Phase I trial of neoadjuvant concurrent chemoradiotherapy with S-1 and weekly irinotecan in locally advanced rectal cancer

14543 Background: S-1 is a novel, orally administered 5-FU analogue and is known of radiosensitizer. The aim of this study was to establish the feasibility and efficacy of S-1 in combination with weekly irionotecan with concurrent pelvic radiotherapy (RT) in patients with locally advanced rectal cancer. Methods: Clinical stage T3–4 or N+(on MRI) rectal adenocarcinoma patients received weekly irinotecan 40mg/m2(day1,8,15,22,29) and S-1 at dose levels of 40, 50, 60 and 70mg/m2 (5days a week from day 1 to 38) according to phase I methodology. Concurrently conventional RT was given at daily fractions of 1.8 Gy on 5 days a week for a total dose of 50.4 (45 + 5.4)Gy. Surgery was performed 4–8 weeks following completion of chemoradiation. Results: A total 16 patients (10M/7F, median age 46 years, ECOG PS0–1) were enrolled between August 2005 and July 2006. One pt withdrew the consent during CCRT. Dose-limiting toxicity (DLT) occurred at 50mg/m2 of S-1 in one of six pts (G4 cerebral infarction). At dose of 60, 70mg/m2 of S-1, no DLT occurred. G3/4 toxicties were rare. Fifthteen pts underwent surgery and R0 resection was achieved in 13 pts. Four pts (25.0%) had a pathological complete response. Conclusions: The recommended dose (RD) for further study is S-1 70mg/m2 with irinotecan and radiotherapy. Neoadjuvant S-1/irinotecan/RT is feasible and well tolerated. Phase II trial is being conducted. No significant financial relationships to disclose.

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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.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.tps144 ◽

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.

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Phase I Trial of Capecitabine and Weekly Irinotecan in Combination With Radiotherapy for Neoadjuvant Therapy of Rectal Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2005.04.171 ◽

2005 ◽

Vol 23 (7) ◽

pp. 1350-1357 ◽

Cited By ~ 82

Author(s):

Ralf-Dieter Hofheinz ◽

Bolko von Gerstenberg-Helldorf ◽

Frederik Wenz ◽

Ulrike Gnad ◽

Uta Kraus-Tiefenbacher ◽

...

Keyword(s):

Rectal Cancer ◽

Phase I ◽

Clinical Stage ◽

Locally Advanced ◽

Dose Intensity ◽

Residual Tumor ◽

Advanced Rectal Cancer ◽

R0 Resection ◽

Phase Ii Trials ◽

Grade 3

Purpose To establish the feasibility and efficacy of capecitabine in combination with weekly irinotecan (CAPIRI) with concurrent pelvic radiotherapy (RT) in patients with locally advanced rectal cancer. Patients and Methods Nineteen patients with rectal cancer clinical stage T3-4, Nx received weekly irinotecan 50 mg/m2 (days 1, 8, 15, 22, 29) and two doses of capecitabine (days 1 through 38; dose level [DL] I, 500 mg/m2 bid; DL II, 625 mg/m2 bid) according to phase I methodology. Three-dimensional conformal RT was given to a dose of 50.4 Gy (45 Gy + 5.4 Gy). Results On DL I, no dose-limiting toxicities occurred, whereas diarrhea grade 3 affected three of seven patients on DL II. Twelve patients were treated on DL I and received a median relative dose-intensity of 100% for both drugs. Grade 3 or 4 adverse events were observed in only one of these patients (asthenia grade 3). All patients underwent surgery and R0 resection was achieved in all patients. Pathologic complete remission was observed in four patients and another five patients had only microfoci of residual tumor. Conclusion Preoperative chemoradiotherapy with CAPIRI is feasible and well tolerated. The preliminary efficacy is good, and the tolerability is at least comparable with data for fluorouracil plus irinotecan chemoradiotherapy. Larger phase II trials of the CAPIRI-RT schedule clearly are warranted.

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Preoperative chemoradiotherapy with capecitabine and oxaliplatin in patients with locally advanced rectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.4_suppl.548 ◽

2011 ◽

Vol 29 (4_suppl) ◽

pp. 548-548

Author(s):

I. Marrodan ◽

E. Azkona ◽

S. Carrera ◽

U. Aresti ◽

B. Calvo ◽

...

Keyword(s):

Rectal Cancer ◽

Clinical Stage ◽

Locally Advanced ◽

Pathologic Complete Response ◽

Neoadjuvant Chemoradiotherapy ◽

Advanced Rectal Cancer ◽

Locally Advanced Rectal Cancer ◽

Sphincter Preservation ◽

High Rate ◽

R0 Resection

548 Background: Locally advanced rectal carcinoma is associated with high rate of abdomino-perineal amputation. We analyzed a cohort of patients (pts) diagnosed of locally advanced rectal cancer, treated with neoadjuvant chemoradiotherapy (QT-RT) with capecitabine and oxaliplatin (XELOX) followed by four cycles of adjuvant XELOX after surgery. Methods: Patients with locally advanced rectal cancer (T3-T4 and/or N+) were treated with oxaliplatin (50mg/m2 day 1, 8, 22 and 29) and capecitabine (1,650mg/m2 on days 1 to 14 and 22 to 35) combined with pelvic radiotherapy (180 cGy/day; 45Gy in 25 fractions). Surgery was scheduled 4 to 6 weeks after completion QT-RT. Four cycles of adjuvant XELOX were administered (capecitabine 2,000mg/m2 on days 1 to 14 and oxaliplatin 130mg/m2 on day 1) every 3 weeks. Main end points assessed were: rate of sphincter preservation, pathologic complete response (pCR) rate and the feasibility of postoperative chemotherapy. Results: From March 2007 to April 2010, 98 pts with locally advanced rectal cancer were included. M/F: 66/32; ECOG 0/1: 19/79; median age: 64 (38-81); upper/mid/distal rectum: 13/50/35; clinical stage: cT3/N- 9, cT2-T3/N+ 72, cT4/N- 4, cT4/N+ 13. Full dose of preoperative QT-RT was administered in 93 pts (95%). Main toxicities were grade 1/2 neurotoxicity (56/4) and grade 2/3 diarrhea (23/10). After treatment 96 pts underwent surgery. Sphincter preservation, R0 resections and pCR were achieved in 57, 93 pts and 17 (18%) patients, respectively, and 65 pts (66%) received all 4 cycles of adjuvant XELOX. Grade 3/4 toxicities included diarrhea 3/0, vomiting 2/0, neurotoxicity 5/0, hand-foot syndrome 1/0, neutropenia 4/0 and thrombopenia 0/4. 3-year progression-free and overall survival were 66% and 72%, respectively. No toxic deaths were reported. Downstaging in T/N stage was achieved in 53/71 pts (55/74%) respectively. Conclusions: Combination preoperative QT-RT with capecitabine and oxaliplatin is a well tolerated regimen and achieves encouraging rates of pCR, R0 resection, sphincter preservation and tumor downstaging in patients with locally advanced rectal cancer. No significant financial relationships to disclose.

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A phase II study of induction PD-1 blockade in subjects with locally advanced mismatch repair-deficient rectal adenocarcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.tps4123 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. TPS4123-TPS4123

Author(s):

Andrea Cercek ◽

Zsofia Kinga Stadler ◽

Jenna L. Cohen ◽

Jill A Weiss ◽

Michelle F. Lamendola-Essel ◽

...

Keyword(s):

Rectal Cancer ◽

Mismatch Repair ◽

Locally Advanced ◽

Pathologic Complete Response ◽

Rectal Adenocarcinoma ◽

Complete Response ◽

Advanced Rectal Cancer ◽

Locally Advanced Rectal Cancer ◽

Blood Draw ◽

Rectal Cancers

TPS4123 Background: The treatment of patients with locally advanced rectal cancer includes total neoadjuvant therapy with chemotherapy, chemoradiation followed by surgery. While most rectal cancers respond to combination induction chemotherapy, patients with mismatch repair deficient (dMMR) or MSI-H tumors have a significantly higher chance of progression with this treatment regimen. dMMR or MSI-H tumors have shown remarkable responses to PD-1 blockade, but the effect of neoadjuvant checkpoint inhibition has not been well studied. In this trial we will determine the pathologic complete response rate (pCR) of neoadjuvant anti-PD-1 blockade followed by standard chemoradiation in dMMR or MSI-H locally advanced rectal cancer. We hypothesize that treatment naïve dMMR or MSI-H rectal cancers will achieve a robust clinical response to PD-1 blockade and that the total neodjuvant therapy with PD-1 blockade followed by chemoradiation will improve pCR rates. Methods: Eligible patients ≥18 years of age with Stage II (T3-4, N-) or Stage III (any T, N+) histologically confirmed dMMR or MSI-H (by NGS) rectal adenocarcinoma will be enrolled. Patients will receive TSR-042 (500mg IV) every 3 weeks for a maximum of 8 cycles (6 months of treatment). Imaging, internal endoscopic exam and ctDNA blood draw will be performed at 6 weeks and every 3 months during induction anti-PD-1 treatment. Adverse events and surgical complications will be graded according to the NCI CTCAE v5 and the Clavien-Dindo classification, respectively. Following neoadjuvant checkpoint blockade, patients will undergo conventional chemoradiotherapy followed by surgical resection. The primary endpoint is pathologic complete response compared with historical control in pMMR patients. Patients will be followed up every 6 months for assessment of disease-free survival for up to five years. Clinical trial information: NCT04165772 .

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Neoadjuvant capecitabine and oxaliplatin (XELOX) with bevacizumab for locally advanced rectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.4_suppl.566 ◽

2013 ◽

Vol 31 (4_suppl) ◽

pp. 566-566 ◽

Cited By ~ 2

Author(s):

Junichi Hasegawa ◽

Tsunekazu Mizushima ◽

Ho Min Kim ◽

Yasuhiro Miyake ◽

Hiroyoshi Takemoto ◽

...

Keyword(s):

Rectal Cancer ◽

Locally Advanced ◽

Complete Response ◽

Advanced Rectal Cancer ◽

Locally Advanced Rectal Cancer ◽

R0 Resection ◽

Tumor Cell Death ◽

Pathological Effect ◽

Median Diameter ◽

Rectal Obstruction

566 Background: Chemoradiotherapy (CRT) followed by surgery is a standard treatment for locally advanced rectal cancer. Although preoperative CRT decreases local recurrence (LR), pelvic radiation is associated with long-term morbidity. We conducted this study to evaluate the feasibility of neoadjuvant XELOX with bevacizumab (Bmab) in patients (pts) with locally advanced rectal cancer. Methods: Pts with T4 or lymph node (LN) positive rectal cancer were treated with 3 cycles of XELOX with Bmab and one additional cycle of XELOX. Total mesorectal excision was performed 3-8 weeks after the last chemotherapy. The primary endpoint was to assess feasibility and secondary endpoints were R0 resection rate, down staging rate, pathological complete response (pCR) rate and pathological effect over grade 2 (tumor cell death in more than two-thirds of the entire lesion). Results: Twenty five pts were recruited between December 2009 and November 2011. Characteristics of pts were as the following: male/female, 18/7; median age, 63 years (range, 37-75); median diameter of tumor, 52.8mm (range, 38.3-110); T2-T3/T4a/T4b, 7/8/10 and N0/N1/N2, 3/14/8. In 4% of the pts (7 pts), following grade 3-4 adverse events occurred; neutropenia, hypertension, bleeding, rectal obstruction, pelvic infection, anorexia and nausea. The down staging rate of T2-T3/T4a/T4b and N1/N2 were 29/63/50 % and 86/63 %, respectively. Seven pts (28%) discontinued the treatment after 2-3 cycles of XELOX with Bmab (13% in T2-T4a, 50% in T4b). The rate of conducting surgery was 92% and all of them had R0 resections. Postoperative complications were found in 9 pts (39%). The pCR rate was 4%, and the rate of pathological effect over grade 2 was 61%. Two LR (LN positive) and two distant recurrences (1 lung, 1 liver) were reported. Conclusions: XELOX with Bmab followed by surgery was safely performed for locally advanced rectal cancer. The down staging rate was 50% even in T4b pts although half of T4b pts discontinued the study treatment. Based on these preliminary results, we are planning a phase II trial of perioperative XELOX and surgery in locally advanced rectal cancer. Clinical trial information: 000003219.

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Pd1 antibody sintilimab for dMMR/MSI-H locally advanced rectal cancer: An open-label, phase 2, single-arm study (cohort A).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e15602 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e15602-e15602

Author(s):

Gong Chen ◽

Feng Wang ◽

Weiwei Xiao ◽

Ying Jin ◽

Rong-Xin Zhang ◽

...

Keyword(s):

Clinical Trial ◽

Rectal Cancer ◽

Partial Response ◽

Locally Advanced ◽

Rectal Adenocarcinoma ◽

Complete Response ◽

Advanced Rectal Cancer ◽

Locally Advanced Rectal Cancer ◽

Hepatic Flexure ◽

Watch And Wait

e15602 Background: Immunotherapy has shown satisfactory effect for dMMR/MSI-H colorectal cancer patients. Whether Pd-1 antibody would bring benefit for dMMR/MSI-H locally advanced rectal cancer (LARC) patients in neoadjuvant setting is worthy of investigation. This is a clinical trial with two cohorts according the MMR/MSI status(clinicalTrials.gov, NCT04304209). Methods: LARC patients with dMMR or MSI-H tumor will enter Cohort A and receive neoadjuvant Pd1 antibody sintilimab for four cycles and subsequent surgery or watch and wait, followed by adjuvant four cycles of Pd1 antibody sintilimab with or without chemotherapy. Main inclusion criteria include: cT3-4N0M0 or cTxN+M0 rectal adenocarcinoma, dMMR/MSI-H confirmed by immunohistochemistry (IHC) or gene test, aged 18-75y; ECOG performance 0-1; no previous anti-tumor treatment for rectal adenocarcinoma. Primary outcome is pathologic complete response (pCR) rate. We use a Simon two-stage optimum design to test the null hypothesis of a 15% pCR rate, the historical response rate to standard neoadjuvant chemoradiotherapy (NACRT), against the desired alternative of 30% pCR rate. This had a one-sided type I error of 5% and a power of 80%. In the first stage of this design, 19 patients will be accrued. If 3 or fewer pCR was observed, the study was to be terminated and declared negative. If the trial goes on to the second stage, a total of 55 patients will be studied. The study was deemed to have met its primary endpoint if confirmed pCR were observed in 13 or more patients. Considering 10% dropout rate, a total of 61 patients will be enrolled. Whole exome sequencing, bulk RNA sequencing, single cell RNA sequencing and IHC of the rectal primary tumor are planned. The study started in October, 2019. Results: Eight patients have been enrolled and six have response evaluation results. Four patients achieved clinical complete response (cCR) after 4 cycles of neoadjuvant Pd1 antibody sintilimab treatment and three of them enter watch and wait strategy and finished the adjuvant 4 cycles of Pd1 antibody sintilimab treatment. The 4th patient was diagnosed as lynch syndrome, but molecular test was not feasible for the tumors located at the sigmoid and hepatic flexure because of ileus. He received subtotal colectomy and tumors at the sigmoid and hepatic flexure also achieved pCR. The 5th patient has partial response after 4 and 8 cycles of sintilimab treatment, and then received Dixon surgery and pathology showed major reponse (5% cancer cell left only in the mucosal layer, ypTis). The 6th patient has partial response after 4 and 8 cycles of sintilimab treatment, and sintilimab was still continued concerning intact bladder conservation. No grade 3 toxicity was noted yet. Conclusions: Pd1 antibody sintilimab achieved 4CR (pCR+cCR) in 6 dMMR/MSI-H LARC patients with limited toxicities. Pd1 antibody is quite effective and may be an alternative for these patients. Clinical trial information: NCT04304209.

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Preoperative chemoradiotherapy (QT-RT) with capecitabine and oxaliplatin (CAPOX) in patients with locally advanced rectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e14628 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e14628-e14628

Author(s):

Aintzane Sancho ◽

Ines Marrodan ◽

Begoña Calvo ◽

Alberto Muñoz ◽

Joan Manel Mane ◽

...

Keyword(s):

Rectal Cancer ◽

Locally Advanced ◽

Complete Response ◽

Advanced Rectal Cancer ◽

Preoperative Chemoradiotherapy ◽

Locally Advanced Rectal Cancer ◽

Sphincter Preservation ◽

High Rate ◽

R0 Resection ◽

Pelvic Mri

e14628 Background: Locally advanced rectal carcinoma is associated with high rate of abdomino-perineal amputation. We analyzed a cohort of patients (pts) diagnosed of locally advanced rectal cancer, treated with neoadjuvant QT-RT with CAPOX followed by four cycles of adjuvant CAPOX after surgery. Methods: Pts with locally advanced rectal cancer (T3-T4 and/or N+) were treated with oxaliplatin (50mg/m2 day 1, 8, 22 and 29) and capecitabine (1650mg/m2 on days 1 to 14 and 22 to 35) combined with pelvic radiotherapy (180cGy/day; 45Gy in 25 fractions). Surgery was scheduled 4 to 6 weeks after completion QT-RT. Four cycles of adjuvant XELOX were administered (capecitabine 2000mg/m2 on days 1 to 14) and oxaliplatin (130mg/m2 day 1) every 3 weeks. The main end points assessed were: rate of sphincter preservation, pathological complete response (pCR) rate, toxicity and feasibility of postoperative chemotherapy. Local staging was done with pelvic MRI and/or EUS. Results: From Sept 2005 to Nov 2012, 201 pts with locally advanced rectal cancer were included. Pts characteristics: M/F 135/66; ECOG 0/1/2: 48/149/4; median age 65 (28-81); upper/mid/distal rectum 29/105/67; stage cT3/N- 21, cT2-T3/N+ 140, cT4/N- 6, cT4/N+ 34. Full dose preoperative QT-RT was administered in 192 (95%). The main toxicities were diarrhea grade 2/3: 42/24 and neurotoxicity grade 1/2: 94/7. After treatment 198 pts underwent surgery. Sphincter preservation and R0 resections were achieved in 125 and 184 respectively. pCR was achieved in 35 pts (17.4%). 145 pts (72%) received all 4 cycles of adjuvant XELOX. Grade 3/4 toxicities included vomiting 3/0, diarrhea 7/0, skin-foot syndrome 2/0, mucositis 1/0, neurotoxicity 6/0, neutropenia 10/1 and thromopenia 6/1. Downstaging in T/N was achieved in 108/144 pts (53.7/71.6%) respectively. 3-year progression-free and overall survival were 75% and 83% respectively. No toxic deaths were reported. Conclusions: Combination QT-RT based in capecitabine and oxaliplatin is a well tolerated regimen and achieved encouring rates of pCR, R0 resection, sphincter preservation and tumor downstaging in patients with locally advanced rectal cancer.

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