Phase I study of the poly(ADP-ribose) polymerase inhibitor, AG014699, in combination with temozolomide in patients with advanced solid tumors.
OBJECTIVE
One mechanism of tumor resistance to cytotoxic therapy is repair of damaged DNA. Poly(ADP-ribose) polymerase (PARP)-1 is a nuclear enzyme involved in base excision repair, one of the five major repair pathways. PARP inhibitors are emerging as a new class of agents that can potentiate chemotherapy and radiotherapy. The article reports safety, efficacy, pharmacokinetic, and pharmacodynamic results of the first-in-class trial of a PARP inhibitor, AG014699, combined with temozolomide in adults with advanced malignancy.


METHODS
Initially, patients with solid tumors received escalating doses of AG014699 with 100 mg/m2/d temozolomide x 5 every 28 days to establish the PARP inhibitory dose (PID). Subsequently, AG014699 dose was fixed at PID and temozolomide escalated to maximum tolerated dose or 200 mg/m2 in metastatic melanoma patients whose tumors were biopsied. AG014699 and temozolomide pharmacokinetics, PARP activity, DNA strand single-strand breaks, response, and toxicity were evaluated.


RESULTS
Thirty-three patients were enrolled. PARP inhibition was seen at all doses; PID was 12 mg/m2 based on 74% to 97% inhibition of peripheral blood lymphocyte PARP activity. Recommended doses were 12 mg/m2 AG014699 and 200 mg/m2 temozolomide. Mean tumor PARP inhibition at 5 h was 92% (range, 46-97%). No toxicity attributable to AG014699 alone was observed. AG014699 showed linear pharmacokinetics with no interaction with temozolomide. All patients treated at PID showed increases in DNA single-strand breaks and encouraging evidence of activity was seen.


CONCLUSIONS
The combination of AG014699 and temozolomide is well tolerated, pharmacodynamic assessments showing proof of principle of the mode of action of this new class of agents.
Plummer
Ruth
R
Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom. ruth.plummer@ncl.ac.uk
Jones
Christopher
C
Middleton
Mark
M
Wilson
Richard
R
Evans
Jeffrey
J
Olsen
Anna
A
Curtin
Nicola
N
Boddy
Alan
A
McHugh
Peter
P
Newell
David
D
Harris
Adrian
A
Johnson
Patrick
P
Steinfeldt
Heidi
H
Dewji
Raz
R
Wang
Diane
D
Robson
Lesley
L
Calvert
Hilary
H
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D020552:Comet Assay; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D053960:DNA Breaks / Q000187:drug effects; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D000077204:Temozolomide
D007211:Indoles; D003606:Dacarbazine; C531549:rucaparib; D019389:Cytochrome P-450 CYP2D6; D000077204:Temozolomide