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

• Status: Unknown status
• Trial end date: 2017-09-01
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Sheba Medical Center
• Collaborators: Karyopharm Therapeutics Inc; Karyopharm Therapeutics, Inc
• Treatments: Capecitabine

Criteria

Inclusion Criteria:

1. Written informed consent in accordance with Sheba Medical Center guidelines.

2. Age ≥18 years. Patients with locally advanced non-metastatic rectal cancer, defined as minimum T3 or N1 per AJCC 7th edition, (i.e. T3N0 or T1N1 would be eligible for enrolment, but not T2N0).

3. Histologically confirmed diagnosis of rectal adenocarcinoma.

4. ECOG Performance Status 0-1

5. Hematological function: total WBC count > 2,000/mm3; absolute neutrophil count (ANC) > 1,000/mm3; platelet count >= 150,000/mm3 - 1,000,000/mm3

6. Adequate hepatic function within 14 days prior to study entry: total bilirubin <2 times the upper limit of normal (ULN) (except patients with Gilbert's syndrome who must have a total bilirubin of <3 times ULN); both AST and ALT (aspartate and alanine aminotransferases) <2.5 times ULN.

7. Adequate renal function within 14 days prior to study entry, defined as creatinine <=1.5*upper normal limit and/or estimated creatinine clearance of ≥30 mL/min, calculated using the formula of Cockcroft and Gault (140-Age) • Mass (kg)/(72 • creatinine mg/dL); multiply by 0.85 if female.

8. Female patients of childbearing potential must agree to use dual methods of contraception and have a negative serum pregnancy test at screening, and male patients must use an effective barrier method of contraception if sexually active with a female of child-bearing potential. Acceptable methods of contraception are condoms with contraceptive foam, oral, implantable or injectable contraceptives, contraceptive patch, intrauterine device, diaphragm with spermicidal gel, or a sexual partner who is surgically sterilized or post-menopausal. For both male and female patients, effective methods of contraception must be used throughout the study and for three months following the last dose.

9. Willing to undergo biopsy prior to starting treatment to obtain fresh-frozen tissue.

Exclusion Criteria:

1. Received radiation, chemotherapy, or immunotherapy, or any other anticancer therapy ≤2 weeks prior to study entry. Patients who received an investigational anticancer study within 3 weeks prior to study entry are excluded.

2. Malignancy diagnosed within the 5 years prior to study entry (however non-melanotic skin cancers, in-situ carcinomas of cervix are allowed).

3. Previous radiation therapy to the pelvis (superficial radiation to the skin in the pelvic area is acceptable).

4. Previous 'low anterior resection' or 'abdominoperineal resection' for rectal cancer.

5. Major surgery within four weeks before study entry;

6. Unstable cardiovascular function:

1. symptomatic ischemia, or

2. uncontrolled clinically significant conduction abnormalities (ie: ventricular tachycardia on antiarrhythmics are excluded, whereas 1st degree AV block or asymptomatic LAFB/RBBB will not be excluded), or

3. congestive heart failure (CHF) of NYHA Class ≥3

4. myocardial infarction (MI) within 3 months;

7. Uncontrolled infection requiring parenteral antibiotics, antivirals, or antifungals within one week prior to first dose; patients with controlled infection or on prophylactic antibiotics are permitted in the study;

8. Known to be HIV seropositive;

9. Known active hepatitis A, B, or C infection; or known to be positive for HCV RNA or HBsAg (HBV surface antigen);

10. Any underlying condition that would significantly interfere with the absorption of an oral medication.

11. Serious psychiatric or medical conditions that could interfere with treatment;

12. Patients with coagulation problem and active bleeding in the last month (peptic ulcer, epistaxis, spontaneous bleeding) - however bleeding from the rectal cancer itself is not an exclusion criteria.

13. Patients who are pregnant or lactating.