Nuclear Export Inhibition for Radiosensitization; a Proof-of-Concept Phase I Clinical Trial of Neoadjuvant KPT-330 Plus Chemoradiation in Locally Advanced Rectal Cancer

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.

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Efficacy and safety of sequential neoadjuvant chemotherapy and short-course radiation therapy followed by delayed surgery in locally advanced rectal cancer: a single-arm phase II clinical trial with subgroup analysis between the older and young patients

Radiation Oncology Journal ◽

10.3857/roj.2021.00654 ◽

2021 ◽

Author(s):

Alimohammad Bananzadeh ◽

Ali Akbar Hafezi ◽

NamPhong Nguyen ◽

Shapour Omidvari ◽

Ahmad Mosalaei ◽

...

Keyword(s):

Clinical Trial ◽

Rectal Cancer ◽

Radiation Therapy ◽

Neoadjuvant Chemotherapy ◽

Locally Advanced ◽

Young Patients ◽

Advanced Rectal Cancer ◽

Locally Advanced Rectal Cancer ◽

Efficacy And Safety ◽

Short Course

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Preoperative chemoradiation with S-1 plus oxaliplatin in patients with locally advanced rectal cancer: Results of a phase II study and the role of apparent diffusion coefficient (ADC) by diffusion-weighted magnetic resonance imaging (DW MRI) for prediction of pathologic responses.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.4_suppl.629 ◽

2011 ◽

Vol 29 (4_suppl) ◽

pp. 629-629

Author(s):

E. M. Lee ◽

J. L. Hong ◽

J. L. Lee ◽

S. Y. Kim ◽

Y. S. Park ◽

...

Keyword(s):

Rectal Cancer ◽

Phase I ◽

Phase Ii ◽

Phase Ii Study ◽

Locally Advanced ◽

Pathologic Complete Response ◽

Advanced Rectal Cancer ◽

Locally Advanced Rectal Cancer ◽

Preoperative Chemoradiation ◽

Curative Surgery

629 Background: We conducted a phase II study of preoperative chemoradiation (CRT) with S-1, a novel oral fluoropyrimidine, plus oxaliplatin in patients (pts) with locally advanced rectal cancer. Tumor ADCs were measured by DW-MRI and were evaluated as a predictive marker for pathologic responses. Methods: Radiotherapy was delivered to a total 50.4 Gy. The recommended doses were determined by a previous phase I study; oxaliplatin 50 mg/m2/week on D1, 8, 22 and 29, and S-1 80 mg/m2/day on D1-14 and D22-35. Total mesorectal excision was performed within 6 ± 2 weeks. Primary endpoint was pathologic complete response (pCR) rate. The value of tumor ADCs by DW-MRI was measured before and after CRT, and was correlated with pathologic responses after surgery. Results: A total of 38 patients were enrolled; 22 (57.9%) were men and the median age was 54 years (range, 28-67). Of 35 patients who underwent curative surgery, 28 patients underwent sphincter-saving operations. There was no grade 4 toxicity, and grade 3 toxicities included leukopenia (2.7%), neutropenia (2.7%), anorexia (2.7%), nausea (2.7%) and diarrhea (8.8%). The pCR rate was 25.7% (8/35, 95% CI [10.9-42.1]) and additional 10 patients (28.6%) showed near total regressions of tumor. Tumor ADCs by DW-MRI were calculated in 38 patients (including phase I part). The post-CRT ADC and the ADC changes (ΔADC) were significantly correlated with pCR rate (post-CRT ADC: 1.52±0.46 vs. 1.07±0.58, p=0.037, ΔADC: 44.5% vs. -7.6%, p=0.026). Conclusions: Preoperative CRT with S-1 plus oxaliplatin showed promising results in pathologic responses and favorable toxicities profiles. Tumor ADC by DW-MRI seems to be a useful method for predicting responses. No significant financial relationships to disclose.

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Clinical downstaging and quality of life after neoadjuvant chemotherapy in patients with locally advanced rectal cancer: Interim analysis from a phase II clinical trial.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e15178 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e15178-e15178

Author(s):

Ahmed Abdalla ◽

Amr M. Aref ◽

Amer Alame ◽

Danny Ma ◽

Mohammed Barawi ◽

...

Keyword(s):

Quality Of Life ◽

Clinical Trial ◽

Rectal Cancer ◽

Neoadjuvant Chemotherapy ◽

Phase Ii ◽

General Health ◽

Locally Advanced ◽

Advanced Rectal Cancer ◽

Locally Advanced Rectal Cancer

e15178 Background: The role of neoadjuvant FOLFOX in achieving clinical downstaging and improvement in quality of life (QOL) in patients with locally advanced rectal cancer (LARC) remains to be established. We are conducting a phase II prospective clinical trial to evaluate the use of six cycles of FOLFOX as neoadjuvant chemotherapy in patients with T2-T3/N0-N+ rectal cancer. We now report tumor clinical downstaging and patient-reported QOL in our first patient cohort. Methods: Eleven Patients enrolled in our phase II prospective trial. Patients received three months of FOLFOX (infusional fluorouracil, leucovorin, and oxaliplatin) administered every two weeks. After three weeks of recovery, each patient was treated with conventional chemo-radiotherapy (5FU or capecitabine) All patients had an MRI and endorectal ultrasound at baseline and after completion of FOLFOX. A compilation of validated QOL questionnaires were also administered before and after FOLFOX. Results: A total of 11 patients completed the chemotherapy regimen. Based on pelvic MRI, complete clinical response (T0N0) was achieved by seven patients (64%), one patient (9%) was clinically downstaged but three (27%) didn’t have any changes following FOLFOX. Importantly, we found no disease progression during the FOLFOX course. QOL assessment after FOLFOX regimen showed trend towards improvement in general health, mobility, bladder control and psychological health. These changes in QOL were not statistically significant due to the small sample size. Patients self-grading of their general health before starting FOLFOX was 50% compared to 75% after. Of the five patients with pain at time of diagnosis, four reported complete pain relief while the fifth reported improvement from extreme to moderate pain. Three patients reported improvement in their anxiety/depression. In terms of bowel function, although there was trend towards improvement in the urgency subscale, other bowel functions subscales were unchanged. In general, scores for mobility, selfcare, and bladder function were slightly better after FOLFOX. Conclusions: This study suggests that adding only six cycles of neoadjuvant FOLFOX before CRT not only resulted in clinical downstaging of (LARC) but showed a trend toward improved QOL. This result provides some reassurance for oncologists that this approach does not diminish QOL with no risk of disease progression during the time of neoadjuvant chemotherapy. These findings need to be validated in a larger phase III trial.

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