scholarly journals Thymidylate Synthase Genotype-Directed Neoadjuvant Chemoradiation for Patients With Rectal Adenocarcinoma

2011 ◽  
Vol 29 (7) ◽  
pp. 875-883 ◽  
Author(s):  
Benjamin R. Tan ◽  
Fabienne Thomas ◽  
Robert J. Myerson ◽  
Barbara Zehnbauer ◽  
Kathryn Trinkaus ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Thymidylate Synthase ◽  
Randomized Study ◽  
Locally Advanced ◽  
Rectal Adenocarcinoma ◽  
Risk Groups ◽  
Advanced Rectal Cancer ◽  
Recurrence Rates ◽  
Poor Risk ◽  
Good Risk

Purpose Downstaging (DS) of rectal cancers is achieved in approximately 45% of patients with neoadjuvant fluorouracil (FU) -based chemoradiotherapy (CRT). Polymorphisms in the thymidylate synthase gene (TYMS) had previously defined two risk groups associated with disparate tumor DS rates (60% v 22%). We conducted a prospective single-institution phase II study using TYMS genotyping to direct neoadjuvant CRT for patients with rectal cancer. Patients and Methods Patients with T3/T4, N0-2, M0-1 rectal adenocarcinoma were evaluated for germline TYMS genotyping. Patients with TYMS *2/*2, *2/*3, or *2/*4 (good risk) were treated with standard chemoradiotherapy using infusional FU at 225 mg/m2/d. Patients with TYMS *3/*3 or *3/*4 (poor risk) were treated with FU/RT plus weekly intravenous irinotecan at 50 mg/m2. The primary end point was pathologic DS. Secondary end points included complete tumor response (ypT0), toxicity, recurrence rates, and overall survival. Results Overall, 135 patients were enrolled, of whom 27.4% (37 of 135) were considered poor risk. The prespecified statistical goals were achieved, with DS and ypT0 rates reaching 64.4% and 20% for good-risk and 64.5% and 42% for poor-risk patients, respectively. Conclusion To our knowledge, this is the first study to prospectively use TYMS genotyping to direct neoadjuvant CRT in patients with rectal cancer. High rates of DS and ypT0 were achieved among both risk groups when personalized treatment was based on TYMS genotype. These results are encouraging, and further evaluation of this genotype-based strategy using a randomized study design for locally advanced rectal cancer is warranted.

TYMS genotype-directed neoadjuvant chemoradiation for rectal cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4028-4028
Author(s):  
H. L. McLeod ◽  
R. J. Myerson ◽  
B. Zehnbauer ◽  
K. Trinkaus ◽  
R. S. Malyapa ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Randomized Study ◽  
Locally Advanced ◽  
Pathologic Complete Response ◽  
Rectal Adenocarcinoma ◽  
Transrectal Ultrasound ◽  
Risk Groups ◽  
Recurrence Rates ◽  
Risk Patients ◽  
Good Risk

4028 Background: Downstaging (DS) of rectal cancers is achieved in 45% of pts with neoadjuvant 5FU and radiation (XRT). A 28bp repeats in the thymidine synthase gene (TYMS) appears to define disparate DS rates (60% vs 22%). We conducted a prospective single-institution Phase II study using TYMS genotyping to direct neoadjuvant chemoRT for pts with rectal cancer. Methods: Pts with T3/ T4, N0–2, M0–1 rectal adenocarcinoma staged with transrectal ultrasound (TRUS) or CT/MRI are eligible. After informed consent is obtained, pts with TYMS *2/*2, *2/*3, or *2/*4 (Good-risk) are treated with 50.4 Gy 3-D XRT and 5FU continuous infusion at 225 mg/m2/d throughout XRT. Patients with TYMS *3/*3 or *3/*4 (Bad-risk) are treated with 5FU and XRT plus irinotecan at 50 mg/m2 IV weekly x 5. Pts underwent restaging and resection 6–10 weeks after therapy. The 1o endpoints are DS and pathologic complete response (pCR) rates. 2o endpoints include toxicity, recurrence rates and OS. Adjuvant therapy was directed by the pt's physician. The study was powered to ascertain whether DS was significantly >45% in ‘good risk‘ patients and >22% in ‘bad risk‘ patients. Results: Overall, 135 pts (median age 56, range 26–85; M:F 2:1; black-18, white-119) are enrolled, of which 27.4% (37/135) are ‘bad risk‘. DS, pCR and toxicity rates were evaluable in 121 patients and are shown below. The rate of DS met the a priori criteria for significance for both the ‘good risk‘ and ‘bad risk‘ groups. 1 death/1 perforation was observed in each group. Conclusions: This is the first study to prospectively use TYMS genotyping to direct neoadjuvant chemoXRT in pts with rectal cancer. The high efficacy of 5FU/XRT in ‘good risk‘ pts was prospectively confirmed. High rates of DS and pCR were also achieved among ‘bad risk‘ pts with the addition of irinotecan to neoadjuvant 5FU/XRT. These results are encouraging for the conduct of a randomized study of genotype-guided neoadjuvant therapy for locally advanced rectal cancer. [Table: see text] [Table: see text]

scholarly journals Outcome of Adjuvant Concurrent Chemo-Radiation in Operated Locally Advanced Rectal Cancer

2015 ◽  
Vol 5 (3) ◽  
pp. 139-144
Author(s):  
Syed Arshad Mustafa ◽  
M Ismail ◽  
Saquib Zaffar ◽  
Ghulam Hassan ◽  
Waseem Qureshi ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Cancer Patients ◽  
Randomized Study ◽  
Locally Advanced ◽  
Advanced Rectal Cancer ◽  
Treatment Interruption ◽  
Locally Advanced Rectal Cancer ◽  
Adjuvant Radiation ◽  
Recurrence Rates ◽  
High Death

Background: Rectal cancer is one of the most common cancers in Kashmir, India. The clinical course of patients treated with surgery alone has been characterized by a high death rate and also by the pain and disability associated with pelvic recurrence of the tumor. Adjuvant radiation combined with chemotherapy has been studied for prevention of such recurrences. We treat more than 200 rectal cancer patients annually at our center. Most of the patients registered at our center are those who have been already subjected to surgery at the peripheral hospitals. We studied role of 5-fluorouracil (5-FU) and calcium leucovorin concurrently with radiotherapy in Dukes’ stage B2 and C and toxicities thereof in the adjuvant setting.Objective: To assess the outcome of concurrent chemoradiation in operated locally advanced treated cancer patients.Materials and Methods: In operated Dukes’ B2 and C rectal cancer patients, we conducted a prospective non-randomized study comprising of 40 patients between 2012 and 2014. Patients were treated with two hours protracted infusion of calcium leucovorin 500 mg/m2 on day 1 followed by 5-fluorouracil 500 mg/m2 on days 1 to 5 and repeated four weekly for total of six cycles. Radiotherapy of 45 Gray in 20 fractions was delivered concurrently with chemotherapy for first two cycles.Results: Combination of chemotherapy and radiotherapy in a concurrent setting appears to be more efficient in reducing local recurrence rates and improving survival than either modality alone. Toxicities with this schedule were mostly gastrointestinal mucositis, but no treatment interruption was needed.Conclusion: A combination of 5-fluorouracil and radiotherapy can be administered in operated locally advanced rectal cancer patients.J Enam Med Col 2015; 5(3): 139-144

A multicenter phase Ib/II study of DNA-PK inhibitor peposertib (M3814) in combination with capecitabine and radiotherapy in patients with locally advanced rectal cancer.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. TPS144-TPS144
Author(s):  
Paul Bernard Romesser ◽  
Emma B. Holliday ◽  
Tony Philip ◽  
Rocio Garcia-Carbonero ◽  
Jaume Capdevila ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Colon Cancer ◽  
Phase Ii ◽  
Locally Advanced ◽  
Neoadjuvant Treatment ◽  
Rectal Adenocarcinoma ◽  
Complete Response ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Phase Ib

TPS144 Background: Perioperative radiotherapy and chemotherapy, followed by total mesorectal excision, is the standard of care for patients with locally advanced rectal cancer (LARC). However, 1/3 of these patients still develop distant metastases, indicating the need for more effective therapies. In addition, strategies that increase pathological complete response rates are needed to enable non-surgical management of LARC. DNA-dependent protein kinase (DNA-PK) regulates a key DNA damage repair pathway for double-strand break repair. Peposertib (M3814), a potent, selective, orally administered DNA-PK inhibitor, has been shown to potentiate the effect of ionizing radiation in a human colon cancer xenograft model and several colon cancer cell lines. Peposertib is being investigated in several different trials across multiple indications. This Phase Ib/II study (NCT03770689) aims to evaluate the safety, tolerability, pharmacokinetics (PK), and efficacy of the neoadjuvant treatment combination of peposertib, capecitabine, and radiotherapy (RT) in patients with LARC. Methods: Patients aged ≥18 years with histologically confirmed and resectable Stage II/III rectal adenocarcinoma are eligible. Induction chemotherapy is permitted, but residual disease must first be documented by MRI, digital rectal examination and endoscopy. Patients who received other anticancer therapies or those with prior pelvic RT are excluded. At open-label Phase Ib (open), 18–30 patients (n = 3 per cohort) will receive peposertib + capecitabine (orally, 825 mg/m2 twice daily [BID]) + RT (45–50.4 Gy), 5 days/week. Peposertib 50 mg once daily (QD) was the starting dose. Additional dose levels will range between 100─800 mg QD. Dose escalation is determined by the safety monitoring committee and guided by a Bayesian 2-parameter logistic regression model. At Phase II (planned), 150 patients will be randomized (1:1) to receive oral capecitabine (825 mg/m2 BID) + RT (45–50 Gy), with either oral peposertib (recommended phase II dose [RP2D] or placebo, QD for 5 days/week. Primary objectives are to define a maximum tolerated dose and RP2D (Phase Ib), and to evaluate the efficacy of peposertib + capecitabine + RT in terms of pathological/clinical complete response (Phase II). Secondary objectives include assessment of antitumor activity (Phase Ib), quality of life outcomes (Phase II), and PK of peposertib, and the safety and tolerability of the combination therapy (both phases). To date, one patient has received peposertib 50 mg QD, six patients peposertib 100 mg QD, three patients peposertib 150 mg QD, and three patients peposertib 250 mg QD. Clinical trial information: NCT03770689.

Rectal cancer and systemic therapy of colorectal cancer

2016 ◽  
pp. 408-443
Author(s):  
Regina Beets-Tan ◽  
Bengt Glimelius ◽  
Lars Påhlman
Keyword(s):  
Rectal Cancer ◽  
Locally Advanced ◽  
Treatment Decision ◽  
Well Being ◽  
Risk Groups ◽  
Preoperative Chemoradiotherapy ◽  
Recurrence Rates ◽  
Short Course ◽  
Rectal Cancer Treatment ◽  
Long Course

In rectal cancer treatment, surgery is most important. Dissection outside the mesorectal fascia, total mesorectal excision is required for cure in most cases; a local procedure is possible in the earliest tumours. Appropriate staging is required prior to treatment decision to stratify patients into risk groups. In early tumours surgery alone is sufficient whereas in intermediate cancers local recurrence rates are too high and preoperative radiotherapy is indicated. A short-course schedule is convenient, low toxic, although some prefer long-course chemoradiotherapy. The addition of a fluoropyrimidine enhances the radiotherapy. In locally advanced tumours preoperative chemoradiotherapy is required. The value of adjuvant chemotherapy in rectal cancer is controversial, particularly if preoperative chemoradiotherapy was used. Palliative chemotherapy prolongs life and improves well-being in patients with metastatic disease. Targeted drugs further improves the results to some extent. In some patients, chemotherapy may convert non-readily resectable metastases to resectable, and result in long-term cure.

Postremission Therapy in Adult Acute Myeloid Leukemia (AML): A Randomized Comparison of Intensified Consolidation Therapy without Maintenance Therapy Against Conventional Consolidation with Maintenance Therapy -JALSG AML-97 Trial-.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 868-868 ◽  
Author(s):  
Shuichi Miyawaki ◽  
Hisashi Sakamaki ◽  
Shigeki Ohtake ◽  
Fumiharu Yagasaki ◽  
Kinuko Mitani ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Induction Therapy ◽  
Risk Group ◽  
Randomized Study ◽  
Risk Groups ◽  
Consolidation Therapy ◽  
Poor Risk ◽  
Short Course ◽  
To Receive ◽  
Good Risk

Abstract Between 1997 and 2001, JALSG conducted a randomized study to assess the optimal post remission therapy for adult AML in the first CR. The JALSG AML97 enrolled 809 previously untreated AML patients (pts) aged 15–64 yrs. Induction therapy consisted of cytarabine (100mg/m2 day1–7) and idarubicin (IDR 12mg/m2 day1– 3). If the patients did not achieve remission after the first induction therapy, the same therapy was given once more. Pts were categorized into good, intermediate or poor risk groups by risk factors based on the previous JALSG AML studies. All CR pts were randomized to receive either the intensified short course post remission regimen (arm A) or the conventional JALSG’s post remission regimen for AML including maintenance therapy (arm B). Arm A: 1) AraC 200mg/m2 day1–5+ Mitoxantrone (MTZ) 7mg/m2 day1–3, 2) AraC 200mg/m2 day1–5+Daunorubicin (DNR) 50mg/m2 day1–3, 3) AraC 200mg/ m2 day1–5+ Aclacinomycin (ACR) 20mg/m2 day1–5, 4) AraC 200mg/m2 day1–5+ Etoposide (ETP) 100mg/m2 day1–5 + Vincristine (VCR) 0.8mg/m2 day 8 + Vindesine (VDS) 2 mg/m2 day10. Arm B: 1) AraC 200mg/m2 day1–5 + MTZ 7mg/m2 day1–3, 2) Behenoyl AraC (BHAC) 200mg/m2 day1–7 + ETP 100mg/m2 day1–5 + DNR 50mg/m2 day1–3 + 6 mercptopurine (6MP) day1–7, 3) BHAC 200mg/m2 day1–7 + ACR 14mg/m2 day1–7, and then 6 courses maintenance therapy: 1) BHAC 170mg/m2 day1–5 + DNR 50mg/m2 day1,4+6MP day1–7, 2) BHAC 170mg/m2 day1–5 + MTZ 5mg/m2 day1–3, 3) BHAC 170mg/m2day1–5 + ETP 80mg/m2 day1,5,7 + VDS 2mg/m2 day1,8, 4) BHAC 170mg/m2 day1–5 + ACR 14mg/m2 day1–4 + 6MP day1–7, 5) BHAC 170mg/m2 day1–5 + DNR 50mg/m2 day1–4 + 6MP day1–7, 6) BHAC 170mg/m2 day1–5 + ETP 80mg/m2 day1,5,7 + VDS 2mg/m2 day1,8. Result: Of the 809 pts registered, 789 pts (median age: 45 years) were evaluable. 621 pts (78.7%) achieved CR after one or two courses of induction therapy. The 5-year OS rate of arm A was 45.6% and of arm B 53.2% (p=0.3259). The 5-year DFS rate of CR patients was 34.8% in arm A and 28.9% in arm B (p=0.4978). Among the good risk group, the 5-year OS rate of arm A was 62.1% and of arm B 70.2% (p=0.5068), and the 5-year DFS rate of arm A was 53.4% and of arm B 42.0% (p=0.3719). Among the intermediate risk group, the 5-year OS rate of arm A was 35.6% and of arm B 45.5% (p=0.4776), and the 5-year DFS rate of arm A was 26.0% and of arm B 26.1% (p=0.9653). Among the poor risk group, the 5-year OS rate of arm A was 29.7% and of arm B was 33.4% (p=0.6523), and the 5-year DFS rate of arm A was 20.4% and of arm B was 13.5% (p=0.6339). In conclusion: JALSG’s conventional post remission therapy consisting of 3 courses of consolidation and 6 courses of maintenance therapy could be replaced by a shorter duration of intensified consolidation therapy.

Polymorphisms of thymidylate synthase as prognostic factor in rectal cancer.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 433-433
Author(s):  
V. Arrazubi ◽  
J. Suarez ◽  
D. Guerrero ◽  
K. Cambra ◽  
M. L. Gomez Dorronsoro ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Thymidylate Synthase ◽  
Locally Advanced ◽  
Neoadjuvant Chemoradiotherapy ◽  
Disease Free Survival ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Tumour Regression ◽  
The Difference

433 Background: Neoadjuvant fluoropyrimidine-based chemotherapy (ChT) plus radiotherapy (Rt) is a standard approach for locally advanced rectal cancer. Polymorphisms of thymidylate synthase (TS), the target for fluoropyrimidines, are recognized prognostic factors in colon cancer. The aim of this study was to evaluate the prognostic value of the polymorphisms of TS in rectal cancer after neoadjuvant ChT plus Rt. Methods: We studied one-hundred consecutive patients with stage II/III rectal cancer between November 2001 and March 2009. Patients underwent surgery 6-8 weeks after neoadjuvant Rt (5,040 cGy) plus fluoropyrimidine-based ChT. DNA was extracted from paraffin embedded biopsies. TS1494del6 and 5′-28bp repeat +G/C SNP polymorphisms were determined. Results: Sixty-seven percent were men and median age was 67 years. ypT stage was: T0 9%, T1 2%, T2 27%, T3 60% and T4 2%; 32% had locoregional adenopathies. The median follow-up was 45 months and relapse occurred in 20% of patients. Polimorphisms could be determined in 98% of pt: -6bp/-6bp 10%, - 6bp/+6bp 39%, +6bp/+6bp 51% and 2R/2R 72%, 2R/3R 21%, 3R/3R 6%. The grade of pathological tumour regression was not associated with polymorphisms. Relapses occurred in 40% of patients -6bp/-6bp, 22% of patients -6bp/+6bp and 21% of patients +6bp/+6bp. The difference in disease- free survival (DFS) between the first and the third groups was stadistically significative (p=0.049). No relation between 5′-28bp repeat +G/C SNP polymorphism and DFS was found. Conclusions: Our data suggest that the TS1494del6 polimorphism may be an important prognosis factor in rectal cancer receiving neoadjuvant chemoradiotherapy. No significant financial relationships to disclose.

Association of perineural invasion with outcomes after neodjuvant chemoradiation for locally advanced rectal adenocarcinoma.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 750-750
Author(s):  
Priyanka Vinod Chablani ◽  
Phuong Nguyen ◽  
Charles Andrew Robinson ◽  
Xueliang Jeff Pan ◽  
Steve Andrew Walston ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Perineural Invasion ◽  
Locally Advanced ◽  
Prognostic Significance ◽  
Rectal Adenocarcinoma ◽  
Residual Tumor ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Resected Specimen ◽  
Free Survival

750 Background: Perineural invasion (PNI) as a prognostic indicator has not been well studied in patients with rectal adenocarcinoma treated with neoadjuvant chemoradiation (nCRT). In this study, we investigated the incidence and prognostic significance of PNI in patients with stages II-III locally advanced rectal cancer treated with nCRT. Methods: We performed a retrospective study of 110 consecutive patients treated with nCRT for locally advanced rectal adenocarcinoma at a single institution from 2004 to 2011. 88 of these patients had residual tumor in the resected specimen after nCRT. We evaluated the association of PNI with clinical outcomes, including disease-free survival (DFS), distant-metastasis-free survival (DMFS), and overall survival (OS), using log-rank and Cox proportional hazard modeling. Results: Of the 88 patients with residual tumor at surgery, 14 patients (16%) had PNI and 74 patients (84%) did not. Baseline distribution of selected variables in the PNI+ and PNI- groups are shown in Table 1. Median follow-up was 27 months (range 0.9 to 84 months). The median DFS was 13.5 months for PNI+ patients and 39.8 months for PNI- patients (p<0.0001). The median DMFS was 13.5 months for PNI+ patients and median not reached (> 40 months) for PNI- patients (p<0.0001). We did not detect a significant association between the presence of PNI and worse OS, perhaps due to a high rate of censored patients in the OS analysis. In a multivariate model including pT stage, pN stage, tumor location, tumor size, type of surgery, and radial margin status, PNI remained a significant predictor of DFS (HR 16.8, 95% CI, 3.7–75.5, p<0.0002) and DMFS (HR 18.9, 95% CI, 4.4–81.9, p<0.0001). Conclusions: For patients with locally advanced rectal cancer treated with nCRT prior to surgical resection, PNI found at the time of surgery is significantly associated with worse DFS and DMFS. [Table: see text]

Short-course radiation followed by mFOLFOX-6 plus avelumab for locally advanced rectal adenocarcinoma.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 139-139
Author(s):  
Ali Shamseddine ◽  
Youssef Zeidan ◽  
Ibrahim Moustafa Khalifeh ◽  
Joseph Gergi Kattan ◽  
Rim Turfa ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Interim Analysis ◽  
Response Rate ◽  
Locally Advanced ◽  
Rectal Adenocarcinoma ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Pathologic Response ◽  
Short Course ◽  
Pathologic Response Rate

139 Background: Total neoadjuvant treatment (TNT) for locally advanced rectal cancer is becoming an accepted approach over the last few years with increasing pathologic complete response (pCR) and compliance of patients for chemotherapy in comparison with the current standard of care i.e., fluoropyrimidine based chemoradiation followed by surgery and adjuvant chemotherapy. Sequential use checkpoint inhibitors after radiation therapy (RT) has demonstrated synergistic effect in vivo leading to decrease in size of irradiated and non-irradiated secondary tumors outside the radiation field (abscopal effect). Methods: This is an investigator initiated; open-label, single-arm multicenter phase II study, adopting Simon’s two-stage aiming at evaluating the pCR rate and safety of using short-course radiation therapy (25 Grays in 5 fractions), followed by 6 cycles of mFOLFOX-6 plus Avelumab (anti PDL1), then total mesorectal excision(TME) in patients with locally-advanced, potentially resectable rectal adenocarcinoma. Results: 13 out of 44 patients were accrued from 20, July till 28, Dec 2018 in the first stage of the study (30% from total sample size). They all met the inclusion criteria and received full protocol treatment. 12 out of the 13 completed TME. 1 of the 13 had progression of disease, so surgery was aborted and patient was dropped out the study. The sample consisted of 9 (69%) males and 4 (31%) females with median age of 62 (33.0, 73.0) years. The first interim analysis revealed 3 patients (25%) achieved pCR (tumor regression grade: TRG = 0) out of 12 as compared to the historical control group with pCR of 16%. For the rest of the patients, 3 (25%) had major pathologic response rate (pRR) with TRG = 1 (< 10% viable cells is tumor bed).In total, 6 out of 12 patients (50%) had major pathologic response rate. As for safety, no serious adverse events of grade 3 and 4 were reported. Conclusions: Based on the first interim analysis results, incorporation of Avelumab and short course radiotherapy is tolerable in patients with locally advanced rectal cancer treated with TNT. The study will resume recruitment to reach the target accrual. Clinical trial information: NCT03503630.

A multicenter phase Ib/II study of DNA-PK inhibitor peposertib (M3814) in combination with capecitabine and radiotherapy in patients with locally advanced rectal cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS4117-TPS4117
Author(s):  
Paul Bernard Romesser ◽  
Emma B. Holliday ◽  
Tony Philip ◽  
Barbara Sarholz ◽  
Mirjam Kuipers ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Colon Cancer ◽  
Phase Ii ◽  
Locally Advanced ◽  
Neoadjuvant Treatment ◽  
Rectal Adenocarcinoma ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Phase Ib ◽  
To Receive

TPS4117 Background: Preoperative chemo-radiotherapy with or without sequential chemotherapy, followed by surgical intervention, is standard of care for patients with locally advanced rectal cancer (LARC). However, 1/3 of these patients still develop distant metastases, indicating the need for more effective therapies. DNA-dependent protein kinase (DNA-PK) regulates a key DNA damage repair pathway for double-strand break repair. Peposertib (M3814), a potent, selective, orally administered DNA-PK inhibitor, has been shown to potentiate the effect of ionizing radiation in a human colon cancer xenograft model and several colon cancer cell lines. Peposertib is being investigated in several different trials across multiple indications. This Phase Ib/II study (NCT03770689) aims to evaluate the safety, tolerability, pharmacokinetics (PK), and efficacy of the neoadjuvant treatment combination of peposertib, capecitabine, and radiotherapy (RT) in patients with LARC. Methods: Patients aged ≥18 years with histologically confirmed and resectable Stage II/III rectal adenocarcinoma are eligible. Induction chemotherapy is permitted, but residual disease must first be documented by MRI, digital rectal examination and endoscopy. Patients who received other anticancer therapies or those with prior pelvic RT are excluded. During open-label Phase Ib (open), 18–30 patients (n = 3 per cohort) are due to receive peposertib + capecitabine (orally, 825 mg/m2 twice daily [BID]) + RT (45–50 Gy), 5 days/week. Peposertib 50 mg once daily (QD) is the starting dose. Additional dose levels will be between 100─800 mg QD. Dose escalation is determined by the safety monitoring committee and guided by a Bayesian 2-parameter logistic regression model. At Phase II (planned), 150 patients will be randomized (1:1) to receive oral capecitabine (825 mg/m2 BID) + RT (45–50 Gy), with either oral peposertib (recommended phase II dose [RP2D]) or placebo, QD for 5 days/week. Primary objectives are to define a maximum tolerated dose and RP2D (Phase Ib), and to evaluate the efficacy of peposertib + capecitabine + RT in terms of pathological/clinical complete response (Phase II). Secondary objectives include assessment of antitumor activity (Phase Ib), quality of life outcomes (Phase II), and PK of peposertib, and the safety and tolerability of the combination therapy (both phases). One patient has received peposertib 50 mg QD and six patients have received peposertib 100 mg QD. Patients are currently receiving peposertib 150 mg QD. Clinical trial information: NCT03770689 .

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