title: Phase I studies of CBP501, a G2 checkpoint abrogator, as monotherapy and in combination with cisplatin in patients with advanced solid tumors.
abstract: OBJECTIVE
  Two phase I dose-escalation studies were conducted to determine the maximum tolerated dose (MTD) and safety profile of the G(2) checkpoint abrogator CBP501, as a single agent and in combination with cisplatin.
  
  
  METHODS
  Patients with advanced solid tumors were treated with CBP501 alone (D1/D8/D15, q4w, from 0.9 mg/m(2)), or with cisplatin (both on D1, q3w, from 3.6 mg/m(2) CBP501, 50 mg/m(2) cisplatin). Dose escalation proceeded if dose-limiting toxicity (DLT) was observed in 1 or less of 3 to 6 patients; CBP501 dose increments were implemented according to the incidence of toxicity. MTD was determined from DLTs occurring during the first two cycles.
  
  
  RESULTS
  In the combination study, the DLT was a histamine-release syndrome (HRS) occurring 10 to 60 minutes after initiating infusion that was attenuated by prophylaxis comprising dexamethasone, diphenhydramine, ranitidine, and loratadine. The MTD was 25 mg/m(2) CBP501 and 75 mg/m(2) cisplatin, with two patients at the highest dose (36.4 mg/m(2) CBP501, 75 mg/m(2) cisplatin) experiencing grade 3 HRS. The only DLT with monotherapy was transient G(3) rise of troponin in one patient. Grade 3 to 4 treatment-related events were rare. Promising activity was observed with CBP501/cisplatin, mainly in ovarian and mesothelioma patients who had previously progressed on platinum-containing regimens. Among ovarian cancer patients, low expression of DNA repair proteins was associated with partial response or stable disease.
  
  
  CONCLUSIONS
  CBP501 is well tolerated in patients as monotherapy and with cisplatin. At the recommended phase II dose (RP2D), the combination is feasible and HRS manageable with prophylaxis. Evidence of antitumor activity was observed in platinum-resistant patients.
authors.affiliation: Dana-Farber Cancer Institute, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02215, USA. geoffrey_shapiro@dfci.harvard.edu
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: Shapiro
authors.forename: Raoul
authors.initials: R
authors.lastname: Tibes
authors.forename: Michael S
authors.initials: MS
authors.lastname: Gordon
authors.forename: Bryan Y
authors.initials: BY
authors.lastname: Wong
authors.forename: Joseph Paul
authors.initials: JP
authors.lastname: Eder
authors.forename: Mitesh J
authors.initials: MJ
authors.lastname: Borad
authors.forename: David S
authors.initials: DS
authors.lastname: Mendelson
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Vogelzang
authors.forename: Bruno R
authors.initials: BR
authors.lastname: Bastos
authors.forename: Glen J
authors.initials: GJ
authors.lastname: Weiss
authors.forename: Cristian
authors.initials: C
authors.lastname: Fernandez
authors.forename: William
authors.initials: W
authors.lastname: Sutherland
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Sato
authors.forename: William E
authors.initials: WE
authors.lastname: Pierceall
authors.forename: David
authors.initials: D
authors.lastname: Weaver
authors.forename: Scott
authors.initials: S
authors.lastname: Slough
authors.forename: Ernesto
authors.initials: E
authors.lastname: Wasserman
authors.forename: Donald W
authors.initials: DW
authors.lastname: Kufe
authors.forename: Daniel
authors.initials: D
authors.lastname: Von Hoff
authors.forename: Takumi
authors.initials: T
authors.lastname: Kawabe
authors.forename: Sunil
authors.initials: S
authors.lastname: Sharma
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage* / Q000009:adverse effects; D018450:Disease Progression; D005260:Female; D016195:G2 Phase / Q000187:drug effects; D018816:Genes, cdc / Q000187:drug effects; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D020687:cdc25 Phosphatases / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; C517976:Cdc25C phosphatase (211-221); D010446:Peptide Fragments; D020687:cdc25 Phosphatases; D002945:Cisplatin