👤 A Postel-Vinay

We aimed to determine the safety and efficacy of nintedanib, an oral anti-angiogenic tyrosine kinase inhibitor, in combination with pembrolizumab, an anti-PD1 immunotherapy, in patients with advanced solid tumors (PEMBIB trial; NCT02856425). In this monocentric phase Ib dose escalation cohort, we evaluated escalating doses of nintedanib (Dose level 1 (DL1) = 150 mg bid [bis in die, as twice a day]; DL2 = 200 mg bid, oral delivery) in combination with pembrolizumab (200 mg Q3W, IV). Patients received a 1-week lead-in dose of nintedanib monotherapy prior starting pembrolizumab. The primary objective was to establish the maximum tolerated dose (MTD) of the combination based on dose limiting toxicity (DLT) occurrence during the first 4 weeks. Secondary objectives were to assess the anti-tumor efficacy and to identify the associated immune and angiogenic parameters in order to establish the recommended nintedanib dose for expansion cohorts. Flow cytometry (FC), Immuno-Histo-Chemistry (IHC) and electrochemiluminescence multi-arrays were prospectively performed on baseline & on-treatment tumor and blood samples to identify immune correlates of efficacy. A total of 12/13 patients enrolled were evaluable for DLT (1 patient withdrew consent prior receiving pembrolizumab). Three patients at 200 mg bid experienced a DLT (grade 3 liver enzymes increase). Four patients developed grade 1-2 immune related adverse events (irAE). Eight patients died because of cancer progression. Median follow-up was 23.7 months (95%CI: 5.55-40.5). Three patients developed a partial response (PR) (ORR = 25%) and five patients (42%) had durable clinical benefit (DCB), defined as PR or stable disease (SD) ≥ 6 months. At baseline, patients with DCB had higher plasma levels of Tie2, CXCL10, CCL22 and circulating CD4 Nintedanib 150 mg bid is the recommended dose for combination with pembrolizumab and is currently investigated in multiple expansion cohorts. Early tumoral and circulating immune factors were associated with cancer outcome under nintedanib & pembrolizumab therapy. ClinicalTrials.gov, NCT02856425 . Registered August 4, 2016 - Prospectively registered. Show less

Stargardt's disease is an autosomal recessive condition characterised by a rapid and bilateral loss of central vision at around 7 to 12 years, with typical changes in the macular and perimacular region. It is one of the most frequent causes of macular degeneration in childhood and accounts for 7% of all retinal dystrophies. Considering that inclusions of lipofuscin-like substances are observed in retinal pigmentary cells of patients with Stargardt's disease on the one hand, and that the early symptoms of neuronal ceroid lipofuscinosis (CLN3) are suggestive of Stargardt's disease on the other hand (age of loss of visual acuity, appearance of the fundus), we decided to test allelism of Stargardt's disease with the infantile (CLN1) and juvenile forms of neuronal ceroid lipofuscinosis (CLN3), which map to chromosomes 1p32 and 16p12-p11 respectively. Using highly informative microsatellite DNA markers in eight multiplex families, we were able to exclude Stargardt's disease from the vicinity of the CLN1 and CLN3 loci. These results strongly reject the hypothesis of allelism of Stargardt's disease with the neuronal forms of ceroid lipofuscinosis. Show less