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

Colorectal Neoplasm Clinical Trial

— 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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02384850
• Other study ID #: SENTINEL
• Status: Terminated
• Phase: Phase 1
• Start date: March 2015
• Est. completion date: March 9, 2017

Study information

• Verified date: February 2022
• Source: GSO Global Clinical Research BV
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 10
• Est. completion date: March 9, 2017
• Est. primary completion date: March 9, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Colorectal Neoplasm
• Colorectal Neoplasms

Intervention

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.
• Oxaliplatin
85 mg/m² IV over 2 hours, Day 1 of a two-weeks cycle
• 5-FU
400 mg/m² IV bolus, Day 1 of a two-weeks cycle 2,400 mg/m² continuous infusion IV, Days 1-3
• Folinic Acid
400 mg/m2 IV over 2 hours, Day 1 of a two-weeks cycle

Locations

Country	Name	City	State
Belgium	University Hospital Antwerpen	Antwerpen
Germany	University Hospital Hamburg	Hamburg

Sponsors (2)

Lead Sponsor	Collaborator
GSO Global Clinical Research BV	Karyopharm Therapeutics Inc

Countries where clinical trial is conducted

Belgium,  Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	28 days of treatment
Secondary	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.	2 years
Secondary	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.	2 years
Secondary	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	2 years
Secondary	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)	treatment start to up to 30 days after last dose