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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology

3412 - Phase 1/2 study of valproic acid (VPA) and short-course radiotherapy (SCRT) plus capecitabine (CAP) as preoperative treatment in low-moderate risk rectal cancer (V-shoRT-R3).

Date

21 Oct 2018

Session

Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology

Presenters

Alfredo Budillon

Citation

Annals of Oncology (2018) 29 (suppl_8): viii150-viii204. 10.1093/annonc/mdy281

Authors

A. Budillon1, P. Delrio2, B. Pecori2, F. Tatangelo3, E. Di Gennaro1, C. Romano2, V. D'Angelo2, P. Marone2, C. Granata4, E. Cavalacanti5, A. De Stefano2, U. Pace2, F. Bianco2, A. Petrillo6, S. Lastoria6, G. Botti3, P. Muto7, F. Perrone8, M.C. Piccirillo8, A. Avallone9

Author affiliations

  • 1 Experimental Pharmacology Unit, Istituto Nazionale Tumori – I.R.C.C.S - Fondazione Pascale, 80131 - Napoli/IT
  • 2 Abdominal Oncology, Istituto Nazionale Tumori – I.R.C.C.S - Fondazione Pascale, 80131 - Napoli/IT
  • 3 Pathology, Istituto Nazionale Tumori – I.R.C.C.S - Fondazione Pascale, 80131 - Napoli/IT
  • 4 Radiology, Istituto Nazionale Tumori – I.R.C.C.S - Fondazione Pascale, 80131 - Napoli/IT
  • 5 Clinical Pathology, Istituto Nazionale Tumori – I.R.C.C.S - Fondazione Pascale, 80131 - Napoli/IT
  • 6 Radiology, Istituto Nazionale Tumori, IRCCS, Fondazione "G. Pascale", 80131 - Naples/IT
  • 7 Radiotherapy, Istituto Nazionale Tumori – I.R.C.C.S - Fondazione Pascale, 80131 - Napoli/IT
  • 8 Translational Research, Istituto Nazionale Tumori – I.R.C.C.S - Fondazione Pascale, 80131 - Napoli/IT
  • 9 Abdominal Oncology, Istituto Nazionale Tumori, IRCCS, Fondazione "G. Pascale", 80131 - Naples/IT
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Resources

Abstract 3412

Background

Recurrence with distant metastases is the predominant pattern of failure in locally advanced rectal cancer (LARC), thus the integration of new agents into preoperative fluoropyrimidine-based chemo-radiotherapy represents a clinical challenge to intensify the therapeutic strategy. We have recently reported synergistic antitumor interaction between valproic acid (VPA), an histone-deacetylase inhibitor, capecitabine (CAP) and radiotherapy in colorectal cancer preclinical models.

Methods

We planned two parallel phase-1 studies in low-moderate risk LARC patients (pts) to assess the safety of preoperative short-course radiotherapy (SCRT) (5 Gy/day on days 1 to 5 days) combined with (a) CAP alone (4 increasing dose levels: 500 to 825 mg/m2/bid, on days -1 to 20), or (b) CAP as above plus VPA (orally on days -14 to 21, with an intra-patient titration for a target serum level of 50-100 μg/ml), followed by surgery 8 weeks after the end of SCRT. Within each of the two phase-1 trials, maximum tolerated dose (MTD) was defined as the dose level that produces a dose-limiting toxicity (DLT) occurring within 5 weeks from day 1 of treatment in more than one-third of pts. Correlative studies on pharmacokinetic and pharmacodynamics biomarkers on both tumor and peripheral blood samples as well as FDG-PET were also planned.

Results

From Apr 2013 and Oct 2018, 28 pts were enrolled in the two phase-1 studies. Median age was 61 (range 46-71), 100% were PS 0. No DLT occurred with CAP alone, but a symptomatic angina occurred in a patient at the first dose level of CAP plus VPA. However, no DLT was observed within the further 3 pts enrolled at the same level, nor at the following dose levels. All but one pts underwent R0 resection. TRG1 was obtained in 6 pts, TRG2 in 11 pts, TRG3 in 8 pts and TRG4 in 3 pts.

Conclusions

The addition of CAP to preoperative SCRT +/- VPA is feasible and 825 mg/m2/bid is the recommended dose that will be used in an ongoing phase-2 trial, aimed to explore whether the addition of VPA and/or CAP to preoperative SCRT might increase TRG1 rate in low-moderate risk LARC pts.

Clinical trial identification

NCT01898104.

Legal entity responsible for the study

Istituto Nazionale Tumori Fondazione G. Pascale.

Funding

Italian Ministry of Health, Grant RF-2011-02346914 to AB.

Editorial Acknowledgement

Disclosure

All authors have declared no conflicts of interest.

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