Phase 1 study of AMG 386, a selective angiopoietin 1/2-neutralizing peptibody, in combination with chemotherapy in adults with advanced solid tumors.
OBJECTIVE
To evaluate the safety, pharmacokinetics, and antitumor activity of AMG 386, an investigational selective angiopoietin 1/2-neutralizing peptibody, in combination with FOLFOX-4 (F), carboplatin/paclitaxel (C/P), or docetaxel (D), in adult patients with advanced solid tumors.


METHODS
Three cohorts of patients (F, n = 6; C/P, n = 8; D, n = 12) received one full cycle of chemotherapy alone during the pretreatment phase, followed by administration of AMG 386 10 mg/kg i.v. weekly in combination with chemotherapy until disease progression or intolerance. Safety and tolerability, tumor response, pharmacokinetic profiles, and biomarkers were assessed.


RESULTS
Twenty-six patients were enrolled; 22 received treatment with AMG 386. No dose-limiting toxicities or grade 3 or 4 adverse events related to AMG 386 were reported. The most common adverse events were diarrhea and hypomagnesemia (n = 3 each). One patient developed grade 2 hypertension and one had grade 1 subconjunctival eye hemorrhage. No neutralizing antibodies to AMG 386 were detected. There were no pharmacokinetic interactions between AMG 386 and F, C/P, or D. One patient receiving AMG 386 plus C/P for bladder cancer refractory to gemcitabine/cisplatin had a complete response at week 8. The remaining best tumor responses were partial response (n = 3, one from each cohort), stable disease > or =8 weeks (n = 13), and progressive disease (n = 1).


CONCLUSIONS
Weekly administration of AMG 386 in combination with three common chemotherapy regimens was well tolerated in patients with advanced solid tumors. No pharmacokinetic interactions between AMG 386 and any of the tested chemotherapy regimens were noted. Promising antitumor activity was observed with all three treatment combinations.
Mita
Alain C
AC
Institute for Drug Development, San Antonio, Texas 78229, USA. mita@uthscsa.edu
Takimoto
Chris H
CH
Mita
Monica
M
Tolcher
Anthony
A
Sankhala
Kamalesh
K
Sarantopoulos
John
J
Valdivieso
Manuel
M
Wood
Leslie
L
Rasmussen
Erik
E
Sun
Yu-Nien
YN
Zhong
Z Don
ZD
Bass
Michael B
MB
Le
NgocDiep
N
LoRusso
Patricia
P
D000328:Adult; D042683:Angiopoietin-1 / Q000037:antagonists & inhibitors; D042702:Angiopoietin-2 / Q000037:antagonists & inhibitors; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D015507:Drugs, Investigational / Q000008:administration & dosage; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011993:Recombinant Fusion Proteins / Q000009:adverse effects / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000008:administration & dosage
D042683:Angiopoietin-1; D042702:Angiopoietin-2; D015507:Drugs, Investigational; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; C551398:trebananib