Phase I Study of the Poly(ADP-Ribose) Polymerase Inhibitor, AG014699, in Combination with Temozolomide in Patients with Advanced Solid Tumors

Abstract

Purpose: One mechanism of tumor resistance to cytotoxic therapy is repair of damaged DNA.Poly(ADP-ribose) polymerase (PARP)-1is 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. Experimental Design: Initially, patients with solid tumors received escalating doses of AG014699 with 100 mg/m 2 /d temozolomide  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/m 2 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/m 2 based on 74% to 97% inhibition of peripheral blood lymphocyte PARP activity. Recommended doses were 12 mg/m 2 AG014699 and 200 mg/m 2 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.Multiple pathways contribute to the repair of damaged DNA (1). Defects in these pathways are a cause of cancer susceptibility (2, 3), but, when intact, their activity is a factor in tumor resistance to widely used DNA-damaging cancer treatments (e.g., cytotoxic drugs and ionizing radiation; ref. 4). Several novel agents are being developed which target DNA repair in an attempt to improve cancer treatment (5), including agents that may exploit tumor DNA repair defects (e.g., BRCA1 and BRCA2) by inducing ''synthetic lethality'' (6, 7).Base excision repair is a complex process that repairs DNA single-strand breaks caused by endogenous reactive species and anticancer agents (8). Poly(ADP-ribose) polymerase-1 (PARP) is a key enzyme in this pathway, binding to and being activated by the DNA break, effectively acting as a molecular nick sensor (9), and recruiting additional repair factors. Preclinical evidence has shown that inhibiting PARP potentiates cytotoxics, particularly alkylating agents and topoisomerase I inhibitors, and radiotherapy (10 -12). Several PARP

Mild hyperthermia inhibits homologous recombination, induces BRCA2 degradation, and sensitizes cancer cells to poly (ADP-ribose) polymerase-1 inhibition

“…This induced synthetic lethality renders innately HR-proficient tumor cells highly sensitive to PARP-1 inhibitors. Our results might have direct clinical relevance, because recent trials demonstrated that both HSP90 and PARP-1 inhibitors are generally well tolerated (35,36). Moreover, because our approach is not based on genetic deficiency, as is the case in hereditary BRCA2-deficient tumors, it is not likely that a previously described mechanism of resistance to the inhibitor will be relevant (37,38).…”

Doxorubicin-induced suppression of poly(ADP-ribose) polymerase-1 (PARP-1) activity and expression and its implication for PARP inhibitors in clinical trials

“…Measurement of PARP activity PARP activity was measured by modiWcation of a previously described method [8] validated to GCLP standard and used as a pharmacodynamic endpoint for clinical trials [9]. BrieXy, maximally stimulated PARP activity was measured in triplicate samples of 10 4 cells permeabilised with icecold digitonin (0.15 mg/ml in water) in a reaction mixture containing 350 mol/l NAD + as substrate in excess and 10 g/ml PARP-activating oligonucleotide (CGGAATT CCG) (Europrim, Invitrogen, UK) that mimics DNA strand breaks, in a reaction buVer of 100 mmol/l Tris-HCl and 120 mmol/l MgCl 2 (pH 7.8) in a Wnal volume of 100 l at 26°C in an oscillating water bath.…”

Effectiveness and Safety of Poly (ADP-ribose) Polymerase Inhibitors in Cancer Therapy: A Systematic Review and Meta-analysis

“…Of all the 2274 patients, several types of cancers were reported, such as ovarian, lung, breast, and gastric cancers. Besides these, many trials [26][27][28][29][30][31][32] in different kinds of cancers not eligible for inclusion are still under way. Although the results have not come out, it is possible that PARP inhibitors may work in patients against some certain types of tumors.…”