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

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 .

scholarly journals Mutational and Clinical Predictors of Pathologic Complete Response in the Treatment of Locally Advanced Rectal Cancer

2013 ◽  
Vol 45 (1) ◽  
pp. 34-39 ◽  
Author(s):  
Andrea L. Russo ◽  
David P. Ryan ◽  
Darrell R. Borger ◽  
Jennifer Y. Wo ◽  
Jackie Szymonifka ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Locally Advanced ◽  
Pathologic Complete Response ◽  
Complete Response ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Clinical Predictors

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.

Intensification of neoadjuvant therapy in patients with locally advanced rectal cancer

2021 ◽  
Vol 11 (2) ◽  
pp. 19-28
Author(s):  
Z. Z. Mamedli ◽  
A. V. Polynovskiy ◽  
D. V. Kuzmichev ◽  
S. I. Tkachev ◽  
A. A. Aniskin
Keyword(s):  
Rectal Cancer ◽  
Locally Advanced ◽  
Pathologic Complete Response ◽  
Disease Free Survival ◽  
Complete Response ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Control Group ◽  
Free Survival ◽  
Disease Free

The aim of the study: to increase the frequency of achieving pathologic complete response and increase disease-free survival in the investigational group of patients with locally advanced rectal cancer T3(MRF+)–4N0–2M0 by developing a new strategy for neoadjuvant therapy.Materials and methods. In total, 414 patients were assigned to treatment. Control group I included 89 patients who underwent radiotherapy (RT) 52–56 Gy/26–28 fractions with concurrent capecitabine twice daily 5 days per week. Control group II included 160 patients who underwent RT 52–56 Gy/26–28 fractions with concurrent capecitabine twice daily 5 days per week and oxaliplatin once a week, during the course of RT. Study group III consisted of 165 patients. This group combined RT 52–56 Gy/26–28 fractions with concurrent capecitabine twice daily 5 days per week and additional consecutive CapOx cycles. This group was divided into 2 subgroups: subgroup IIIa included 106 patients with consolidating chemotherapy (after CRT); subgroup IIIb included 59 patients who underwent “sandwich” treatment. Therapy consisted of conducting from 1 to 2 cycles of induction CapOx (up to CRT) and from 1 to 2 cycles of consolidating CapOx with an interval of 7 days. In the interval between the courses of drug therapy, RT 52–56 Gy/26–28 fractions was performed. According to the results of the control examination, further treatment tactics were determined. The primary end points were 5-year disease-free survival and the achievement of a pathologic complete response.Results. Pathologic complete response was significantly more often recorded in patients in the investigational group III (17.48 %; p = 0.021) compared with control groups (7.95 % in the I group and 8.28 % in the II group). 5-year disease-free survival in patients in the study groups was: 71.5 % in the III group, 65.6 % in the II group and 56.9 % in the I group.Conclusion. The shift in emphasis on strengthening the neoadjuvant effect on the tumor and improving approaches to drug therapy regimens have significantly improved disease-free survival of patients with locally advanced rectal cancer.

scholarly journals Clinical predictive factors of pathologic complete response in locally advanced rectal cancer

Oncotarget ◽  
2016 ◽  
Vol 7 (22) ◽  
pp. 33374-33380 ◽  
Author(s):  
Francesca De Felice ◽  
Luciano Izzo ◽  
Daniela Musio ◽  
Anna Lisa Magnante ◽  
Nadia Bulzonetti ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Predictive Factors ◽  
Locally Advanced ◽  
Pathologic Complete Response ◽  
Complete Response ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer

scholarly journals Molecular and Kinetic Analyses of Circulating Tumor Cells as Predictive Markers of Treatment Response in Locally Advanced Rectal Cancer Patients

Cells ◽  
2019 ◽  
Vol 8 (7) ◽  
pp. 641 ◽  
Author(s):  
Bianca C. Troncarelli Flores ◽  
Virgilio Souza e Silva ◽  
Emne Ali Abdallah ◽  
Celso A.L. Mello ◽  
Maria Letícia Gobo Silva ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Protein Expression ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Excision Repair ◽  
Locally Advanced ◽  
Pathologic Complete Response ◽  
Complete Response ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer

Neoadjuvant chemoradiation (NCRT) followed by total mesorectal excision is the standard treatment for locally advanced rectal cancer (LARC). To justify a non-surgical approach, identification of pathologic complete response (pCR) is required. Analysis of circulating tumor cells (CTCs) can be used to evaluate pCR. We hypothesize that monitoring of thymidylate synthase (TYMS) and excision repair protein, RAD23 homolog B (RAD23B), can be used to predict resistance to chemotherapy/radiotherapy. Therefore, the aims of this study were to analyze CTCs from patients with LARC who underwent NCRT plus surgery for expression of TYMS/RAD23B and to evaluate their predictive value. Blood samples from 30 patients were collected prior to NCRT (S1) and prior to surgery (S2). CTCs were isolated and quantified by ISET®, proteins were analyzed by immunocytochemistry, and TYMS mRNA was detected by chromogenic in situ hybridization. CTC counts decreased between S1 and S2 in patients exhibiting pCR (p = 0.02) or partial response (p = 0.01). Regarding protein expression, TYMS was absent in 100% of CTCs from patients with pCR (p = 0.001) yet was expressed in 83% of non-responders at S2 (p < 0.001). Meanwhile, RAD23B was expressed in CTCs from 75% of non-responders at S1 (p = 0.01) and in 100% of non-responders at S2 (p = 0.001). Surprisingly, 100% of non-responders expressed TYMS mRNA at both timepoints (p = 0.001). In addition, TYMS/RAD23B was not detected in the CTCs of patients exhibiting pCR (p = 0.001). We found 83.3% of sensitivity for TYMS mRNA at S1 (p = 0.001) and 100% for TYMS (p = 0.064) and RAD23B (p = 0.01) protein expression at S2. Thus, TYMS mRNA and/or TYMS/RAD23B expression in CTCs, as well as CTC kinetics, have the potential to predict non-response to NCRT and avoid unnecessary radical surgery for LARC patients with pCR.

Phase Ib/II study of neoadjuvant chemoradiotherapy with CRLX101 and capecitabine for locally advanced rectal cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15144-e15144 ◽  
Author(s):  
Andrew Wang ◽  
Autumn Jackson McRee ◽  
A. William Blackstock ◽  
Bert H. O'Neil ◽  
Dominic T. Moore ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Single Agent ◽  
Locally Advanced ◽  
Pathologic Complete Response ◽  
Neoadjuvant Chemoradiotherapy ◽  
Complete Response ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Phase Ib ◽  
Grade 3

e15144 Background: There is strong interest in the development of novel agents to further improve the therapeutic ratio of neoadjuvant chemoradiotherapy for rectal cancer. CRLX101 is an investigational nanoparticle-drug conjugate with a camptothecin payload. The purpose of this Phase Ib/II study is to assess toxicity and to evaluate whether the addition of CRLX101 to chemoradiotherapy can improve pathologic complete response (pCR) for rectal cancer. Methods: This is a single-arm multicenter Phase Ib/II study examining the addition of CRLX101 to a standard capecitabine-based chemoradiotherapy regimen. Phase Ib employs a 3+3 dose escalation design with starting dose of 12 mg/m2 every other week (QOW). Dose level +1 was 15 mg/m2 (MTD for CRLX101 single agent QOW). Upon reaching MTD for QOW dosing, protocol was modified to evaluate QW CRLX101 dosing starting at 12 mg/m2 and 15 mg/m2as +1 level. Secondary endpoints included pCR and clinical outcome. Results: A total of 32 patients were enrolled on the trial. 26/32 had T3-4, 9/32 had N2 and 16/32 had N1 disease. For QOW dosing, 9 patients completed treatment without DLT and MTD was identified as 15 mg/m2 QOW. 14 patients were treated on the Phase II portion of the study at 15 mg/m2 QOW prior to the initiation of weekly dosing Phase Ib cohorts. For QW dosing, 0/3 patients experienced DLT at 12 mg/m2 and 1/6 patients experienced DLT at 15 mg/m2. The DLT was skin desquamation requiring treatment delay. QW MTD was identified as 15 mg/m2. Toxicities (all grade 3 except lymphopenia) that could possibly be attributed to CRLX101 are in Table 1. Full clinical and pathologic staging were available for 29/32 patients. Mean neoadjuvant rectal (NAR) score was 19 with standard deviation of 15. At the weekly MTD, 3/6 patients had pCR. Conclusions: CRLX101 weekly at 15 mg/m2+ standard capecitabine-based chemoradiotherapy appears to be well tolerated, with promising pCR rates that warrants further evaluation. A larger PhII trial should be considered with this regimen. Clinical trial information: NCT02010567. [Table: see text]

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