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The Safety and Tolerability of Veliparib (V) plus Capecitabine (C) and Radiation (RT) in Subjects with Locally Advanced Rectal Cancer (LARC): Results of a Phase 1b Study
International Journal of Radiation Oncology Biology Physics
S22 Oral Scientific Abstract 38; Table
SCHEMA
WEEK
1-2
3-5
6-7
8-10
11
THERAPY
FOLFOX
25.2 Gy in 1.8 Gy/fx with oxaliplatin and CI Z 5-FU
FOLFOX
25.2 Gy in 1.8 Gy/fx with oxaliplatin and CI Z 5-FU
FOLFOX
Mater Newcastle Hospital, Newcastle, Australia, 4Monash Medical Centre, East Bentleigh, Australia Purpose/Objective(s): The 5-fluorouracil (5-FU) chemotherapy dose used during chemoradiation for locally advanced rectal cancer is adequate for radiosensitization but suboptimal for possible micrometastatic disease. The aim of this study was to determine the tolerability rate, dose intensity, complete pathologic response rate, and toxicity rates of a novel preoperative regimen of split-course chemoradiation with interdigitating chemotherapy in the setting of a multi-center study. This trial was performed under the auspices of the Trans-Tasman Radiation Oncology Group. Materials/Methods: Eligible patients for this study were those with MRIstaged T3-4 Nany M0 adenocarcinoma of the rectum. The preoperative treatment regimen consisted of FOLFOX chemotherapy (oxaliplatin 100 mg/m2 day 1, 5-FU 400 mg/m2 bolus day 1, leucovorin 200 mg/m2 day 1, then continuous infusion 2.4 g/m2 over 46 hours) given in week 1, 6, and 11 with split-course pelvic radiotherapy (25.2 Gy in 3 weeks in 1.8 Gy/fx with concurrent oxaliplatin 85 mg/m2 day 1, and 5-FU continuous infusion 200 mg/m2/day) given in week 3-5, and week 8-10. Surgery was to be performed 4 to 6 weeks later. In total, patients received, in 11 weeks, 3 courses of FOLFOX and pelvic radiation 50.4 Gy with concurrent oxaliplatin and 5-FU. Results: Forty-one patients were recruited with 40 analyzable patients. The median age was 61.5 (range 29-77) years. Seventy-two percent were men. MRI-stage of the rectal primary was T3 88% and T4 12%. N-stage was N0 20%, N1 52%, N2 28%. Thirty-eight patients (95%) reached week eleven of the treatment (80% CI Z [87% - 99%]). All patients received the planned radiation dose of 50.4 Gy. Relative dose intensity of 75% was achieved by 92% and 98% of patients for oxaliplatin and 5-FU respectively. During the preoperative protocol therapy period, grade 3 toxicity included neutropenia 25%, diarrhea 10%, ALT 10%, fatigue 5%, proctitis 5%, and urinary frequency 5%. All grade 4 toxicities were neutropenia 7.5%. Peripheral neuropathy grade 1, 2, and 3 (worst grade) were 77.5%, 17.5%, 2.5%, respectively. Pathologic CR rate was 20%. There was no 30day perioperative mortality. Conclusions: It is feasible to deliver intensive chemotherapy and radiotherapy in an integrated fashion prior to surgery for patients with locally advanced rectal cancer. This regimen is well tolerated with a high response rate. Further study is warranted. Author Disclosure: S. Ngan: None. M. Bressel: None. B. McClure: None. S. Chander: None. J. McKendrick: None. M. Steel: None. J. Mackay: None. P. Cooray: None. M. Kumar: None. A. Strickland: None. A. Heriot: None. T. Leong: None. M. Michael: None.
39 The Safety and Tolerability of Veliparib (V) plus Capecitabine (C) and Radiation (RT) in Subjects with Locally Advanced Rectal Cancer (LARC): Results of a Phase 1b Study B. Czito,1 M. Mulcahy,2 W. Schelman,3 H. Vaghefi,4 J. Gayle,5 A. Deluca,6 H. Xiong,6 W. Munasinghe,6 D. Matthew,6 K. Holen,6 and M. Michael7; 1 Duke University Medical Center, Durham, NC, 2Northwestern University, Chicago, IL, 3University of Wisconsin Carbone Cancer Center, Madison, IL, 4Indiana University Health, Goshen Center for Cancer Care, Goshen, IN, 5Scottsdale Healthcare, Scottsdale, AZ, 6AbbVie, Inc., North Chicago, IL, 7Peter MacCallum Cancer Center, Melbourne, Australia Purpose/Objective(s): Patients (pts) with LARC treated with neoadjuvant RT/C and then surgery have significant relapse rates with low rates of complete response. V is a potent, orally bioavailable PARP inhibitor that has been shown to enhance the efficacy of chemotherapy and RT in preclinical models. This study sought to establish the
12-14
15-17 Surgery
recommended phase 2 dose (RPTD) as well as to assess safety, pharmacokinetics (PK), and preliminary activity of V + RT/C in pts with LARC. Materials/Methods: Pts with stage II-III rectal cancer received RT (50.4 Gy/1.8 Gy/fraction) with C (825 mg/m2 BID) five days per week (W) for 5.5W. Dosing of V (BID, 20mg-400mg) continued from W1D2 to 2 days past RT. Pts underwent surgery 5-10W following RT. Assessments include identification of RPTD with the Exposure Adjusted Continual Reassessment Method, adverse events (AEs), PK, and pathological response: no disease present on pathologic review (ypCR), microscopic disease only (yCR), and tumor downstaging. Results: As of December 8, 2013, 18 pts have been enrolled, 12/6 male/ female, median age 55 years; 1 pt discontinued due to an AE. The most common treatment-emergent AEs (> 20% pts, n 4) were diarrhea (39%), nausea (39%), fatigue (33%), radiation skin injury (33%), dysuria (22%), and constipation (22%). One Grade 3/4 event of diarrhea and one post-operative event of anastomosis dehiscence were deemed at least possibly related to V. One dose limiting toxicity (DLT) occurred at 70 mg BID V (radiation skin injury requiring dose interruption); 1 pt at 400 mg BID described ongoing intolerable nausea not meeting the criteria of a DLT. The RPTD is 400 mg V in combination with RT/C. PK results from 16 pts suggest that V PK was approximately dose proportional when administered with RT/C and that V had no effect on the PK of C. To date, 11/15 (73%) pts have been downstaged post-surgery; with 4/16 (25%) ypCR and 4/16 (25%) yCR. Conclusions: V at 400 mg in combination with RT/C has an acceptable safety profile, and the combination will move forward in an expanded cohort to better define toxicity and efficacy. Escalations of V resulted in approximately dose proportional increases in the V PK with no clear effect on C PK. Author Disclosure: B. Czito: E. Research Grant; AbbVie. G. Consultant; Pfizer. M. Mulcahy: None. W. Schelman: None. H. Vaghefi: F. Honoraria; Bayer. G. Consultant; Bayer. J. Gayle: None. A. Deluca: A. Employee; AbbVie, Inc. M. Stock; AbbVie, Inc. H. Xiong: A. Employee; AbbVie, Inc. M. Stock; AbbVie, Inc. W. Munasinghe: A. Employee; AbbVie, Inc. M. Stock; AbbVie, Inc. D. Matthew: A. Employee; AbbVie, Inc. M. Stock; AbbVie, Inc. K. Holen: A. Employee; AbbVie, Inc. M. Stock; AbbVie, Inc.. M. Michael: None.
40 Preoperative Radiotherapy with a Simultaneous Integrated Boost Compared to Chemoradiation therapy for T3-4 Rectal Cancer: Interim Analysis of a Multicentric Randomized Trial B. Engels,1 A. De Paoli,2 G. Cattari,3 F. Munoz,4 S. Vagge,5 D. Norkus,6 P. Gabriele,3 G. Tabaro,2 H. Versmessen,1 and M. De Ridder1; 1UZ Brussels, Vrije Universiteit Brussels, Brussels, Belgium, 2Centro di Riferimento Oncologico-CRO, Aviano 33081, Italy, 3IRCC, Candiolo, Italy, 4University of Torino, Turin, Italy, 5IRCCS San Martino-IST, Genoa, Italy, 6Institute of Oncology, Vilnius University, Vilnius, Lithuania Purpose/Objective(s): The addition of chemotherapy to preoperative radiotherapy (RT) has been established as the standard of care for patients with cT3-4 rectal cancer. As an alternative strategy, we reported previously in a phase II study a limited toxicity and high 5-year local control rate with preoperative image-guided and intensity-modulated RT (IG-IMRT) with a simultaneous integrated boost (SIB), without concomitant chemotherapy. Here, we compared this strategy to chemoRT in an international multicentric randomized trial (NCT 01224392).
S22 Oral Scientific Abstract 38; Table
SCHEMA
WEEK
1-2
3-5
6-7
8-10
11
THERAPY
FOLFOX
25.2 Gy in 1.8 Gy/fx with oxaliplatin and CI Z 5-FU
FOLFOX
25.2 Gy in 1.8 Gy/fx with oxaliplatin and CI Z 5-FU
FOLFOX
Mater Newcastle Hospital, Newcastle, Australia, 4Monash Medical Centre, East Bentleigh, Australia Purpose/Objective(s): The 5-fluorouracil (5-FU) chemotherapy dose used during chemoradiation for locally advanced rectal cancer is adequate for radiosensitization but suboptimal for possible micrometastatic disease. The aim of this study was to determine the tolerability rate, dose intensity, complete pathologic response rate, and toxicity rates of a novel preoperative regimen of split-course chemoradiation with interdigitating chemotherapy in the setting of a multi-center study. This trial was performed under the auspices of the Trans-Tasman Radiation Oncology Group. Materials/Methods: Eligible patients for this study were those with MRIstaged T3-4 Nany M0 adenocarcinoma of the rectum. The preoperative treatment regimen consisted of FOLFOX chemotherapy (oxaliplatin 100 mg/m2 day 1, 5-FU 400 mg/m2 bolus day 1, leucovorin 200 mg/m2 day 1, then continuous infusion 2.4 g/m2 over 46 hours) given in week 1, 6, and 11 with split-course pelvic radiotherapy (25.2 Gy in 3 weeks in 1.8 Gy/fx with concurrent oxaliplatin 85 mg/m2 day 1, and 5-FU continuous infusion 200 mg/m2/day) given in week 3-5, and week 8-10. Surgery was to be performed 4 to 6 weeks later. In total, patients received, in 11 weeks, 3 courses of FOLFOX and pelvic radiation 50.4 Gy with concurrent oxaliplatin and 5-FU. Results: Forty-one patients were recruited with 40 analyzable patients. The median age was 61.5 (range 29-77) years. Seventy-two percent were men. MRI-stage of the rectal primary was T3 88% and T4 12%. N-stage was N0 20%, N1 52%, N2 28%. Thirty-eight patients (95%) reached week eleven of the treatment (80% CI Z [87% - 99%]). All patients received the planned radiation dose of 50.4 Gy. Relative dose intensity of 75% was achieved by 92% and 98% of patients for oxaliplatin and 5-FU respectively. During the preoperative protocol therapy period, grade 3 toxicity included neutropenia 25%, diarrhea 10%, ALT 10%, fatigue 5%, proctitis 5%, and urinary frequency 5%. All grade 4 toxicities were neutropenia 7.5%. Peripheral neuropathy grade 1, 2, and 3 (worst grade) were 77.5%, 17.5%, 2.5%, respectively. Pathologic CR rate was 20%. There was no 30day perioperative mortality. Conclusions: It is feasible to deliver intensive chemotherapy and radiotherapy in an integrated fashion prior to surgery for patients with locally advanced rectal cancer. This regimen is well tolerated with a high response rate. Further study is warranted. Author Disclosure: S. Ngan: None. M. Bressel: None. B. McClure: None. S. Chander: None. J. McKendrick: None. M. Steel: None. J. Mackay: None. P. Cooray: None. M. Kumar: None. A. Strickland: None. A. Heriot: None. T. Leong: None. M. Michael: None.
39 The Safety and Tolerability of Veliparib (V) plus Capecitabine (C) and Radiation (RT) in Subjects with Locally Advanced Rectal Cancer (LARC): Results of a Phase 1b Study B. Czito,1 M. Mulcahy,2 W. Schelman,3 H. Vaghefi,4 J. Gayle,5 A. Deluca,6 H. Xiong,6 W. Munasinghe,6 D. Matthew,6 K. Holen,6 and M. Michael7; 1 Duke University Medical Center, Durham, NC, 2Northwestern University, Chicago, IL, 3University of Wisconsin Carbone Cancer Center, Madison, IL, 4Indiana University Health, Goshen Center for Cancer Care, Goshen, IN, 5Scottsdale Healthcare, Scottsdale, AZ, 6AbbVie, Inc., North Chicago, IL, 7Peter MacCallum Cancer Center, Melbourne, Australia Purpose/Objective(s): Patients (pts) with LARC treated with neoadjuvant RT/C and then surgery have significant relapse rates with low rates of complete response. V is a potent, orally bioavailable PARP inhibitor that has been shown to enhance the efficacy of chemotherapy and RT in preclinical models. This study sought to establish the
12-14
15-17 Surgery
recommended phase 2 dose (RPTD) as well as to assess safety, pharmacokinetics (PK), and preliminary activity of V + RT/C in pts with LARC. Materials/Methods: Pts with stage II-III rectal cancer received RT (50.4 Gy/1.8 Gy/fraction) with C (825 mg/m2 BID) five days per week (W) for 5.5W. Dosing of V (BID, 20mg-400mg) continued from W1D2 to 2 days past RT. Pts underwent surgery 5-10W following RT. Assessments include identification of RPTD with the Exposure Adjusted Continual Reassessment Method, adverse events (AEs), PK, and pathological response: no disease present on pathologic review (ypCR), microscopic disease only (yCR), and tumor downstaging. Results: As of December 8, 2013, 18 pts have been enrolled, 12/6 male/ female, median age 55 years; 1 pt discontinued due to an AE. The most common treatment-emergent AEs (> 20% pts, n 4) were diarrhea (39%), nausea (39%), fatigue (33%), radiation skin injury (33%), dysuria (22%), and constipation (22%). One Grade 3/4 event of diarrhea and one post-operative event of anastomosis dehiscence were deemed at least possibly related to V. One dose limiting toxicity (DLT) occurred at 70 mg BID V (radiation skin injury requiring dose interruption); 1 pt at 400 mg BID described ongoing intolerable nausea not meeting the criteria of a DLT. The RPTD is 400 mg V in combination with RT/C. PK results from 16 pts suggest that V PK was approximately dose proportional when administered with RT/C and that V had no effect on the PK of C. To date, 11/15 (73%) pts have been downstaged post-surgery; with 4/16 (25%) ypCR and 4/16 (25%) yCR. Conclusions: V at 400 mg in combination with RT/C has an acceptable safety profile, and the combination will move forward in an expanded cohort to better define toxicity and efficacy. Escalations of V resulted in approximately dose proportional increases in the V PK with no clear effect on C PK. Author Disclosure: B. Czito: E. Research Grant; AbbVie. G. Consultant; Pfizer. M. Mulcahy: None. W. Schelman: None. H. Vaghefi: F. Honoraria; Bayer. G. Consultant; Bayer. J. Gayle: None. A. Deluca: A. Employee; AbbVie, Inc. M. Stock; AbbVie, Inc. H. Xiong: A. Employee; AbbVie, Inc. M. Stock; AbbVie, Inc. W. Munasinghe: A. Employee; AbbVie, Inc. M. Stock; AbbVie, Inc. D. Matthew: A. Employee; AbbVie, Inc. M. Stock; AbbVie, Inc. K. Holen: A. Employee; AbbVie, Inc. M. Stock; AbbVie, Inc.. M. Michael: None.
40 Preoperative Radiotherapy with a Simultaneous Integrated Boost Compared to Chemoradiation therapy for T3-4 Rectal Cancer: Interim Analysis of a Multicentric Randomized Trial B. Engels,1 A. De Paoli,2 G. Cattari,3 F. Munoz,4 S. Vagge,5 D. Norkus,6 P. Gabriele,3 G. Tabaro,2 H. Versmessen,1 and M. De Ridder1; 1UZ Brussels, Vrije Universiteit Brussels, Brussels, Belgium, 2Centro di Riferimento Oncologico-CRO, Aviano 33081, Italy, 3IRCC, Candiolo, Italy, 4University of Torino, Turin, Italy, 5IRCCS San Martino-IST, Genoa, Italy, 6Institute of Oncology, Vilnius University, Vilnius, Lithuania Purpose/Objective(s): The addition of chemotherapy to preoperative radiotherapy (RT) has been established as the standard of care for patients with cT3-4 rectal cancer. As an alternative strategy, we reported previously in a phase II study a limited toxicity and high 5-year local control rate with preoperative image-guided and intensity-modulated RT (IG-IMRT) with a simultaneous integrated boost (SIB), without concomitant chemotherapy. Here, we compared this strategy to chemoRT in an international multicentric randomized trial (NCT 01224392).