A phase 2 study of the PARP inhibitor veliparib plus temozolomide in patients with heavily pretreated metastatic colorectal cancer.

Abstract

BACKGROUND:

Poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors such as veliparib are potent sensitizing agents and have been safely combined with DNA-damaging agents such as temozolomide. The sensitizing effects of PARP inhibitors are magnified when cells harbor DNA repair defects.

METHODS:

A single-arm, open-label, phase 2 study was performed to investigate the disease control rate (DCR) after 2 cycles of veliparib plus temozolomide in patients with metastatic colorectal cancer (mCRC) refractory to all standard therapies. Fifty patients received temozolomide (150 mg/m2 /d) on days 1 to 5 and veliparib (40 mg twice daily) on days 1 to 7 of each 28-day cycle. Another 5 patients with mismatch repair-deficient (dMMR) tumors were also enrolled. Twenty additional patients were then treated with temozolomide at 200 mg/m2 /d. Archived tumor specimens were used for immunohistochemistry to assess mismatch repair, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), and O(6)-methylguanine-DNA methyltransferase (MGMT) protein expression levels.

RESULTS:

The combination was well tolerated, although some patients required dose reductions for myelosuppression. The primary endpoint was successfully met with a DCR of 24% and 2 confirmed partial responses. The median progression-free survival was 1.8 months, and the median overall survival was 6.6 months. PTEN protein expression and MGMT protein expression were not predictors of DCR. There was also a suggestion of worse outcomes for patients with dMMR tumors.

CONCLUSIONS:

In this heavily pretreated mCRC population, a combination of veliparib and temozolomide was well tolerated with temozolomide doses up to 200 mg/m2 /d, and it was clinically active. PARP inhibitor-based therapy merits further exploration in patients with mCRC. Cancer 2018;124:2337-46. © 2018 American Cancer Society.

• Authors: Michael J Pishvaian, Rebecca S Slack, Wei Jiang, A Ruth He, Jimmy J Hwang, Amy Hankin, Karen Dorsch-Vogel, Divyesh Kukadiya, Louis M Weiner, John L Marshall, Jonathan R Brody
• Journal: Cancer (Cancer) Vol. 124 Issue 11 Pg. 2337-2346 (06 01 2018) ISSN: 1097-0142 [Electronic] United States
• PMID: 29579325 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 American Cancer Society.

Chemical References

• Benzimidazoles
• Poly(ADP-ribose) Polymerase Inhibitors
• veliparib
• Temozolomide

Topics

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects)
• Benzimidazoles (administration & dosage, adverse effects)
• Chemotherapy, Adjuvant (adverse effects, methods)
• Colectomy
• Colorectal Neoplasms (pathology, therapy)
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Female
• Humans
• Male
• Middle Aged
• Poly(ADP-ribose) Polymerase Inhibitors (administration & dosage, adverse effects)
• Proctectomy
• Prospective Studies
• Radiosurgery (methods)
• Temozolomide (administration & dosage, adverse effects)
• Treatment Outcome