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

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

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.

Publication types

  • Clinical Trial, Phase II
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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

Associated data

  • ClinicalTrials.gov/NCT01051596