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Cancer. 2018 Jun 1;124(11):2337-2346. doi: 10.1002/cncr.31309. Epub 2018 Mar 26.

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

Author information

1
Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC.
2
The University of Texas MD Anderson Cancer Center, Houston, Texas.
3
Carolinas Medical Center, Charlotte, North Carolina.
4
Jefferson Pancreas, Biliary, and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
5
Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania.
6
Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.

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.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT01051596.

KEYWORDS:

O(6)-methylguanine-DNA methyltransferase (MGMT); colorectal cancer; mismatch repair genes; phosphatase and tensin homolog deleted on chromosome 10 (PTEN); temozolomide; veliparib

PMID:
29579325
PMCID:
PMC5992024
DOI:
10.1002/cncr.31309
[Indexed for MEDLINE]
Free PMC Article

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