In patients with advanced RCC, CCI-779 showed antitumor activity and encouraging survival and was generally well tolerated over the three dose levels tested.

A single 100 mg dose of intravenous tigecycline produced considerably higher tissue/fluid concentrations in bile, gall bladder, colon and lung compared with simultaneous serum concentrations. On average, the systemic exposure of tigecycline in bone, SF and CSF ranged from 11% to 41% of serum concentrations. The results in bone are inconsistent with previous radiolabelled studies in animals and it is unclear if tight binding to bone (versus low bone uptake) or poor extraction of tigecycline for LC/MS/MS detection or both may have contributed to the differences we observed in humans.

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Purpose Evaluate safety and determine the recommended phase II dose (RP2D) of ensartinib (X-396), a potent anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), and evaluate preliminary pharmacokinetics and antitumor activity in a first-in-human, phase I/II clinical trial primarily in patients with non-small cell lung cancer (NSCLC). Experimental Design In dose escalation, ensartinib was administered at doses of 25−250 mg once daily in patients with advanced solid tumors; in dose expansion, patients with advanced ALK-positive NSCLC were administered 225 mg once daily. Patients who had received prior ALK TKI(s) and patients with brain metastases were allowed. Results Thirty-seven patients enrolled in dose escalation, and 60 enrolled in dose expansion. The most common treatment-related toxicities were rash (56%), nausea (36%), pruritus (28%), vomiting (26%), and fatigue (22%); 23% of patients experienced a treatment-related Grade 3-4 toxicity (primarily rash and pruritus). The maximum tolerated dose was not reached, but the RP2D was chosen as 225 mg based on the frequency of rash observed at 250 mg without improvement in activity. Among the ALK-positive efficacy evaluable patients treated at ≥200 mg, the response rate (RR) was 60% and median progression-free survival (PFS) was 9.2 months. RR in ALK TKI naïve patients was 80% and median PFS was 26.2 months. In patients with prior crizotinib only, the RR was 69% and median PFS was 9.0 months. Responses were also observed in the central nervous system, with an intracranial RR of 64%. Conclusions Ensartinib was active and generally well tolerated in patients with ALK-positive NSCLC.

ObjectivesWe report the largest clinical experience using tigecycline-containing regimens for salvage treatment of patients with Mycobacterium abscessus and Mycobacterium chelonae.Patients and methodsData were collected from 52 patients on emergency/compassionate use (n = 38) or two open-label studies (n = 7 patients each). Based on information that was available, 46 (88.5%) of the subjects received antibiotic therapy prior to treatment with tigecycline. Treatment groups were evaluated based on length of tigecycline therapy (<1 and ≥1 month). ClinicalTrials.gov identifiers: Study 205, NCT00600600 and Study 310, NCT00205816.ResultsThe most commonly used concomitant antimicrobials were macrolides, amikacin and linezolid. Pulmonary disease was the most common presentation (36/52; 69.2%), and 58.3% of these patients had underlying cystic fibrosis. The majority were M. abscessus complex (n = 30) or M. chelonae/abscessus (n = 4). With therapy ≥1 month (mean, 255.0 ± 265.7 days), 10/15 patients (66.7%) with cystic fibrosis and 16/26 (61.5%) overall were considered improved. Skin/soft-tissue/bone infections were the most common extrapulmonary infections. With therapy ≥1 month (mean, 143 ± 123 days), 9/12 patients (75.0%) were considered improved. Nine of the 16 cases reported as failures regardless of site of infection occurred in patients who stopped treatment due to adverse events. There were eight deaths; none was related to tigecycline.ConclusionsTigecycline given for ≥1 month as part of a multidrug regimen resulted in improvement in >60% of patients with M. abscessus and M. chelonae infections, including those with underlying cystic fibrosis, despite failure of prior antibiotic therapy. Adverse events were reported in >90% of cases, the most common being nausea and vomiting.