Phase I dose-escalation study of AZD7762, a checkpoint kinase inhibitor, in combination with gemcitabine in US patients with advanced solid tumors.
OBJECTIVE
AZD7762 is a Chk1 kinase inhibitor which increases sensitivity to DNA-damaging agents, including gemcitabine. We evaluated the safety of AZD7762 monotherapy and with gemcitabine in advanced solid tumor patients.


METHODS
In this Phase I study, patients received intravenous AZD7762 on days 1 and 8 of a 14-day run-in cycle (cycle 0; AZD7762 monotherapy), followed by AZD7762 plus gemcitabine 750-1,000 mg/m(2) on days 1 and 8, every 21 days, in ascending AZD7762 doses (cycle 1; combination therapy).


RESULTS
Forty-two patients received AZD7762 6 mg (n = 9), 9 mg (n = 3), 14 mg (n = 6), 21 mg (n = 3), 30 mg (n = 7), 32 mg (n = 6), and 40 mg (n = 8), in combination with gemcitabine. Common adverse events (AEs) were fatigue [41 % (17/42) patients], neutropenia/leukopenia [36 % (15/42) patients], anemia/Hb decrease [29 % (12/42) patients] and nausea, pyrexia and alanine aminotransferase/aspartate aminotransferase increase [26 % (11/42) patients each]. Grade ≥3 AEs occurred in 19 and 52 % of patients in cycles 0 and 1, respectively. Cardiac dose-limiting toxicities occurred in two patients (both AZD7762 monotherapy): grade 3 troponin I increase (32 mg) and grade 3 myocardial ischemia with chest pain, electrocardiogram changes, decreased left ventricular ejection fraction, and increased troponin I (40 mg). AZD7762 exposure increased linearly. Gemcitabine did not affect AZD7762 pharmacokinetics. Two non-small-cell lung cancer patients achieved partial tumor responses (AZD7762 6 mg/gemcitabine 750 mg/m(2) and AZD7762 9 mg cohort).


CONCLUSIONS
The maximum-tolerated dose of AZD7762 in combination with gemcitabine 1,000 mg/m(2) was 30 mg. Although development of AZD7762 is not going forward owing to unpredictable cardiac toxicity, Chk1 remains an important therapeutic target.
Marlene and Stewart Greenebaum Cancer Center, University of Maryland, 22 S. Greene Street, Baltimore, MD, 21201, USA, esausville@umm.edu.
Edward
E
Sausville
Patricia
P
Lorusso
Michael
M
Carducci
Judith
J
Carter
Mary F
MF
Quinn
Lisa
L
Malburg
Nilofer
N
Azad
David
D
Cosgrove
Richard
R
Knight
Peter
P
Barker
Sonya
S
Zabludoff
Felix
F
Agbo
Patricia
P
Oakes
Adrian
A
Senderowicz
D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D000071877:Checkpoint Kinase 1; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D011494:Protein Kinases / Q000378:metabolism; D013876:Thiophenes / Q000008:administration & dosage / Q000009:adverse effects; D014508:Urea / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D000093542:Gemcitabine
C532363:3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide; D000964:Antimetabolites, Antineoplastic; D013876:Thiophenes; D003841:Deoxycytidine; D014508:Urea; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D000093542:Gemcitabine