DD-3

Prior studies suggested excessive toxicity for central lung tumors treated with 3-fraction stereotactic body radiation therapy (SBRT). This may be related to the high biologically equivalent dose assuming alpha/beta of 10 (BED) of 54 Gy in 3 fractions (BED = 151.2), as 50-60 Gy in 5 fractions (BED = 100.0-132.0) was well-tolerated in RTOG 0813. We initiated a prospective phase IB/II trial to test the hypothesis that a dose-deescalated regimen of 45 Gy in 3 fractions (BED 112.5) would be safe and efficacious in central lung tumors.

We enrolled patients with primary or secondary lung tumors ≤5cm in a central but not ultra-central tumor location defined as within 2 cm of (but not abutting) tracheobronchial tree, esophagus, or heart. Patients were either medically inoperable or refused surgical intervention. Co-primary endpoints were safety and efficacy, defined as local control (LC). Secondary endpoints included lobar control, regional control (LRC), distant control (DC), progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS). Organ-at-risk dose constraints were consistent with those of RTOG 0236. The Bayesian predictive probability approach was utilized for continuous monitoring after 10 patients were treated and have mature assessment of toxicity, after which interim analysis was planned. We recommended terminating the trial for safety if there was sufficient evidence that the rate of grade ≥3 was greater than 0.25 (predictive probability >0.80).

As of the data cut-off date of 1/26/23, the trial was open for 34 months (including a nearly-immediate suspension due to the COVID-19 pandemic). A total of 17 patients have been treated on protocol with a median follow-up of 12 months. No grade ≥3 adverse events attributable to SBRT have occurred to date, though one patient died of unrelated cardiac arrhythmias 1 month after SBRT completion (Table 1). Maximum CTCAE grade 2 adverse events attributable to SBRT occurred in 17.6% of patients. The predictive probability of concluding unacceptably high toxicity rate by the end of the trial based on toxicity data in the current stage is 0.62%. To date, there have been 0 local recurrences, 1 regional recurrence without local recurrence (8 months after SBRT completion, successfully salvaged with definitive chemoradiotherapy without additional toxicities), and 1 distant recurrence without local recurrence (6 months after SBRT in a patient with lung metastasis from colon adenocarcinoma).

Interim analysis of the DD3 trial suggests that for patients with central but not ultra-central lung tumors, an SBRT regimen of 45 Gy in 3 fractions warrants continued trial accrual and follow-up given no grade ≥3 toxicities or local recurrences in the early follow-up period among the first 17 patients enrolled.

Leprosy (causative, Mycobacterium leprae) continues to be the persisting public health problem with stable incidence rates, owing to the emergence of dapsone resistance that being the principal drug in the ongoing multidrug therapy. Hence, to overcome the drug resistance, structural modification through medicinal chemistry was used to design newer dapsone derivative(s) (DDs), against folic acid biosynthesis pathway. The approach included theoretical modeling, molecular docking, and molecular dynamic (MD) simulation as well as binding free energy estimation for validation of newly designed seven DDs, before synthesis. Theoretical modeling, docking, and MD simulation studies were used to understand the mode of binding and efficacy of DDs against the wild‐type and mutant dihydropteroate synthases (DHPS). Principal component analysis was performed to understand the conformational dynamics of DHPS‐DD complexes. Furthermore, the overall stability and negative‐binding free energy of DHPS‐DD complexes were deciphered using Molecular Mechanics/Poisson‐Boltzmann Surface Area technique. Molecular mechanics study revealed that DD3 possesses higher binding free energy than dapsone against mutant DHPS. Energetic contribution analysis portrayed that van der Waals and electrostatic energy contributes profoundly to the overall negative free energy, whereas polar solvation energy opposes the binding. Finally, DD3 was synthesized and characterized using Fourier‐transform infrared spectroscopy, UV, liquid chromatography‐mass spectrometry, and proton nuclear magnetic resonance techniques. This study suggested that DD3 could be further promoted as newer antileprosy agent. The principles of medicinal chemistry and bioinformatics tools help to locate effective therapeutics to minimize resources and time in current drug development modules.