NCT02137356

Selinexor Combined With Standard Chemoradiation as Neoadjuvant Treatment in Locally Advanced Rectal Cancer

An Investigator Sponsored Phase I Trial of Selinexor Combined With Standard Capecitabine Based Chemoradiation as a Neoadjuvant Treatment in Locally Advanced Rectal Cancer

• Status: Unknown
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 28 (estimated)
• Sponsor: Sheba Medical Center · Other Government
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

Locally advanced rectal cancer (T3, T4 or lymph node positive tumors) are conventionally treated with 5FU / capecitabine based chemoradiation prior to surgical resection. This treatment is associated with only a 15-20% pathological complete response. Selinexor (KPT-330) is a Selective Inhibitor of Nuclear Export (SINE) XPO1 antagonist that has demonstrated radiosensitization with in vivo models and has suggested single agent activity against colorectal cancers in a Phase I trial. Here we perform a Phase I/Ib trial of standard chemoradiation combined with Selinexor. We hypothesize that tumors treated with this new combination will demonstrate an increased response rate compared to those treated with capecitabine-radiation alone.

Detailed description

The American Cancer Society estimated that in 2012 there were 40,290 new cases of rectal cancer in the United States. In the 1980's the standard of care was surgical resection alone, unfortunately this was associated with high rates of local recurrence (30%) in node positive or T3-4 disease. Randomized studies demonstrated the efficacy of adding post-operative and subsequently pre-operative chemo-radiation. Preoperative radiation, either on its own or with concomitant chemotherapy, decreases local recurrence, increases disease-free and overall survival and improves rates of sphincter preservation. The current standard of care in the United States and Israel, for patients with node positive or T3 of T4 disease is preoperative chemo-radiation. The radiation is delivered to a dose of 45-55 Gy delivered over 5-6 weeks. The chemotherapy traditionally employed was infusional 5- fluorouracil (5FU). In recent years this has been replaced by an oral 5FU derivative, Capecitabine\[15\]. Some European centers favor an intense short-course preoperative radiation regimen of 25Gy over 5 days. This regimen is rarely used in Israel (or the United States) for logistical reasons (surgery needs to be rigidly scheduled immediately after completion of radiation) and concerns about long-term side effects. Pathological complete response is when at the time of operation no cancerous tissue is found in the operative specimen. Pathological complete response is indicative of both the sensitivity of the tumor and the effectiveness of the preoperative chemotherapeutic regimen. Pathological complete response is associated with an excellent prognosis in terms of local recurrence, distal recurrence and overall survival. Standard preoperative chemoradiation is associated with a pathological complete response of 15-20%. For patients with locally advanced disease receiving standard chemoradiation, the 5 year local recurrence rate is expected to be 6% and 5 year survival 68%. This open label study is therefore proposed to examine the combination of chemoradiation with Selinexor, a SINE XPO1 antagonist, that is being evaluated in Phase 1 studies in solid and hematological malignancies and that has shown single agent activity in heavily pretreated patients with CRC. The long-term goal of the project Is to establish a new treatment for patients with rectal cancer that will improve their cure rate and lengthen their overall survival.

Conditions

• Rectal Neoplasms

Interventions

Type	Name	Description
RADIATION	standard dose pelvic radiation therapy	radiation therapy to pelvis delivered using standard conformal or IMRT techniques. 50.4-55 Gy
DRUG	standard dose capecitabine	825 mg/m2 twice daily, 5 days a week (max dose 2000mg twice daily), only on days when radiation is delivered
DRUG	dose-escalated selinexor treatment	Selinexor oral drug will be given twice weekly according to the dose escalation schedule described in the protocol. Selinexor will be started on the day radiation begins, until the end of week 6.

Timeline

• Start date: 2014-12-01
• Primary completion: 2017-06-01
• Completion: 2017-09-01
• First posted: 2014-05-13
• Last updated: 2015-09-03

Locations

1 site across 1 country: Israel