A phase II study to evaluate safety and efficacy of neoadjuvant pembrolizumab and radiotherapy in localized MSS rectal cancer.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. TPS272-TPS272
Author(s):  
Thibaud Kossler ◽  
Buchs Nicolas ◽  
Valérie Dutoit ◽  
Giacomo Puppa ◽  
Petros Tsantoulis ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Checkpoint Inhibitors ◽  
Locally Advanced ◽  
Tumor Regression Grade ◽  
Systemic Steroid ◽  
Ratio Test ◽  
Quality Of Surgery ◽  
Regression Grade

TPS272 Background: Locally advanced rectal cancer remains a clinical challenge with few improvements noted over the past few decades. Although immunotherapy has no current clinical role in microsatellite stable (MSS) colorectal cancer, preclinical models suggest that radiotherapy (RT) can enhance neoantigen presentation, modulate the microenvironment, and improve the likelihood of anti-tumor activity with checkpoint inhibitors use. This prospective phase II trial will test that hypothesis in addition to confirming safety of this approach using a “window-of-opportunity” study design with the anti-PD-1 agent Pembrolizumab. Methods: This monocentric phase II trial, will enroll patients (pts) with rectal cancer who are undergoing neoadjuvant short course RT (scRT) (25 Gy in 5 fractions). according to the standard of care. Eligible includes pts with MSS stage II-III rectal cancer with adequate organ function and availability of pre-treatment tumor, who are undergoing scRT with intention to proceed to surgical resection. Standard ineligibility criteria include active infections, systemic steroid use, or other conditions making immunotherapy use unsafe. Treatment includes 4 doses of Pembrolizumab (200mg IV, once every 3 wks), the first dose being given before the first scRT fraction. Surgery will be performed within 12-16 weeks of the final scRT dose. Primary endpoint is tumor regression grade (TRG) using the Mandard regression grade score targeting a 30% pathological complete response (pCR) compared to 10% in historical controls. Secondary endpoints include OS, DFS, toxicity, local and distant relapse-free survival, negative surgical margins, QoL, quality of surgery and exploratory assessments of tumor infiltrating lymphocytes, profiling of circulating immune cell populations, and molecular predictors of response. A safety stopping rule is planned based on Wald’s sequential probability ratio test for the occurrence of the safety outcome. Enrollment target is 25 pts. Support: MSD. Clinical trial information: NCT04109755 .

NSABP FR-2: Phase II study of durvalumab following neoadjuvant chemoRT in stage II-IV rectal cancer.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. TPS727-TPS727
Author(s):  
Thomas J. George ◽  
Greg Yothers ◽  
James J. Lee ◽  
Samuel A. Jacobs ◽  
Melvin Deutsch ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Locally Advanced ◽  
Neoadjuvant Chemoradiotherapy ◽  
Stage Iv ◽  
Sphincter Preservation ◽  
Stage Ii ◽  
Systemic Steroid ◽  
Clinical Role

TPS727 Background: Locally advanced rectal cancer remains a clinical challenge with few improvements noted over the past few decades. Although immunotherapy has no current clinical role in microsatellite stable (MSS) colorectal cancer, preclinical models suggest that radiotherapy (RT) can enhance neoantigen presentation, modulate the microenvironment, and improve the likelihood of anti-tumor activity with checkpoint inhibitor use. This prospective phase II trial will test that hypothesis in addition to confirming safety of this approach using a “window-of-opportunity” study design with the anti-PD-L1 agent durvalumab (MEDI4736). Methods: This multi-center phase II trial is currently enrolling patients (pts) with rectal cancer who are undergoing standard NCCN guideline-compliant neoadjuvant chemoradiotherapy (CRT). Eligibility includes pts with MSS stage II-IV rectal cancer with adequate organ function and pre-treatment diagnostic tumor available for profiling who are undergoing CRT with intentions to proceed to surgical resection. Stage IV disease must be limited such that the primary pelvic tumor requires definitive management. Standard ineligibility criteria include active infections, systemic steroid use, or other conditions making immunotherapy use unsafe. Treatment includes durvalumab (750mg IV infusion once every 2 wks) for 4 total doses beginning within 3-7 days after CRT completion. Surgery must be within 8-12 wks of the final CRT dose. Primary endpoint is a demonstrated improvement in Neoadjuvant Rectal Cancer (NAR) score compared to historical controls targeting a 20% relative risk reduction in DFS and 3-4% absolute OS improvement. Secondary endpoints include OS, DFS, toxicity, pCR, cCR, therapy completion, negative surgical margins, sphincter preservation, off-target “abscopal” effects for the subset of stage IV pts, and exploratory assessments of tumor infiltrating lymphocytes, circulating immunologic profiles, and molecular predictors of response. A safety run-in phase has completed as a precedent to full enrollment. Enrollment now continues to 47 total pts to achieve 41 surgically evaluable pts. NCT03102047. Support: AstraZeneca-Medimmune, NSABP Foundation Clinical trial information: NCT03102047.

NSABP FR-2: Phase II study of durvalumab following neoadjuvant chemoRT in stage II-IV rectal cancer.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. TPS264-TPS264
Author(s):  
Thomas J. George ◽  
Greg Yothers ◽  
Samuel A. Jacobs ◽  
Gene Grant Finley ◽  
Hiral D. Parekh ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Locally Advanced ◽  
Neoadjuvant Chemoradiotherapy ◽  
Stage Iv ◽  
Tumor Infiltrating Lymphocytes ◽  
Sphincter Preservation ◽  
Stage Ii ◽  
Systemic Steroid

TPS264 Background: Clinical improvements for locally advanced rectal cancer have been relatively static over the past few decades. While immunotherapy shows no benefit in microsatellite stable (MSS) colorectal cancer, preclinical models suggest that radiotherapy (RT) can enhance neoantigen presentation, modulate the microenvironment, and improve the likelihood of anti-tumor activity with checkpoint inhibitor use. Using a “window-of-opportunity” study design, this prospective phase II trial will determine the safety and activity of this approach with the anti-PD-L1 agent durvalumab (MEDI4736). Methods: This multi-center phase II trial is currently enrolling patients (pts) with rectal cancer who are undergoing standard NCCN guideline-compliant neoadjuvant chemoradiotherapy (CRT). Eligibility includes pts with MSS stage II-IV rectal cancer with adequate organ function and pre-treatment diagnostic tumor available for profiling with intent to proceed to surgical resection after CRT. Stage IV disease must be limited such that the primary pelvic tumor requires definitive management. Standard ineligibility criteria include active infections, systemic steroid use, or other conditions making immunotherapy use unsafe. Treatment includes durvalumab (750mg IV infusion once every 2 wks) for 4 total doses beginning within 3-7 days after CRT completion. Surgery must be within 8-12 wks of the final CRT dose. Primary endpoint is a demonstrated improvement in Neoadjuvant Rectal Cancer (NAR) score compared to historical controls targeting a 20% relative risk reduction in DFS and 3-4% absolute OS improvement. Secondary endpoints include OS, DFS, toxicity, pCR, cCR, therapy completion, negative surgical margins, sphincter preservation, off-target “abscopal” effects for the subset of stage IV pts, and exploratory assessments of tumor infiltrating lymphocytes, tumor Immunoscore, circulating immunologic profiles, and molecular predictors of response. A safety run-in phase has completed as a precedent to full enrollment. Enrollment now continues to 47 total pts to achieve 41 surgically evaluable pts. Support: AstraZeneca-Medimmune, NSABP Foundation. Clinical trial information: NCT03102047.

Phase II study of durvalumab following neoadjuvant chemoRT in stage II-IV rectal cancer: NSABP FR-2.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS3620-TPS3620
Author(s):  
Thomas J. George ◽  
Greg Yothers ◽  
James J. Lee ◽  
Melvin Deutsch ◽  
Samuel A. Jacobs ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Locally Advanced ◽  
Neoadjuvant Chemoradiotherapy ◽  
Stage Iv ◽  
Sphincter Preservation ◽  
Stage Ii ◽  
Systemic Steroid ◽  
Clinical Role

TPS3620 Background: Locally advanced rectal cancer remains a clinical challenge with few improvements noted over the past few decades. Although immunotherapy has no current clinical role in microsatellite stable (MSS) colorectal cancer, preclinical models suggest that radiotherapy (RT) can enhance neoantigen presentation, modulate the microenvironment, and improve the likelihood of anti-tumor activity with checkpoint inhibitor use. This prospective phase II trial will test that hypothesis in addition to confirming the safety of this approach using a “window-of-opportunity” study design with the anti-PD-L1 agent durvalumab (MEDI4736). Methods: This multi-center phase II trial is currently enrolling patients (pts) with rectal cancer who are undergoing standard NCCN guideline-compliant neoadjuvant chemoradiotherapy (CRT). Eligibility includes pts with MSS stage II-IV rectal cancer with adequate organ function and pre-treatment diagnostic tumor available for profiling who are undergoing CRT with intent to proceed to surgical resection. Stage IV disease must be limited such that the primary pelvic tumor requires definitive management. Standard ineligibility criteria include active infections, systemic steroid use, or other conditions making immunotherapy use unsafe. Treatment includes durvalumab (750mg IV infusion once every 2 wks) for 4 total doses beginning within 3-7 days after CRT completion. Surgery must be within 8-12 wks of the final CRT dose. Primary endpoint is a demonstrated improvement in Neoadjuvant Rectal Cancer (NAR) score compared to historical controls targeting a 20% relative risk reduction in DFS and 3-4% absolute OS improvement. Secondary endpoints include OS, DFS, toxicity, pCR, cCR, therapy completion, negative surgical margins, sphincter preservation, off-target “abscopal” effects for the subset of stage IV pts, and exploratory assessments of tumor infiltrating lymphocytes, circulating immunologic profiles, and molecular predictors of response. A safety run-in phase has completed as a precedent to full enrollment. Enrollment now continues to 47 total pts to achieve 41 surgically evaluable pts. Support: AstraZeneca-Medimmune, NSABP Foundation. Clinical trial information: NCT03102047.

scholarly journals Evaluation of potential tumor markers that may predict neoadjuvant treatment efficiency in rectal cancer

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Fatma Demet Arslan ◽  
Ayse Kocak ◽  
Cengiz Aydın ◽  
Emel Ebru Pala ◽  
Dilek Oncel ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rectal Cancer ◽  
Tumor Markers ◽  
Locally Advanced ◽  
Neoadjuvant Treatment ◽  
Beclin 1 ◽  
Tumor Regression Grade ◽  
Protein Levels ◽  
Study Gene Expression ◽  
Regression Grade

AbstractObjectivesThe recurrence of rectal cancer or its resistance to neoadjuvant treatment develops due to the adaptation to hypoxia, apoptosis or autophagy. Survivin, one of the inhibitors of apoptosis; Beclin 1, which is a positive regulator in the autophagy pathway; and hypoxia-inducible factor-1α (HIF-1α) and carbonic anhydrase-9 (CA9), which are associated with tumor tissue hypoxia, may be related to resistance to treatment. Our aim was to evaluate the potential tumor markers that may help to monitor the response to neoadjuvant treatment in locally advanced rectal cancer (RC).MethodsTwenty-five patients with locally advanced RC were included in the study. Gene expression and protein levels of Beclin 1, Survivin, HIF-1α, and CA9 were analyzed in fresh tissue specimens and blood samples. The relationships of these markers to tumor staging and regression grade were evaluated.ResultsHigher blood CA9 gene expression levels and lower blood HIF-1α protein levels were found in the response group according to tumor regression grade. After neoadjuvant treatment, tissue Beclin 1 and blood Survivin gene expressions and tissue CA9, blood Beclin 1 and blood HIF-1α protein levels decreased significantly.ConclusionBeclin 1, Survivin, HIF-1α ve CA9 may help to predict the effects of the applied treatment approach.

scholarly journals Radiotherapy Scheme Effect on PD-L1 Expression for Locally Advanced Rectal Cancer

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 2071
Author(s):  
Jihane Boustani ◽  
Valentin Derangère ◽  
Aurélie Bertaut ◽  
Olivier Adotevi ◽  
Véronique Morgand ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Tumor Regression ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Tumor Regression Grade ◽  
The Impact

In locally advanced rectal cancer, radiotherapy (RT) followed by surgery have improved locoregional control, but distant recurrences remain frequent. Although checkpoint inhibitors have demonstrated objective response in several cancers, the clinical benefit of PD-1/PD-L1 blockade remains uncertain in rectal cancer. We collected data from biopsies and surgical specimens in 74 patients. The main objective was to evaluate the impact of neoadjuvant RT and fractionation on PD-L1 expression. Secondary objectives were to study the relation between PD-L1 expression and tumor regression grade (TRG), progression-free survival (PFS), overall survival (OS), and CD8 TILs infiltration. Median rates of cells expressing PD-L1 pre- and post-RT were 0.15 (range, 0–17) and 0.5 (range, 0–27.5), respectively (p = 0.0005). There was no effect of RT fractionation on PD-L1+ cell rates. We found no relation between CD8+ TILs infiltration and PD-L1 expression and no difference between high-PD-L1 or low-PD-L1 expression and TRG. High-to-high PD-L1 expression profile had none significant higher OS and PFS compared to all other groups (p = 0.06). Median OS and PFS were higher in biopsies with >0.08 PD-L1+ cells. High-to-high PD-L1 profile and ypT0-2 were significantly associated with higher OS and PFS. This study did not show the differential induction of PD-L1 expression according to fractionation.

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