Regorafenib in combination with FOLFOX or FOLFIRI as first- or second-line treatment of colorectal cancer: results of a multicenter, phase Ib study.

BACKGROUND: Metastatic colorectal cancer (mCRC) is commonly treated with 5-fluorouracil, folinic acid, and oxaliplatin or irinotecan. The multitargeted kinase inhibitor, regorafenib, was combined with chemotherapy as first- or second-line treatment of mCRC to assess safety and pharmacokinetics (primary objectives) and tumor response (secondary objective). PATIENTS AND METHODS: Forty-five patients were treated every 2 weeks with 5-fluorouracil 400 mg/m(2) bolus then 2400 mg/m(2) over 46 h, folinic acid 400 mg/m(2), and either oxaliplatin 85 mg/m(2) or irinotecan 180 mg/m(2). On days 4-10, patients received regorafenib 160 mg orally once daily. RESULTS: The median duration of treatment was 108 (range 2-345 days). Treatment was stopped for adverse events or death (17 patients), disease progression (11 patients), and consent withdrawal or investigator decision (11 patients). Six patients remained on regorafenib at data cutoff (two without chemotherapy). Drug-related adverse events occurred in 44 patients [grade ≥ 3 in 32 patients: mostly neutropenia (17 patients) and leukopenia, hand-foot skin reaction, and hypophosphatemia (four patients each)]. Thirty-three patients achieved disease control (partial response or stable disease) for a median of 126 (range 42-281 days). CONCLUSION: Regorafenib had acceptable tolerability in combination with chemotherapy, with increased exposure of irinotecan and SN-38 but no significant effect on 5-fluorouracil or oxaliplatin pharmacokinetics.

Regorafenib (BAY 73-4506) in advanced colorectal cancer: a phase I study.

BACKGROUND: In a phase I dose-escalation study, regorafenib demonstrated tolerability and antitumour activity in solid tumour patients. The study was expanded to focus on patients with metastatic colorectal cancer (CRC). METHODS: Patients received oral regorafenib 60-220 mg daily (160 mg daily in the extension cohort) in cycles of 21 days on, 7 days off treatment. Assessments included toxicity, response, pharmacokinetics and pharmacodynamics. RESULTS: Thirty-eight patients with heavily pretreated CRC (median 4 prior lines of therapy, range 0-7) were enrolled in the dose-escalation and extension phases; 26 patients received regorafenib 160 mg daily. Median treatment duration was 53 days (range 7-280 days). The most common treatment-related toxicities included hand-foot skin reaction, fatigue, voice change and rash. Twenty-seven patients were evaluable for response: 1 achieved partial response and 19 had stable disease. Median progression-free survival was 107 days (95% CI, 66-161). At steady state, regorafenib and its active metabolites had similar systemic exposure. Pharmacodynamic assessment indicated decreased tumour perfusion in most patients. CONCLUSION: Regorafenib showed tolerability and antitumour activity in patients with metastatic CRC. This expanded-cohort phase I study provided the foundation for further clinical trials of regorafenib in this patient population.

The safety of healthy volunteers in First-in-Man trials - an analysis of studies conducted at the Bayer in-house ward from 2000 to 2005.

OBJECTIVE: The Northwick Park incident has focused the attention on the risk of healthy volunteers participating in Phase I First-in-Man (FiM) studies irrespective of biologicals or small molecules being applied. However, only few data on the safety of healthy volunteers receiving small molecules in FiM trials are available. This study reports on the safety of healthy volunteers participating in single dose FiM studies performed with small molecules at the Bayer in-house study ward in Wuppertal from 2000 to 2005. METHODS: From 2000 to 2005, 24 FiM dose escalation studies with small molecules were performed. Twenty studies were performed with oral formulations and four studies with intravenous formulations. 1,094 young healthy male subjects were included into the studies. 77 subjects dropped out before receiving any study medication. The remaining 1,017 study participants (mean age 31.8 ± 6.5 years (range: 18 - 46 years)) received 1,160 treatments, 792 with active drug and 368 with placebo. RESULTS: In total, 586 adverse events (AE) occurred equaling 0.51 AE/treatment and 0.58 AE/ subject. 128 AEs occurred under placebo (0.35/treatment) and 458 under active drug (0.58/treatment). 98.3% of AEs were of mild or moderate intensity. Adverse events with a frequency > 2% were headache (17.1%), nasopharyngitis (7.3%), flushing (7.0%), feeling hot (5.5%), nausea (4.1%), nasal congestion (3.9%), dizziness (3.4%), diarrhea (3.24%), Alanine aminotransferase (ALT) increase (2.6%) and orthostatic hypotension (2.4%). In only 5 out of 1,160 treatments (0.4%) a serious adverse event occurred. Two cases of hypotension were related to the mode of action of CNS compounds and judged to be drug-related while the other three events (muscle enzyme elevation (2 ×), prolonged orthostatic reaction (1 ×) were not drug-related. None of the serious adverse events was medically worrying or required hospitalization. CONCLUSION: The incidence of adverse events in FiM trials with small molecules in our center between 2000 and 2005 and the severity of AEs is comparable to what has been reported previously for Phase I trials with small molecules [3, 4]. It reflects our experience with FiM trials of more than 25 years in which no medically worrying or hospitalization requiring serious adverse event occurred.