Rectal NeoplasmsPhase 1NCT02137356
Selinexor Combined With Standard Chemoradiation as Neoadjuvant Treatment in Locally Advanced Rectal Cancer
A Phase 1 study testing standard dose pelvic radiation therapy, standard dose capecitabine and dose-escalated selinexor treatment in people with Rectal Neoplasms, run by Sheba Medical Center at 1 site in Israel.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Rectal Neoplasms
- What is being tested?
- standard dose pelvic radiation therapy, standard dose capecitabine and dose-escalated selinexor treatment
- Type of treatment
- Pill or oral medicine, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 28 participants
- Where
- 1 siteIsrael
- Study dates
- Dec 2014to Sep 2017
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
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- 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.
Who cannot join
- 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:
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- 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;
- 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.
- Patients who are pregnant or lactating.
Trial locations and contacts
1 site in 1 country.
Israel1 site, 1 recruiting
- Recruiting
Sheba Medical Center
Ramat Gan, 52621
Yaacov R Lawrence, MBBS MA MRCP, 97235304410, Yaacov.Lawrence@sheba.health.gov.il
Aliza Ackerstein, 035308402, aliza.ackerstein@sheba.health.gov.il
About this study
Official title: An Investigator Sponsored Phase I Trial of Selinexor Combined With Standard Capecitabine Based Chemoradiation as a Neoadjuvant Treatment in Locally Advanced Rectal Cancer
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.
Read the 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
- Being tested
- standard dose pelvic radiation therapy, standard dose capecitabine, dose-escalated selinexor treatment
- Keywords
- rectal cancer, rectal adenocarcinoma, Selinexor, capecitabine, chemoradiation, radiation, radiotherapy, neoadjuvant, locally advanced rectal cancer
- Medical subject headings
- Rectal Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
standard dose pelvic radiation therapyRadiation
Also called radiotherapy, radiation therapy
radiation therapy to pelvis delivered using standard conformal or IMRT techniques.
50.4-55 Gy
standard dose capecitabineDrug
Also called xeloda
825 mg/m2 twice daily, 5 days a week (max dose 2000mg twice daily), only on days when radiation is delivered
dose-escalated selinexor treatmentDrug
Also called KPT-330
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.
| Study group | Role | What they receive |
|---|---|---|
| treatment arm | Experimental | standard dose pelvic radiation therapy, standard dose capecitabine, dose-escalated selinexor treatment Receives: Radiation: standard dose pelvic radiation therapy; Drug: standard dose capecitabine; Drug: dose-escalated selinexor treatment |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of patients with adverse events
We will track adverse events in order to determine the safety and tolerability of the intervention.
Measured: Six weeks
Secondary outcomes (1)
Number of patients whose tumors demonstrate pathological complete response at resection
In order to assess the efficacy of the intervention we will count the number of patients whose tumors demonstrate pathological complete response at final resection
Measured: 16 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 May 2014 (estimated)
- Study startDec 2014
- Primary completionJun 2017 (estimated)
- Study completionSep 2017 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Rectal NeoplasmsStudies of the same condition, open and under way.
- More trials run by Sheba Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 28 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Sheba Medical Center
- Sponsor type
- Other government
- Collaborators
- Karyopharm Therapeutics Inc
- Responsible party
- Sponsor
- Investigators
- Yaacov R Lawrence, MBBS MA MRCP, Principal investigator, Sheba Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02137356
- Sponsor's protocol ID
- SHEBA-14-1061-YL-CTIL
- Status last verified
- Sep 2015
- First submitted
- 1 May 2014
- Last updated
- 3 Sep 2015
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 3 Sep 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- An Investigator Sponsored Phase I Trial of Selinexor Combined With Standard Capecitabine Based Chemoradiation as a Neoadjuvant Treatment in Locally Advanced Rectal Cancer
- ClinicalTrials.gov ID
- NCT02137356
- Acronym / sponsor ID
- SHEBA-14-1061-YL-CTIL
- Conditions
- Rectal Neoplasms
- Keywords
- rectal cancer, rectal adenocarcinoma, Selinexor, capecitabine, chemoradiation, radiation, radiotherapy, neoadjuvant
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 28 participants (estimated)
- Lead sponsor
- Sheba Medical CenterOther government
- Collaborators
- Karyopharm Therapeutics Inc
- Study start
- Dec 2014
- Primary completion
- Jun 2017 (estimated)
- Study completion
- Sep 2017 (estimated)
- First posted
- 13 May 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| treatment arm | Experimental | Radiation: standard dose pelvic radiation therapy, Drug: standard dose capecitabine, Drug: dose-escalated selinexor treatmentstandard dose pelvic radiation therapy, standard dose capecitabine, dose-escalated selinexor treatment |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- 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
Key exclusion criteria (17 listed)
- 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;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| standard dose pelvic radiation therapyAlso: radiotherapy, radiation therapyradiation therapy to pelvis delivered using standard conformal or IMRT techniques. 50.4-55 Gy | Radiation | treatment arm |
| standard dose capecitabineAlso: xeloda825 mg/m2 twice daily, 5 days a week (max dose 2000mg twice daily), only on days when radiation is delivered | Drug | treatment arm |
| dose-escalated selinexor treatmentAlso: KPT-330Selinexor 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. | Drug | treatment arm |
Primary outcome
Number of patients with adverse events
Time frame: Six weeks
We will track adverse events in order to determine the safety and tolerability of the intervention.
1 secondary outcome
Number of patients whose tumors demonstrate pathological complete response at resection
Time frame: 16 weeks
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Sep 2015.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Yaacov R Lawrence, MBBS MA MRCP principal investigator
Sheba Medical Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing standard dose pelvic radiation therapy, standard dose capecitabine and dose-escalated selinexor treatment in people with Rectal Neoplasms, run by Sheba Medical Center at 1 site in Israel.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 3 Sep 2015. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Israel. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Each site lists its own contact: choose the nearest one under Trial locations. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of patients with adverse events (time frame: Six weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Sep 2015.