| General information |
| Database: | DB00160 |
| Objective: | a phase I trial of ABT888 (veliparib), a PARP inhibitor, in combination with topotecan, a topoisomerase Itargeted agent, was carried out to determine maximum tolerated dose (MTD), safety, pharmacokinetics, and pharmacodynamics of the combination in patients with refractory solid tumors and lymphomas. |
| Authors: | Kummar S, et al |
| Title: | Phase I study of PARP inhibitor ABT888 in combination with topotecan in adults with refractory solid tumors and lymphomas. |
| Journal: | Cancer Res. |
| Year: | 2011 |
| PMID: | 21795476 |
| Trial Design |
| Clinical Trial Id: | NCT00553189. |
| Agent: | veliparib
|
| Target: | Poly [ADPribose] polymerase1
|
| Cancer Type: | advanced solid tumors |
| Cancer Subtype: | refractory solid tumors and lymphoid malignancies |
| Therapy Type: | com |
| Therapeutic Combination Type: | 2 |
| Therapeutic Combination Content: | ABT888 (veliparib)+topotecan |
| Study Type: | an openlabel, singlearmphase I study of the combination of ABT888 administered orally with topotecan hydrochloride administered intravenously |
| Key Patients Feature: | patients with refractory solid tumors and lymphomas. |
| Biomarker: | levels of poly(ADPribose) (PAR) and the DNA damage marker ¦ÃH2AX were measured in tumor and peripheral blood mononuclear cells (PBMC). |
| Biomark Analysis: | A more than 75% reduction in PAR levels was observed in 3 paired tumor biopsy samples; |
| Control Group Info: | single arm |
| Treatment Info: | Varying schedules and doses of intravenous topotecan in combination with ABT888 (10 mg) administered orally twice a day (BID) were evaluated. Plasma and urine pharmacokinetics were assessed and levels of poly(ADPribose) (PAR) and the DNA damage marker ¦ÃH2AX were measured in tumor and peripheral blood mononuclear cells (PBMC). |
| Primary End Point: | maximum tolerated dose (MTD), safety, pharmacokinetics, and pharmacodynamics |
| Secondary End Point: | NA |
| Patients Number: | 24 |
| Trial Results |
| DLT_MTD: | Significant myelosuppression limited the ability to coadminister ABT888 with standard doses of topotecan, necessitating dose reductions. The MTD was established as topotecan 0.6 mg/m2/d and ABT888 10 mg BID on days one to five of 21day cycles. |
| Objective Response Rate: | A more than 75% reduction in PAR levels was observed in 3 paired tumor biopsy samples; a greater than 50% reduction was observed in PBMCs from 19 of 23 patients with measurable levels. Increases in ¦ÃH2AX response in circulating tumor cells (CTC) and PBMCs were observed in patients receiving ABT888 with topotecan. |
| Disease Control Rate: | NA |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | NA |
| Median OS A vs. C: | NA |
| Adverse Event(agent arm): | Significant myelosuppression |
| Conclusions: | Results of this trial reveal that PARP inhibition can modulate the capacity to repair topoisomerase Imediated DNA damage in the clinic. |