Refametinib (BAY86-9766) in Combination With Regorafenib (Stivarga, BAY73-4506) in Patients With Advanced or Metastatic Cancer
Condition: Neoplasms
MeSH terms: Neoplasm Metastasis
Intervention: Refametinib (BAY86-9766); Regorafenib (Stivarga, BAY73-4506)
Intervention description: 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 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.
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 20.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Patients with Cancer

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.
    

Eligibility 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