mechanistic interaction of a PARP inhibitor, ABT-888, with a topoisomerase I inhibitor, topotecan, in PBMCs, tumor, and CTCs. Results of this trial reveal that PARP inhibition can modulate the capacity to repair topoisomerase I-mediated DNA damage in the clinic.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In a small pilot trial, topotecan decreased HIF-1α protein expression in 4 out of 7 paired tumor biopsies taken from patients before and after treatment.
“In a small pilot trial, topotecan decreased HIF-1α protein expression in 4 out of 7 paired tumor biopsies taken from patients before and after treatment (Kummar et al., 2011).”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Kummar et al., 2011
The Results (Pharmacodynamics; page unavailable) report paired tumor biopsies assessed for PAR or γH2AX, not HIF-1α. Searches for HIF-1α and hypoxia-inducible factor found no passage reporting a decrease in HIF-1α protein expression in 4 of 7 paired biopsies. (LLM, conf=0.76)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy
Farmer, H., McCabe, N., Lord, C. J., Tutt, A. N. J., Johnson, D. A., Richardson, T. B., Santarosa, M., Dillon, K. J., Hickson, I., Knights, C., et al. (2005) · Nature · doi:10.1038/nature03445 · Cited by 6,683
Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase
Bryant, H. E., Schultz, N., Thomas, H. D., Parker, K. M., Flower, D., Lopez, E., Kyle, S., Meuth, M., Curtin, N. J., & Helleday, T. (2005) · Nature · doi:10.1038/nature03443 · Cited by 5,198
Bonner, W. M., Redon, C. E., Dickey, J. S., Nakamura, A. J., Sedelnikova, O. A., Solier, S., & Pommier, Y. (2008) · Nature reviews. Cancer · doi:10.1038/nrc2523 · Cited by 1,623
Self-citationErickson-Miller, C. L., May, R. D., Tomaszewski, J., Osborn, B., Murphy, M. J., Page, J. G., & Parchment, R. E. (1997) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s002800050600 · Cited by 111
Self-citation
Flagged first, then by citations
Research works printed but not linked: 21
- Ame, 2004, The PARP superfamily, Bioessays, 26, 882, 10.1002/bies.20085 · DOI
- Jagtap, 2005, Poly(ADP-ribose) polymerase and the therapeutic effects of its inhibitors, Nat Rev Drug Discov, 4, 421, 10.1038/nrd1718 · DOI
- Donawho, 2007, ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models, Clin Cancer Res, 13, 2728, 10.1158/1078-0432.CCR-06-3039 · DOI
- Miknyoczki, 2003, Chemopotentiation of temozolomide, irinotecan, and cisplatin activity by CEP-6800, a poly(ADP-ribose) polymerase inhibitor, Mol Cancer Ther, 2, 371
- Pommier, 2006, Topoisomerase I inhibitors: camptothecins and beyond, Nat Rev Cancer, 6, 789, 10.1038/nrc1977 · DOI
- Smith, 2005, The novel poly(ADP-Ribose) polymerase inhibitor, AG14361, sensitizes cells to topoisomerase I poisons by increasing the persistence of DNA strand breaks, Clin Cancer Res, 11, 8449, 10.1158/1078-0432.CCR-05-1224 · DOI
- Pommier, 2006, Repair of topoisomerase I-mediated DNA damage, Prog Nucleic Acid Res Mol Biol, 81, 179, 10.1016/S0079-6603(06)81005-6 · DOI
- Zhang, 2011, Poly(ADP-ribose) polymerase and XPF-ERCC1 participate in distinct pathways for the repair of topoisomerase I-induced DNA damage in mammalian cells, Nucleic Acids Res, 39, 3607, 10.1093/nar/gkq1304 · DOI
- Tolcher, 1997, A phase I study of topotecan followed sequentially by doxorubicin in patients with advanced malignancies, Clin Cancer Res, 3, 755
- Therasse, 2000, New guidelines to evaluate the response to treatment in solid tumors, J Natl Cancer Inst, 92, 205, 10.1093/jnci/92.3.205 · DOI · Paper page
- Beijnen, 1990, High-performance liquid chromatographic analysis of the new antitumour drug SK&F 104864-A (NSC 609699) in plasma, J Pharm Biomed Anal, 8, 789, 10.1016/0731-7085(90)80122-6 · DOI
- Phillips, 2009, Liquid chromatographic determination of NSC 737664 (ABT-888: an inhibitor of poly(ADP-ribose) polymerase (PARP)) in plasma and urine in a phase 0 clinical trial, J Liq Chromatogr Relat Technol, 32, 261, 10.1080/10826070802603351 · DOI
- Kummar, 2009, Phase 0 clinical trial of the poly (ADP-ribose) polymerase inhibitor ABT-888 in patients with advanced malignancies, J Clin Oncol, 27, 2705, 10.1200/JCO.2008.19.7681 · DOI
- Kinders, 2008, Preclinical modeling of a phase 0 clinical trial: qualification of a pharmacodynamic assay of poly (ADP-ribose) polymerase in tumor biopsies of mouse xenografts, Clin Cancer Res, 14, 6877, 10.1158/1078-0432.CCR-08-0214 · DOI
- Wang, 2010, Monitoring drug-induced γH2AX as a pharmacodynamic biomarker in individual circulating tumor cells, Clin Cancer Res, 16, 1073, 10.1158/1078-0432.CCR-09-2799 · DOI
- Kinders, 2010, Development of a validated immunofluorescence assay for gammaH2AX as a pharmacodynamic marker of topoisomerase I inhibitor activity, Clin Cancer Res, 16, 5447, 10.1158/1078-0432.CCR-09-3076 · DOI
- Ardizzoni, 1997, Topotecan, a new active drug in the second-line treatment of small-cell lung cancer: a phase II study in patients with refractory and sensitive disease, J Clin Oncol, 15, 2090, 10.1200/JCO.1997.15.5.2090 · DOI
- ten, 1997, Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer, J Clin Oncol, 15, 2183, 10.1200/JCO.1997.15.6.2183 · DOI
- Long, 2005, Randomized phase III trial of cisplatin with or without topotecan in carcinoma of the uterine cervix: a Gynecologic Oncology Group Study, J Clin Oncol, 23, 4626, 10.1200/JCO.2005.10.021 · DOI
- Plummer, 2006, First and final report of a phase II study of the poly(ADP-ribose) polymerase (PARP) inhibitor, AG014699, in combination with temozolomide (TMZ) in patients with metastatic malignant melanoma (MM), J Clin Oncol, 24., 10.1200/jco.2006.24.18_suppl.8013 · DOI
- Giaccone, 2010, A phase I combination study of olaparib (AZD2281; KU-0059436) and cisplatin (C) plus gemcitabine (G) in adults with solid tumors, J Clin Oncol, 28., 10.1200/jco.2010.28.15_suppl.3027 · DOI
Cited by
Sorted by citations
DNA repair dysregulation from cancer driver to therapeutic target
Curtin, N. J. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3399 · Cited by 1,051
PARP inhibitor upregulates PD-L1 expression and enhances cancer-associated immunosuppression
Jiao, S., Xia, W., Yamaguchi, H., Wei, Y., Chen, M.-K., Hsu, J.-M., Hsu, J. L., Yu, W.-H., Du, Y., Lee, H.-H., et al. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-3215 · Cited by 981
Homologous Recombination Deficiency: Exploiting the Fundamental Vulnerability of Ovarian Cancer
Konstantinopoulos, P. A., Ceccaldi, R., Shapiro, G. I., & D'Andrea, A. D. (2015) · Cancer Discovery · doi:10.1158/2159-8290.cd-15-0714 · Cited by 945
Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer
Wigerup, C., Påhlman, S., & Bexell, D. (2016) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2016.04.009 · Cited by 687
Use of the γ-H2AX assay to monitor DNA damage and repair in translational cancer research
Ivashkevich, A., Redon, C. E., Nakamura, A. J., Martin, R. F., & Martin, O. A. (2012) · Cancer Letters · doi:10.1016/j.canlet.2011.12.025 · Cited by 462
Therapeutic applications of PARP inhibitors: Anticancer therapy and beyond
Curtin, N. J., & Szabo, C. (2013) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2013.01.006 · Cited by 369
Cheng, H., Zhang, Z., Borczuk, A., Powell, C. A., Balajee, A. S., Lieberman, H. B., & Halmos, B. (2013) · Carcinogenesis · doi:10.1093/carcin/bgs393 · Cited by 99
Deng, S., Vlatkovic, T., Li, M., Zhan, T., Veldwijk, M. R., & Herskind, C. (2022) · Cancers · doi:10.3390/cancers14194874 · Cited by 62
Targeting the DNA Damage Response Pathway as a Novel Therapeutic Strategy in Colorectal Cancer
Catalano, F., Borea, R., Puglisi, S., Boutros, A., Gandini, A., Cremante, M., Martelli, V., Sciallero, S., & Puccini, A. (2022) · Cancers · doi:10.3390/cancers14061388 · Cited by 44
Li, C., Qin, C., Li, X., Wang, J., Li, Y., & Sun, Q. (2026) · International Journal of Oncology · doi:10.3892/ijo.2026.5845 · Cited by 3
Metadata
- Authors
- Kummar, S., Chen, A., Ji, J., Zhang, Y., Reid, J. M., Ames, M., Jia, L., Weil, M., Speranza, G., Murgo, A. J., Kinders, R., Wang, L., Parchment, R. E., Carter, J., Stotler, H., Rubinstein, L., Hollingshead, M., Melillo, G., Pommier, Y., Bonner, W., Tomaszewski, J. E., & Doroshow, J. H.
- Affiliations
- Mayo Clinic (US)
- ORCID
- Venue
- Cancer Research
- Published
- 2011-08-30
- Volume
- 71
- Issue
- 17
- Pages
- 5626-5634
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC3166628
- OpenAlex
- W2114572046
- Cited by
- 259
- References
- 4
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 6 · 2023: 17 · 2022: 11 · 2021: 8 · 2020: 11 · 2019: 18 · 2018: 14 · 2017: 25 · 2016: 19 · 2015: 30 · 2014: 39 · 2013: 21 · 2012: 22
- FWCI
- 13.56
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (HHSN261200800001C)
- National Cancer Institute (HHSN261200800001E), ZIABC011078)
- Topics
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer therapeutics and mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- veliparib, PARP inhibitors, topotecan, topoisomerase I inhibitor, combination chemotherapy, refractory solid tumors, lymphoma, maximum tolerated dose, myelosuppression, pharmacokinetics, pharmacodynamics, poly(ADP-ribose), γH2AX, DNA repair, circulating tumor cells, drug interactions
- MeSH terms
- Adult, Aged, Animals, Antineoplastic Combined Chemotherapy Protocols, Benzimidazoles, Drug Administration Schedule, Female, Humans, Lymphoma, Male, Mice, Nude, Middle Aged, Neoplasms, Poly(ADP-ribose) Polymerases, Topotecan, Maximum Tolerated Dose, Xenograft Model Antitumor Assays, Mice, Topoisomerase I Inhibitors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
