Investigational New Drugs

We report a case of a 38-year-old woman who was diagnosed with stage IV lung adenocarcinoma, harboring an epidermal growth factor receptor (EGFR) L858R mutation on exon 21 and a T790 M mutation on exon 20. The patient was treated with osimertinib, a third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI) following treatment with nivolumab, an anti-Programmed Cell Death 1 (anti-PD1) antibody. After initiating osimertinib treatment, the patient began to complain of low-grade fever and shortness of breath without hypoxemia, and her chest radiograph and a CT scan revealed a remarkable antitumor response, although faint infiltrations were observed in the bilateral lung field. Bronchoalveolar lavage fluid mainly contained lymphocytes (CD4+/CD8+ ratio of 0.3), and a transbronchial lung biopsy specimen showed lymphocytic alveolitis with partial organization in several alveolar spaces. Therefore we diagnosed the patient with osimertinib-induced interstitial lung disease (ILD) after treatment with anti-PD1 antibody. We considered anti-PD1 therapies may be the risk factor of EGFR-TKI-induced ILD.

Introduction Cetuximab is registered for use in colorectal cancer (CRC) patients with RAS wild-type tumours only. Simvastatin blocks the mevalonate pathway and thereby interferes with the post-translational modification (prenylation) of KRAS. We hypothesize that the activitated KRAS pathway in KRAS mutant tumors can be inhibited by simvastatin rendering these tumors sensitive to the EGFR inhibitor cetuximab. Methods A Simon two-stage, single-arm, phase II study was performed to test the efficacy and safety of the addition of simvastatin to cetuximab in patients with a KRAS mutation in their CRC tumour who were previously treated with fluoropyrimidine, oxaliplatin and irinotecan based regimens. The primary endpoint was to test the percentage of patients alive and free from progression 12.5 weeks after the first administration of cetuximab. Our hypothesis was that at least 40 % was free from progression, comparable to, though slightly lower than in KRAS wild-type patients. Results Four of 18 included patients (22.2 %) were free from progression at the primary endpoint time. The time to progression in these 4 patients ranged from 20.3 to 47 weeks. Conclusion Based on the current study we conclude that the theoretical concept of KRAS modulation with simvastatin was not applicable in the clinic, as we were not able to restore sensitivity to cetuximab in CRC patients harbouring a somatic KRAS mutation.

Glioblastoma multiforme (GBM) is a malignant CNS tumor with a poor prognosis. GBM shows aberrant glycosylation with hypersialylation. This property is a potential target for therapy. This study investigates the growth inhibitory efficacy of poly-guanidine (GuaDex), with an affinity for sialic acid (Sia). Glioma cell cultures and patient-derived glioma cell lines (PDGCLs) expressing Prominin-1 (CD133) were used. Human fibroblasts and astrocyte-derived cells were used as controls. Temozolomide (standard GBM drug, TMZ) and DMSO were used as a comparison. GuaDex at 1–10 µM concentrations, were incubated for 3.5–72 h and with PDGCLs cells for 6–24 h. The cytotoxicity was estimated with a fluorometric cytotoxicity assay (FMCA). Fluorescence-labelled GuaDex was used to study the cell interactions. Sia expression was confirmed with a fluorescence labelled Sia binding lectin. Expression of glial fibrillary acidic protein was determined. GuaDex induction of growth inhibition was fast, showing after less than 5 min incubation while the control cells were not affected even after 50 min incubation. The growth inhibitory effect on PDGCLs spheroids was persistent still showing after 4 weeks post-treatment. The growth inhibition of GuaDex was induced at low µM concentrations while TMZ induced only a slight inhibition at mM concentrations. GuaDex efficacy appears significant and warrants further studies.

Purpose NK105 is a new drug delivery system formulation for paclitaxel (PTX) whose recommended dose (RD)　is 150 mg PTX equivalent/m2 administered every 3 weeks, as determined in a phase I trial. This study aimed to evaluate the efficacy and safety of NK105 in patients with advanced gastric cancer after failure of first-line chemotherapy. Experimental design Eligible patients had measurable disease and one chemotherapeutic regimen except taxane. NK105 (150 mg PTX equivalent/m2) was administered by a 30-minute intravenous infusion every 3 weeks without anti-allergic premedication until disease progression, unacceptable toxicity or patient refusal. The primary efficacy endpoint was best overall response rate (ORR) post baseline. The secondary endpoints were progression-free survival (PFS), time to treatment failure (TTF) and overall survival (OS). All adverse events were reported using CTCAE v3.0. Results Between November 2007 and July 2009, 57 patients were enrolled and 56 were evaluable for efficacy. Two complete responses and 12 partial responses were observed for an ORR of 25%. The median PFS was 3.0 months, the median TTF was 2.8 months, and the median OS was 14.4 months. Drug related toxicity was mainly mild (grades 1–2) to severe (grades 3–4); other data: neutropenia (64.9%); leukopenia (17.5%); lymphopenia (8.8%); neuropathy-sensory (1.8%); fatigue (3.5%); and stomatitis (1.8%). There were no treatment-related deaths. Conclusions This study of NK105 (150 mg PTX equivalent/m2) proves the concept for the modest activity and tolerability of a new drug delivery system formulation for PTX. A phase III trial will be evaluated to clarify survival benefit.

Introduction New drug development is a time- and resource-consuming process. Phase 1 trials constitute a major key-step of this development. Shortening the accrual time is of major importance. Methods 292 published phase-1-trials were retrospectively reviewed to establish the determinants of accrual time using Log-rank test and then Cox Model. Results Out of 292 trials (1997–2008), only 107 reports (36%) described the accrual time (median: 20 months, 5–72). Phase-2-recommended dose was established in 87 studies (81%). Most studies investigated regimens including cytotoxic drugs (77%) or molecular targeted therapies (29%). Under univariate analysis, two parameters shortened the accrual time: studies conducted in USA vs. other places (19 vs. 21 months p = 0.03) and regimen with more than 2 dose-escalated drugs (13 vs. 21 months, p = 0.003). One parameter was significantly associated with longer accrual time: starting dose justified by animal toxicology data vs. previous clinical trials (22 vs. 19 months, p = 0.03). Most of parameters did not significantly affect the accrual time: nature of investigated drugs, duration of treatment cycle, phase 1 dedicated to specific tumoral subtypes, number of centers, method of drug escalation (classical 3+3 vs. accelerated titration design), type of increment (modified Fibonacci method vs. others) and presence of expansion of cohort at the phase-II-recommended dose. Cox model analysis retained one determinant: starting dose justified by animal toxicology data: HR = 2.00 [1.45–5.20], p = 0.047. Conclusion Few parameters influence the accrual time of dose-escalation phase-1 trials. Real first-in-man phase 1 studies based on starting dose estimated from animal toxicological data require longer accrual time.

BBR 3438, a member of the 9-aza-anthrapyrazole family designed to decrease anthracycline dependent cardiotoxicity and to improve efficacy provided high in vivo activity in gastric carcinoma xenograft models. The present study was carried out to assess the efficacy and safety of BBR 3438 applied at a dose of 50 mg/m2 four-weekly as an 1-hour infusion to pretreated patients with gastric cancer. Twenty-seven patients received at least one administration of BBR 3438. Lymph nodes and liver were the most common sites of metastases. A total of 94 cycles were administered (median 2, range 1–6). The main toxicity consisted of (worst per patient [%]; NCIC CTC grades 1/2/3/4) neutropenia 7/7/19/52 (one case of febrile neutropenia), stomatitis 15/19/4/-, nausea 22/26/7/-, vomiting 19/7/7/-, alopecia 15/33/-/-. Neutrophil nadir (520/μl) was reached after a median 15 days. The median time to recovery to ≤grade 1 neutropenia was 13.5 days. The median average cumulative dose of BBR 3438 was 166.8 mg, and the median dose intensity was 48.8 mg/m2. Left ventricular ejection function (LVEF) was monitored with multiple-gated angiography (MUGA). Median LVEF values at baseline and at the end of cycle 2 were 67.5% and 65%, respectively, and no patient showed a relevant decrease of LVEF. In 25 patients evaluable for response no remission was observed. Four patients (16%) had stable disease. Median time to progression was 51 days, median overall survival was 64 days. In all, the feasibility and tolerability of BBR 3438 applied 4-weekly at a dose of 50 mg/m2 was confirmed and neither relevant LVEF decreases nor hints of cardiac toxicity were observed. In terms of antitumor activity, BBR 3438 was found to be ineffective in the treatment of gastric cancer.

Background Intra-patient variability in sorafenib pharmacokinetics has been poorly investigated to date. We hypothesized that sorafenib clearance could decrease over time, as seen with imatinib. Patients and methods Sorafenib plasma concentrations were determined by liquid chromatography, every 2 weeks, in consecutive hepatocellular carcinoma patients treated with sorafenib. Sorafenib dose-normalized area under the concentration-time curve (AUC) was determined from a population pharmacokinetics model, and its kinetics was analyzed in order to identify possible alterations of exposure over time. Results Fifteen hepatocellular carcinoma patients with Child-Pugh A cirrhosis, in whom sorafenib dosing remained unchanged from initiation of treatment to disease progression, were eligible for this analysis. Sorafenib AUC significantly decreased over time: the median AUC during the third month of treatment was lower than that observed after one month of treatment (43.0 vs. 60.3 mg/L.h, p = 0.008). Most importantly, median sorafenib AUC at the time of progression was almost two-fold lower than that observed after one month of therapy (33.2 vs. 60.3 mg/L.h, p = 0.007). These findings suggest an induction of expression of efflux transporters in the gut wall, or an induction of sorafenib metabolism. Conclusions In patients with progressive disease in whom exposure markedly decreased from baseline, sorafenib dose escalation could be considered, aiming to restore an adequate drug exposure and possibly anti-tumor activity.