Assessment Of Maximum Tolerated Dose Research Articles

Radiopaque Iodosilane-Coated Lipid Hybrid Nanoparticle Contrast Agent for Dual-Modality Ultrasound and X-ray Bioimaging.

Here, we report the synthesis of robust hybrid iodinated silica-lipid nanoemulsions (HSLNEs) for use as a contrast agent for ultrasound and X-ray applications. We engineered iodinated silica nanoparticles (SNPs), lipid nanoemulsions, and a series of HSLNEs by a low-energy spontaneous nanoemulsification process. The formation of a silica shell requires sonication to hydrolyze and polymerize/condensate the iodomethyltrimethoxysilane at the oil/water interface of the nanoemulsion droplets. The resulting nanoemulsions (NEs) exhibited a homogeneous spherical morphology under transmission electron microscopy. The particles had diameters ranging from 20 to 120 nm with both negative and positive surface charges in the absence and presence of cetyltrimethylammonium bromide (CTAB), respectively. Unlike CTAB-coated nanoformulations, the CTAB-free NEs showed excellent biocompatibility in murine RAW macrophages and human U87-MG cell lines in vitro. The maximum tolerated dose assessment was evaluated to verify their safety profiles in vivo. In vitro X-ray and ultrasound imaging and in vivo computed tomography were used to monitor both iodinated SNPs and HSLNEs, validating their significant contrast-enhancing properties and suggesting their potential as dual-modality clinical agents in the future.

Umbralisib in combination with ibrutinib in patients with relapsed or refractory chronic lymphocytic leukaemia or mantle cell lymphoma: a multicentre phase 1–1b study

Patients with relapsed or refractory high-risk chronic lymphocytic leukaemia or mantle cell lymphoma often do not derive durable benefit from ibrutinib monotherapy. We hypothesised that dual B-cell receptor pathway blockade would be tolerable and efficacious. We investigated a next-generation phosphoinositide-3-kinase-δ inhibitor (PI3K-δi), umbralisib, plus a Bruton tyrosine kinase inhibitor (BTKi), ibrutinib, in relapsed or refractory chronic lymphocytic leukaemia and mantle cell lymphoma. We did an investigator-initiated, multicentre, phase 1-1b study of patients from five sites in the USA (academic and community sites). Patients were 18 years and older with relapsed or refractory chronic lymphocytic leukaemia or mantle cell lymphoma, with an Eastern Cooperative Oncology Group performance status of 2 or less, and were given umbralisib orally once daily (400 mg, 600 mg, or 800 mg) and ibrutinib orally once daily (420 mg for chronic lymphocytic leukaemia or 560 mg for mantle cell lymphoma) until disease progression or unacceptable toxicity. The phase 1 dose-escalation cohorts for each histology escalated independently in a standard 3 × 3 design. The primary endpoints were intention-to-treat assessment of maximum-tolerated dose, safety, and dose-limiting toxicities. This trial is ongoing and is registered with ClinicalTrials.gov, number NCT02268851. Between Dec 5, 2014, and March 7, 2018, we enrolled 44 patients, of which 42 were given at least one dose of study drug (chronic lymphocytic leukaemia, n=21; mantle cell lymphoma, n=21). Patients had a median age of 68 years (range 48-85) and had a median of two (IQR 1-3) previous therapies. No dose-limiting toxicities were observed and the maximum-tolerated dose of umbralisib was not reached. The recommended phase 2 dose of umbralisib when given in combination with ibrutinib was 800 mg once daily. The most frequent adverse events included diarrhoea (22 [52%] patients, 10% of whom had grade 3), infection (21 [50%], 17% grade 3-4), and transaminitis (ten [24%], 2% grade 3). Serious adverse events occurred in 12 (29%) patients and included lipase elevation, atrial fibrillation, hypophosphataemia, adrenal insufficiency, transaminitis, and infections. Umbralisib plus ibrutinib is well tolerated and active in relapsed or refractory chronic lymphocytic leukaemia and mantle cell lymphoma, with a recommended phase 2 dose of umbralisib 800 mg once daily. To the best of our knowledge, these are the first clinical data on a BTKi and PI3K-δi doublet in B-cell malignancies, and the results suggest that this approach is feasible and worthy of further study. TG Therapeutics, Leukemia and Lymphoma Society Therapy Accelerator Program.

Pegylated liposomal doxorubicin and cyclophosphamide in early recurrent ovarian carcinoma: phase I dose-finding study

This single-arm phase I dose-escalation study determines the optimal dose of the non-platinum treatment pegylated liposomal doxorubicin (PLD) plus cyclophosphamide (CPM) every 4 weeks in early recurrent ovarian carcinoma. Twenty-one women with ovarian carcinoma relapsing within 12 months of first-line surgery and platinum-taxane chemotherapy received escalating doses of PLD (35-45 mg/m(2)) and CPM (500-600 mg/m(2)) every 4 weeks for at least two cycles. Primary objective was assessment of maximum-tolerated dose (MTD) over the first two cycles. Secondary objectives were to assess safety over 2 cycles, efficacy evaluated every two cycles (response evaluation criteria in solid tumours criteria) and overall survival (OS). The PLD-CPM MTD was 40/600 mg/m(2) with 2/3 patients treated at 45/500 mg/m(2), showing DLTs with Grade 3/4 oesophagitis, thrombopenia/neutropenia, leucopoenia, and Grade 3 stomatitis/asthenia during the first cycle of treatment. Four severe toxicities were reported by three patients during the two first cycles, namely Grade 4 anaemia, and Grade 3 stomatitis. The most common treatment-related toxicities were anaemia (71.4 %), nausea (61.9 %), neutropenia (57.1 %), asthenia (52.4 %), leucopoenia (47.6 %), stomatitis (42.9 %), skin (28.6 %) and palmar-plantar-erythrodysesthesia (19 %). No treatment-related deaths were reported. The overall response rate (complete and partial) was 31 %, and median OS was 8.2 months [95 % CI (3.3-13.2)]. The combination of PLD and CPM is feasible and may be considered particularly in cases where platinum-based treatment is not suitable. The recommended doses for a phase II trial are PLD 40 mg/m(2) plus CPM 600 mg/m(2) every 4 weeks.