title: Eltrombopag with gemcitabine-based chemotherapy in patients with advanced solid tumors: a randomized phase I study.
abstract: Preventing chemotherapy-induced thrombocytopenia could avoid chemotherapy dose reductions and delays. The safety and maximum tolerated dose of eltrombopag, an oral thrombopoietin receptor agonist, with gemcitabine-based therapy was evaluated. Patients with advanced solid tumors and platelets ≤300 × 10(9) /L receiving gemcitabine plus cisplatin or carboplatin (Group A) or gemcitabine monotherapy (Group B) were randomized 3:1 to receive eltrombopag or placebo at a starting dose of 100 mg daily administered on days -5 to -1 and days 2-6 starting from cycle 2 of treatment. Nineteen patients (Group A, n = 9; Group B, n = 10) received eltrombopag 100 mg and seven (Group A, n = 3; Group B, n = 4) received matching placebo. Nine eltrombopag patients in Group A and eight in Group B had 38 and 54 occurrences of platelet counts ≥400 × 10(9) /L, respectively. Mean platelet nadirs across cycles 2-6 were 115 × 10(9) /L and 143 × 10(9) /L for eltrombopag-treated patients versus 53 × 10(9) /L and 103 × 10(9) /L for placebo-treated patients in Groups A and B, respectively. No dose-limiting toxicities were reported for eltrombopag; however, due to several occurrences of thrombocytosis, a decision was made not to dose-escalate eltrombopag to >100 mg daily. In Groups A and B, 14% of eltrombopag versus 50% of placebo patients required chemotherapy dose reductions and/or delays for any reason across cycles 3-6. Eltrombopag 100 mg once daily administered 5 days before and after day 1 of chemotherapy was well tolerated with an acceptable safety profile, and will be further tested in a phase II trial. Fewer patients receiving eltrombopag required chemotherapy dose delays and/or reductions compared with those receiving placebo.
authors.affiliation: Rhode Island Hospital, Providence, Rhode Island.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Winer
authors.forename: Howard
authors.initials: H
authors.lastname: Safran
authors.forename: Boguslawa
authors.initials: B
authors.lastname: Karaszewska
authors.forename: Donald A
authors.initials: DA
authors.lastname: Richards
authors.forename: Lee
authors.initials: L
authors.lastname: Hartner
authors.forename: Frederic
authors.initials: F
authors.lastname: Forget
authors.forename: Rodryg
authors.initials: R
authors.lastname: Ramlau
authors.forename: Kirushna
authors.initials: K
authors.lastname: Kumar
authors.forename: Bhabita
authors.initials: B
authors.lastname: Mayer
authors.forename: Brendan M
authors.initials: BM
authors.lastname: Johnson
authors.forename: Conrad A
authors.initials: CA
authors.lastname: Messam
authors.forename: Yasser
authors.initials: Y
authors.lastname: Mostafa Kamel
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001565:Benzoates / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D006834:Hydrazines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D010976:Platelet Count; D011720:Pyrazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D001565:Benzoates; D006834:Hydrazines; D011720:Pyrazoles; D003841:Deoxycytidine; C520809:eltrombopag; D000093542:Gemcitabine
keywords: Blood platelets; cancer; eltrombopag; thrombocytopenia; thrombosis