Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 2/2014

Open Access 01-08-2014 | Original Article

Phase 1 dose-escalation study of the PARP inhibitor CEP-9722 as monotherapy or in combination with temozolomide in patients with solid tumors

Authors: Ruth Plummer, Peter Stephens, Louiza Aissat-Daudigny, Anne Cambois, Gilbert Moachon, Peter D. Brown, Mario Campone

Published in: Cancer Chemotherapy and Pharmacology | Issue 2/2014

Login to get access

Abstract

Purpose

Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme important in DNA repair. PARP-1 activation at points of DNA strand break results in poly(ADP-ribose) polymer formation, opening the DNA structure, and allowing access of other repair enzymes. CEP-9722 inhibits PARP-1 and PARP-2 and is designed to potentiate DNA-damaging chemotherapies.

Methods

This dose-escalating phase 1 study assessed the safety, maximum tolerated dose (MTD), and pharmacokinetics/pharmacodynamics of CEP-9722 plus temozolomide in adults with solid tumors. Tumor response was also assessed. Participants received a 14-day cycle of CEP-9722 (days 1 and 3–5 or days 1–5), followed by 28-day cycles of CEP-9722 plus temozolomide 150 mg/m2 on days 1–5. The initial CEP-9722 dose (cohort 1) was 150 mg/day; dose escalation followed a modified Fibonnaci sequence.

Results

Twenty-six patients received CEP-9722 150–1,000 mg/day combined with temozolomide. Dose-limiting toxicities of asthenia and persistent weight loss at 1,000 mg/day resulted in 750 mg/day being defined as the MTD and recommended dose for further study. Overall, 24 (92 %) patients had treatment-related adverse events (TRAEs), mostly grade 1 or 2, with nausea, vomiting, and diarrhea having the strongest relation to CEP-9722. Four patients had grade 3 TRAEs (asthenia, myositis, diarrhea, and fatigue). Systemic exposure generally increased with dosage, with high inter- and intra-patient variability at all doses. Pharmacodynamic assessment confirmed PARP inhibition although no dose response was apparent. One patient with melanoma achieved a partial response (1,000 mg/day).

Conclusions

CEP-9722 was adequately tolerated with temozolomide; the MTD was 750 mg/day. Only limited clinical activity was observed.
Appendix
Available only for authorised users
Literature
1.
Jagtap P, Szabó C (2005) Poly(ADP-ribose) polymerase and the therapeutic effects of its inhibitors. Nat Rev Drug Discov 4:421–440PubMedCrossRef
2.
Plummer ER, Calvert H (2007) Targeting poly(ADP-ribose) polymerase: a two-armed strategy for cancer therapy. Clin Cancer Res 13:6252–6256PubMedCrossRef
3.
Ame J, Rolli V, Schreiber V et al (1999) PARP-2, a novel mammalian DNA damage dependent poly(ADP-ribose) polymerase. J Biol Chem 274:17860–17868PubMedCrossRef
4.
de Murcia JM, Niedergang C, Trucco C et al (1997) Requirement of poly(ADP-ribose) polymerase in recovery from DNA damage in mice and in cells. Proc Natl Acad Sci USA 94:7303–7307PubMedCentralPubMedCrossRef
5.
6.
7.
Jones C, Plummer ER (2008) PARP inhibitors and cancer therapy: early results and potential applications. Br J Radiol 81(spec no 1):S2–S5PubMedCrossRef
8.
Chalmers AJ (2009) The potential role and application of PARP inhibitors in cancer treatment. Br Med Bull 89:23–40PubMedCrossRef
9.
Plummer R, Jones C, Middleton M et al (2008) Phase I study of the poly(ADP-ribose) polymerase inhibitor, AG014699, in combination with temozolomide in patients with advanced solid tumors. Clin Cancer Res 14:7917–7923PubMedCentralPubMedCrossRef
10.
Samol J, Ranson M, Scott E et al (2012) Safety and tolerability of the poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib (AZD2281) in combination with topotecan for the treatment of patients with advanced solid tumors: a phase I study. Investig New Drugs 30:1493–1500CrossRef
11.
12.
Kummar S, Chen A, Ji J et al (2011) Phase I study of PARP inhibitor ABT-888 in combination with topotecan in adults with refractory solid tumors and lymphomas. Cancer Res 71:5626–5634PubMedCentralPubMedCrossRef
13.
Bryant HE, Schultz N, Thomas HD et al (2005) Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 414:913–917CrossRef
14.
Tutt A, Robson M, Garber JE et al (2010) Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet 376:235–244PubMedCrossRef
15.
Miknyoczki S, Chang H, Grobelny J et al (2007) The selective poly(ADP-ribose) polymerase-1(2) inhibitor, CEP-8983, increases the sensitivity of chemoresistant tumor cells to temozolomide and irinotecan but does not potentiate myelotoxicity. Mol Cancer Ther 6:2290–2302PubMedCrossRef
16.
Giaccone G, Rajan A, Kelly RJ et al (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(Suppl 15):abstract 3027
17.
Engvall E, Perlmann P (1971) Enzyme-linked immunosorbent assay (ELISA) quantitative assay of immunoglobulin G. Immunochemistry 8:871–874PubMedCrossRef
18.
Farmer H, McCabe N, Lord CJ et al (2005) Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434:917–921PubMedCrossRef
19.
Ashworth A (2008) A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair. J Clin Oncol 26:3785–3790PubMedCrossRef
20.
Audeh MW, Carmichael J, Penson RT et al (2010) Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet 376:245–251PubMedCrossRef
21.
Kaye SB, Lubinski J, Matulonis U et al (2012) Phase II, open-label, randomized, multicenter study comparing the efficacy and safety of olaparib, a poly (ADP-ribose) polymerase inhibitor, and pegylated liposomal doxorubicin in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer. J Clin Oncol 30:372–379PubMedCrossRef
22.
Ledermann J, Harter P, Gourley C et al (2012) Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med 366:1382–1392PubMedCrossRef
23.
Plummer R, Lorigan P, Steven N et al (2013) A phase II study of the potent PARP inhibitor, Rucaparib (PF-01367338, AG014699), with temozolomide in patients with metastatic melanoma demonstrating evidence of chemopotentiation. Cancer Chemother Pharmacol 71:1191–1199PubMedCrossRef
24.
Metadata
Title
Phase 1 dose-escalation study of the PARP inhibitor CEP-9722 as monotherapy or in combination with temozolomide in patients with solid tumors
Authors
Ruth Plummer
Peter Stephens
Louiza Aissat-Daudigny
Anne Cambois
Gilbert Moachon
Peter D. Brown
Mario Campone
Publication date
01-08-2014
Publisher
Springer Berlin Heidelberg
Published in
Cancer Chemotherapy and Pharmacology / Issue 2/2014
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-014-2486-9

Other articles of this Issue 2/2014

Cancer Chemotherapy and Pharmacology 2/2014 Go to the issue

Original Article

Influence of genetic polymorphisms of FPGS, GGH, and MTHFR on serum methotrexate levels in Chinese children with acute lymphoblastic leukemia

Original Article

Circulating biomarkers in hepatocellular carcinoma

Review Article

Role of pregnane X receptor in chemotherapeutic treatment

Original Article

A phase II trial of Cremorphor EL-free paclitaxel (Genexol-PM) and gemcitabine in patients with advanced non-small cell lung cancer

Original Article

Evaluation of the effect of food and ketoconazole on the pharmacokinetics of the smoothened inhibitor PF-04449913 in healthy volunteers

Original Article

Enhanced skin toxicity associated with the combination of clofarabine plus cytarabine for the treatment of acute leukemia
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits