Refametinib (BAY86-9766) in Combination With Regorafenib (Stivarga, BAY73-4506) in Patients With Advanced or Metastatic Cancer

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase 1b/2, Multi-center, Uncontrolled, Open-label, Dose Escalation Study of Refametinib (BAY86-9766) in Combination With Regorafenib (BAY73-4506) in Patients With Advanced or Metastatic Cancer

Conditions
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Neoplasms

Intervention / Treatment
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* Drug: Refametinib (BAY86-9766)
* Drug: Regorafenib (Stivarga, BAY73-4506)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ph1b-Refametinib/Regorafenib Cohort 0<br>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. | Drug: Refametinib (BAY86-9766)<br>* 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.<br>Drug: Regorafenib (Stivarga, BAY73-4506)<br>* 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.<br>|
| Experimental: Ph1b-Refametinib/Regorafenib Cohort -1<br>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. | Drug: Refametinib (BAY86-9766)<br>* 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.<br>Drug: Regorafenib (Stivarga, BAY73-4506)<br>* 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.<br>|
| Experimental: Ph1b-Refametinib/Regorafenib Cohort -1a<br>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. | Drug: Refametinib (BAY86-9766)<br>* 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.<br>Drug: Regorafenib (Stivarga, BAY73-4506)<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 (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. | 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 (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. | 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 (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. | 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 (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. | 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 (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. | 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 (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. | 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 (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. | 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 (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. | 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 (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. | Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose | 
| 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. | Up to 12 months | 
| 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. | At Cycle 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 (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. | 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 (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. | 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 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. | 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 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. | 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 (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. | 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 (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. | 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 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. | Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose | 
| 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. | From start of treatment until progression is documented | 
| 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. | Up to 12 months after last patient first visit | 
| 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. | From start of treatment until progression is documented | 
| 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. | From start of treatment until progression is documented | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Patients with Cancer