A phase Ib/IIa trial of 9 repurposed drugs combined with temozolomide for the treatment of recurrent glioblastoma: CUSP9v3

BACKGROUND: The dismal prognosis of glioblastoma (GBM) may be related to the ability of GBM cells to develop mechanisms of treatment resistance. We designed a protocol called Coordinated Undermining of Survival Paths combining 9 repurposed non-oncological drugs with metronomic temozolomide - version 3 - (CUSP9v3) to address this issue. The aim of this phase Ib/IIa trial was to assess the safety of CUSP9v3. METHODS: Ten adults with histologically confirmed GBM and recurrent or progressive disease were included. Treatment consisted of aprepitant, auranofin, celecoxib, captopril, disulfiram, itraconazole, minocycline, ritonavir, and sertraline added to metronomic low-dose temozolomide. Treatment was continued until toxicity or progression. Primary endpoint was dose-limiting toxicity defined as either any unmanageable grade 3–4 toxicity or inability to receive at least 7 of the 10 drugs at ≥ 50% of the per-protocol doses at the end of the second treatment cycle. RESULTS: One patient was not evaluable for the primary endpoint (safety). All 9 evaluable patients met the primary endpoint. Ritonavir, temozolomide, captopril, and itraconazole were the drugs most frequently requiring dose modification or pausing. The most common adverse events were nausea, headache, fatigue, diarrhea, and ataxia. Progression-free survival at 12 months was 50%. CONCLUSIONS: CUSP9v3 can be safely administered in patients with recurrent GBM under careful monitoring. A randomized phase II trial is in preparation to assess the efficacy of the CUSP9v3 regimen in GBM

A demonstration of improved constraints on primordial gravitational waves with delensing

International audienceWe present a constraint on the tensor-to-scalar ratio, r, derived from measurements of cosmic microwave background (CMB) polarization B-modes with “delensing,” whereby the uncertainty on r contributed by the sample variance of the gravitational lensing B-modes is reduced by cross-correlating against a lensing B-mode template. This template is constructed by combining an estimate of the polarized CMB with a tracer of the projected large-scale structure. The large-scale-structure tracer used is a map of the cosmic infrared background derived from Planck satellite data, while the polarized CMB map comes from a combination of South Pole Telescope, bicep/Keck, and Planck data. We expand the bicep/Keck likelihood analysis framework to accept a lensing template and apply it to the bicep/Keck dataset collected through 2014 using the same parametric foreground modeling as in the previous analysis. From simulations, we find that the uncertainty on r is reduced by ∼10%, from σ(r)=0.024 to 0.022, which can be compared with a ∼26% reduction obtained when using a perfect lensing template or if there were zero lensing B-modes. Applying the technique to the real data, the constraint on r is improved from r0.05<0.090 to r0.05<0.082 (95% C.L.). This is the first demonstration of improvement in an r constraint through delensing