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Safety and tolerability of veliparib combined with capecitabine plus radiotherapy in patients with locally advanced rectal cancer: a phase 1b study.

Publication ,  Journal Article
Czito, BG; Deming, DA; Jameson, GS; Mulcahy, MF; Vaghefi, H; Dudley, MW; Holen, KD; DeLuca, A; Mittapalli, RK; Munasinghe, W; He, L; Ngan, SY ...
Published in: Lancet Gastroenterol Hepatol
June 2017

BACKGROUND: Further optimisation of present standard chemoradiation is needed in patients with locally advanced rectal cancer. Veliparib, an oral poly(ADP-ribose) polymerase inhibitor, has been shown to enhance the antitumour activity of chemotherapy and radiotherapy in preclinical models. We aimed to establish the maximum tolerated dose and establish the recommended phase 2 dose of veliparib combined with neoadjuvant capecitabine and radiotherapy. METHODS: This phase 1b, open-label, multicentre, dose-escalation study was done at six hospitals (one in Australia and five in the USA). Patients were eligible if they were aged 18 years or more and were newly diagnosed with stage II to III locally advanced, resectable adenocarcinoma of the rectum with a distal tumour border of less than 12 cm from anal verge. Patients were ineligible if they had received anticancer therapy or surgery (except colostomy or ileostomy) 28 days or less before the first dose of study drug, previous pelvic radiotherapy, or previous treatment with poly (ADP-ribose) polymerase inhibitors. Enrolled patients received capecitabine (825 mg/m2 orally twice daily) with radiotherapy (50·4 Gy in 1·8 Gy fractions daily, approximately 5 days consecutively per week for about 5·5 weeks). Veliparib (20-400 mg orally twice daily) was administered daily starting on day 2 of week 1 and continuing until 2 days after radiotherapy completion. Patients underwent total mesorectal excision 5-10 weeks after radiotherapy completion. The primary objectives were to establish the maximum tolerated dose and recommended phase 2 dose of veliparib plus capecitabine and radiotherapy, with an exposure-adjusted continual reassessment methodology. Efficacy and safety analyses were done per protocol. The reported study has completed accrual and all analyses are final. This trial is registered with ClinicalTrials.gov, number NCT01589419. FINDINGS: Between June 12, 2012, and Jan 13, 2015, 32 patients received veliparib (22 in the dose-escalation group; ten in the safety expansion group); 31 were assessable for efficacy (<400 mg, n=16; 400 mg, n=15). During dose escalation, grade 2 dose-limiting toxic effects occurred in two patients; no grade 3-4 dose-limiting toxic effects were noted. Therefore, the maximum tolerated dose was not reached; the recommended phase 2 dose was selected as 400 mg twice daily. The most common treatment-emergent adverse events in all 32 patients were nausea (17 [53%]), diarrhoea (16 [50%]), and fatigue (16 [50%]). Grade 3 diarrhoea was noted in three (9%) of 32 patients; no grade 4 events were reported. Veliparib pharmacokinetics were dose proportional, with no effect on capecitabine pharmacokinetics. Tumour downstaging after surgery was noted in 22 (71%) of 31 patients; nine (29%) of 31 patients achieved a pathological complete response. INTERPRETATION: Veliparib plus capecitabine and radiotherapy had an acceptable safety profile and showed a dose-proportional pharmacokinetic profile with no effect on the pharmacokinetics of capecitabine. Preliminary antitumour activity warrants further evaluation. FUNDING: AbbVie Inc.

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Published In

Lancet Gastroenterol Hepatol

DOI

EISSN

2468-1253

Publication Date

June 2017

Volume

2

Issue

6

Start / End Page

418 / 426

Location

Netherlands

Related Subject Headings

  • Rectal Neoplasms
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Neoplasm Staging
  • Neoadjuvant Therapy
  • Nausea
  • Middle Aged
  • Maximum Tolerated Dose
  • Male
  • Humans
  • Female
 

Citation

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Czito, B. G., Deming, D. A., Jameson, G. S., Mulcahy, M. F., Vaghefi, H., Dudley, M. W., … Michael, M. (2017). Safety and tolerability of veliparib combined with capecitabine plus radiotherapy in patients with locally advanced rectal cancer: a phase 1b study. Lancet Gastroenterol Hepatol, 2(6), 418–426. https://doi.org/10.1016/S2468-1253(17)30012-2
Czito, Brian G., Dustin A. Deming, Gayle S. Jameson, Mary F. Mulcahy, Houman Vaghefi, Matthew W. Dudley, Kyle D. Holen, et al. “Safety and tolerability of veliparib combined with capecitabine plus radiotherapy in patients with locally advanced rectal cancer: a phase 1b study.Lancet Gastroenterol Hepatol 2, no. 6 (June 2017): 418–26. https://doi.org/10.1016/S2468-1253(17)30012-2.
Czito BG, Deming DA, Jameson GS, Mulcahy MF, Vaghefi H, Dudley MW, et al. Safety and tolerability of veliparib combined with capecitabine plus radiotherapy in patients with locally advanced rectal cancer: a phase 1b study. Lancet Gastroenterol Hepatol. 2017 Jun;2(6):418–26.
Czito, Brian G., et al. “Safety and tolerability of veliparib combined with capecitabine plus radiotherapy in patients with locally advanced rectal cancer: a phase 1b study.Lancet Gastroenterol Hepatol, vol. 2, no. 6, June 2017, pp. 418–26. Pubmed, doi:10.1016/S2468-1253(17)30012-2.
Czito BG, Deming DA, Jameson GS, Mulcahy MF, Vaghefi H, Dudley MW, Holen KD, DeLuca A, Mittapalli RK, Munasinghe W, He L, Zalcberg JR, Ngan SY, Komarnitsky P, Michael M. Safety and tolerability of veliparib combined with capecitabine plus radiotherapy in patients with locally advanced rectal cancer: a phase 1b study. Lancet Gastroenterol Hepatol. 2017 Jun;2(6):418–426.
Journal cover image

Published In

Lancet Gastroenterol Hepatol

DOI

EISSN

2468-1253

Publication Date

June 2017

Volume

2

Issue

6

Start / End Page

418 / 426

Location

Netherlands

Related Subject Headings

  • Rectal Neoplasms
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Neoplasm Staging
  • Neoadjuvant Therapy
  • Nausea
  • Middle Aged
  • Maximum Tolerated Dose
  • Male
  • Humans
  • Female