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

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