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

NCT02137356 | Unknown Phase 1

• 1 other identifier: SHEBA-14-1061-YL-CTIL
• Study Type: interventional
• Target: 28
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Rectal Neoplasms

Keywords

rectal cancer; rectal adenocarcinoma; Selinexor; capecitabine; chemoradiation; radiation; radiotherapy; neoadjuvant; locally advanced rectal cancer

Outcome Measures

Primary Outcomes (1)

• Number of patients with adverse events

  We will track adverse events in order to determine the safety and tolerability of the intervention.

  Six weeks

Secondary Outcomes (1)

• Number of patients whose tumors demonstrate pathological complete response at resection

  16 weeks

Study Arms (1)

treatment arm

EXPERIMENTAL

standard dose pelvic radiation therapy, standard dose capecitabine, dose-escalated selinexor treatment

Radiation: standard dose pelvic radiation therapy; Drug: standard dose capecitabine; Drug: dose-escalated selinexor treatment

Interventions

standard dose pelvic radiation therapy RADIATION

radiation therapy to pelvis delivered using standard conformal or IMRT techniques. 50.4-55 Gy

Also known as: radiotherapy, radiation therapy

treatment arm

standard dose capecitabine DRUG

825 mg/m2 twice daily, 5 days a week (max dose 2000mg twice daily), only on days when radiation is delivered

Also known as: xeloda

treatment arm

dose-escalated selinexor treatment DRUG

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.

Also known as: KPT-330

treatment arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent in accordance with Sheba Medical Center guidelines.
• 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).
• Histologically confirmed diagnosis of rectal adenocarcinoma.
• ECOG Performance Status 0-1
• Hematological function: total WBC count \> 2,000/mm3; absolute neutrophil count (ANC) \> 1,000/mm3; platelet count \>= 150,000/mm3 - 1,000,000/mm3
• 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.
• 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.
• 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.
• Willing to undergo biopsy prior to starting treatment to obtain fresh-frozen tissue.

You may not qualify if:

• 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.
• Malignancy diagnosed within the 5 years prior to study entry (however non-melanotic skin cancers, in-situ carcinomas of cervix are allowed).
• Previous radiation therapy to the pelvis (superficial radiation to the skin in the pelvic area is acceptable).
• Previous 'low anterior resection' or 'abdominoperineal resection' for rectal cancer.
• Major surgery within four weeks before study entry;
• Unstable cardiovascular function:
• symptomatic ischemia, or
• 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
• congestive heart failure (CHF) of NYHA Class ≥3
• myocardial infarction (MI) within 3 months;
• 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;
• Known to be HIV seropositive;
• Known active hepatitis A, B, or C infection; or known to be positive for HCV RNA or HBsAg (HBV surface antigen);
• Any underlying condition that would significantly interfere with the absorption of an oral medication.
• Serious psychiatric or medical conditions that could interfere with treatment;

Sponsors & Collaborators

• Sheba Medical Center: lead
• Karyopharm Therapeutics Inc: collaborator

Study Sites (1)

Sheba Medical Center

Ramat Gan, 52621, Israel

RECRUITING

MeSH Terms

Conditions

Rectal Neoplasms

Interventions

Radiotherapy; Capecitabine; selinexor

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Therapeutics; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Fluorouracil; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Study Officials

• Yaacov R Lawrence, MBBS MA MRCP

  Sheba Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 1, 2014
• First Posted: May 13, 2014
• Study Start: December 1, 2014
• Primary Completion: June 1, 2017
• Study Completion: September 1, 2017
• Last Updated: September 3, 2015

Record last verified: 2015-09

Locations

IL (1)