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Objective Cobimetinib, a MEK1/2 inhibitor, was administered to patients with advanced solid tumors to assess safety, pharmacokinetics, pharmacodynamics, and anti-tumor activity. Methods For dose-escalation, a 3 + 3 design was used. Oral cobimetinib was administered once daily on a 21-day on/7-day off (21/7) or a 14-day on/14-day off (14/14) schedule. Serial plasma samples were collected for pharmacokinetic (PK) analysis on Day 1 and at steady state. In expansion stages, patients with RAS or RAF mutant tumors were treated at the maximum tolerated dose (MTD) of the 21/7 or 14/14 schedule. Results Ninety-seven patients received cobimetinib. In the 21/7 dose escalation, 36 patients enrolled in 8 cohorts (0.05 mg/kg-80 mg). Dose-limiting toxicities (DLTs) were Grade 4 hepatic encephalopathy, Grade 3 diarrhea, and Grade 3 rash. In the 14/14 dose escalation, 20 patients enrolled in 4 cohorts (60-125 mg). DLTs were Grade 3 rash and Grade 3 blurred vision associated with presence of reversible subretinal fluid. The MTD was 60 mg on 21/7 schedule and 100 mg on 14/14 schedule. Cobimetinib PK showed dose-proportional increases in exposure. The most frequent adverse events attributed to cobimetinib were diarrhea, rash, fatigue, edema, nausea, and vomiting. In patients treated at the 60-mg (21/7) or 100-mg (14/14) dose, one unconfirmed complete response and 6 confirmed partial responses were observed. All responses occurred in melanoma patients; 6 harbored the BRAF(V600E) mutation. Conclusions Cobimetinib is generally well tolerated and durable responses were observed in BRAF(V600E) mutant melanoma patients. Evaluation of cobimetinib in combination with other therapies is ongoing.

In this phase I, dose‐escalation study, we sought to determine the maximum tolerated dose (MTD) of the anaplastic lymphoma kinase/c‐ROS oncogene 1 receptor (ALK/ROS1) inhibitor ceritinib in combination with gemcitabine‐based chemotherapy in patients with advanced solid tumors. Secondary objectives were characterization of the safety profile, pharmacokinetics and preliminary efficacy of these combinations, and identification of potential biomarkers of efficacy. Ceritinib was combined with gemcitabine (Arm 1), gemcitabine/nab‐paclitaxel (Arm 2) or gemcitabine/cisplatin (Arm 3). Drug concentrations in plasma were measured by tandem mass spectrometric detection (LC‐MS/MS). We analyzed archival tumor tissue for ALK, ROS1, hepatocyte growth factor receptor (c‐MET) and c‐Jun N‐terminal kinase (JNK) expression by immunohistochemistry. Arm 2 closed early secondary to toxicity. Twenty‐one patients were evaluable for dose‐limiting toxicity (DLT). There was one DLT in Arm 1 (grade 3 ALT increase) and three DLTs in Arm 3 (grade 3 acute renal failure, grade 3 thrombocytopenia, grade 3 dyspnea). The MTD of ceritinib was determined to be 600 mg (Arm 1) and 450 mg orally daily (Arm 3). Main toxicities were hematologic, constitutional and gastrointestinal as expected by the chemotherapy backbone. The apparent clearance for ceritinib decreased substantially after repeated dosing; cisplatin did not significantly affect the pharmacokinetics of ceritinib. The overall response rate was 20%; the median progression‐free survival was 4.8 months. Three out of five response‐evaluable cholangiocarcinoma patients had clinical benefit. Increased expression of c‐MET was associated with a lack of clinical benefit. Ceritinib in combination with gemcitabine and gemcitabine/cisplatin has a manageable toxicity profile. Further development of this strategy in tumors with ALK or ROS1 fusions is warranted. What's new? ALK/ROS1 inhibitors have in vitro and in vivo synergy with cytotoxic agents and can effectively kill tumour cell subpopulations that either lack ALK/ROS1 aberrations or are resistant to ALK/ROS1 inhibition. In this phase I trial, the authors show that the highly selective oral ALK/ROS1 inhibitor ceritinib can be combined with gemcitabine‐based chemotherapy in humans with a manageable toxicity profile. Furthermore, c‐MET expression as measured by immunohistochemistry could be a potential negative predictive biomarker for treatment benefit. The results pave the way for further development of this combination strategy in tumours with ALK or ROS1 fusions. [ABSTRACT FROM AUTHOR]

We conducted a phase I study to assess safety, pharmacokinetics, pharmacodynamics, and activity of lonafarnib plus gemcitabine. Subjects received oral lonafarnib twice daily and gemcitabine on days 1, 8, and 15 every 28 days; multiple dose levels were explored. Lonafarnib had no apparent effect on gemcitabine PK. Mean lonafarnib half-life ranged from 4 to 7 hr; median Tmax values ranged from 4 to 8 hr. Two patients had partial response; seven patients had stable disease at least 6 months. Oral lonafarnib at 150 mg a.m./100 mg p.m. plus gemcitabine at 1,000 mg/m2 is the maximum tolerated dose with acceptable safety and tolerability. [ABSTRACT FROM AUTHOR]

Background: Pyrazoloacridine (PZA) is thefirst of a new class of rationallysynthesized acridine derivatives to undergoclinical testing as an anticancer agent. We previously demonstrated cytotoxicsynergy between combinations of PZA andplatinum compounds. Subsequent studiesrevealed that PZA inhibits removal ofplatinum-DNA adducts in cultured A549cells. Based on these results, weundertook a phase I study of thecombination of PZA and carboplatin (CBDCA). Patients and methods: Twenty-eightpatients received 76 28-day courses (median2.5, range 1–6) of CBDCA (30-minuteinfusion) followed by PZA (3-hourinfusion), through six dose levels [PZA/CBDCA] (200/AUC 3,400/AUC 3, 400/AUC 4,400/AUC 5, 500/AUC 5, 600/AUC5 mg/m2/AUC). Pharmacokineticanalyses were performed to evaluate thedisposition of PZA. Retention ofplatinum-DNA adducts in peripheral bloodmononuclear cells of patients was alsoevaluated. Results: The most common anddose-limiting toxicity wasmyelosuppression, consisting of neutropeniaand leukopenia. Non-hematologic toxicitiesof anorexia, nausea and stomatitis weremild to moderate. In six patientsevaluated at the MTD, CBDCA did not appearto affect the pharmacokinetics of PZA. Onepatient with malignant melanoma had apartial response. Disease stabilizationfor greater than 4 courses of treatmentoccurred in 4 patients. Conclusion: The combination of PZAand CBDCA was well tolerated and may haveutility in some tumor types. [ABSTRACT FROM AUTHOR]