title: Clinical factors of response in patients with advanced ovarian cancer participating in early phase clinical trials.
abstract: Drug resistance to conventional anticancer therapies is almost inevitable in patients with advanced ovarian cancer (AOC), limiting their available treatment options. Novel phase I trial therapies within a dedicated drug development unit may represent a viable alternative; however, there is currently little evidence for patient outcomes in such patients. To address this, we undertook a retrospective review of patients with AOC allocated to phase I trials in the Drug Development Unit at Royal Marsden Hospital (RMH) between June 1998 and October 2010. A total of 200 AOC patients with progressive disease were allocated to ≥1 trial each, with a total of 281 allocations. Of these, 135 (68%) patients commenced ≥1 trial (mean 1.4 [1-8]), totaling 216 allocated trials; 65 (32%) patients did not start due to deterioration resulting from rapidly progressive disease (63 patients) or patient choice (2 patients). Response Evaluation Criteria in Solid Tumours (RECIST) complete/partial responses (CR/PR) were observed in 43 (20%) of those starting trials, including those on poly(ADP-ribose) polymerase (PARP) inhibitors (18/79 [23%]), antiangiogenics (9/65 [14%]) and chemotherapy combinations (14/43 [33%]). Factors associated with CR/PR included: fewer prior treatments, platinum-sensitive disease, CR/PR with prior therapy, (the United States-based) Eastern Cooperative Oncology Group (ECOG) performance status score, fewer metastatic sites, higher albumin and haemoglobin levels, lower white cell counts and baseline CA125 levels, germline BRCA1/2 mutations and better RMH Prognostic Score. Mean survival was 32° months for patients who achieved CR/PR. Treatments were generally well tolerated. Most patients with AOC (134/200 [67%]) received ≥1 subsequent line of therapy after phase I trials. Our data suggest that phase I trial referrals should be considered earlier in the AOC treatment pathway and before the onset of rapid disease progression particularly with the emergence of promising novel agents in the era of precision medicine.
authors.affiliation: Royal Marsden NHS Foundation Trust, Downs Road, London SM2 5PT, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: George
authors.affiliation: Royal Marsden NHS Foundation Trust, Downs Road, London SM2 5PT, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Kristeleit
authors.affiliation: Royal Marsden NHS Foundation Trust, Downs Road, London SM2 5PT, UK.
authors.forename: Saeed
authors.initials: S
authors.lastname: Rafii
authors.affiliation: Royal Marsden NHS Foundation Trust, Downs Road, London SM2 5PT, UK.
authors.forename: Caroline O
authors.initials: CO
authors.lastname: Michie
authors.affiliation: Royal Marsden NHS Foundation Trust, Downs Road, London SM2 5PT, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Bowen
authors.affiliation: Royal Marsden NHS Foundation Trust, Downs Road, London SM2 5PT, UK.
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Michalarea
authors.affiliation: Royal Marsden NHS Foundation Trust, Downs Road, London SM2 5PT, UK.
authors.forename: Tom
authors.initials: T
authors.lastname: van Hagen
authors.affiliation: Royal Marsden NHS Foundation Trust, Downs Road, London SM2 5PT, UK.
authors.forename: Mabel
authors.initials: M
authors.lastname: Wong
authors.affiliation: Royal Marsden NHS Foundation Trust, Downs Road, London SM2 5PT, UK.
authors.forename: Grigorios
authors.initials: G
authors.lastname: Rallis
authors.affiliation: Royal Marsden NHS Foundation Trust, Downs Road, London SM2 5PT, UK.
authors.forename: L Rhoda
authors.initials: LR
authors.lastname: Molife
authors.affiliation: Royal Marsden NHS Foundation Trust, Downs Road, London SM2 5PT, UK.
authors.forename: Juanita
authors.initials: J
authors.lastname: Lopez
authors.affiliation: Royal Marsden NHS Foundation Trust, Downs Road, London SM2 5PT, UK; The Institute of Cancer Research, Cotswold Road, London SM2 5NG, UK.
authors.forename: Udai
authors.initials: U
authors.lastname: Banerji
authors.affiliation: Royal Marsden NHS Foundation Trust, Downs Road, London SM2 5PT, UK.
authors.forename: Susana N
authors.initials: SN
authors.lastname: Banerjee
authors.affiliation: Royal Marsden NHS Foundation Trust, Downs Road, London SM2 5PT, UK.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Gore
authors.affiliation: Royal Marsden NHS Foundation Trust, Downs Road, London SM2 5PT, UK; The Institute of Cancer Research, Cotswold Road, London SM2 5NG, UK.
authors.forename: Johann S
authors.initials: JS
authors.lastname: de Bono
authors.affiliation: Royal Marsden NHS Foundation Trust, Downs Road, London SM2 5PT, UK.
authors.forename: Stan B
authors.initials: SB
authors.lastname: Kaye
authors.affiliation: Royal Marsden NHS Foundation Trust, Downs Road, London SM2 5PT, UK; The Institute of Cancer Research, Cotswold Road, London SM2 5NG, UK. Electronic address: timothy.yap@icr.ac.uk.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Yap
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018394:CA-125 Antigen / Q000378:metabolism; D018269:Carcinoma, Endometrioid / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002296:Carcinosarcoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017321:Clinical Trials, Phase I as Topic; D055808:Drug Discovery; D004739:England; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D006106:Granulosa Cell Tumor / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006454:Hemoglobins / Q000378:metabolism; D061325:Hereditary Breast and Ovarian Cancer Syndrome / Q000235:genetics; D006801:Humans; D007958:Leukocyte Count; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D009362:Neoplasm Metastasis; D018297:Neoplasms, Cystic, Mucinous, and Serous / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D012189:Retrospective Studies; D012709:Serum Albumin / Q000378:metabolism; D012720:Severity of Illness Index; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D018394:CA-125 Antigen; D006454:Hemoglobins; C451759:MUC16 protein, human; D008565:Membrane Proteins; D012709:Serum Albumin
keywords: Antiangiogenics; Ovarian cancer; Phase I trials; Poly(ADP-ribose) Polymerase (PARP) inhibitors; Precision medicine; RMH prognostic score