title: A phase 2 study of SP1049C, doxorubicin in P-glycoprotein-targeting pluronics, in patients with advanced adenocarcinoma of the esophagus and gastroesophageal junction.
abstract: OBJECTIVE
  To evaluate the antitumor activity of SP1049C, a novel P-glycoprotein targeting micellar formulation of doxorubicin, consisting of doxorubicin and two non-ionic block copolymers (pluronics), in patients with advanced adenocarcinoma of the esophagus and gastroesophageal junction (GEJ).
  
  
  METHODS
  Patients with metastatic or locally advanced unresectable adenocarcinoma of the esophagus or GEJ who had not previously received systemic chemotherapy and had measurable disease were treated with SP1049C 75 mg/m(2) (doxorubicin equivalents) as a brief intravenous infusion every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was the objective response rate in patients who had received a least one course of SP1049C and had undergone tumor assessment, whereas, secondary endpoints included the objective response rate, progression-free survival (PFS), overall survival, and safety in the intent-to-treat (ITT) population. A review of scans was also conducted post-hoc by a blinded panel of radiologists.
  
  
  RESULTS
  Twenty-one patients, of which 19 were evaluable for response, were treated with at least one dose of SP1049C. Nine patients had a partial response (PR) and eight patients had either a minor response or stable disease as their best response. The objective response rate was 47% (95% CI: 24.4-71) in the evaluable patient population, whereas the objective response rate was 43% (95% CI: 21.8-65.9) in the ITT population. The post-hoc radiological review confirmed that all nine responders had a PR; seven of the nine had a PR that was confirmed by a subsequent scan, whilst two patients had unconfirmed PRs. The median overall survival and PFS were 10.0 months (95%CI: 4.8-11.2) and 6.6 months (95% CI: 4.5-7.6), respectively. Neutropenia was the principal toxicity of SP1049C. Four patients developed an absolute percentage decrement of at least 15% in their left ventricular ejection fraction, none of which decreased to below 45% nor were symptomatic.
  
  
  CONCLUSIONS
  SP1049C has a notable single-agent activity in patients with adenocarcinoma of the esophagus and GEJ, as well as an acceptable safety profile. These results, in addition to the results of preclinical studies demonstrating superior antitumor activity of SP1049C compared with doxorubicin in a standard formulation, indicate that further evaluations of SP1049C alone or combined with other relevant therapeutics in this disease setting are warranted.
authors.affiliation: Department of Medical Oncology, Christie Hospital NHS Trust, Wilmslow Road, Manchester M20 4BX, UK. juan.valle@christie.nhs.uk
authors.forename: Juan W
authors.initials: JW
authors.lastname: Valle
authors.forename: Anne
authors.initials: A
authors.lastname: Armstrong
authors.forename: Chris
authors.initials: C
authors.lastname: Newman
authors.forename: Valery
authors.initials: V
authors.lastname: Alakhov
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Pietrzynski
authors.forename: Julie
authors.initials: J
authors.lastname: Brewer
authors.forename: Sue
authors.initials: S
authors.lastname: Campbell
authors.forename: Pippa
authors.initials: P
authors.lastname: Corrie
authors.forename: Eric K
authors.initials: EK
authors.lastname: Rowinsky
authors.forename: Malcolm
authors.initials: M
authors.lastname: Ranson
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D004317:Doxorubicin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D004943:Esophagogastric Junction / Q000473:pathology* / Q000503:physiopathology; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009367:Neoplasm Staging; D020442:Poloxamer / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D013318:Stroke Volume
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; C487707:SP 1049C; D020442:Poloxamer; D004317:Doxorubicin