Phase I/II Study of Preoperative Oxaliplatin, Fluorouracil, and External-Beam Radiation Therapy in Patients With Locally Advanced Rectal Cancer: Cancer and Leukemia Group B 89901

2006 ◽  
Vol 24 (16) ◽  
pp. 2557-2562 ◽  
Author(s):  
David P. Ryan ◽  
Donna Niedzwiecki ◽  
Donna Hollis ◽  
Brent E. Mediema ◽  
Scott Wadler ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Phase I ◽  
Continuous Infusion ◽  
Locally Advanced ◽  
Pathologic Complete Response ◽  
Rectal Adenocarcinoma ◽  
External Beam Radiation ◽  
Beam Radiation ◽  
Grade 3 ◽  
Experienced Grade

Purpose The addition of oxaliplatin to fluorouracil in patients with advanced colorectal cancer improves survival. This phase I/II study evaluated the addition of weekly oxaliplatin to preoperative continuous infusion fluorouracil (FU) and external-beam radiation therapy (RT) in patients with locally advanced rectal adenocarcinoma. Patients and Methods Patients with clinical T3/T4 rectal adenocarcinoma and no evidence of metastases were treated with weekly oxaliplatin, continuous infusion FU 200 mg/m2 intravenously, and RT. A total of 6 weekly doses of oxaliplatin were planned. RT dose was 1.8 Gy/fraction to a total dose of 50.4 Gy. In the phase I portion, oxaliplatin was escalated from 30 to 60 mg/m2. Results Forty-four patients were entered onto the study, 18 on the phase I portion and 26 on the phase II portion. The maximum-tolerated dose (MTD) for oxaliplatin was determined to be 60 mg/m2. At the MTD, 12 patients experienced grade 3 or 4 diarrhea, two patients experienced grade 3 neutropenia, and one patient experienced grade 3 thrombocytopenia. Fifty-six percent of patients entered at the MTD completed all 6 weeks of oxaliplatin. Eight (25%) of 32 patients enrolled at the phase II dose experienced a pathologic complete response. Conclusion In this multicenter study, the addition of oxaliplatin to intravenous continuous infusion FU and RT for patients with locally advanced rectal cancer was associated with a high pathologic complete response rate but more toxicity than when FU is used alone. A regimen of weekly oxaliplatin, continuous infusion FU, and radiation therapy is now being evaluated by the National Surgical Adjuvant Breast and Bowel Project.

Phase I study of preoperative capecitabine and lenvatinib with external radiation therapy in locally advanced rectal adenocarcinoma.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 694-694
Author(s):  
Jessica Frakes ◽  
Rutika Mehta ◽  
Sarah E. Hoffe ◽  
Iman Imanirad ◽  
Maria E Martinez Jimenez ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Rectal Cancer ◽  
Radiation Therapy ◽  
Phase I ◽  
Phase I Study ◽  
Locally Advanced ◽  
Vascular Endothelial Cell ◽  
Rectal Adenocarcinoma ◽  
External Beam Radiation ◽  
Beam Radiation

694 Background: Despite routine use of neoadjuvant chemoradiation, patients with advanced rectal tumors experience significant rates of treatment failure and recurrence. Radiation resistance is a particular problem. Dual targeting of PDGF and VEGFR (Vascular endothelial cell growth factor receptor) in combination with radiation can enhance tumor response. Lenvatinib inhibits the kinase activities of VEGFR1-3, FGFR1-4, PDGFRα, KIT, and RET and in vivo results show that it effectively delays the growth of human colorectal xenografts. Methods: This is a phase I clinical trial of lenvatinib in combination with capecitabine administered with radiation. Patients with stage II or III rectal cancer confirmed by endoscopic ultrasound or MRI were eligible for the study. In this 3+3 phase I study with 3 cohorts, patients were treated with escalating doses of lenvatinib administered in combination with standard doses of capecitabine (850 mg/m2 PO BID D1-5 weekly for 5 ½ to 6 weeks) and external beam radiation therapy (180 cGY on D1-5 weekly for 5 ½ to 6 weeks). Patients underwent surgery 6-10 weeks after neoadjuvant therapy. Results: Nine patients have been enrolled in the 3 cohorts with the median age of 51 years. Lenvatinib dosing started at 14 mg PO daily (cohort 1) and was safely escalated to 20 mg PO daily (cohort 2) followed by 24 mg PO daily (cohort 3). There were no DLTs at the maximum tested dose of lenvantinib (24 mg). 5 patients have undergone low anterior resection and 4 have had abdominoperineal resection. The pathological complete response (pCR) rate was 33.33%, and downstaging was observed in 100% of patients. Median neoadjuvant rectal cancer score (NAR) was 8.7. Three pts had grade 3 events (2 hypertension (HTN), 1 lymphopenia) without any grade 4 events. Most common AEs were HTN and fatigue. No perioperative complications were observed. Tissues for all pts have been collected for planned correlative studies. Conclusions: This study shows that the combination of lenvatinib with capecitabine, and EBRT is well tolerated. NAR score and downstaging rates are encouraging. Currently we are enrolling 10 additional pts at the maximum tested dose of lenvatinib to further evaluate efficacy and safety. Clinical trial information: NCT02935309.

scholarly journals S0356: A Phase II Clinical and Prospective Molecular Trial With Oxaliplatin, Fluorouracil, and External-Beam Radiation Therapy Before Surgery for Patients With Esophageal Adenocarcinoma

2011 ◽  
Vol 29 (34) ◽  
pp. 4555-4560 ◽  
Author(s):  
Lawrence P. Leichman ◽  
Bryan H. Goldman ◽  
Pierre O. Bohanes ◽  
Heinz J. Lenz ◽  
Charles R. Thomas ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Neoadjuvant Therapy ◽  
Esophageal Adenocarcinoma ◽  
Phase Ii ◽  
Locally Advanced ◽  
Pathologic Complete Response ◽  
External Beam Radiation Therapy ◽  
External Beam Radiation ◽  
External Beam ◽  
Beam Radiation

Purpose Pathologic complete response (pCR) after neoadjuvant therapy for locally advanced esophageal adenocarcinoma is associated with improved survival. The Southwest Oncology Group designed a trimodality, phase II, single-arm trial with objectives of achieving a pCR rate of 40% with prospective exploratory analyses of intratumoral molecular markers postulated to affect response and survival. Patients and Methods Patients with clinically staged II or III esophageal adenocarcinoma received oxaliplatin 85 mg/m2 on days 1, 15, and 29; protracted-infusion fluorouracil (PI-FU) 180 mg/m2/d on days 8 through 43; and external-beam radiation therapy (EBRT) 5 days a week at 1.8 Gy/d for 25 fractions; surgery was performed 28 to 42 days after neoadjuvant therapy. Chemotherapy was planned after surgery. Tumors were analyzed for mRNA expression and polymorphisms in genes involved in drug metabolism and DNA repair. Results Ninety-three patients were evaluable. Two deaths (2.2%) were attributable to preoperative therapy, and two deaths (2.2%) were attributable to surgery. Grade 3 and 4 toxicities were recorded for 47.3% and 19.4% of patients, respectively. Seventy-nine patients (84.9%) underwent surgery; 67.7% of patients had R0 resections. Twenty-six patients (28.0%) had confirmed pCR (95% CI, 19.1% to 38.2%). At a median follow-up of 39.2 months, estimates of median and 3-year overall survival (OS) were 28.3 months and 45.1%, respectively. Intratumoral ERCC-1 gene expression was inversely related to progression-free survival and OS. Conclusion Neoadjuvant oxaliplatin, PI-FU, and EBRT for esophageal adenocarcinoma is active and tolerable. Because the regimen failed to meet the primary end point, it does not define a new standard. However, future trials can be built on this platform to validate the role of ERCC-1 in determining the best systemic regimen for individual patients.

A phase I study of erlotinib, bevacizumab, and external beam radiation therapy (RT) for patients with localized pancreatic carcinoma (PC).

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 281-281 ◽  
Author(s):  
B. G. Czito ◽  
C. Willett ◽  
P. Kennedy-Newton ◽  
D. S. Tyler ◽  
H. Hurwitz ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Phase I Study ◽  
Locally Advanced ◽  
Exploratory Laparotomy ◽  
External Beam Radiation ◽  
Beam Radiation ◽  
Level 1

281 Background: Localized PC is commonly managed with chemoradiotherapy, with or without surgical resection. The optimal combination of agents and doses is the subject of continued investigation. This phase I study examines the combination of two targeted radiosensitizing agents in combination with radiation therapy. Methods: Eligible patients had resectable, borderline resectable or locally advanced adenocarcinoma. Patients received RT (1.8 Gy qd to 50.4 Gy) concurrent with bevacizumab and erlotinib. Dose-level 1 was bevacizumab 10 mg/kg weeks 1, 3 and 5 and erlotinib 100 mg daily, RT days only. Drug doses were escalated depending on encountered toxicity. The primary endpoint was determination of the maximally tolerated dose of this combination. Secondary endpoints included toxicity and activity assessment. Results: Nine patients were enrolled in the phase I study. Maximal EUS/CT stage was T2N0 (n=1), T3N0 (n=1), T3N1 (n=2) or T4N0 (n=5). Of 3 patients in dose-level 1, two had radiographic stable disease (SD) and one partial response (PR). One pt underwent exploratory laparotomy and found to be unresectable, experiencing prolonged postoperative incisional healing. Three patients were then enrolled at dose-level 2 (bevacizumab 10 mg/kg, erlotinib 125 mg). Two had SD and one progressive disease (PD). One pt underwent exploratory laparotomy, aborted due to previously undetected hepatic metastases. Three patients were then enrolled at dose-level 3 (bevacizumab 10 mg/kg, erlotinib 150 mg). One pt had SD and two PR. One pt underwent distal pancreatectomy, experiencing postoperative pancreatic leak and abscess formation. All patients with elevated CA 19-9 at baseline had a decrease, with amedian decrease of 69% (R:13-93%). Dose-limiting toxicity (DLT) was not encountered at any dose-level. Primary non-dose limiting toxicities in all cohorts included NCI CTCAE v3.0 grade 1-2 nausea/vomiting, rash, diarrhea, fatigue, and anorexia. Conclusions: Concurrent chemoradiotherapy utilizing erlotinib and bevacizumab is reasonably well-tolerated. The recommended phase II dose is bevacizumab 10 mg/kg weeks 1, 3, and 5 and erlotinib 150 mg RT days only. Phase II accrual is underway. [Table: see text]

Phase I study of preoperative capecitabine and lenvatinib with external radiation therapy in locally advanced rectal adenocarcinoma.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 125-125
Author(s):  
Ankita Tandon ◽  
Jessica Frakes ◽  
Rutika Mehta ◽  
Sarah E. Hoffe ◽  
Maria E Martinez Jimenez ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Growth Factor ◽  
Locally Advanced ◽  
Pathologic Complete Response ◽  
Rectal Adenocarcinoma ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
External Beam Radiation ◽  
Beam Radiation ◽  
Rectal Pain

125 Background: Neoadjuvant chemo-radiation is a standard of care for locally advanced rectal cancer. Patients with pathologic complete response (pCR) have improved outcomes with less local and systemic failure. Dual targeting with platelet derived growth factor (PDGF) and vascular endothelial growth factor receptor (VEGFR) in combination with radiation can escalate tumor response with radiation. Lenvatinib is an oral multi-kinase inhibitor and had shown potent anti-tumor activity in xenograft models cultured with human colorectal cancer (CRC) lines. Methods: Patients with stage II or III rectal cancer, confirmed by endoscopic ultrasound or MRI, were recruited in 3 cohorts of 3 patients per dose level, with an expansion cohort at the MTD. Lenvatinib oral daily dose started at 14 mg (cohort 1) and was escalated to 20 mg (cohort 2) followed by 24 mg (cohort 3). In this 3+3 design, patients received dose escalation of lenvatinib with standard doses of capecitabine (850 mg/m2 PO BID) concurrent with external beam radiation on days 1-5 weekly for 28 treatments. Following completion patients underwent surgery in 6-10 weeks. Results: Twenty patients with median age of 55 were enrolled in 3 cohorts (1 patient was ineligible). There were no dose limiting toxicity at the maximum tested dose of lenvatinib (24 mg). Two patients are still awaiting surgery. 12 patients have undergone low anterior resection and 5 patients have had abdominoperineal resection. Therefore, out of 17 patients, 29.4% (5/17) showed pCR, and downstaging was observed in 71% of the patients (12/17). The mean neoadjuvant rectal cancer score (NAR) was 11.4 and median NAR was 8.43. Six patients had grade 3 adverse events (AEs) (1 rectal pain,1 transaminitis, 2 lymphopenia, 1 HTN, 1 with both leukocytosis and hyponatremia). No grade 4 AEs were noted. Most common AEs were hypertension, rectal pain, nausea, diarrhea, fatigue and dermatitis. No peri operative complications were observed. Conclusions: The study shows that the combination of lenvatinib and capecitabine with radiation is well tolerated in locally advanced rectal cancer with promising mean NAR score. The encouraging results will need to be validated in a randomized study. Clinical trial information: NCT02935309.

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