scholarly journals 411 INNATE: immunotherapy during neoadjuvant therapy for rectal cancer to elucidate local and systemic therapeutic responses

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A442-A442
Author(s):  
Nina Sanford ◽  
Eslam Elghonaimy ◽  
Adel Kardosh ◽  
Syed Kazmi ◽  
Javier Salgado Pogacnik ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Rectal Cancer ◽  
Neoadjuvant Therapy ◽  
Phase Ii ◽  
Pathologic Complete Response ◽  
Phase Ii Trials ◽  
Correlative Analysis ◽  
Link Type ◽  
Short Course ◽  
Folfox Chemotherapy

BackgroundThe relative risk of developing rectal cancer has quadrupled in young adults over the last 40 years and approximately 50% of patients develop recurrence within 3 years. Thus, there is a critical need for new approaches to improve survival but cancer Immunotherapy has had little impact on colorectal cancer. The anti-CD40 agonist immunotherapy is emerging and APX005M has shown promise in phase I and ongoing phase II trials. Anti-CD40 can stimulate both innate and adaptive immune responses and a greater response can be achieved combining anti-CD40 with radiation therapy (RT) in animal models. We developed the INNATE trial, a phase II randomized trial of neoadjuvant short course RT followed by chemotherapy with or without the addition of APX005M for rectal cancer (NCT04130854).MethodsThe INNATE trial is a multi-center, 58 patient, 3:2 randomization clinical trial, that adds APX005M to short course RT (SCRT) and subsequent FOLFOX chemotherapy prior to definitive radiation. Eligibility includes stage III and high risk stage II rectal cancer and candidates for standard neoadjuvant therapy and no contraindications for immunotherapy or radiation. Patients receive 5Gy x 5 fractions over five days and if randomized to experimental arm will receive APX005M on day 3 of radiation. After a two week break patients receive an optional endoscopy and biopsy followed by standard FOLFOX chemotherapy with APX005M infusion after disconnection of 5-FU chemotherapy pump. Study arm receives APX005M with 5 of 6 cycles of FOLFOX. After treatment patients undergo restating, endoscopy, and trans abdominal resection. The primary endpoint is pathologic complete response with the null estimated to be 20% and alternative 50% for a power of 0.8 and type 1 error of 0.1. Secondary endpoints include overall survival, toxicity analysis, and disease free survival. For correlative analysis, tissue is collected pre-treatment, two weeks after RT, and at surgery, then blood collected during treatment and at follow up.ResultsTo date 16 patients have been randomized and initiated treatment. The treatment is well tolerated. Fiveteen patients received pre- and post-SCRT biopsies. The study team plans correlative analysis including single cell RNA sequencing, multiplex imunohistochemistry, and bulk sequencing. Preliminary data shows changes in the immune tumor microenvironment from patients treated as their own control and between SCRT versus SCRT + APX00M.ConclusionsThe INNATE trial shows feasibility of incorporating novel immunotherapies with an emerging standard of care incorporating short course RT. It serves as an important platform for scientific and clinical investigation.Trial RegistrationClinicaltrialsgov: NCT04130854Ethics ApprovalThe clinical trial has institutional review board approval at the University of Texas Southwestern, Oregon Health and Sciences University, Wake Forest, and Moffitt. All patients have provided informed consent.

Voltage: Investigator-initiated clinical trial of nivolumab monotherapy and subsequent radical surgery following preoperative chemoradiotherapy in patients with microsatellite stable locally advanced rectal cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3606-3606 ◽  
Author(s):  
Takayuki Yoshino ◽  
Hideaki Bando ◽  
Yuichiro Tsukada ◽  
Koji Inamori ◽  
Satoshi Yuki ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Rectal Cancer ◽  
Phase I ◽  
Phase Ii ◽  
Tumor Regression ◽  
Locally Advanced ◽  
Pathologic Complete Response ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Fisher Exact Test

3606 Background: Chemoradiotherapy (CRT) with surgery (S) is standard for patients (pts) with locally-advanced rectal cancer (LARC), and nivolumab (nivo) is active in microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). We studied nivo and radical S following CRT (50.4 Gy with capecitabine 1,650 mg/m2) in T3–4 NanyM0 LARC. Methods: Phase I included testing of a recommended phase II dosing schedule (RP2S). Efficacy and safety were studied in phase II pts and those given RP2S in phase I. In Cohort A-1, for microsatellite stable (MSS) LARC pts, the primary endpoint was centrally confirmed pathologic complete response (pCR) rate using AJCC tumor regression grading. The estimated required sample size assuming null and alternative hypotheses pCR = 10% and 30% was 37 pts, with a 1-sided alpha of 5% and power of 90%. Cohort A-2 was exploratory and included a maximum of 5 MSI-H pts. Results: Nivo 240 mg q2 weeks x 5 cycles, following CRT but pre-S, was the RP2S. From 1/17 to 6/18, 37 pts were enrolled in Cohort A-1. Eleven pts (30%; 90% CI 18-44%) showed pCR (AJCC grade (gr) 0). Including the 3 pts (8%) graded AJCC 1, 14 (38%) had major pathologic responses. In addition, clinical CR was observed in 1 pt (3%) refusing S after nivo. Both MSI-H LARC Cohort A-2 pts showed pCRs. Immune-related severe adverse events were observed in 2 pts (gr 3 myasthenia and gr 2 interstitial nephritis); both fully recovered and had S. No treatment-related deaths were observed. pCR rates of 60% (6/10) and 19% (5/27) (p = 0.038, Fisher exact test) were seen in pts with tumor cells with PD-L1 ≥1% and < 1% IHC staining, respectively, performed on biopsy samples taken pre-CRT. Rates of 62% (8/13) and 10% (1/10) (p = 0.029) were seen in 23 pts with samples analyzable by flow cytometry, according to CD8+ lymphocyte /regulatory T cell (CD8/Treg) ratios ≥2 and < 2, respectively. Conclusions: A promising pCR rate of 30%, with mild toxicity, was shown in MSS LARC pts treated with nivo plus radical S. PD-L1 expression and elevated CD8/Treg ratio may be better predictors of nivo benefit, warranting further study in a larger cohort. Clinical trial information: NCT02948348.

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.

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 platform utilizing total neoadjuvant therapy (TNT) in rectal cancer: Nrg-GI002.

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. TPS3638-TPS3638 ◽  
Author(s):  
Thomas J. George ◽  
Greg Yothers ◽  
Theodore S. Hong ◽  
Marcia McGory Russell ◽  
Patricia A. Ganz ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Rectal Cancer ◽  
Neoadjuvant Therapy ◽  
Phase Ii ◽  
Phase Ii Clinical Trial ◽  
Total Neoadjuvant Therapy

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.

Cetuximab, capecitabine, and oxaliplatin (Cet-CapOx) with concurrent radiotherapy (RT) in advanced rectal cancer (RC): Results of a phase I/II trial

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4042-4042 ◽  
Author(s):  
D. Arnold ◽  
M. Hipp ◽  
T. Liersch ◽  
K. Dellas ◽  
O. Koelbl ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Phase I ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Standard Dose ◽  
Perioperative Complications ◽  
Pathologic Complete Response ◽  
Complete Response ◽  
Advanced Rectal Cancer ◽  
Phase Ii Trials

4042 Background: CapOx given concurrently with neoadjuvant RT in rectal cancer is well tolerated and has achieved high rates of pathologic complete response (pCR) in phase II trials. Cetuximab is active in metastatic colorectal cancer. Synergy of cetuximab with RT resulted in improved survival (vs. RT alone) in head and neck cancer. This trial was to evaluate feasibility and efficacy of Cet-CapOx in RT of rectal cancer, with maximal tolerated dose as primary endpoint in phase I, and pCR as primary endpoint in phase II. Method: Patients (pts) had to have untreated, T3–4 and/or N+ disease per MRI or CT plus endoscopic ultrasound, M1 allowed, normal organ function. During conventionally fractionated RT (1.8 Gy for 28 days [d]), cetuximab was given in standard dose (400 mg/m2 on d - 7, then 6 weekly doses of 250 mg/m2, to d35). CapOx was administered as in the phase II trial of our group (Rödel et al, J Clin Oncol 2007), with oxaliplatin (50 mg/m2 d 1,8,22 and 29) plus capecitabine (d1–14 and d22–35) at 3 dose levels: 1,000, 1,300 and 1,650 mg/m2/day. Results: 60 pts were enrolled: Median age 62 [35–83] yrs., male 61%, T3/T4 83/17%, N+ 85%, M1 20%. 7/ 3/ 50 pts. were treated on levels 1/ 2/ 3: as only 1 pt. experienced DLT (diarrhea 4°) on level 1 and none on level 2, level 3 was chosen for phase II (n=50 pts.). Most common toxicity was CTC grade 3 diarrhea in 14% of pts. Full dose of all drugs and of RT was administered in >90% of cycles. No grade 4 toxicity occurred. 53/60 pts underwent resection after completed chemoradiation without increase of perioperative complications when compared to historic controls of CapOx-RT alone. Radiologic downstaging (17 pts. evaluated so far) was seen in 35% for T category and in 67% for N category. Pathologic complete response (45 pts. evaluable) was observed in 9% of pts, another 38% had “good regression” (>50% of tumor cells). Conclusion: CapOx can safely be combined with cetuximab without requiring dose reduction of chemo- or radiotherapy and leads to significant downstaging. However, the relatively low rate of pathologic responses underachieved the assumptions. [Table: see text]

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..

scholarly journals Study Protocol of A Phase II Study to Evaluate Safety and Efficacy of Neo-adjuvant Pembrolizumab and Radiotherapy in Localized Rectal Cancer

2021 ◽  
Author(s):  
Claudia Corro ◽  
Nicolas C. Buchs ◽  
Matthieu Tihy ◽  
Andre Durham-Faivre ◽  
Philippe Bichard ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Rectal Cancer ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Phase Ii ◽  
Research Program ◽  
Safety And Efficacy ◽  
T Cell Infiltration ◽  
Short Course ◽  
Short Course Radiotherapy

Background: Reshaping the tumor microenvironment by novel immunotherapies represents a key strategy to improve the treatment of cancers. Nevertheless, responsiveness to these treatments is often correlated with the extent of the T cell infiltration at the tumor site. Remarkably, microsatellite stable rectal cancer is characterized by poor infiltration and, therefore, do not respond to immune checkpoint blockade. To date, the only available curative option for these patients relies on extensive surgery. With the aim to broaden the application of promising immunotherapies, it is necessary to develop alternative approaches to promote T cell infiltration into the tumor microenvironment of these tumors. In this regard, recent evidence shows that radiotherapy may have profound immunostimulatory effects, hinting at the possibility of combining it with immunotherapy. The combination of long-course chemoradiotherapy and immunotherapy was recently shown to be safe and yielded promising results in rectal cancer, however short-course radiotherapy and immunotherapy have never been tested in these tumors. Methods: Our clinical trial investigates the clinical and biological impact of combining pembrolizumab with short-course radiotherapy in the neo-adjuvant treatment of localized microsatellite stable rectal cancer. This phase II non-randomized study will recruit 25 patients who will receive short-course preoperative radiotherapy (5Gy x 5 days) and four injections of pembrolizumab starting on the same day and on weeks 4, 7 and 10. Radical surgery will be performed after three weeks from the last pembrolizumab injection. Our clinical trial also includes an extensive research program involving the transcriptomic and proteomic analysis of blood and tumor samples throughout the course of the treatment. Discussion: Our study is the first clinical trial to provide with safety and efficacy information of this novel treatment approach in rectal cancer, leading to a major breakthrough in the treatment of this cancer. Additionally, the translational research program will offer better insight into immunological changes within the tumor and blood during treatment. Taken together, our work will help optimizing future treatment combinations and, possibly, better selecting patients.

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