Phase 1 Trial To Evaluate mFOLFOX6 With Selinexor In Patients With Metastatic Colorectal Cancer (SENTINEL)

February 7, 2022 updated by: GSO Global Clinical Research BV

An Investigator Initiated Phase 1 Trial To Evaluate mFOLFOX6 With Selinexor (KPT-330), An Oral Selective Inhibitor Of Nuclear Export (SINE), In Patients With Metastatic Colorectal Cancer

This trial will evaluate the combination treatment of established chemotherapy regimen mFOLFOX6 with Selinexor, an oral Selective Inhibitor Of Nuclear Export, in patients with metastatic Colorectal Cancer. The purpose is to determine the maximum tolerated dose (MTD) of selinexor in combination with mFOLFOX6.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

This was a multi center, open-label, non-randomized phase I trial study to determine the MTD of a combination of mFOLFOX6 (Folinic Acid (Leucovorin)-Fluorouracil-Oxaliplatin) and selinexor in patients with metastatic colorectal cancer.

After screening and registration in the study, all enrolled patients were to be treated with oxaliplatin (85 mg/m² IV over 2 hours, Day 1), 5-FU (5-Fluorouracil 400 mg/m2 IV bolus, Day 1), leukovorin (400 mg/m2 IV over 2 hours, Day 1), and 5-FU (2,400 mg/m² continuous infusion, Days 1-3) every 2 weeks and escalating doses of selinexor as follows:

Patients in Dose Level 1 were to receive oral selinexor 40 mg on day 1, 3, and 8.

Patients in Dose Level 2 were to receive oral selinexor 60 mg on day 1, 3, and 8.

Patients in Dose Level 3 were to receive oral selinexor 80 mg on day 1, 3, and 8.

Patients in Dose Level -1 were to receive oral selinexor 20 mg on day 1, 3, and 8.

The MTD was defined as the highest dose level at which six patients had been treated with no toxicity and tolerance of the dose escalation of Selinexor with mFOLFOX6 was evaluated.

Six patients were to be initially treated in a cohort. Safety data were monitored in real time. As soon as last patient of the cohort (either 6th or 9th) reached day 28, safety data of all patients within that cohort were reviewed for decision about opening up a new cohort by moving to the next dose level or expand the cohort or discontinue dose escalation.

Study Type

Interventional

Enrollment (Actual)

10

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Belgium
      • Antwerpen, Belgium, 1200
        • University Hospital Antwerpen
  • Germany
      • Hamburg, Germany, 20246
        • University Hospital Hamburg

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Patients with histologically confirmed diagnosis of colorectal cancer presenting with unresectable stage IV (UICC) disease (primary tumor may be present)
  2. Patients who are feasible for treatment with FOLFOX (prior adjuvant or palliative treatment is allowed)
  3. ECOG (Eastern Cooperative Oncology Group) Performance status ≤ 1
  4. Life expectancy > 3 months
  5. Age ≥18 years

  6. Haematologic function as follows (5% deviation allowed):

    • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
    • platelets ≥ 100 x109/L
    • hemoglobin ≥ 9 g/dl or 5.59 mmol/l

  7. Adequate liver function as follows (10% deviation allowed)

    • serum alanine transaminase (ALT) ≤ 2.5 x ULN (in case of liver metastases < 5 x ULN)
    • total bilirubin ≤ 1.5 x ULN (patients with Gilbert's syndrome total bilirubin ≤2.5 x ULN)

  8. Adequate renal function as follows (10% deviation allowed)

    · creatinine ≤ 1.5 x ULN

  9. Signed written informed consent
  10. Women of child-bearing potential must have a negative pregnancy test

Exclusion Criteria:

adequately controlled with appropriate therapy or would compromise the patient's ability to tolerate this therapy; 2. Treatment with any systemic anticancer therapy ≤ 3 weeks prior to cycle 1 day 1 3. Uncontrolled active infection (Hepatitis B and C infection are NOT exclusion criteria) and/or known HIV infection; 4. Renal failure requiring haemodialysis or peritoneal dialysis; 5. Patients who are pregnant or breast-feeding; 6. Patients with significantly diseased or obstructed gastrointestinal tract, malabsorption, uncontrolled vomiting or diarrhea resulting in inability to swallow oral medications; 7. Presence of symptomatic Central nervous system (CNS) metastasis 8. Unresolved toxicity from previous anti-cancer therapy or incomplete recovery from surgery, in particular oxaliplatin-induced peripheral neuropathy > grade 1.

9. Any of the following within the 12 months prior to study drug administration: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, pulmonary embolism, deep vein thrombosis, or other thromboembolic event.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: NA
  • Interventional Model: SEQUENTIAL
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Selinexor + mFOLFOX6
Different Dose Levels of Selinexor will be evaluated in combination with mFOLFOX6 (see interventions)
Drug: Selinexor
Dose Level 1: 40 mg on day 1, 3 and 8 in a two-weeks cycle. Dose Level 2: 60 mg on day 1, 3 and 8 in a two-weeks cycle. Dose Level 3: 80 mg on day 1, 3 and 8 in a two-weeks cycle. Dose Level -1: 20 mg on day 1, 3 and 8 in a two-weeks cycle.
Other Names:
  • KPT-330
Drug: Oxaliplatin
85 mg/m² IV over 2 hours, Day 1 of a two-weeks cycle
Other Names:
  • oxalatoplatin
Drug: 5-FU
400 mg/m² IV bolus, Day 1 of a two-weeks cycle 2,400 mg/m² continuous infusion IV, Days 1-3
Other Names:
  • 5-fluorouracil
Drug: Folinic Acid
400 mg/m2 IV over 2 hours, Day 1 of a two-weeks cycle
Other Names:
  • leucovorin

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Numbers of Patients With Dose Limiting Toxicities
Time Frame: 28 days of treatment

Primary objective is the determination of the maximum tolerated dose (MTD) of selinexor in combination with mFOLFOX6 in patients with metastatic colorectal cancer.

Criteria to assess MTD was the experience of AEs > grade 3, discontinuation from study treatment due to adverse events or withdrawal of consent by the patients.
28 days of treatment

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall Response Rate
Time Frame: 2 years

Secondary objectives are to determine the efficacy and tolerability of selinexor in combination with mFOLFOX6 in patients with metastatic colorectal cancer by

- Overall response rate (RR) (acc. to RECIST v1.1)

Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed byCT or MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
2 years
Progression Free Survival (PFS)
Time Frame: 2 years

Secondary objectives are to determine the efficacy and tolerability of selinexor in combination with mFOLFOX6 in patients with metastatic colorectal cancer by

- Progression free survival (PFS) The disease status was measured by CT/MRI and evaluated according to RECIST 1.1 criteria every 8 weeks during treatment, at End of Treatment and every 3 weeks during Follow-up to determine time until patient has Progressive Disease (PD). PD is defined according to RECIST v1.1 at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression.
2 years
Number of Patients Still Alive at End of Study (Overall Survival)
Time Frame: 2 years

Secondary objectives are to determine the efficacy and tolerability of selinexor in combination with mFOLFOX6 in patients with metastatic colorectal cancer by

- Overall survival (OS)

Overall survial is defined as length of time from start of treatment that patients are still alive. For this time-to-event variables the Kaplan-Meier method was intended to be used
2 years
Number of Patients Experiencing Adverse Events
Time Frame: treatment start to up to 30 days after last dose

Secondary objectives are to determine the efficacy and tolerability of selinexor in combination with mFOLFOX6 in patients with metastatic colorectal cancer by

- Toxicity (acc. to NCI Common Terminology Criteria for Adverse Events (CTC AE) v4.03)
treatment start to up to 30 days after last dose

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

GSO Global Clinical Research BV

Collaborators

Karyopharm Therapeutics Inc

Investigators

  • Principal Investigator: Carsten Bokemeyer, Prof. Dr., University Hospital Hamburg

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

March 1, 2015

Primary Completion (ACTUAL)

March 9, 2017

Study Completion (ACTUAL)

March 9, 2017

Study Registration Dates

First Submitted

March 2, 2015

First Submitted That Met QC Criteria

March 4, 2015

First Posted (ESTIMATE)

March 10, 2015

Study Record Updates

Last Update Posted (ACTUAL)

April 8, 2022

Last Update Submitted That Met QC Criteria

February 7, 2022

Last Verified

February 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • SENTINEL

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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