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

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by Bayer
Sponsor:
Information provided by (Responsible Party):
Bayer
ClinicalTrials.gov Identifier:
NCT02168777
First received: June 18, 2014
Last updated: August 8, 2014
Last verified: August 2014
  Purpose

Phase I: Determine the maximum tolerated dose of combination of Regorafenib with Refamentinib 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 Intervention Phase
Neoplasms
Drug: Refametinib (BAY86-9766)
Drug: Regorafenib (Stivarga, BAY73-4506)
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by Bayer:

Primary Outcome Measures:
  • Number of participants with adverse events during Phase 1b as a measure of safety and tolerability [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
  • Maximum drug concentration in plasma after multiple dose (Cmax,md) for refametinib [ Time Frame: Day 1 at 0 (pre-dose), 0.5, 1, 2, 4 and 8 hours post-dose and Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8 and 12 hours post-dose ] [ Designated as safety issue: No ]
  • Cmax,md for refametinib metabolite M-11 [ Time Frame: Day 1 at 0 (pre-dose), 0.5, 1, 2, 4 and 8 hours post-dose and Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8 and 12 hours post-dose ] [ Designated as safety issue: No ]
  • Area under the plasma concentration-time curve from 0 to 12 h after multiple dose (AUC(0-12)md) for refametinib [ Time Frame: Day 1 at 0 (pre-dose), 0.5, 1, 2, 4 and 8 hours post-dose and Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8 and 12 hours post-dose ] [ Designated as safety issue: No ]
  • AUC(0-12)md for refametinib metabolite M-11 [ Time Frame: Day 1 at 0 (pre-dose), 0.5, 1, 2, 4 and 8 hours post-dose and Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8 and 12 hours post-dose ] [ Designated as safety issue: No ]
  • Cmax,md for regorafenib [ Time Frame: Day 1 at 0 (pre-dose), 0.5, 1, 2, 4, 8 and 24 hours post-dose and Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose ] [ Designated as safety issue: No ]
    In dosing cohorts that use regorafenib 2 weeks on / 2 weeks off regimen, multiple dose PK samples will be collected on Day 14 instead of Day 21.

  • Cmax,md for regorafenib metabolite M-2 [ Time Frame: Day 1 at 0 (pre-dose), 0.5, 1, 2, 4, 8 and 24 hours post-dose and Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose ] [ Designated as safety issue: No ]
    In dosing cohorts that use regorafenib 2 weeks on / 2 weeks off regimen, multiple dose PK samples will be collected on Day 14 instead of Day 21.

  • Cmax,md for regorafenib metabolite M-5 [ Time Frame: Day 1 at 0 (pre-dose), 0.5, 1, 2, 4, 8 and 24 hours post-dose and Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose ] [ Designated as safety issue: No ]
    In dosing cohorts that use regorafenib 2 weeks on / 2 weeks off regimen, multiple dose PK samples will be collected on Day 14 instead of Day 21.

  • Area under the plasma concentration-time curve from 0 to 24 h after multiple dose (AUC(0-24)md) for regorafenib [ Time Frame: Day 1 at 0 (pre-dose), 0.5, 1, 2, 4, 8 and 24 hours post-dose and Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose ] [ Designated as safety issue: No ]
    In dosing cohorts that use regorafenib 2 weeks on / 2 weeks off regimen, multiple dose PK samples will be collected on Day 14 instead of Day 21.

  • AUC(0-24)md for regorafenib metabolite M-2 [ Time Frame: Day 1 at 0 (pre-dose), 0.5, 1, 2, 4, 8 and 24 hours post-dose and Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose ] [ Designated as safety issue: No ]
    In dosing cohorts that use regorafenib 2 weeks on / 2 weeks off regimen, multiple dose PK samples will be collected on Day 14 instead of Day 21.

  • AUC(0-24)md for regorafenib metabolite M-5 [ Time Frame: Day 1 at 0 (pre-dose), 0.5, 1, 2, 4, 8 and 24 hours post-dose and Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose ] [ Designated as safety issue: No ]
    In dosing cohorts that use regorafenib 2 weeks on / 2 weeks off regimen, multiple dose PK samples will be collected on Day 14 instead of Day 21.

  • Number of participants with adverse events during Phase 2 as a measure of safety and tolerability [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
  • Tumor response during Phase 2 as assessed by RECIST v. 1.1 [ Time Frame: 6 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Maximum drug concentration in plasma (Cmax) for refametinib and its metabolite M-11 [ Time Frame: Day 1 at 0 (pre-dose), 0.5, 1, 2, 4 and 8 hours post-dose ] [ Designated as safety issue: No ]
  • Time to reach maximum drug concentration in plasma after single (first) dose (tmax) for refametinib and its metabolite M-11 [ Time Frame: Day 1 at 0 (pre-dose), 0.5, 1, 2, 4 and 8 hours post-dose ] [ Designated as safety issue: No ]
  • Area under the plasma concentration-time curve from 0 to 8 h (AUC(0-8)) for refametinib and its metabolite M-11 [ Time Frame: Day 1 at 0 (pre-dose), 0.5, 1, 2, 4 and 8 hours post-dose ] [ Designated as safety issue: No ]
  • Time to reach maximum drug concentration in plasma after multiple dose (tmax,md) for refametinib and its metabolite M-11 [ Time Frame: Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8 and 12 hours post-dose ] [ Designated as safety issue: No ]
  • Cmax for regorafenib and its metabolites M-2 and M-5 [ Time Frame: Day 1 at 0 (pre-dose), 0.5, 1, 2, 4, 8 and 24 hours post-dose ] [ Designated as safety issue: No ]
  • tmax for regorafenib and its metabolites M-2 and M-5 [ Time Frame: Day 1 at 0 (pre-dose), 0.5, 1, 2, 4, 8 and 24 hours post-dose ] [ Designated as safety issue: No ]
  • Area under the plasma concentration-time curve from 0 to 24 h (AUC(0-24)) for regorafenib and its metabolites M-2 and M-5 [ Time Frame: Day 1 at 0 (pre-dose), 0.5, 1, 2, 4, 8 and 24 hours post-dose ] [ Designated as safety issue: No ]
  • tmax,md for regorafenib and its metabolites M-2 and M-5 [ Time Frame: Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose ] [ Designated as safety issue: No ]
  • Tumor response during Phase 1b as assessed by RECIST v. 1.1 [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
  • Overall survival during Phase 2 [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Time to progression during Phase 2 [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Progression-free survival during Phase 2 [ Time Frame: 6 months ] [ Designated as safety issue: No ]

Estimated Enrollment: 180
Study Start Date: June 2014
Estimated Study Completion Date: April 2017
Estimated Primary Completion Date: April 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Refametinib/Regorafenib (Ph 1b)
Initial Phase 1b arm to determine recommended Phase 2 dose (RP2D) via dose-escalation. Single arm, uncontrolled, open-label
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: Refametinib/Regorafenib (Ph 2, CRC)
Phase 2 cohort, only to be started after completion of arm 1. Target population for this group: Colorectal cancer (CRC)
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: Refametinib/Regorafenib (Ph 2, NSCLC)
Phase 2 cohort, only to be started after completion of arm 1. Target population for this group: Non-small-cell lung cancer (NSCLC)
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: Refametinib/Regorafenib (Ph 2, BC)
Phase 2 cohort, only to be started after completion of arm 1. Target population for this group: Breast cancer
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.


  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
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 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).
  • 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
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02168777

Contacts
Contact: Bayer Clinical Trials Contact clinical-trials-contact@bayerhealthcare.com
Contact: For trial location information (Phone Menu Options '3' or '4') (+)1-888-84 22937

Locations
United States, Connecticut
Not yet recruiting
New Haven, Connecticut, United States, 06520
United States, Michigan
Recruiting
Detroit, Michigan, United States, 48201
United States, Missouri
Recruiting
St. Louis, Missouri, United States, 63110
United States, North Carolina
Recruiting
Chapel Hill, North Carolina, United States, 27599
United States, Texas
Not yet recruiting
Houston, Texas, United States, 77030
Sponsors and Collaborators
Bayer
Investigators
Study Director: Bayer Study Director Bayer
  More Information

Additional Information:
No publications provided

Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT02168777     History of Changes
Other Study ID Numbers: 17064, 2013-004861-15
Study First Received: June 18, 2014
Last Updated: August 8, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Bayer:
Patients with Cancer

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

ClinicalTrials.gov processed this record on August 19, 2014