Giovanna Speranza

Phase I Study of PARP Inhibitor ABT-888 in Combination with Topotecan in Adults with Refractory Solid Tumors and Lymphomas

A phase I trial of ABT-888 (veliparib), a PARP inhibitor, in combination with topotecan, a topoisomerase I-targeted 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. Varying schedules and doses of intravenous topotecan in combination with ABT-888 (10 mg) administered orally twice a day (BID) were evaluated. Plasma and urine pharmacokinetics were assessed and levels of poly(ADP-ribose) (PAR) and the DNA damage marker γH2AX were measured in tumor and peripheral blood mononuclear cells (PBMC). Twenty-four patients were enrolled. Significant myelosuppression limited the ability to coadminister ABT-888 with standard doses of topotecan, necessitating dose reductions. Preclinical studies using athymic mice carrying human tumor xenografts also informed schedule changes. The MTD was established as topotecan 0.6 mg/m²/d and ABT-888 10 mg BID on days one to five of 21-day cycles. Topotecan did not alter the pharmacokinetics of ABT-888. 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 γH2AX response in circulating tumor cells (CTC) and PBMCs were observed in patients receiving ABT-888 with topotecan. We show a mechanistic interaction of a PARP inhibitor, ABT-888, with a topoisomerase I inhibitor, topotecan, in PBMCs, tumor, and CTCs. Results of this trial reveal that PARP inhibition can modulate the capacity to repair topoisomerase I-mediated DNA damage in the clinic.

Adenocarcinoma of the small bowel: changes in the landscape?

Purpose of review Small bowel adenocarcinoma (SBA) is a rare cancer with a poor prognosis and little information to guide its management. In recent years, improved diagnostic imaging and an increase in reported experience with use of chemotherapy may alter the way we manage SBA. This review will summarize recent advances in characterization, imaging, and treatment of SBA. Recent findings Recent advances in less invasive imaging tools may permit earlier and increased diagnosis of SBA. Surgery remains the mainstay of treatment, and the role of adjuvant chemotherapy is still unclear. However, the use of adjuvant therapy is increasing. Chemotherapy with newer regimens may provide clinical benefit in the metastatic setting. Nearly all results are from retrospective studies. Targeted therapies have not been extensively studied. Summary The rarity of the disease and difficulty in diagnosis contribute to the lack of prospective trials evaluating therapies for SBA. Retrospective studies suggest a benefit for combination chemotherapy regimens. Prospective evaluation of newer chemotherapeutic agents and targeted therapies is needed to improve outcomes in this disease.