The previously funded STTR (Fast Track Phase I/II, preclinical studies) project (R41/R42 CA173980-01A) helped us in developing desired NIR PS (Photobac) with a great potential for both cancer imaging and therapy. An efficient method for the synthesis of Photobac was also established in a GMP facility. Following the US FDA guidelines, the pharmacokinetic (PK), pharmacodynamic (PD) and toxicity of Photobac in various doses were also investigated in mice, rats and dogs. Histopathology results did not show any organ toxicity. Photobac even at a 20-fold higher than the therapeutic dose (single dose needed for the treatment) was not lethal. No metabolite formation and organ toxicity even at higher than the desired therapeutic dose was observed. The biodistribution of C-14 Photobac at variable time points was also determined in mice and rats [7, 8]. Results with C-14 Photobac in rats and fluorescence results in mice suggest that Photobac crosses the blood brain barrier (BBB). A positive pre-IND response from the US FDA on our request for the use of Photobac to treat Gliomas was pleasing & exciting (Application # PIND 136905). As suggested by the FDA review committee, the revision of human patient Phase I protocol has been accomplished. NIR PS Photobac has also received an ?Orphan Drug? status from the US FDA for imaging and therapy of Glioblastoma (fluorescence-guided surgery + PDTof recurrence tumors) (# DRU-2017-6153), which further encouraged us to move this technology to Phase I human clinical trials. To achieve our goal, the proposed study (SBIR: Preclinical and Clinical)) has been divided into following aims:
Aim 1 (a): To investigate the PDT efficacy of Photobac in rat glioma model and using Simphotek?s proprietary computational device FPDosi? (Beeson et al. J. Biomed. Opt. 24(3), 035006, 2019) compare light dose to experiments. Details are presented in the letter of support from Simphotek.
Aim 1 (b): To compile the Photobac CMC (chemistry, manufacturing and control), drug-formulation, stability of drug substance and drug product, analytical details, PK/PD, toxicity, in vitro & in vivo data and Phase I clinical protocol for an IND submission to the US FDA for fluorescence image guided surgery + PDT of glioblastoma. The cost of the IND submission will be paid by Photolitec, LLC.
Aim 2 : To compile the details of PS (Photobac)-customized NIR laser instrument (787 nm, developed with the help of Biolitec) following the US FDA guidelines, and submit it for approval (combined IND-Aim 1].
Aim 3 : To perform Phase I trial with Photobac-PDT, fluorescence-guided treatment (surgery + PDT) of glioblastoma at a single light dose and variable drug doses for selecting the best treatment parameters.
Aim 4 : To provide tissue samples from glioblastoma, corresponding non-tumor tissue, untreated tumors, Photobac-PDT treated tumors and recurrent tumors after previous surgery, chemotherapy, radiation and chemotherapy treatment, for Photobac specificity using 3D cell-culture system, and STAT3 crosslinks analysis.
Aim 5 : Establish a correlation between the cell-uptake on patients? tumors (at various stages) implanted in mice, photo-induced STAT3 dimerization and a long-term PDT response [7]. Translate these findings to enhance the optimal treatment parameter(s) of glioblastoma patients.
This project in focused on developing a Near infrared photosensitizer (Photobac) for cancer-imaging (fluorescence guided surgery) and photodynamic therapy of Glioblastoma, and includes Phase I clinical trials also. The FDA response on a pre-IND meeting was very encouraging, and as suggested the IND submission on Photobac-PDT for treating glioblastoma is being prepared accordingly. Recently, Photobac also received an ?Orphan Drug Status? from the US FDA, which has been very encouraging to Photolitec. The results obtained for PK/PD and Toxicity studies with Photobac in mice, rats and dogs at variable doses did not show any organ toxicity. Photolitec is a spin-off of Roswell Park Cancer Institute, and the Phase I clinical studies will be performed in RPCI under the supervision of Dr. Fenstermaker, a neurosurgeon, Prof Wilson & Potter, renowned physicists, who have extensive experience of basic and clinical PDT. Prof. Pandey, well known for his contributions in PDT (one of the photosensitizers developed by him is currently in Phase II Clinical trials of head & neck cancer) will help in coordinating scientists, clinicians and other research and administrative personnel between the RPCI , Photolitec and the US FDA.
