Procedures
bleeding, DLTs, tumor, neutropenia, febrile neutropenia, fever, toxicity, toxicities, thrombocytopenia, diarrhea, fatigue, keratoacanthomas, melanoma, skin carcinoma, infection, nausea, vomiting
DISEASE PROGRESSION, BLEEDING, TUMOR, NEUTROPENIA, FEBRILE NEUTROPENIA, MELANOMA, THROMBOCYTOPENIA, KERATOACANTHOMAS, SOLID TUMOR, SKIN CARCINOMA, INFECTION, LYMPHOMA, EVENTS, SEQUELAE
Tovorafenib was administered orally (tablet formulation), with patients fasting (except for water) for at least 2 h before and at least 2 h after taking their dose. Treatment was to be continued until disease progression, unacceptable toxicity, or the patient discontinued for any other reason, for a maximum duration of 12 months. Treatment could be continued beyond 12 months if it was determined that a patient would derive benefit from such continued therapy.In the dose escalation phase, a 3 + 3 design was used to evaluate tovorafenib administered with continuous dosing on Q2D and QW dosing regimens. Prior to the initiation of QW dose escalation, the initial cycle length of 22 days was changed to 28 days by protocol amendment to improve clinical feasibility and better facilitate future combination studies. Patients enrolled prior to this protocol amendment in an ongoing Q2D dose escalation cohort continued on the 22-day cycle schedule until the cohort was full and all patients had been evaluated for dose-limiting toxicity (DLT). For both Q2D and QW regimens, dose escalation progressed according to the incidence of DLT in the first treatment cycle (either 22 days or 28 days). DLTs were defined as: grade 4 neutropenia lasting ≥ 7 consecutive days; febrile neutropenia (defined as an ANC ≤ 1000 cells/μL and fever ≥ 38.5 °C) or documented infection ≥ grade 3 with ANC ≤ 1000 cells/μL; grade 4 thrombocytopenia (platelet count < 25,000/μL), tovorafenib-related thrombocytopenia requiring platelet transfusion, or tovorafenib-related bleeding requiring medical attention; treatment delays of ≥ 14 days due to any toxicity; ALT and AST toxicities (ALT or AST > 7.5 × ULN for greater than 14 days or ALT or AST > 7.5 × ULN accompanied by an elevation in total bilirubin of > 3 × ULN [not explained by obstruction] regardless of duration); nonhematological toxicity ≥ grade 3 (with the exception of: nausea, vomiting, and diarrhea except if they persisted at ≥ grade 3 for > 3 days despite adequate supportive care measures [at the investigator’s discretion, patients who experienced nausea, vomiting, or diarrhea after taking tovorafenib could receive antiemetic or antidiarrheal medication prior to subsequent doses]; isolated laboratory abnormalities ≥ grade 3 that resolved to ≤ grade 1 in ≤ 7 days without clinical sequelae or the need for therapeutic intervention; fatigue ≥ grade 3 for ≤ 7 days; development of keratoacanthomas or skin carcinoma unless unusually aggressive or metastatic), provided the site investigator considered such events were at least possibly related to study treatment. The MTD was defined as the highest dose level that generated DLT in 0/3 or 1/6 patients. On a case-by-case basis, the sponsor in collaboration with the principal investigators determined if intrapatient dose escalation was appropriate. Patients who had any dose reductions were not permitted to dose escalate.The starting dose for the Q2D dose escalation phase was 20 mg, which was equivalent to one-tenth of the highest non-severely toxic dose (HNSTD) established in monkey toxicology studies. Dose escalation included planned dose levels of 40 mg, 80 mg, 135 mg, 200 mg, and 280 mg. Once the MTD and/or RP2D of Q2D tovorafenib was established, patients with melanoma were enrolled into 1 of 6 Q2D melanoma expansion cohorts (approximately 16 patients per cohort), based on tumor genotype and treatment history (Supplementary Table S1). In addition, a seventh Q2D cohort was to enroll sufficient patients (approximately 16) with any advanced solid tumor (excluding lymphoma) to ensure that 12 patients completed protocol-specified dosing and PK assessments scheduled during cycle 1.The study was initially designed to investigate a Q2D schedule. Subsequently, a protocol amendment introduced planned QW dose escalation cohorts. The alteration in the dosing regimen from Q2D to QW was expected to reduce drug accumulation and increase 