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

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ClinicalTrials.gov Identifier: NCT02168777
Recruitment Status : Terminated
First Posted : June 20, 2014
Results First Posted : January 26, 2018
Last Update Posted : January 26, 2018
Sponsor:
Information provided by (Responsible Party):
Bayer

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.


Condition or disease Intervention/treatment Phase
Neoplasms Drug: Refametinib (BAY86-9766) Drug: Regorafenib (Stivarga, BAY73-4506) Phase 1

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.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 20 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : June 23, 2014
Actual Primary Completion Date : October 23, 2015
Actual Study Completion Date : April 5, 2016

Resource links provided by the National Library of Medicine

Drug Information available for: Regorafenib
U.S. FDA Resources

Arm Intervention/treatment
Experimental: 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.
Drug: 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 2, the recommended Phase 2 dose (RP2D) for refametinib-regorafenib combination therapy will be used.

Drug: Regorafenib (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.

Experimental: 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.
Drug: 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 2, the recommended Phase 2 dose (RP2D) for refametinib-regorafenib combination therapy will be used.

Drug: Regorafenib (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.

Experimental: 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.
Drug: 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 2, the recommended Phase 2 dose (RP2D) for refametinib-regorafenib combination therapy will be used.

Drug: Regorafenib (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.




Primary Outcome Measures :
  1. Maximum Drug Concentration in Plasma After Multiple Dose (Cmax,md) for Refametinib [ Time Frame: 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.

  2. Maximum Drug Concentration in Plasma After Multiple Dose (Cmax,md) for Refametinib Metabolite M-11 [ Time Frame: 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.

  3. Area Under the Plasma Concentration-time Curve From 0 to 12 h After Multiple Dose (AUC(0-12)md) for Refametinib [ Time Frame: 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.

  4. Area Under the Plasma Concentration-time Curve From 0 to 12 h After Multiple Dose (AUC(0-12)md) for Refametinib Metabolite M-11 [ Time Frame: 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.

  5. Maximum Drug Concentration in Plasma After Multiple Dose (Cmax,md) for Regorafenib [ Time Frame: 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.

  6. Maximum Drug Concentration in Plasma After Multiple Dose (Cmax,md) for Regorafenib Metabolite M-2 [ Time Frame: 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.

  7. Maximum Drug Concentration in Plasma After Multiple Dose (Cmax,md) for Regorafenib Metabolite M-5 [ Time Frame: 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.

  8. Area Under the Plasma Concentration-time Curve From 0 to 24 h After Multiple Dose (AUC(0-24)md) for Regorafenib [ Time Frame: 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.

  9. Area Under the Plasma Concentration-time Curve From 0 to 24 h After Multiple Dose (AUC(0-24)md) for Regorafenib Metabolite M-2 [ Time Frame: 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.

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

  11. Tumor Response During Phase 2 as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 [ Time Frame: 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.

  12. Number of Participants With Dose Limiting Toxicities (DLTs) [ Time Frame: 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.


Secondary Outcome Measures :
  1. Maximum Drug Concentration in Plasma After Single (First) Dose (Cmax) for Refametinib and Its Metabolite M-11 [ Time Frame: 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.

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

  3. 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 [ Time Frame: 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.

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

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

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

  7. 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 Frame: 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.

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

  9. Tumor Response During Phase 1b as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 [ Time Frame: 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.

  10. Overall Survival During Phase 2 [ Time Frame: 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.

  11. Time to Progression During Phase 2 [ Time Frame: 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.

  12. Progression-free Survival During Phase 2 [ Time Frame: 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02168777


Locations
United States, Connecticut
New Haven, Connecticut, United States, 06510
United States, Michigan
Detroit, Michigan, United States, 48201
United States, Missouri
Saint Louis, Missouri, United States, 63110
United States, North Carolina
Chapel Hill, North Carolina, United States, 27599
United States, Texas
Houston, Texas, United States, 77030
Sponsors and Collaborators
Bayer
Investigators
Study Director: Bayer Study Director Bayer

Additional Information:
Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT02168777     History of Changes
Other Study ID Numbers: 17064
2013-004861-15 ( EudraCT Number )
First Posted: June 20, 2014    Key Record Dates
Results First Posted: January 26, 2018
Last Update Posted: January 26, 2018
Last Verified: June 2017

Keywords provided by Bayer:
Patients with Cancer

Additional relevant MeSH terms:
Neoplasm Metastasis
Neoplastic Processes
Neoplasms
Pathologic Processes