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

Primary Purpose

Colorectal Neoplasm

Status

Terminated

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

Selinexor

Oxaliplatin

5-FU

Folinic Acid

About this trial

This is an interventional treatment trial for Colorectal Neoplasm focused on measuring metastatic

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Patients with histologically confirmed diagnosis of colorectal cancer presenting with unresectable stage IV (UICC) disease (primary tumor may be present)
Patients who are feasible for treatment with FOLFOX (prior adjuvant or palliative treatment is allowed)
ECOG (Eastern Cooperative Oncology Group) Performance status ≤ 1
Life expectancy > 3 months
Age ≥18 years
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
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)
Adequate renal function as follows (10% deviation allowed)
· creatinine ≤ 1.5 x ULN
Signed written informed consent
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.

Sites / Locations

University Hospital Antwerpen
University Hospital Hamburg

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Selinexor + mFOLFOX6

Arm Description

Different Dose Levels of Selinexor will be evaluated in combination with mFOLFOX6 (see interventions)

Outcomes

Primary Outcome Measures

Numbers of Patients With Dose Limiting Toxicities

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.

Secondary Outcome Measures

Overall Response Rate

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.

Progression Free Survival (PFS)

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.

Number of Patients Still Alive at End of Study (Overall Survival)

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

Number of Patients Experiencing Adverse Events

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)

Full Information

NCT ID

NCT02384850

First Posted

March 2, 2015

Last Updated

February 7, 2022

Sponsor

GSO Global Clinical Research BV

Collaborators

Karyopharm Therapeutics Inc

1. Study Identification

Unique Protocol Identification Number

NCT02384850

Brief Title

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

Acronym

SENTINEL

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

February 2022

Overall Recruitment Status

Terminated

Study Start Date

March 2015 (undefined)

Primary Completion Date

March 9, 2017 (Actual)

Study Completion Date

March 9, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

GSO Global Clinical Research BV

Collaborators

Karyopharm Therapeutics Inc

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Colorectal Neoplasm

Keywords

metastatic

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Sequential Assignment

Model Description

Dose level 1: Oxaliplatin at a dose of 85 mg/m2 IV over two hours (Day 1) 5-FU 400 mg/m2 IV bolus (Day 1) Leucovorin 400 mg/m2 IV over two hours (Day 1) 5-FU 2400 mg/m2 IV over 46 hours (Day 1-3) Selinexor 40 mg, PO (Day 1, 3 and 8) Dose level 2: Oxaliplatin at a dose of 85 mg/m2 IV over two hours (Day 1) 5-FU 400 mg/m2 IV bolus (Day 1) Leucovorin 400 mg/m2 IV over two hours (Day 1) 5-FU 2400 mg/m2 iv over 46 hours (Day 1-3) Selinexor 60 mg, PO (Day 1, 3 and 8) Dose level 3: Oxaliplatin at a dose of 85 mg/m2 iv over two hours (Day 1) 5-FU 400 mg/m2 iv bolus (Day 1) Leucovorin 400 mg/m2 iv over two hours (Day 1) 5-FU 2400 mg/m2 iv over 46 hours (Day 1-3) Selinexor 80 mg, PO (Day 1, 3 and 8) Dose level -1: Oxaliplatin at a dose of 85 mg/m2 IV over two hours (Day 1) 5-FU 400 mg/m2 IV bolus (Day 1) Leucovorin 400 mg/m2 IV over two hours (Day 1) 5-FU 2400 mg/m2 IV over 46 hours (Day 1-3) Selinexor 20 mg, PO (Day 1, 3 and 8)

Masking

None (Open Label)

Allocation

N/A

Enrollment

10 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Selinexor + mFOLFOX6

Arm Type

Experimental

Arm Description

Different Dose Levels of Selinexor will be evaluated in combination with mFOLFOX6 (see interventions)

Intervention Type

Drug

Intervention Name(s)

Selinexor

Other Intervention Name(s)

KPT-330

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Oxaliplatin

Other Intervention Name(s)

oxalatoplatin

Intervention Description

85 mg/m² IV over 2 hours, Day 1 of a two-weeks cycle

Intervention Type

Drug

Intervention Name(s)

5-FU

Other Intervention Name(s)

5-fluorouracil

Intervention Description

400 mg/m² IV bolus, Day 1 of a two-weeks cycle 2,400 mg/m² continuous infusion IV, Days 1-3

Intervention Type

Drug

Intervention Name(s)

Folinic Acid

Other Intervention Name(s)

leucovorin

Intervention Description

400 mg/m2 IV over 2 hours, Day 1 of a two-weeks cycle

Primary Outcome Measure Information:

Title

Numbers of Patients With Dose Limiting Toxicities

Description

Time Frame

28 days of treatment

Secondary Outcome Measure Information:

Title

Overall Response Rate

Description

Time Frame

2 years

Title

Progression Free Survival (PFS)

Description

Time Frame

2 years

Title

Number of Patients Still Alive at End of Study (Overall Survival)

Description

Time Frame

2 years

Title

Number of Patients Experiencing Adverse Events

Description

Time Frame

treatment start to up to 30 days after last dose

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Patients with histologically confirmed diagnosis of colorectal cancer presenting with unresectable stage IV (UICC) disease (primary tumor may be present) Patients who are feasible for treatment with FOLFOX (prior adjuvant or palliative treatment is allowed) ECOG (Eastern Cooperative Oncology Group) Performance status ≤ 1 Life expectancy > 3 months Age ≥18 years 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 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) Adequate renal function as follows (10% deviation allowed) · creatinine ≤ 1.5 x ULN Signed written informed consent 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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Carsten Bokemeyer, Prof. Dr.

Organizational Affiliation

University Hospital Hamburg

Official's Role

Principal Investigator

Facility Information:

Facility Name

University Hospital Antwerpen

City

Antwerpen

ZIP/Postal Code

1200

Country

Belgium

Facility Name

University Hospital Hamburg

City

Hamburg

ZIP/Postal Code

20246

Country

Germany

12. IPD Sharing Statement

Citations:

PubMed Identifier

32598257

Citation

Nilsson S, Stein A, Rolfo C, Kranich AL, Mann J, Papadimitriou K, Theile S, Amberg S, Bokemeyer C. Selinexor (KPT-330), an Oral Selective Inhibitor of Nuclear Export (SINE) Compound, in Combination with FOLFOX in Patients with Metastatic Colorectal Cancer (mCRC) - Final Results of the Phase I Trial SENTINEL. Curr Cancer Drug Targets. 2020;20(10):811-817. doi: 10.2174/1568009620666200628105727.

Results Reference

derived

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

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