Phase II trial PD-L1/PD-1 blockade avelumab with chemoradiotherapy for locally advanced resectable T3B-4/N1-2 rectal cancer: The Ave-Rec trial.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS3622-TPS3622
Author(s):  
Michael Michael ◽  
Rachel Wong ◽  
Sanjeev Singh Gill ◽  
David Goldstein ◽  
Sam Ngan ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Sample Size ◽  
Phase Ii ◽  
Fdg Pet ◽  
Immune Cell ◽  
Response Rate ◽  
Locally Advanced ◽  
Pathological Response ◽  
Pelvic Mri ◽  
Distant Relapse

TPS3622 Background: Standard neoadjuvant long course chemoradiotherapy (LCCRT) for locally advanced rectal cancer (LARC) results in a complete pathological response rate of 10-30%: but 20-40% of patients (pts) are non-responders, 10-15% have local recurrence. Tumoural immune infiltrates are predictive of response. Preclinical studies show that radiotherapy (RT) via interferon signaling is immuno-stimulatory, enhancing local/distant tumour cell death. RT also stimulates PDL1 production and the immunosuppressive activity of myeloid derived suppressor cells. Hence PDL1 inhibition may be required to enhance the immuno-stimulatory effects of RT. Hypothesis: In pts with resectable LARC, the anti-PDL1 antibody Avelumab post LCCRT may enhance the pathological/imaging response rates whilst potentially reducing local/distant relapse rates. Methods: (1) Trial Design: Phase II single arm trial, across 6 Australian sites (2) Endpoints: (a) Primary; Pathological response rate post-LCCRT, as documented by central pathologist, (b) Secondary; MRI/FDG PET imaging responses at 8 weeks post LCCRT (pre-surgery). Toxicity. (c) Exploratory; Tumoural immune cell subsets/checkpoint expression (by multiplex immunohistochemistry and in-vitro functional assays) and ctDNA analysis at baseline and during treatment. Distant relapse-free survival and the documentation of sites of relapse. (3) Sample size: An increase in the proportion of pathological complete responses by > 25% (from 10% to 35%) will be considered clinically important. Power = 90%, α = 0.05, 41 pts are required– an additional 4 pts to allow for drop-out. Total sample size = 45pts. Treatment: All pts to receive standard LCCRT (50.4Gy RT plus 5FU [225mg/m2/day/CI] or Capecitabine [825mg/m2 BID on RT days] over 5.5 weeks). Post LCCRT (prior to surgery), pts receive 4 cycles Avelumab (10mg/kg, q2 weeks). Surgical resection 10-12 weeks post LCCRT. Fresh tumour biopsy and ctDNA sampling pre LCCRT, pre Cycle 1 Avelumab and at surgery. Response by FDG PET and pelvic MRI pre surgery. Pts to be followed up for 2 years. Major Inclusion Criteria: Pts with LARC, MRI stage T3b-4/N1-2/M0, planned for LCCRT followed by curative resection, tumoural lower border within 12cm from the anal verge, measurable disease (RECIST1.1), ECOG 0-1, adequate organ function and no contraindications to Avelumab therapy. Current Enrolment: 11 of the planned 45 patients enrolled. Clinical trial information: NCT03299660.

Concurrent radiotherapy (RT) and chemotherapy (CT) with oxaliplatin as primary treatment of advanced rectal cancer: a phase II study

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13507-13507 ◽  
Author(s):  
A. Alberti ◽  
F. Tomei ◽  
E. Miele ◽  
N. Pizzardi ◽  
S. Ramponi ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Total Dose ◽  
Sample Size ◽  
Phase Ii ◽  
Locally Advanced ◽  
Advanced Rectal Cancer ◽  
Sphincter Preservation ◽  
Pathological Response ◽  
Tumor Bed ◽  
Concomitant Boost

13507 Background: Combined pre-operative RT and CT increase the possibility for conservative surgery in locally advanced rectal cancer. Most clinical trials show that responding patients could obtain a reduction of local relapse and an improvement of overall survival, especially when a complete pathological response is obtained (pCR 9–29%). The aim of our study was to determine the activity of RT concomitant to oxaliplatin (OHP) in combination with c.i. 5-fluorouracil (5FU). Methods: Primary endpoint was pCR. Sample size was defined according to Simon Two-Stage phase II design (planned sample size: 29 evaluable patients). From May 2002 to November 2005, 33 patients (15 males, 18 females) were enrolled: median age was 64 years (range 21–74); clinical stage was cT3/cT4 cN0 or cTany cN+ M0. In 24 patients rectal cancer was ≤ 5 cm from anal verge. Weekly OHP 60 mg/m2 was administered in combination with c.i. 5FU 225 mg/ m2 for 5 days per week. Twelve patients received conventional RT (CRT): 25 fractions with 1.8 Gy, total dose 50.4 Gy on the pelvis and a boost on tumor bed with 3 fractions of 1.8 Gy. 21 patients received hyperfractionated RT (HRT): 1.2 Gy b.i.d. for 5 days per week for 4 weeks and a concomitant boost on tumor bed with daily 3 Gy (total dose 54–56 Gy on tumor bed, 48–50 Gy on the pelvis). Patients underwent surgery after 6–8 weeks from the end of treatment. Results: All patients were evaluable for pathological response. Sphincter preservation was obtained in 30 patients (=90.9%), a clinical down-staging in 30 patients (=90.9%). Overall, 12 patients (=36.4%) experienced a pCR: 9 of 21 patients (=42.8%) who received HRT obtained a pCR; 3 of 12 patients (=25%) who received CRT showed a pCR. Treatment was well tolerated. No G3–4 toxicity was observed. Conclusions: The results of our study are promising in terms of sphincter preservation, clinical down-staging and pCR. Moreover in this trial patients who received HRT obtained an encouraging outcome. No significant financial relationships to disclose.

Multicenter randomized phase II clinical trial of preoperative chemoradiotherapy by S-1 versus UFT to rectal cancer for personalized therapy (UMIN ID: 000001704).

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 499-499
Author(s):  
Takashi Iwata
Keyword(s):  
Clinical Trial ◽  
Rectal Cancer ◽  
Adverse Events ◽  
Phase Ii ◽  
Response Rate ◽  
Locally Advanced ◽  
Preoperative Chemoradiotherapy ◽  
Pathological Response ◽  
Phase Ii Clinical Trial ◽  
Randomized Phase Ii

499 Background: Preoperative chemoradiotherapy (CRT) in rectal cancer reduces the local recurrence rate after operation and preserves the anus, but it is difficult to predict the effects of CRT. Multicenter randomized phase II clinical trial of preoperative chemoradiotherapy by S-1 vs UFT for rectal cancer was conducted to compare the toxicity and efficacy of CRT using oral DPD-inhibitory fluoropyrimidines (UFT versus S-1, (UMIN ID: 000001704)) in patients with locally advanced rectal cancer. Methods: In this randomized phase II study, during April 2008 to October 2010, rectal cancer patients (n=59) who underwent preoperative CRT were randomly divided into two groups; S-1 group (n=30, 80 mg/m2/day, 5 days/w x 4 w), and UFT (n=29, 300 mg/m2/day, 5 days/w x 4 w). Both groups were combined with 40Gy radiotherapy (2 Gy ×5 days/w × 4 weeks,total 40 Gy). The pathological response rate, clinical response rate by RECIST, and frequency of adverse events of CRT were compared between S-1 group and UFT group. Results: Response to CRT determined by histopathologic examination of surgically resected specimens and RECIST were as follows: responders (grade 2 or 3) were 60% (S-1) and 52% (UFT) (p=0.52). S-1 group showed 54% of response rate in pathological response, whereas UFT group showed 45% (p=0.43). In adverse events, frequence of Grade 2 and 3 diarrhea was significantly higher in S-1 group compared with UFT group. There was no difference between the two groups in compliance (S-1group: 83%, UFT group: 97%). Conclusions: Both S-1 and UFT were safely used for preoperative CRT. S-1 tended to show higher response rate than UFT, although diarrhea in S-1 was higher than in UFT. Clinical trial information: 000001704.

scholarly journals Short-term results of a phase II study of preoperative docetaxel/cisplatin/S-1 therapy for locally advanced gastric cancer

2020 ◽  
Author(s):  
Kazuhito Tsuchida ◽  
Tsutomu Sato ◽  
Toru Aoyama ◽  
Yosuke Atsumi ◽  
Kazuki Kano ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Advanced Gastric Cancer ◽  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Study ◽  
Locally Advanced ◽  
Expected Value ◽  
Pathological Response ◽  
Surgical Morbidity ◽  
Macroscopic Type

Abstract Background A multi-institutional phase II study was conducted to evaluate the efficacy and safety of preoperative docetaxel, cisplatin and S-1 therapy in marginally resectable advanced gastric cancer. Methods Patients with macroscopic type 4, large macroscopic type 3 and bulky lymph node metastasis received two cycles of preoperative docetaxel, cisplatin and S-1 therapy (docetaxel 40 mg/m2 and cisplatin 60 mg/m2 on day 1, and S-1 80 mg/m2 for 14 days, every 4 weeks). The primary endpoint was the pathological response rate, with an expected value of 65%. Results Thirty-one patients were enrolled in this study. The pathological response rate was 54.8%, and it was higher than the threshold value but lower than the expected rate. The R0 resection rate was 93.5%. The frequencies of grade 3–4 toxicities during docetaxel, cisplatin and S-1 therapy were 41.9% for neutropenia, 6.5% for febrile neutropenia and 32.3% for nausea/vomiting. Grade 2 and 3 surgical morbidities occurred in 23.3 and 6.7% of the patients, respectively. Conclusions Preoperative docetaxel, cisplatin and S-1 therapy was feasible in terms of chemotherapy-related toxicities and surgical morbidity, but the effect did not achieve the expected value. The association between the pathological response rate and survival will be evaluated in the final analysis of this clinical trial.

scholarly journals Efficacy and safety-in analysis of short-course radiation followed by mFOLFOX-6 plus avelumab for locally advanced rectal adenocarcinoma

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Ali Shamseddine ◽  
Youssef H. Zeidan ◽  
Ziad El Husseini ◽  
Malek Kreidieh ◽  
Monita Al Darazi ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Locally Advanced ◽  
Pathologic Complete Response ◽  
Pathologic Response ◽  
Cytotoxic T Cell ◽  
Short Course ◽  
Pathologic Response Rate

Abstract Background Neoadjuvant chemotherapy and short-course radiotherapy followed by resection has been gaining recognition in the treatment of rectal cancer. Avelumab is a fully human immunoglobulin that binds Programmed Death-Ligand 1 (PD-L1) and prevents the suppression of the cytotoxic T cell immune response. This phase II trial evaluates the safety and pathologic response rate of short-course radiation followed by 6 cycles of mFOLFOX6 with avelumab in patients with locally advanced rectal cancer (LARC). Methods This study is prospective single-arm, multicenter phase II trial adopting Simon’s two-stage. Short-course radiation is given over 5 fractions to a total dose of 25 Gy. mFOLFOX6 plus avelumab (10 mg/kg) are given every 2 weeks for 6 cycles. Total mesorectal excision is performed 3–4 weeks after the last cycle of avelumab. Follow up after surgery is done every 3 months to a total of 36 months. Adverse event data collection is recorded at every visit. Results 13 out of 44 patients with LARC were enrolled in the first stage of the study (30% from total sample size). All patients met the inclusion criteria and received the full short-course radiation course followed by 6 cycles of mFOLFOX6 plus avelumab. 12 out of the 13 patients completed TME while one patient had progression of disease and was dropped out of the study. The sample consisted of 9 (69%) males and 4 (31%) females with median age of 62 (33–73) years. The first interim analysis revealed that 3 (25%) patients achieved pathologic complete response (pCR) (tumor regression grade, TRG 0) out of 12. While 3 (25%) patients had near pCR with TRG 1. In total, 6 out of 12 patients (50%) had a major pathologic response. All patients were found to be MMR proficient. The protocol regimen was well tolerated with no serious adverse events of grade 4 reported. Conclusion In patients with LARC, neoadjuvant radiation followed by mFOLFOX6 with avelumab is safe with a promising pathologic response rate. Trial Registration Number and Date of Registration ClinicalTrials.gov NCT03503630, April 20, 2018. https://clinicaltrials.gov/ct2/show/NCT03503630?term=NCT03503630&draw=2&rank=1.

A phase II clinical trial of neoadjuvant trabectedin in patients with nonmetastatic advanced myxoid/round cell liposarcoma (MRCL)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 10525-10525
Author(s):  
A. Gronchi ◽  
A. Le Cesne ◽  
N. B. Bui ◽  
E. Palmerini ◽  
G. Demetri ◽  
...  
Keyword(s):  
Phase Ii ◽  
Response Rate ◽  
Objective Response ◽  
Locally Advanced ◽  
Soft Tissue Sarcomas ◽  
Pathological Response ◽  
Phase Iii ◽  
Significant Activity ◽  
Tumor Mass ◽  
Preliminary Results

10525 Background: Trabectedin (ET-743, Yondelis), a marine-derived alkaloid has demonstrated significant activity in the treatment of soft tissue sarcomas (STS) in phase III trials, and has recently received EMEA approval in this indication. A subtype that accounts for 10% of STS, MRCL, displays the fusion FUS-CHOP in 95% of all cases. Preliminary results of neoadjuvant trabectedin (T) in advanced MRCL show reduction in the radiological density of the tumor, clinical improvement, and a pathological complete response (pCR) in the resected tumor mass. A phase II study to further determine the response to T in the MRCL population is presented. Methods: In this multicenter Phase II trial, patients (pts) with locally advanced (stage III) or locally recurrent MRCL were treated for 3 - 6 cycles with T (1.5 mg/m2 q3wk) in the neoadjuvant setting. Main endpoints were: pCR rate, objective response rate by RECIST, and correlation of molecular parameters from tissue samples with clinical outcomes. Results: Twenty-five pts with locally advanced MRCL have been recruited, of whom 20 are evaluable. All had the translocation (t12q13, 16p11) which causes the chimeric FUS-CHOP. Median age was 53 (23–75) and male:female ratio was 1. Thirteen pts completed therapy and underwent curative surgery. Pathological assessment was performed in 10 pts: 2 achieved pCR, 1 as per central pathology review and 1 by local pathology assessment. In addition, 1 pt had a very good pathological response. Ten patients remain to be histologically evaluated. Response rate by RECIST from pts who completed therapy was: 6 partial responses (46%) and 7 disease stabilizations. Remarkably, pathological response does not entirely correlate with response by RECIST since the pts with pCR still had radiological disease but no malignant component was found in the excised tumor mass (only connective and reactive tissue). Two serious adverse reactions of severe rhabdomyolysis, and asthenia, nausea and transaminase elevation were reported. Most common toxicities were liver enzyme elevation, neutropenia and thrombocytopenia. Conclusions: These preliminary results in terms of objective and complete pathologic responses, strongly suggest that T may have a role in the neoadjuvant setting in pts with MRCL. [Table: see text]

scholarly journals Early prediction of pathological response in locally advanced rectal cancer based on sequential 18F-FDG PET

2012 ◽  
Vol 52 (3) ◽  
pp. 619-626 ◽  
Author(s):  
Mathieu Hatt ◽  
Ruud van Stiphout ◽  
Adrien le Pogam ◽  
Guido Lammering ◽  
Dimitris Visvikis ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Fdg Pet ◽  
Locally Advanced ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Pathological Response ◽  
Early Prediction ◽  
18F Fdg
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