Definition of dose limiting toxicity (DLT)

Toxicities were graded based on the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Dose limiting toxicities (DLT) were based on adverse events occurring in the first 28 day cycle. Hematologic DLT was defined as any treatment related grade 4 hematologic toxicity with the exception of lymphopenia and anemia, grade 3 neutropenia with fever; or grade 3 thrombocytopenia. Non-hematologic DLTs were initially defined as any grade 3 or 4 related non-hematologic toxicity. The protocol was subsequently amended to exclude grade 3 rash, diarrhea, infection, fever, or photosensitivity that resolved to grade ≤ 2 within 7 days of appropriate medical management in the DLT definition. This was based on additional Genentech/Roche trial experience supporting that these specific side effects can be well managed and should not constitute a DLT. Any related grade 2 non-hematological toxicity that persisted for more than 7 days and was considered sufficiently medically significant or sufficiently intolerable by patients to warrant treatment interruption and/or dose reduction was also considered dose-limiting.