Colorectal Neoplasm
Conditions
Keywords
metastatic
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.
Interventions
DRUGSelinexor
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.
DRUGOxaliplatin
85 mg/m² IV over 2 hours, Day 1 of a two-weeks cycle
DRUG5-FU
400 mg/m² IV bolus, Day 1 of a two-weeks cycle 2,400 mg/m² continuous infusion IV, Days 1-3
DRUGFolinic Acid
400 mg/m2 IV over 2 hours, Day 1 of a two-weeks cycle
Sponsors
Karyopharm Therapeutics Inc
GSO Global Clinical Research BV
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention 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)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Numbers of Patients With Dose Limiting Toxicities | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate | 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. |
| Progression Free Survival (PFS) | 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. |
| Number of Patients Still Alive at End of Study (Overall Survival) | 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 |
| Number of Patients Experiencing Adverse Events | 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) |
Countries
Belgium, Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Selinexor 40mg + mFOLFOX6 Selinexor: Dose Level 1: 40 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 | 4 |
| Selinexor 20mg + mFOLFOX6 Selinexor: 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 | 6 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 2 | 2 |
Baseline characteristics
| Characteristic | Selinexor 40mg + mFOLFOX6 | Selinexor 20mg + mFOLFOX6 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 3 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 3 Participants | 7 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 6 Participants | 10 Participants |
| Region of Enrollment Belgium | 0 participants | 2 participants | 2 participants |
| Region of Enrollment Germany | 4 participants | 4 participants | 8 participants |
| Sex: Female, Male Female | 2 Participants | 4 Participants | 6 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 2 / 6 |
| other Total, other adverse events | 4 / 4 | 6 / 6 |
| serious Total, serious adverse events | 2 / 4 | 3 / 6 |
Outcome results
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.
Time frame: 28 days of treatment
Population: The study was closed due to toxicity despite dose reduction to 20 mg Seiinexor.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Selinexor 40 mg+ mFOLFOX6 | Numbers of Patients With Dose Limiting Toxicities | Discontinuation due to Adverse events | 2 Participants |
| Selinexor 40 mg+ mFOLFOX6 | Numbers of Patients With Dose Limiting Toxicities | Discontinuation due to Withdrawal of Consent | 2 Participants |
| Selinexor 40 mg+ mFOLFOX6 | Numbers of Patients With Dose Limiting Toxicities | Discontinuation due to Progressive Disease | 0 Participants |
| Selinexor 20mg + mFOLFOX6 | Numbers of Patients With Dose Limiting Toxicities | Discontinuation due to Adverse events | 2 Participants |
| Selinexor 20mg + mFOLFOX6 | Numbers of Patients With Dose Limiting Toxicities | Discontinuation due to Withdrawal of Consent | 2 Participants |
| Selinexor 20mg + mFOLFOX6 | Numbers of Patients With Dose Limiting Toxicities | Discontinuation due to Progressive Disease | 2 Participants |
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)
Time frame: treatment start to up to 30 days after last dose
Population: All 10 patients were treated with at least one dose of Selinexor.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Selinexor 40 mg+ mFOLFOX6 | Number of Patients Experiencing Adverse Events | Patients with AEs of any CTCAE Grade | 4 Participants |
| Selinexor 40 mg+ mFOLFOX6 | Number of Patients Experiencing Adverse Events | Patients with AEs of at least CTCAE Grade 3 | 4 Participants |
| Selinexor 40 mg+ mFOLFOX6 | Number of Patients Experiencing Adverse Events | Patients with Selinexor related AEs of any Grade | 4 Participants |
| Selinexor 40 mg+ mFOLFOX6 | Number of Patients Experiencing Adverse Events | Patients with Selinexor related AEs of at least Grade 3 | 4 Participants |
| Selinexor 40 mg+ mFOLFOX6 | Number of Patients Experiencing Adverse Events | Patients with chemotherapy related AEs of any Grade | 4 Participants |
| Selinexor 40 mg+ mFOLFOX6 | Number of Patients Experiencing Adverse Events | Patients with chemotherapy related AEs of at least Grade 3 | 4 Participants |
| Selinexor 40 mg+ mFOLFOX6 | Number of Patients Experiencing Adverse Events | Patients with AEs leading to discontinuation | 2 Participants |
| Selinexor 40 mg+ mFOLFOX6 | Number of Patients Experiencing Adverse Events | Patients with at least 1 SAE | 2 Participants |
| Selinexor 40 mg+ mFOLFOX6 | Number of Patients Experiencing Adverse Events | Patients with at least 1 SAE related to Selinexor | 1 Participants |
| Selinexor 40 mg+ mFOLFOX6 | Number of Patients Experiencing Adverse Events | Patients with at least 1 SAE related to chemotherapy | 1 Participants |
| Selinexor 20mg + mFOLFOX6 | Number of Patients Experiencing Adverse Events | Patients with at least 1 SAE | 3 Participants |
| Selinexor 20mg + mFOLFOX6 | Number of Patients Experiencing Adverse Events | Patients with AEs of any CTCAE Grade | 6 Participants |
| Selinexor 20mg + mFOLFOX6 | Number of Patients Experiencing Adverse Events | Patients with chemotherapy related AEs of at least Grade 3 | 3 Participants |
| Selinexor 20mg + mFOLFOX6 | Number of Patients Experiencing Adverse Events | Patients with AEs of at least CTCAE Grade 3 | 6 Participants |
| Selinexor 20mg + mFOLFOX6 | Number of Patients Experiencing Adverse Events | Patients with at least 1 SAE related to chemotherapy | 3 Participants |
| Selinexor 20mg + mFOLFOX6 | Number of Patients Experiencing Adverse Events | Patients with Selinexor related AEs of any Grade | 4 Participants |
| Selinexor 20mg + mFOLFOX6 | Number of Patients Experiencing Adverse Events | Patients with AEs leading to discontinuation | 2 Participants |
| Selinexor 20mg + mFOLFOX6 | Number of Patients Experiencing Adverse Events | Patients with Selinexor related AEs of at least Grade 3 | 5 Participants |
| Selinexor 20mg + mFOLFOX6 | Number of Patients Experiencing Adverse Events | Patients with at least 1 SAE related to Selinexor | 1 Participants |
| Selinexor 20mg + mFOLFOX6 | Number of Patients Experiencing Adverse Events | Patients with chemotherapy related AEs of any Grade | 6 Participants |
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
Time frame: 2 years
Population: Due to sparse data set, no analysis with Kaplan-Meier methods was done.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Selinexor 40 mg+ mFOLFOX6 | Number of Patients Still Alive at End of Study (Overall Survival) | 0 Participants |
| Selinexor 20mg + mFOLFOX6 | Number of Patients Still Alive at End of Study (Overall Survival) | 2 Participants |
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.
Time frame: 2 years
Population: Due to the low number of patients, no conclusions can be drawn from analysis of the efficacy data.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Selinexor 40 mg+ mFOLFOX6 | Overall Response Rate | 0 Participants |
| Selinexor 20mg + mFOLFOX6 | Overall Response Rate | 1 Participants |
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.
Time frame: 2 years
Population: Four patients withdrew consent to further participate in the study before the first tumour assessment had been performed. No data on PD were available for those patients. Additionally, for two patients in cohort 2, no information on PD during the follow-up period is available.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Selinexor 40 mg+ mFOLFOX6 | Progression Free Survival (PFS) | NA months |
| Selinexor 20mg + mFOLFOX6 | Progression Free Survival (PFS) | NA months |