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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.

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.

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.

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.

Refametinib (BAY86-9766)

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.

Regorafenib (Stivarga, BAY73-4506)

Bayer Study Director

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.

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.

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

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

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 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 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 for Refametinib metabolite M-11. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.

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 for Regorafenib metabolite M-2. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.

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 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 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 for Regorafenib metabolite M-5. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.

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.

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 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 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 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 for Refametinib and its metabolite M-11. Median and full range were reported.

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 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 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 for Regorafenib and its metabolites M-2 and M-5. Median and full range were reported.

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 (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 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 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.

Bayer

One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.

Ph1b - Refametinib/Regorafenib Cohort 0

Ph1b - Refametinib/Regorafenib Cohort -1

Ph1b - Refametinib/Regorafenib Cohort -1a

Ph1b-Refametinib/Regorafenib Cohort 0

Ph1b-Refametinib/Regorafenib Cohort -1

Ph1b-Refametinib/Regorafenib Cohort -1a

Total

Age, Continuous

Sex: Female, Male

Colon and rectal cancer

Other

Non-small cell lung cancer

Breast cancer

Pancreatic adenocarcinoma

Cancer types

The sponsor decided not to conduct the Phase 2 part of the study due to strategic portfolio re-prioritization.

Therapeutic Area Head

Pharmacokinetic (PK) analysis set for multiple dose.

Maximum Drug Concentration in Plasma After Multiple Dose (Cmax,md) for Refametinib

Maximum Drug Concentration in Plasma After Multiple Dose (Cmax,md) for Refametinib Metabolite M-11

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 (AUC(0-12)md) for Refametinib Metabolite M-11

Maximum Drug Concentration in Plasma After Multiple Dose (Cmax,md) for Regorafenib

Maximum Drug Concentration in Plasma After Multiple Dose (Cmax,md) for Regorafenib Metabolite M-2

Maximum Drug Concentration in Plasma After Multiple Dose (Cmax,md) for Regorafenib Metabolite M-5

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 (AUC(0-24)md) for Regorafenib Metabolite M-2

Area Under the Plasma Concentration-time Curve From 0 to 24 h After Multiple Dose (AUC(0-24)md) for Regorafenib Metabolite M-5

Phase 2 part of study: Participants will receive the recommended Phase 2 dose (RP2D) for Refametinib and Regorafenib combination therapy determined in Phase 1b part. Target population for this group will be metastatic colorectal cancer (CRC).

Ph2 - Refametinib/Regorafenib (CRC)

Phase 2 part of study: Participants will receive the recommended Phase 2 dose (RP2D) for Refametinib and Regorafenib combination therapy determined in Phase 1b part. Target population for this group will be non-small-cell lung cancer (NSCLC).

Ph2 - Refametinib/Regorafenib (NSCLC)

Phase 2 part of study: Participants will receive the recommended Phase 2 dose (RP2D) for Refametinib and Regorafenib combination therapy determined in Phase 1b part. Target population for this group will be Her-2 negative breast cancer (BC).

Ph2 - Refametinib/Regorafenib (BC)

Tumor Response During Phase 2 as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1

Refametinib

Metabolite M-11

Maximum Drug Concentration in Plasma After Single (First) Dose (Cmax) for Refametinib and Its Metabolite M-11

Time to Reach Maximum Drug Concentration in Plasma After Single (First) Dose (Tmax) for Refametinib and Its Metabolite M-11

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

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.

Time to Reach Maximum Drug Concentration in Plasma After Multiple Dose (Tmax,md) for Refametinib and Its Metabolite M-11

Regorafenib

Metabolite M-2

Metabolite M-5

Maximum Drug Concentration in Plasma After Single (First) Dose (Cmax) for Regorafenib and Its Metabolites M-2 and M-5

Time to Reach Maximum Drug Concentration in Plasma After Single (First) Dose (Tmax) for Regorafenib and Its Metabolites M-2 and M-5

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

Time to Reach Maximum Drug Concentration in Plasma After Multiple Dose (Tmax,md) for Regorafenib and Its Metabolites M-2 and M-5

Stable Disease

Progressive Disease

Tumor Response During Phase 1b as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1

Overall Survival During Phase 2

Time to Progression During Phase 2

Progression-free Survival During Phase 2

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.

Spots Global Cancer Trial Database for Refametinib (BAY86-9766) in Combination With Regorafenib (Stivarga, BAY73-4506) in Patients With Advanced or Metastatic Cancer

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