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

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.

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