Neoplasms
Conditions
Keywords
Patients with Cancer
Brief summary
Phase I: Determine the maximum tolerated dose of combination of Regorafenib with Refametinib through a dose escalation study, all tumor types that meet certain inclusion/exclusion criteria can be entered. After the recommended dose is determined, the Phase II portion of the study will evaluate tolerability and efficacy of the combination treatment in patients with breast cancer, lung cancer, or colorectal cancer, respectively.
Detailed description
Number of treatment-emergent Adverse Events (AEs) will be reported in Adverse Events section. Study was originally designed with both Phase I and Phase II part, but sponsor decided not to conduct Phase 2 part due to strategic portfolio re-prioritization.
Interventions
Refametinib twice daily (b.i.d.) in combination with intermittent regorafenib once daily (q.d.) at the assigned dose level. In Phase 2, the recommended Phase 2 dose (RP2D) for refametinib-regorafenib combination therapy will be used.
DRUGRegorafenib (Stivarga, BAY73-4506)
Refametinib twice daily (b.i.d.) in combination with intermittent regorafenib once daily (q.d.) at the assigned dose level. In Phase 1b dose escalation, regorafenib will be administered in a 3-weeks-on / 1-week-off schedule except in one cohort, that uses regorafenib 2 weeks on / 2 weeks off regimen (dose level -2). In Phase 2, the recommended Phase 2 dose (RP2D) for refametinib-regorafenib combination therapy will be used.
Sponsors
Bayer
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Criteria for the Phase 1b: * Patients with locally advanced or metastatic solid tumors who have either relapsed following, or progressed through, standard therapy; have a current disease state for which there is no standard effective therapy; is not a candidate for, or is unwilling to undergo, standard therapy in cases where no curative option exists. * Cohort-specific criteria for Phase 2: * CRC (Colorectal cancer): Patients with metastatic CRC and known KRAS (Kirsten rat sarcoma viral oncogene homolog) status who are eligible for treatment with regorafenib in accordance with the approved labeling. * NSCLC (Non-small-cell lung cancer): Patients with NSCLC and known KRAS status after platinum based chemotherapy. * Breast cancer: Patients with Her-2 negative breast cancer after anthracycline and taxane based chemotherapy. * Baseline tumor tissue to conduct molecular and / or genetic studies should be available from all study patients enrolled in this study. (optional in Phase 1b) * Patients must have at least one uni-dimensional measurable lesion by CT or MRI according to Response Evaluation Criteria in Solid Tumors (RECIST)version 1.1. (applicable only in Phase 2) * Male or female patients ≥ 18 years of age (only female patients in breast cancer cohort of Phase 2). * Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 * Life expectancy of at least 3 months * Adequate bone marrow, liver and renal function * Cardiac function within normal range
Exclusion criteria
* Prior treatment with refametinib or regorafenib. * Metastatic brain or meningeal tumors * Uncontrolled hypertension despite optimal medical management * History of cardiac disease * Arterial or venous thrombotic or embolic events * Any hemorrhage or bleeding event * History or current evidence of retinal vein occlusion (RVO) or central serous retinopathy (CSR). * Any condition that was unstable or which could jeopardize the safety of the patient and his/her compliance in the study. * Excluded previous therapies and medications: * Radiotherapy within 3 weeks prior to start of treatment * Systemic anticancer therapy including cytotoxic therapy, signal transduction inhibitors, immunotherapy, and hormonal therapy during this trial or within 28 days or 5 drug half-lives (if drug half-life in patients is known), whichever is shorter (or within 6 weeks for mitomycin C) before start of the study treatment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting Toxicities (DLTs) | At Cycle 1 | Dose-limiting toxicities (DLTs) were analyzed in the maximum tolerated dose (MTD) analysis set, in which only the six first patients of each dose escalation Cohort could be included according to the modified Rolling-6 method that was applied in this study. |
| Maximum Drug Concentration in Plasma After Multiple Dose (Cmax,md) for Refametinib | Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8 and 12 hours post-dose | Maximum drug concentration in plasma after multiple dose for Refametinib. Geometric mean and percentage geometric coefficient of variation (%CV) were reported. |
| Maximum Drug Concentration in Plasma After Multiple Dose (Cmax,md) for Refametinib Metabolite M-11 | Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8 and 12 hours post-dose | Maximum drug concentration in plasma after multiple dose for Refametinib metabolite M-11. Geometric mean and percentage geometric coefficient of variation (%CV) were reported. |
| Area Under the Plasma Concentration-time Curve From 0 to 12 h After Multiple Dose (AUC(0-12)md) for Refametinib | Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8 and 12 hours post-dose | Area under the plasma concentration-time curve from 0 to 12 h after multiple dose for Refametinib. Geometric mean and percentage geometric coefficient of variation (%CV) were reported. |
| Area Under the Plasma Concentration-time Curve From 0 to 12 h After Multiple Dose (AUC(0-12)md) for Refametinib Metabolite M-11 | Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8 and 12 hours post-dose | Area under the plasma concentration-time curve from 0 to 12 h after multiple dose for Refametinib metabolite M-11. Geometric mean and percentage geometric coefficient of variation (%CV) were reported. |
| Maximum Drug Concentration in Plasma After Multiple Dose (Cmax,md) for Regorafenib | Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose | Maximum drug concentration in plasma after multiple dose for Regorafenib. Geometric mean and percentage geometric coefficient of variation (%CV) were reported. |
| Maximum Drug Concentration in Plasma After Multiple Dose (Cmax,md) for Regorafenib Metabolite M-2 | Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose | Maximum drug concentration in plasma after multiple dose for Regorafenib metabolite M-2. Geometric mean and percentage geometric coefficient of variation (%CV) were reported. |
| Maximum Drug Concentration in Plasma After Multiple Dose (Cmax,md) for Regorafenib Metabolite M-5 | Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose | Maximum drug concentration in plasma after multiple dose for Regorafenib metabolite M-5. Geometric mean and percentage geometric coefficient of variation (%CV) were reported. |
| Area Under the Plasma Concentration-time Curve From 0 to 24 h After Multiple Dose (AUC(0-24)md) for Regorafenib | Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose | Area under the plasma concentration-time curve from 0 to 24 h after multiple dose for Regorafenib. Geometric mean and percentage geometric coefficient of variation (%CV) were reported. |
| Area Under the Plasma Concentration-time Curve From 0 to 24 h After Multiple Dose (AUC(0-24)md) for Regorafenib Metabolite M-2 | Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose | Area under the plasma concentration-time curve from 0 to 24 h after multiple dose for Regorafenib metabolite M-2. Geometric mean and percentage geometric coefficient of variation (%CV) were reported. |
| Area Under the Plasma Concentration-time Curve From 0 to 24 h After Multiple Dose (AUC(0-24)md) for Regorafenib Metabolite M-5 | Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose | Area under the plasma concentration-time curve from 0 to 24 h after multiple dose for Regorafenib metabolite M-5. Geometric mean and percentage geometric coefficient of variation (%CV) were reported. |
| Tumor Response During Phase 2 as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | Up to 12 months | Tumor Response was defined as the best tumor response (Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD)) observed during trial period assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. CR was defined as disappearance of tumor lesions, PR was defined as a decrease of at least 30% in the sum of tumor lesion sizes, SD was defined as steady state of disease, PD was defined as an increase of at least 20% in the sum of tumor lesions sizes. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Drug Concentration in Plasma After Single (First) Dose (Cmax) for Refametinib and Its Metabolite M-11 | Cycle 1 Day 1 at 0 (pre-dose), 0.5, 1, 2, 4 and 8 hours post-dose | Maximum drug concentration in plasma after single (first) dose for Refametinib and its metabolite M-11. Geometric mean and percentage geometric coefficient of variation (%CV) were reported. |
| Time to Reach Maximum Drug Concentration in Plasma After Single (First) Dose (Tmax) for Refametinib and Its Metabolite M-11 | Cycle 1 Day 1 at 0 (pre-dose), 0.5, 1, 2, 4 and 8 hours post-dose | Time to reach maximum drug concentration in plasma after single (first) dose for Refametinib and its metabolite M-11. Median and full range were reported. |
| Area Under the Plasma Concentration-time Curve From 0 to 8 h (AUC(0-8)) After Single (First) Dose for Refametinib and Its Metabolite M-11 | Cycle 1 Day 1 at 0 (pre-dose), 0.5, 1, 2, 4 and 8 hours post-dose | Area under the plasma concentration-time curve from 0 to 8 h after single (first) dose for Refametinib and its metabolite M-11. Geometric mean and percentage geometric coefficient of variation (%CV) were reported. |
| Time to Reach Maximum Drug Concentration in Plasma After Multiple Dose (Tmax,md) for Refametinib and Its Metabolite M-11 | Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8 and 12 hours post-dose | Time to reach maximum drug concentration in plasma after multiple dose for Refametinib and its metabolite M-11. Median and full range were reported. |
| Maximum Drug Concentration in Plasma After Single (First) Dose (Cmax) for Regorafenib and Its Metabolites M-2 and M-5 | Cycle 1 Day 1 at 0 (pre-dose), 0.5, 1, 2, 4, 8 and 24 hours post-dose | Maximum drug concentration in plasma after single (first) dose for Regorafenib and its metabolites M-2 and M-5. Geometric mean and percentage geometric coefficient of variation (%CV) were reported. |
| Time to Reach Maximum Drug Concentration in Plasma After Single (First) Dose (Tmax) for Regorafenib and Its Metabolites M-2 and M-5 | Cycle 1 Day 1 at 0 (pre-dose), 0.5, 1, 2, 4, 8 and 24 hours post-dose | Time to reach maximum drug concentration in plasma after single (first) dose for Regorafenib and its metabolites M-2 and M-5. Median and full range were reported. |
| Area Under the Plasma Concentration-time Curve From 0 to 24 h (AUC(0-24)) After Single (First) Dose for Regorafenib and Its Metabolites M-2 and M-5 | Cycle 1 Day 1 at 0 (pre-dose), 0.5, 1, 2, 4, 8 and 24 hours post-dose | Area under the plasma concentration-time curve from 0 to 24 h after single (first) dose for Regorafenib and its metabolites M-2 and M-5. Geometric mean and percentage geometric coefficient of variation (%CV) were reported. |
| Time to Reach Maximum Drug Concentration in Plasma After Multiple Dose (Tmax,md) for Regorafenib and Its Metabolites M-2 and M-5 | Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose | Time to reach maximum drug concentration in plasma after multiple dose for Regorafenib and its metabolites M-2 and M-5. Median and full range were reported. |
| Tumor Response During Phase 1b as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | From start of treatment until progression is documented | Tumor Response was defined as the best tumor response (Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progressive Disease (PD)) observed during trial period assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST). CR was defined as disappearance of all target and non-target tumor lesions, PR was defined as a decrease of at least 30% in the sum of diameters of target lesions, SD was defined neither sufficient shrinkage for PR nor sufficient increase for PD, PD was defined as an increase of at least 20% in the sum of diameters of target lesions. |
| Overall Survival During Phase 2 | Up to 12 months after last patient first visit | Overall survival (OS) was defined as the time (days) from the treatment start date to the date of death due to any cause. For participants who were still alive or who were lost to follow-up as of the database cutoff date for the primary completion, OS was censored at the last known alive date on or prior to the database cutoff date. |
| Time to Progression During Phase 2 | From start of treatment until progression is documented | Time to progression was defined as the time (days) from the treatment start date to the disease progression on or following the start date. Participants not experiencing progression at the database cutoff date for primary completion were censored at the last assessment. |
| Progression-free Survival During Phase 2 | From start of treatment until progression is documented | Progression-free survival was defined as the time from date of treatment assignment to date of first observed disease progression or death due to any cause, if death occurred while the participant was in the study and before progression was observed. |
Countries
United States
Participant flow
Recruitment details
Study was planned to have two parts, Phase 1b part and Phase 2 part. For the Phase 1b part, altogether 34 participants were screened, and 14 out of them were screening failures.
Pre-assignment details
The remaining 20 participants were assigned to and started treatment in one of three dose escalation cohorts. The Phase 2 part was not conducted.
Participants by arm
| Arm | Count |
|---|---|
| Ph1b-Refametinib/Regorafenib Cohort 0 Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort 0: Refametinib 30mg twice daily (b.i.d) + Regorafenib 80mg once daily (q.d), 3 weeks on/1 week off. | 2 |
| Ph1b-Refametinib/Regorafenib Cohort -1 Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1: Refametinib 20mg b.i.d + Regorafenib 80mg q.d, 3 weeks on/1 week off. | 7 |
| Ph1b-Refametinib/Regorafenib Cohort -1a Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1a: Refametinib 20mg b.i.d + Regorafenib 120mg q.d, 3 weeks on/1 week off. | 11 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 1 |
| Overall Study | Clinical disease progression | 0 | 1 | 2 |
| Overall Study | Disease recurrence | 0 | 0 | 1 |
| Overall Study | Other reason | 0 | 1 | 0 |
| Overall Study | Radiological disease progression | 0 | 5 | 5 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 2 |
Baseline characteristics
| Characteristic | Ph1b-Refametinib/Regorafenib Cohort 0 | Ph1b-Refametinib/Regorafenib Cohort -1 | Ph1b-Refametinib/Regorafenib Cohort -1a | Total |
|---|---|---|---|---|
| Age, Continuous | 57.0 Years STANDARD_DEVIATION 14.1 | 56.6 Years STANDARD_DEVIATION 5.7 | 58.6 Years STANDARD_DEVIATION 7.3 | 57.8 Years STANDARD_DEVIATION 7.1 |
| Cancer types Breast cancer | 0 Participants | 2 Participants | 2 Participants | 4 Participants |
| Cancer types Colon and rectal cancer | 1 Participants | 0 Participants | 4 Participants | 5 Participants |
| Cancer types Non-small cell lung cancer | 0 Participants | 3 Participants | 1 Participants | 4 Participants |
| Cancer types Other | 1 Participants | 2 Participants | 2 Participants | 5 Participants |
| Cancer types Pancreatic adenocarcinoma | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Female | 1 Participants | 4 Participants | 4 Participants | 9 Participants |
| Sex: Female, Male Male | 1 Participants | 3 Participants | 7 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 2 | 7 / 7 | 11 / 11 |
| serious Total, serious adverse events | 0 / 2 | 4 / 7 | 5 / 11 |
Outcome results
Primary
Area Under the Plasma Concentration-time Curve From 0 to 12 h After Multiple Dose (AUC(0-12)md) for Refametinib
Area under the plasma concentration-time curve from 0 to 12 h after multiple dose for Refametinib. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
Time frame: Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8 and 12 hours post-dose
Population: PK analysis set for multiple dose.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Ph1b-Refametinib/Regorafenib Cohort 0 | Area Under the Plasma Concentration-time Curve From 0 to 12 h After Multiple Dose (AUC(0-12)md) for Refametinib | NA μg*h/L | — |
| Ph1b-Refametinib/Regorafenib Cohort -1 | Area Under the Plasma Concentration-time Curve From 0 to 12 h After Multiple Dose (AUC(0-12)md) for Refametinib | 2399.2 μg*h/L | Geometric Coefficient of Variation 65 |
| Ph1b-Refametinib/Regorafenib Cohort -1a | Area Under the Plasma Concentration-time Curve From 0 to 12 h After Multiple Dose (AUC(0-12)md) for Refametinib | 3632.3 μg*h/L | Geometric Coefficient of Variation 51 |
Primary
Area Under the Plasma Concentration-time Curve From 0 to 12 h After Multiple Dose (AUC(0-12)md) for Refametinib Metabolite M-11
Area under the plasma concentration-time curve from 0 to 12 h after multiple dose for Refametinib metabolite M-11. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
Time frame: Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8 and 12 hours post-dose
Population: PK analysis set for multiple dose.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Ph1b-Refametinib/Regorafenib Cohort 0 | Area Under the Plasma Concentration-time Curve From 0 to 12 h After Multiple Dose (AUC(0-12)md) for Refametinib Metabolite M-11 | NA μg*h/L | — |
| Ph1b-Refametinib/Regorafenib Cohort -1 | Area Under the Plasma Concentration-time Curve From 0 to 12 h After Multiple Dose (AUC(0-12)md) for Refametinib Metabolite M-11 | 1013.4 μg*h/L | Geometric Coefficient of Variation 40 |
| Ph1b-Refametinib/Regorafenib Cohort -1a | Area Under the Plasma Concentration-time Curve From 0 to 12 h After Multiple Dose (AUC(0-12)md) for Refametinib Metabolite M-11 | 1144.7 μg*h/L | Geometric Coefficient of Variation 39 |
Primary
Area Under the Plasma Concentration-time Curve From 0 to 24 h After Multiple Dose (AUC(0-24)md) for Regorafenib
Area under the plasma concentration-time curve from 0 to 24 h after multiple dose for Regorafenib. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
Time frame: Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
Population: PK analysis set for multiple dose.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Ph1b-Refametinib/Regorafenib Cohort 0 | Area Under the Plasma Concentration-time Curve From 0 to 24 h After Multiple Dose (AUC(0-24)md) for Regorafenib | NA μg*h/L | — |
| Ph1b-Refametinib/Regorafenib Cohort -1 | Area Under the Plasma Concentration-time Curve From 0 to 24 h After Multiple Dose (AUC(0-24)md) for Regorafenib | 32359.4 μg*h/L | Geometric Coefficient of Variation 32 |
| Ph1b-Refametinib/Regorafenib Cohort -1a | Area Under the Plasma Concentration-time Curve From 0 to 24 h After Multiple Dose (AUC(0-24)md) for Regorafenib | 34352.2 μg*h/L | Geometric Coefficient of Variation 38 |
Primary
Area Under the Plasma Concentration-time Curve From 0 to 24 h After Multiple Dose (AUC(0-24)md) for Regorafenib Metabolite M-2
Area under the plasma concentration-time curve from 0 to 24 h after multiple dose for Regorafenib metabolite M-2. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
Time frame: Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
Population: PK analysis set for multiple dose.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Ph1b-Refametinib/Regorafenib Cohort 0 | Area Under the Plasma Concentration-time Curve From 0 to 24 h After Multiple Dose (AUC(0-24)md) for Regorafenib Metabolite M-2 | NA μg*h/L | — |
| Ph1b-Refametinib/Regorafenib Cohort -1 | Area Under the Plasma Concentration-time Curve From 0 to 24 h After Multiple Dose (AUC(0-24)md) for Regorafenib Metabolite M-2 | 24139.7 μg*h/L | Geometric Coefficient of Variation 34 |
| Ph1b-Refametinib/Regorafenib Cohort -1a | Area Under the Plasma Concentration-time Curve From 0 to 24 h After Multiple Dose (AUC(0-24)md) for Regorafenib Metabolite M-2 | 25826.2 μg*h/L | Geometric Coefficient of Variation 100 |
Primary
Area Under the Plasma Concentration-time Curve From 0 to 24 h After Multiple Dose (AUC(0-24)md) for Regorafenib Metabolite M-5
Area under the plasma concentration-time curve from 0 to 24 h after multiple dose for Regorafenib metabolite M-5. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
Time frame: Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
Population: PK analysis set for multiple dose.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Ph1b-Refametinib/Regorafenib Cohort 0 | Area Under the Plasma Concentration-time Curve From 0 to 24 h After Multiple Dose (AUC(0-24)md) for Regorafenib Metabolite M-5 | NA μg*h/L | — |
| Ph1b-Refametinib/Regorafenib Cohort -1 | Area Under the Plasma Concentration-time Curve From 0 to 24 h After Multiple Dose (AUC(0-24)md) for Regorafenib Metabolite M-5 | 20531.8 μg*h/L | Geometric Coefficient of Variation 106 |
| Ph1b-Refametinib/Regorafenib Cohort -1a | Area Under the Plasma Concentration-time Curve From 0 to 24 h After Multiple Dose (AUC(0-24)md) for Regorafenib Metabolite M-5 | 24029.3 μg*h/L | Geometric Coefficient of Variation 265 |
Primary
Maximum Drug Concentration in Plasma After Multiple Dose (Cmax,md) for Refametinib
Maximum drug concentration in plasma after multiple dose for Refametinib. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
Time frame: Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8 and 12 hours post-dose
Population: Pharmacokinetic (PK) analysis set for multiple dose.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Ph1b-Refametinib/Regorafenib Cohort 0 | Maximum Drug Concentration in Plasma After Multiple Dose (Cmax,md) for Refametinib | NA μg/L | — |
| Ph1b-Refametinib/Regorafenib Cohort -1 | Maximum Drug Concentration in Plasma After Multiple Dose (Cmax,md) for Refametinib | 315.9 μg/L | Geometric Coefficient of Variation 43 |
| Ph1b-Refametinib/Regorafenib Cohort -1a | Maximum Drug Concentration in Plasma After Multiple Dose (Cmax,md) for Refametinib | 390.7 μg/L | Geometric Coefficient of Variation 52 |
Primary
Maximum Drug Concentration in Plasma After Multiple Dose (Cmax,md) for Refametinib Metabolite M-11
Maximum drug concentration in plasma after multiple dose for Refametinib metabolite M-11. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
Time frame: Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8 and 12 hours post-dose
Population: PK analysis set for multiple dose.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Ph1b-Refametinib/Regorafenib Cohort 0 | Maximum Drug Concentration in Plasma After Multiple Dose (Cmax,md) for Refametinib Metabolite M-11 | NA μg/L | — |
| Ph1b-Refametinib/Regorafenib Cohort -1 | Maximum Drug Concentration in Plasma After Multiple Dose (Cmax,md) for Refametinib Metabolite M-11 | 104.9 μg/L | Geometric Coefficient of Variation 36 |
| Ph1b-Refametinib/Regorafenib Cohort -1a | Maximum Drug Concentration in Plasma After Multiple Dose (Cmax,md) for Refametinib Metabolite M-11 | 112.3 μg/L | Geometric Coefficient of Variation 44 |
Primary
Maximum Drug Concentration in Plasma After Multiple Dose (Cmax,md) for Regorafenib
Maximum drug concentration in plasma after multiple dose for Regorafenib. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
Time frame: Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
Population: PK analysis set for multiple dose.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Ph1b-Refametinib/Regorafenib Cohort 0 | Maximum Drug Concentration in Plasma After Multiple Dose (Cmax,md) for Regorafenib | NA μg/L | — |
| Ph1b-Refametinib/Regorafenib Cohort -1 | Maximum Drug Concentration in Plasma After Multiple Dose (Cmax,md) for Regorafenib | 1966.0 μg/L | Geometric Coefficient of Variation 17 |
| Ph1b-Refametinib/Regorafenib Cohort -1a | Maximum Drug Concentration in Plasma After Multiple Dose (Cmax,md) for Regorafenib | 2206.4 μg/L | Geometric Coefficient of Variation 34 |
Primary
Maximum Drug Concentration in Plasma After Multiple Dose (Cmax,md) for Regorafenib Metabolite M-2
Maximum drug concentration in plasma after multiple dose for Regorafenib metabolite M-2. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
Time frame: Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
Population: PK analysis set for multiple dose.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Ph1b-Refametinib/Regorafenib Cohort 0 | Maximum Drug Concentration in Plasma After Multiple Dose (Cmax,md) for Regorafenib Metabolite M-2 | NA μg/L | — |
| Ph1b-Refametinib/Regorafenib Cohort -1 | Maximum Drug Concentration in Plasma After Multiple Dose (Cmax,md) for Regorafenib Metabolite M-2 | 1409.1 μg/L | Geometric Coefficient of Variation 20 |
| Ph1b-Refametinib/Regorafenib Cohort -1a | Maximum Drug Concentration in Plasma After Multiple Dose (Cmax,md) for Regorafenib Metabolite M-2 | 1642.7 μg/L | Geometric Coefficient of Variation 98 |
Primary
Maximum Drug Concentration in Plasma After Multiple Dose (Cmax,md) for Regorafenib Metabolite M-5
Maximum drug concentration in plasma after multiple dose for Regorafenib metabolite M-5. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
Time frame: Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
Population: PK analysis set for multiple dose.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Ph1b-Refametinib/Regorafenib Cohort 0 | Maximum Drug Concentration in Plasma After Multiple Dose (Cmax,md) for Regorafenib Metabolite M-5 | NA μg/L | — |
| Ph1b-Refametinib/Regorafenib Cohort -1 | Maximum Drug Concentration in Plasma After Multiple Dose (Cmax,md) for Regorafenib Metabolite M-5 | 1148.8 μg/L | Geometric Coefficient of Variation 90 |
| Ph1b-Refametinib/Regorafenib Cohort -1a | Maximum Drug Concentration in Plasma After Multiple Dose (Cmax,md) for Regorafenib Metabolite M-5 | 1485.7 μg/L | Geometric Coefficient of Variation 255 |
Primary
Number of Participants With Dose Limiting Toxicities (DLTs)
Dose-limiting toxicities (DLTs) were analyzed in the maximum tolerated dose (MTD) analysis set, in which only the six first patients of each dose escalation Cohort could be included according to the modified Rolling-6 method that was applied in this study.
Time frame: At Cycle 1
Population: MTD analysis set: all participants who completed Cycle 1 or discontinued during Cycle 1 due to an adverse event or DLT in the dose escalation part.
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| Ph1b-Refametinib/Regorafenib Cohort 0 | Number of Participants With Dose Limiting Toxicities (DLTs) | No | 0 Participants | — |
| Ph1b-Refametinib/Regorafenib Cohort 0 | Number of Participants With Dose Limiting Toxicities (DLTs) | Yes | 2 Participants | — |
| Ph1b-Refametinib/Regorafenib Cohort -1 | Number of Participants With Dose Limiting Toxicities (DLTs) | No | 6 Participants | 106 |
| Ph1b-Refametinib/Regorafenib Cohort -1 | Number of Participants With Dose Limiting Toxicities (DLTs) | Yes | 0 Participants | — |
| Ph1b-Refametinib/Regorafenib Cohort -1a | Number of Participants With Dose Limiting Toxicities (DLTs) | No | 6 Participants | 265 |
| Ph1b-Refametinib/Regorafenib Cohort -1a | Number of Participants With Dose Limiting Toxicities (DLTs) | Yes | 0 Participants | — |
Primary
Tumor Response During Phase 2 as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
Tumor Response was defined as the best tumor response (Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD)) observed during trial period assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. CR was defined as disappearance of tumor lesions, PR was defined as a decrease of at least 30% in the sum of tumor lesion sizes, SD was defined as steady state of disease, PD was defined as an increase of at least 20% in the sum of tumor lesions sizes.
Time frame: Up to 12 months
Population: Phase 2 part was not conducted.
Secondary
Area Under the Plasma Concentration-time Curve From 0 to 24 h (AUC(0-24)) After Single (First) Dose for Regorafenib and Its Metabolites M-2 and M-5
Area under the plasma concentration-time curve from 0 to 24 h after single (first) dose for Regorafenib and its metabolites M-2 and M-5. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
Time frame: Cycle 1 Day 1 at 0 (pre-dose), 0.5, 1, 2, 4, 8 and 24 hours post-dose
Population: PK analysis set for single dose.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Ph1b-Refametinib/Regorafenib Cohort 0 | Area Under the Plasma Concentration-time Curve From 0 to 24 h (AUC(0-24)) After Single (First) Dose for Regorafenib and Its Metabolites M-2 and M-5 | Metabolite M-5 | 499 μg*h/L | — |
| Ph1b-Refametinib/Regorafenib Cohort 0 | Area Under the Plasma Concentration-time Curve From 0 to 24 h (AUC(0-24)) After Single (First) Dose for Regorafenib and Its Metabolites M-2 and M-5 | Regorafenib | 14642.6 μg*h/L | Geometric Coefficient of Variation 32 |
| Ph1b-Refametinib/Regorafenib Cohort 0 | Area Under the Plasma Concentration-time Curve From 0 to 24 h (AUC(0-24)) After Single (First) Dose for Regorafenib and Its Metabolites M-2 and M-5 | Metabolite M-2 | 3964.2 μg*h/L | Geometric Coefficient of Variation 97 |
| Ph1b-Refametinib/Regorafenib Cohort -1 | Area Under the Plasma Concentration-time Curve From 0 to 24 h (AUC(0-24)) After Single (First) Dose for Regorafenib and Its Metabolites M-2 and M-5 | Metabolite M-5 | 654.4 μg*h/L | Geometric Coefficient of Variation 91 |
| Ph1b-Refametinib/Regorafenib Cohort -1 | Area Under the Plasma Concentration-time Curve From 0 to 24 h (AUC(0-24)) After Single (First) Dose for Regorafenib and Its Metabolites M-2 and M-5 | Regorafenib | 13524.8 μg*h/L | Geometric Coefficient of Variation 142 |
| Ph1b-Refametinib/Regorafenib Cohort -1 | Area Under the Plasma Concentration-time Curve From 0 to 24 h (AUC(0-24)) After Single (First) Dose for Regorafenib and Its Metabolites M-2 and M-5 | Metabolite M-2 | 3306.6 μg*h/L | Geometric Coefficient of Variation 452 |
| Ph1b-Refametinib/Regorafenib Cohort -1a | Area Under the Plasma Concentration-time Curve From 0 to 24 h (AUC(0-24)) After Single (First) Dose for Regorafenib and Its Metabolites M-2 and M-5 | Metabolite M-5 | 794.2 μg*h/L | Geometric Coefficient of Variation 95 |
| Ph1b-Refametinib/Regorafenib Cohort -1a | Area Under the Plasma Concentration-time Curve From 0 to 24 h (AUC(0-24)) After Single (First) Dose for Regorafenib and Its Metabolites M-2 and M-5 | Regorafenib | 17475.7 μg*h/L | Geometric Coefficient of Variation 46 |
| Ph1b-Refametinib/Regorafenib Cohort -1a | Area Under the Plasma Concentration-time Curve From 0 to 24 h (AUC(0-24)) After Single (First) Dose for Regorafenib and Its Metabolites M-2 and M-5 | Metabolite M-2 | 6743.1 μg*h/L | Geometric Coefficient of Variation 102 |
Secondary
Area Under the Plasma Concentration-time Curve From 0 to 8 h (AUC(0-8)) After Single (First) Dose for Refametinib and Its Metabolite M-11
Area under the plasma concentration-time curve from 0 to 8 h after single (first) dose for Refametinib and its metabolite M-11. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
Time frame: Cycle 1 Day 1 at 0 (pre-dose), 0.5, 1, 2, 4 and 8 hours post-dose
Population: PK analysis set for single dose.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Ph1b-Refametinib/Regorafenib Cohort 0 | Area Under the Plasma Concentration-time Curve From 0 to 8 h (AUC(0-8)) After Single (First) Dose for Refametinib and Its Metabolite M-11 | Refametinib | 2377.1 μg*h/L | Geometric Coefficient of Variation 63 |
| Ph1b-Refametinib/Regorafenib Cohort 0 | Area Under the Plasma Concentration-time Curve From 0 to 8 h (AUC(0-8)) After Single (First) Dose for Refametinib and Its Metabolite M-11 | Metabolite M-11 | 411 μg*h/L | — |
| Ph1b-Refametinib/Regorafenib Cohort -1 | Area Under the Plasma Concentration-time Curve From 0 to 8 h (AUC(0-8)) After Single (First) Dose for Refametinib and Its Metabolite M-11 | Refametinib | 1267.9 μg*h/L | Geometric Coefficient of Variation 60 |
| Ph1b-Refametinib/Regorafenib Cohort -1 | Area Under the Plasma Concentration-time Curve From 0 to 8 h (AUC(0-8)) After Single (First) Dose for Refametinib and Its Metabolite M-11 | Metabolite M-11 | 212.6 μg*h/L | Geometric Coefficient of Variation 82 |
| Ph1b-Refametinib/Regorafenib Cohort -1a | Area Under the Plasma Concentration-time Curve From 0 to 8 h (AUC(0-8)) After Single (First) Dose for Refametinib and Its Metabolite M-11 | Refametinib | 1314.6 μg*h/L | Geometric Coefficient of Variation 26 |
| Ph1b-Refametinib/Regorafenib Cohort -1a | Area Under the Plasma Concentration-time Curve From 0 to 8 h (AUC(0-8)) After Single (First) Dose for Refametinib and Its Metabolite M-11 | Metabolite M-11 | 206.8 μg*h/L | Geometric Coefficient of Variation 48 |
Secondary
Maximum Drug Concentration in Plasma After Single (First) Dose (Cmax) for Refametinib and Its Metabolite M-11
Maximum drug concentration in plasma after single (first) dose for Refametinib and its metabolite M-11. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
Time frame: Cycle 1 Day 1 at 0 (pre-dose), 0.5, 1, 2, 4 and 8 hours post-dose
Population: PK analysis set for single dose.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Ph1b-Refametinib/Regorafenib Cohort 0 | Maximum Drug Concentration in Plasma After Single (First) Dose (Cmax) for Refametinib and Its Metabolite M-11 | Refametinib | 549.7 μg/L | Geometric Coefficient of Variation 58 |
| Ph1b-Refametinib/Regorafenib Cohort 0 | Maximum Drug Concentration in Plasma After Single (First) Dose (Cmax) for Refametinib and Its Metabolite M-11 | Metabolite M-11 | 58.7 μg/L | Geometric Coefficient of Variation 10 |
| Ph1b-Refametinib/Regorafenib Cohort -1 | Maximum Drug Concentration in Plasma After Single (First) Dose (Cmax) for Refametinib and Its Metabolite M-11 | Refametinib | 273.3 μg/L | Geometric Coefficient of Variation 82 |
| Ph1b-Refametinib/Regorafenib Cohort -1 | Maximum Drug Concentration in Plasma After Single (First) Dose (Cmax) for Refametinib and Its Metabolite M-11 | Metabolite M-11 | 37.0 μg/L | Geometric Coefficient of Variation 83 |
| Ph1b-Refametinib/Regorafenib Cohort -1a | Maximum Drug Concentration in Plasma After Single (First) Dose (Cmax) for Refametinib and Its Metabolite M-11 | Refametinib | 253.0 μg/L | Geometric Coefficient of Variation 38 |
| Ph1b-Refametinib/Regorafenib Cohort -1a | Maximum Drug Concentration in Plasma After Single (First) Dose (Cmax) for Refametinib and Its Metabolite M-11 | Metabolite M-11 | 35.7 μg/L | Geometric Coefficient of Variation 42 |
Secondary
Maximum Drug Concentration in Plasma After Single (First) Dose (Cmax) for Regorafenib and Its Metabolites M-2 and M-5
Maximum drug concentration in plasma after single (first) dose for Regorafenib and its metabolites M-2 and M-5. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
Time frame: Cycle 1 Day 1 at 0 (pre-dose), 0.5, 1, 2, 4, 8 and 24 hours post-dose
Population: PK analysis set for single dose.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Ph1b-Refametinib/Regorafenib Cohort 0 | Maximum Drug Concentration in Plasma After Single (First) Dose (Cmax) for Regorafenib and Its Metabolites M-2 and M-5 | Metabolite M-2 | 234.4 μg/L | Geometric Coefficient of Variation 101 |
| Ph1b-Refametinib/Regorafenib Cohort 0 | Maximum Drug Concentration in Plasma After Single (First) Dose (Cmax) for Regorafenib and Its Metabolites M-2 and M-5 | Regorafenib | 952.0 μg/L | Geometric Coefficient of Variation 34 |
| Ph1b-Refametinib/Regorafenib Cohort 0 | Maximum Drug Concentration in Plasma After Single (First) Dose (Cmax) for Regorafenib and Its Metabolites M-2 and M-5 | Metabolite M-5 | 22.1 μg/L | Geometric Coefficient of Variation 138 |
| Ph1b-Refametinib/Regorafenib Cohort -1 | Maximum Drug Concentration in Plasma After Single (First) Dose (Cmax) for Regorafenib and Its Metabolites M-2 and M-5 | Metabolite M-2 | 194.4 μg/L | Geometric Coefficient of Variation 438 |
| Ph1b-Refametinib/Regorafenib Cohort -1 | Maximum Drug Concentration in Plasma After Single (First) Dose (Cmax) for Regorafenib and Its Metabolites M-2 and M-5 | Regorafenib | 794.2 μg/L | Geometric Coefficient of Variation 128 |
| Ph1b-Refametinib/Regorafenib Cohort -1 | Maximum Drug Concentration in Plasma After Single (First) Dose (Cmax) for Regorafenib and Its Metabolites M-2 and M-5 | Metabolite M-5 | 41.8 μg/L | Geometric Coefficient of Variation 58 |
| Ph1b-Refametinib/Regorafenib Cohort -1a | Maximum Drug Concentration in Plasma After Single (First) Dose (Cmax) for Regorafenib and Its Metabolites M-2 and M-5 | Regorafenib | 1194.6 μg/L | Geometric Coefficient of Variation 56 |
| Ph1b-Refametinib/Regorafenib Cohort -1a | Maximum Drug Concentration in Plasma After Single (First) Dose (Cmax) for Regorafenib and Its Metabolites M-2 and M-5 | Metabolite M-5 | 35.1 μg/L | Geometric Coefficient of Variation 244 |
| Ph1b-Refametinib/Regorafenib Cohort -1a | Maximum Drug Concentration in Plasma After Single (First) Dose (Cmax) for Regorafenib and Its Metabolites M-2 and M-5 | Metabolite M-2 | 367.2 μg/L | Geometric Coefficient of Variation 166 |
Secondary
Overall Survival During Phase 2
Overall survival (OS) was defined as the time (days) from the treatment start date to the date of death due to any cause. For participants who were still alive or who were lost to follow-up as of the database cutoff date for the primary completion, OS was censored at the last known alive date on or prior to the database cutoff date.
Time frame: Up to 12 months after last patient first visit
Population: Phase 2 part was not conducted.
Secondary
Progression-free Survival During Phase 2
Progression-free survival was defined as the time from date of treatment assignment to date of first observed disease progression or death due to any cause, if death occurred while the participant was in the study and before progression was observed.
Time frame: From start of treatment until progression is documented
Population: Phase 2 part was not conducted.
Secondary
Time to Progression During Phase 2
Time to progression was defined as the time (days) from the treatment start date to the disease progression on or following the start date. Participants not experiencing progression at the database cutoff date for primary completion were censored at the last assessment.
Time frame: From start of treatment until progression is documented
Population: Phase 2 part was not conducted.
Secondary
Time to Reach Maximum Drug Concentration in Plasma After Multiple Dose (Tmax,md) for Refametinib and Its Metabolite M-11
Time to reach maximum drug concentration in plasma after multiple dose for Refametinib and its metabolite M-11. Median and full range were reported.
Time frame: Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8 and 12 hours post-dose
Population: PK analysis set for multiple dose. On Day 21, one patient in Cohort 0 was dose reduced and the other patient was not dosed. Therefore no patient was evaluable.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Ph1b-Refametinib/Regorafenib Cohort -1 | Time to Reach Maximum Drug Concentration in Plasma After Multiple Dose (Tmax,md) for Refametinib and Its Metabolite M-11 | Refametinib | 1.6 h |
| Ph1b-Refametinib/Regorafenib Cohort -1 | Time to Reach Maximum Drug Concentration in Plasma After Multiple Dose (Tmax,md) for Refametinib and Its Metabolite M-11 | Metabolite M-11 | 3.0 h |
| Ph1b-Refametinib/Regorafenib Cohort -1a | Time to Reach Maximum Drug Concentration in Plasma After Multiple Dose (Tmax,md) for Refametinib and Its Metabolite M-11 | Refametinib | 4.0 h |
| Ph1b-Refametinib/Regorafenib Cohort -1a | Time to Reach Maximum Drug Concentration in Plasma After Multiple Dose (Tmax,md) for Refametinib and Its Metabolite M-11 | Metabolite M-11 | 4.0 h |
Secondary
Time to Reach Maximum Drug Concentration in Plasma After Multiple Dose (Tmax,md) for Regorafenib and Its Metabolites M-2 and M-5
Time to reach maximum drug concentration in plasma after multiple dose for Regorafenib and its metabolites M-2 and M-5. Median and full range were reported.
Time frame: Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
Population: PK analysis set for multiple dose. On Day 21, one patient in Cohort 0 was dose reduced and the other patient was not dosed. Therefore no patient was evaluable.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Ph1b-Refametinib/Regorafenib Cohort -1 | Time to Reach Maximum Drug Concentration in Plasma After Multiple Dose (Tmax,md) for Regorafenib and Its Metabolites M-2 and M-5 | Regorafenib | 6.0 h |
| Ph1b-Refametinib/Regorafenib Cohort -1 | Time to Reach Maximum Drug Concentration in Plasma After Multiple Dose (Tmax,md) for Regorafenib and Its Metabolites M-2 and M-5 | Metabolite M-2 | 11.5 h |
| Ph1b-Refametinib/Regorafenib Cohort -1 | Time to Reach Maximum Drug Concentration in Plasma After Multiple Dose (Tmax,md) for Regorafenib and Its Metabolites M-2 and M-5 | Metabolite M-5 | 12.0 h |
| Ph1b-Refametinib/Regorafenib Cohort -1a | Time to Reach Maximum Drug Concentration in Plasma After Multiple Dose (Tmax,md) for Regorafenib and Its Metabolites M-2 and M-5 | Regorafenib | 6.0 h |
| Ph1b-Refametinib/Regorafenib Cohort -1a | Time to Reach Maximum Drug Concentration in Plasma After Multiple Dose (Tmax,md) for Regorafenib and Its Metabolites M-2 and M-5 | Metabolite M-2 | 9.4 h |
| Ph1b-Refametinib/Regorafenib Cohort -1a | Time to Reach Maximum Drug Concentration in Plasma After Multiple Dose (Tmax,md) for Regorafenib and Its Metabolites M-2 and M-5 | Metabolite M-5 | 9.4 h |
Secondary
Time to Reach Maximum Drug Concentration in Plasma After Single (First) Dose (Tmax) for Refametinib and Its Metabolite M-11
Time to reach maximum drug concentration in plasma after single (first) dose for Refametinib and its metabolite M-11. Median and full range were reported.
Time frame: Cycle 1 Day 1 at 0 (pre-dose), 0.5, 1, 2, 4 and 8 hours post-dose
Population: PK analysis set for single dose.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Ph1b-Refametinib/Regorafenib Cohort 0 | Time to Reach Maximum Drug Concentration in Plasma After Single (First) Dose (Tmax) for Refametinib and Its Metabolite M-11 | Refametinib | 2.5 h |
| Ph1b-Refametinib/Regorafenib Cohort 0 | Time to Reach Maximum Drug Concentration in Plasma After Single (First) Dose (Tmax) for Refametinib and Its Metabolite M-11 | Metabolite M-11 | 6.0 h |
| Ph1b-Refametinib/Regorafenib Cohort -1 | Time to Reach Maximum Drug Concentration in Plasma After Single (First) Dose (Tmax) for Refametinib and Its Metabolite M-11 | Refametinib | 1.0 h |
| Ph1b-Refametinib/Regorafenib Cohort -1 | Time to Reach Maximum Drug Concentration in Plasma After Single (First) Dose (Tmax) for Refametinib and Its Metabolite M-11 | Metabolite M-11 | 4.0 h |
| Ph1b-Refametinib/Regorafenib Cohort -1a | Time to Reach Maximum Drug Concentration in Plasma After Single (First) Dose (Tmax) for Refametinib and Its Metabolite M-11 | Refametinib | 4.0 h |
| Ph1b-Refametinib/Regorafenib Cohort -1a | Time to Reach Maximum Drug Concentration in Plasma After Single (First) Dose (Tmax) for Refametinib and Its Metabolite M-11 | Metabolite M-11 | 4.0 h |
Secondary
Time to Reach Maximum Drug Concentration in Plasma After Single (First) Dose (Tmax) for Regorafenib and Its Metabolites M-2 and M-5
Time to reach maximum drug concentration in plasma after single (first) dose for Regorafenib and its metabolites M-2 and M-5. Median and full range were reported.
Time frame: Cycle 1 Day 1 at 0 (pre-dose), 0.5, 1, 2, 4, 8 and 24 hours post-dose
Population: PK analysis set for single dose.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Ph1b-Refametinib/Regorafenib Cohort 0 | Time to Reach Maximum Drug Concentration in Plasma After Single (First) Dose (Tmax) for Regorafenib and Its Metabolites M-2 and M-5 | Metabolite M-2 | 23.9 h |
| Ph1b-Refametinib/Regorafenib Cohort 0 | Time to Reach Maximum Drug Concentration in Plasma After Single (First) Dose (Tmax) for Regorafenib and Its Metabolites M-2 and M-5 | Regorafenib | 23.9 h |
| Ph1b-Refametinib/Regorafenib Cohort 0 | Time to Reach Maximum Drug Concentration in Plasma After Single (First) Dose (Tmax) for Regorafenib and Its Metabolites M-2 and M-5 | Metabolite M-5 | 23.9 h |
| Ph1b-Refametinib/Regorafenib Cohort -1 | Time to Reach Maximum Drug Concentration in Plasma After Single (First) Dose (Tmax) for Regorafenib and Its Metabolites M-2 and M-5 | Metabolite M-2 | 8.0 h |
| Ph1b-Refametinib/Regorafenib Cohort -1 | Time to Reach Maximum Drug Concentration in Plasma After Single (First) Dose (Tmax) for Regorafenib and Its Metabolites M-2 and M-5 | Regorafenib | 8.0 h |
| Ph1b-Refametinib/Regorafenib Cohort -1 | Time to Reach Maximum Drug Concentration in Plasma After Single (First) Dose (Tmax) for Regorafenib and Its Metabolites M-2 and M-5 | Metabolite M-5 | 23.6 h |
| Ph1b-Refametinib/Regorafenib Cohort -1a | Time to Reach Maximum Drug Concentration in Plasma After Single (First) Dose (Tmax) for Regorafenib and Its Metabolites M-2 and M-5 | Regorafenib | 7.6 h |
| Ph1b-Refametinib/Regorafenib Cohort -1a | Time to Reach Maximum Drug Concentration in Plasma After Single (First) Dose (Tmax) for Regorafenib and Its Metabolites M-2 and M-5 | Metabolite M-5 | 23.8 h |
| Ph1b-Refametinib/Regorafenib Cohort -1a | Time to Reach Maximum Drug Concentration in Plasma After Single (First) Dose (Tmax) for Regorafenib and Its Metabolites M-2 and M-5 | Metabolite M-2 | 7.6 h |
Secondary
Tumor Response During Phase 1b as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
Tumor Response was defined as the best tumor response (Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progressive Disease (PD)) observed during trial period assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST). CR was defined as disappearance of all target and non-target tumor lesions, PR was defined as a decrease of at least 30% in the sum of diameters of target lesions, SD was defined neither sufficient shrinkage for PR nor sufficient increase for PD, PD was defined as an increase of at least 20% in the sum of diameters of target lesions.
Time frame: From start of treatment until progression is documented
Population: Full analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ph1b-Refametinib/Regorafenib Cohort 0 | Tumor Response During Phase 1b as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | Stable Disease | 1 Participants |
| Ph1b-Refametinib/Regorafenib Cohort 0 | Tumor Response During Phase 1b as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | Progressive Disease | 0 Participants |
| Ph1b-Refametinib/Regorafenib Cohort -1 | Tumor Response During Phase 1b as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | Stable Disease | 2 Participants |
| Ph1b-Refametinib/Regorafenib Cohort -1 | Tumor Response During Phase 1b as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | Progressive Disease | 5 Participants |
| Ph1b-Refametinib/Regorafenib Cohort -1a | Tumor Response During Phase 1b as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | Stable Disease | 5 Participants |
| Ph1b-Refametinib/Regorafenib Cohort -1a | Tumor Response During Phase 1b as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | Progressive Disease | 6 Participants |