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

Study Results

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Basic Information

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Recruitment Status

TERMINATED

Clinical Phase

PHASE1

Total Enrollment

10 participants

Study Classification

INTERVENTIONAL

Study Start Date

2015-03-31

Study Completion Date

2017-03-09

Brief Summary

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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.

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Detailed Description

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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.

Conditions

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Colorectal Neoplasm

Study Design

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Allocation Method

NA

Intervention Model

SEQUENTIAL

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)

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Selinexor + mFOLFOX6

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

Group Type EXPERIMENTAL

Selinexor

Intervention Type DRUG

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

Intervention Type DRUG

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

5-FU

Intervention Type DRUG

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

Folinic Acid

Intervention Type DRUG

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

Interventions

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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.

Intervention Type DRUG

Oxaliplatin

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

Intervention Type 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

Intervention Type DRUG

Folinic Acid

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

Intervention Type DRUG

Other Intervention Names

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KPT-330 oxalatoplatin 5-fluorouracil leucovorin

Eligibility Criteria

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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

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.

Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No