Phase II Randomized Multi-center Trial of Total Neoadjuvant Therapy With and Without CD40 Agonist, APX005M, for Locally Advanced Rectal Adenocarcinoma

2019 ◽  
Author(s):  
Keyword(s):  
Neoadjuvant Therapy ◽  
Phase Ii ◽  
Locally Advanced ◽  
Rectal Adenocarcinoma ◽  
Total Neoadjuvant Therapy

NRG-GI002: A phase II clinical trial platform for total neoadjuvant therapy (TNT) in rectal cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS3629-TPS3629 ◽  
Author(s):  
Thomas J. George ◽  
Greg Yothers ◽  
Theodore S. Hong ◽  
Marcia McGory Russell ◽  
Y. Nancy You ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Rectal Cancer ◽  
High Risk ◽  
Neoadjuvant Therapy ◽  
Surgical Resection ◽  
Phase Ii ◽  
Locally Advanced ◽  
High Risk Patient ◽  
Randomized Phase Ii ◽  
Total Neoadjuvant Therapy

TPS3629 Background: Improvements in outcomes for locally advanced rectal cancer (LARC) have plateaued due to an inability to consistently deliver adjuvant therapy (tx) and thus far ineffective novel therapies. Systematic testing of new chemotherapy and radiation sensitizers are needed to advance treatment outcomes. This randomized phase II modular clinical trial platform utilizes Total Neoadjuvant Therapy (TNT) with parallel experimental arms in LARC. The experimental arms are not intended for direct comparison, but to test a variety of sensitizers or hypotheses in a consistent and relatively homogenous high-risk patient (pt) population with correlative biomarkers. Success of any given experimental arm will be determined by achievement of pathologic endpoints compared to a control arm. Methods: This NCTN multi-arm randomized phase II trial serves as a modular platform to assess novel sensitizers to neoadjuvant chemotherapy and/or chemoradiotherapy (chemoRT) in LARC. Eligibility includes LARC as defined by any ONE of the following criteria: distal location (cT3-4 ≤5cm from the anal verge, any N); bulky (any cT4 or tumor within 3mm of the mesorectal fascia); high risk for metastatic disease (cN2); or not a candidate for sphincter-sparing surgical resection. After randomization, pts receive neoadjuvant FOLFOX x 4mo → chemoRT (capecitabine with 50.4Gy) → surgical resection 8-12 wks later. Based on promising phase I results, the first experimental arm will assess the activity of veliparib added to standard chemoRT (capecitabine + RT). Primary endpoint is to demonstrate improvement in Neoadjuvant Rectal Cancer (NAR) score for the experimental arm vs control representing 20% relative risk reduction in DFS HR and 3-4% absolute OS improvement. Secondary endpoints include comparisons of OS, DFS, toxicity, pCR, cCR, tx completion, negative surgical margins, sphincter preservation, sphincter function including quality of life, and exploratory assessments of molecular and radiographic predictors of response and distant failure. Target accrual is 79 evaluable pts per arm with additional arms added through rolling protocol amendments. NCT02921256. Support: U10 CA-180868, -20, 21, -22; UG-189867; AbbVie. Clinical trial information: NCT02921256.

Survival and organ preservation according to clinical response after total neoadjuvant therapy in locally advanced rectal cancer patients: A secondary analysis from the organ preservation in rectal adenocarcinoma (OPRA) trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3509-3509
Author(s):  
Hannah Thompson ◽  
Jin Ki Kim ◽  
Jonathan B. Yuval ◽  
Floris Verheij ◽  
Sujata Patil ◽  
...  
Keyword(s):  
Clinical Response ◽  
Neoadjuvant Therapy ◽  
Organ Preservation ◽  
Locally Advanced ◽  
Rectal Adenocarcinoma ◽  
Response Assessment ◽  
Complete Response ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Total Neoadjuvant Therapy

3509 Background: Clinical response following neoadjuvant therapy is paramount to identifying locally advanced rectal cancer (LARC) patients suitable for Watch and Wait (WW). A 3-tier schema was devised to stratify clinical response. Patients with a complete clinical response (cCR) are considered for WW, while those with an incomplete clinical response (iCR) are recommended for total mesorectal excision (TME). A near complete response (nCR) tier captures patients with significant, but not complete, response to be considered for WW. This schema’s efficacy has yet to be validated. We investigated survival and organ preservation (OP) rates based on this 3-tier clinical response assessment in patients with LARC who underwent total neoadjuvant therapy (TNT) in a prospective, multi-center clinical trial. Methods: Patients with MRI stage II and III rectal adenocarcinoma were randomized to either induction chemotherapy (FOLFOX or CAPEOX) followed by chemoradiation or chemoradiation followed by consolidation chemotherapy (FOLFOX or CAPEOX). At 8+/-4 weeks following TNT, response on digital rectal and endoscopic examinations was evaluated by the 3-tier schema. The date of this restaging clinical response assessment was used as time zero. The endpoints of rate of OP, disease-free survival (DFS), TME-free DFS, and overall survival (OS) were evaluated using the Kaplan-Meier method with differences analyzed by the log-rank test. Results: Clinical response assessments were available for 294 patients. The median time to assessment after neoadjuvant therapy was 7.9 weeks. Based on the 3-tier schema, 124 patients were categorized as cCR, 113 as nCR, and 57 as iCR. Baseline age, sex, average distance from the anal verge, clinical T classification, and clinical N classification were similar between the response groups. The table shows the 3-year rates of OP, DFS, TME-free DFS, and OS. The median follow-up was 2.36 years. Of the patients with a nCR, the 3-year TME rate was 48% compared with 21% in the cCR group. Conclusions: The 3-tier clinical response assessment has prognostic implications for OP and DFS in patients with LARC who underwent TNT. In patients with a nCR, more than half achieved OP at 3 years. This information should be utilized to counsel patients regarding their expected outcomes. Clinical trial information: NCT02008656. [Table: see text]

Utilizing total neoadjuvant therapy (TNT) in rectal cancer: NRG-GI002, a phase II clinical trial platform.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. TPS814-TPS814 ◽  
Author(s):  
Thomas J. George ◽  
Greg Yothers ◽  
Theodore S. Hong ◽  
Marcia McGory Russell ◽  
Y. Nancy You ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Rectal Cancer ◽  
High Risk ◽  
Neoadjuvant Therapy ◽  
Surgical Resection ◽  
Phase Ii ◽  
Locally Advanced ◽  
High Risk Patient ◽  
Randomized Phase Ii ◽  
Total Neoadjuvant Therapy

TPS814 Background: Improvements in outcomes for locally advanced rectal cancer (LARC) have plateaued due to an inability to consistently deliver adjuvant therapy and thus far ineffective novel therapies. Systematic testing of new chemotherapy and radiation sensitizers are needed to advance treatment outcomes. This randomized phase II modular clinical trial platform utilizes Total Neoadjuvant Therapy (TNT) with parallel experimental arms in LARC. The experimental arms are not intended for direct comparison, but to test a variety of sensitizers or hypotheses in a consistent and relatively homogenous high-risk patient (pt) population with correlative biomarkers. Success of any given experimental arm will be determined by achievement of pathologic endpoints compared to a control arm. Methods: This NCTN multi-arm randomized phase II trial serves as a modular platform to assess novel sensitizers to neoadjuvant chemotherapy and/or chemoradiotherapy (chemoRT) in LARC. Eligibility includes LARC as defined by any ONE of the following criteria: distal location (cT3-4 ≤5cm from the anal verge, any N); bulky (any cT4 or tumor within 3mm of the mesorectal fascia); high risk for metastatic disease (cN2); or not a candidate for sphincter-sparing surgical resection. After randomization, all pts receive neoadjuvant FOLFOX x 4mo → chemoRT (capecitabine with 50.4Gy) → surgical resection 8-12 wks later. Based on promising phase I results, the first experimental arm will assess the activity of veliparib added to standard chemoRT (capecitabine + RT). Primary endpoint is to demonstrate an improvement in Neoadjuvant Rectal Cancer (NAR) score for the experimental arm vs control representing a 20% relative risk reduction in DFS HR and 3-4% absolute OS improvement. Secondary endpoints include comparisons of OS, DFS, toxicity, pCR, cCR, therapy completion, negative surgical margins, sphincter preservation, sphincter function including quality of life, and exploratory assessments of molecular and radiographic predictors of response and distant failure. Target accrual is 79 evaluable pts per arm with additional arms added through rolling protocol amendments. Support: U10 CA-180868, -180822, UG-189867; AbbVie. Clinical trial information: NCT02921256.

NRG-GI002: A phase II clinical trial platform for sensitization testing using total neoadjuvant therapy (TNT) in rectal cancer.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. TPS876-TPS876 ◽  
Author(s):  
Thomas J. George ◽  
Greg Yothers ◽  
Theodore S. Hong ◽  
Marcia McGory Russell ◽  
Y. Nancy You ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Rectal Cancer ◽  
High Risk ◽  
Neoadjuvant Therapy ◽  
Surgical Resection ◽  
Phase Ii ◽  
Locally Advanced ◽  
High Risk Patient ◽  
Randomized Phase Ii ◽  
Total Neoadjuvant Therapy

TPS876 Background: Locally-advanced rectal cancer (LARC) improvements have plateaued due to an inability to consistently deliver adjuvant therapy and effective novel therapies. Systematic testing of new chemotherapy and radiation sensitizers are needed to advance treatment outcomes. This randomized phase II modular clinical trial platform utilizes Total Neoadjuvant Therapy (TNT) with parallel experimental arms (EA) in LARC. The EAs are not intended for direct comparison, but rather to test a variety of sensitizers or hypotheses in a consistent and homogenous high-risk patient (pt) population with correlative biomarkers. Success of any EA will be determined by achievement of pathologic endpoints compared to a control arm. Methods: This NCTN multi-arm randomized phase II trial serves as a modular platform to assess novel sensitizers to neoadjuvant chemotherapy and/or chemoradiotherapy (chemoRT) in LARC. Eligibility includes LARC with any ONE of the following criteria: distal location (cT3-4 ≤5cm from the anal verge, any N); bulky (any cT4 or tumor within 3mm of the mesorectal fascia); high risk for metastatic disease (cN2); or not a candidate for sphincter-sparing surgical resection. After randomization, all pts receive neoadjuvant FOLFOX x 4mo → chemoRT (capecitabine with 50.4Gy) → surgical resection 8-12 wks later. The first EA will assess the activity of veliparib with standard chemoRT. A second EA, testing pembrolizumab concurrently with and following chemoRT, is in development. Primary endpoint is a demonstrated improvement in Neoadjuvant Rectal Cancer (NAR) score for the EA vs control representing a 20% relative risk reduction in DFS HR and 3-4% absolute OS improvement. Secondary endpoints include comparisons of OS, DFS, toxicity, pCR, cCR, therapy completion, negative surgical margins, sphincter preservation, sphincter function including quality of life, and exploratory assessments of molecular and radiographic predictors of response and distant failure. Target accrual is 79 evaluable pts per arm with additional EAs added through protocol amendments. NCT02921256. Support: U10 CA-180868, -180822, UG-189867, U24CA196067; AbbVie Clinical trial information: NCT02921256..

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