SBIR-STTR Award

Prostate cancer (PCa) is the second leading cause of cancer death in American men, with 26,130 deaths and 161,360 new cases estimated in the US in 2017. Radiation therapy is one of the standard therapies for high and intermediate risk patients, and is a non-surgical therapy option for low risk patients. A combined chemo-radiation therapy (CRT) approach has been shown in several trials to improve survival in multiple cancers, compared with monotherapies. However, systemic chemotherapy accompanying CRT typically come at the price of increased toxicity and thus require synchronization of the two modalities to achieve maximum benefit. Here, an immediate need exists to deliver the drug specifically at tumor site in locally recurrent patients while avoiding toxicities associated with systemic delivery and resulting in preferential radiosensitization of the prostate compared to the normal structures. Northeastern University and Theranano LLC in collaboration with clinicians at Brigham and Womens Hospital and Dana Farber Cancer Institute have developed an innovative combinatorial treatment strategy of Local Chemo-Radiation Therapy (LCRT) using a modified brachytherapy spacer platform in the form of a INCeRT (ImplaNts for ChemoRadiation Therapy) spacer loaded with Docetaxel (DTX) to locally radiosensitize the prostate, enabling a synergistic cure with the use of lower radiation doses, thereby leading to less rectal radiation toxicity and minimal chemotherapeutic systemic side effects. These new INCeRT spacers are physically similar to the inert spacers routinely used in prostate brachytherapy but now loaded with formulations of DTX which can be tuned to release the drug payload from a week to several months. The technology has been exclusively licensed to TheraNano LLC for commercialization and translation to the clinic. The phase 1 project goals will be achieved through the following specific aims: Specific Aim 1: Development, scale up and quality control of docetaxel loaded INCeRT brachytherapy spacers. Develop INCeRT brachytherapy spacers loaded with DTX with analysis of quality control, reproducibility, drug loading and drug release using optimized SOPs. Earlier work at Northeastern University has produced INCeRT spacers in batches of

Public Health Relevance Statement:
PROJECTNARRATIVE TITLE: Drug-eluting Brachytherapy Implants for Chemo-radiation Therapy This STTR phase 1 project seeks to demonstrate the feasibility of drug-eluting brachytherapy implants for Local Chemo-Radiation Therapy (LCRT) as a new modality of prostate cancer treatment. LCRT combines radiation therapy with chemotherapy delivered locally to the prostate, utilizing drug releasing spacers similar to those currently used in brachytherapy, to boost the overall treatment efficiency while greatly reducing toxic side effects. The treatment has the potential to improve the lives of all of the thousands of men with localized prostate cancer who are treated each year with radiation therapy.

Project Terms:
Adverse effects; Alternative Therapies; American; Animal Cancer Model; Animals; Brachytherapy; Cancer Etiology; cancer recurrence; cancer therapy; Cessation of life; chemoradiation; chemotherapy; Clinic; Clinical; Clinical Trials; Collaborations; combinatorial; Combined Modality Therapy; commercialization; curative treatments; Dana-Farber Cancer Institute; Data; Development; Disease; Disease-Free Survival; docetaxel; Dose; Drug Utilization; External Beam Radiation Therapy; Formulation; Foundations; Goals; Hospitals; image guided radiation therapy; immunotoxicity; Implant; improved; in vivo; innovation; International; Kinetics; Lead; Letters; Licensing; Local Therapy; Low Dose Radiation; Malignant neoplasm of prostate; Malignant Neoplasms; manufacturing scale-up; men; Modality; Mus; Operative Surgical Procedures; Patient risk; Patients; PC3 cell line; Pharmaceutical Preparations; Phase; phase 2 study; Plants; Price; Process; Prostate; prostate cancer model; Prostate Cancer therapy; Quality Control; Radiation; Radiation therapy; Radiation Toxicity; Radiation-Sensitizing Agents; Radiosensitization; radiosensitizing; rectal; Recurrence; Reproducibility; Research Design; scale up; Site; Small Business Technology Transfer Research; Structure; success; Technology; Therapeutic; Therapeutic Effect; Toxic effect; Translating; Translations; treatment choice; Treatment Efficacy; treatment strategy; tumor; Tumor Suppression; Universities; Visual; Weight; Woman; Work

Theranano LLC in collaboration with internationally renowned prostate brachytherapy clinicians at Brigham and Womens Hospital and Dana Farber Cancer Institute and biomaterials experts at Northeastern University have developed an innovative combinatorial treatment strategy of Local ChemoRadiation Therapy (LCRT) using a modified brachytherapy spacer platform in the form of a INCeRT (ImplaNts for ChemoRadiation Therapy) spacer loaded with Docetaxel (DTX) to locally radiosensitize the prostate, enabling a synergistic cure with the use of lower radiation doses, thereby leading to less rectal radiation toxicity and minimal chemotherapeutic systemic side effects. Extensive results have demonstrated the efficacy and safety of the technology: (i) As monotherapy, in PC3 tumored mice, therapeutic doses of DTX can be delivered using intratumoral INCeRT spacers that lead to complete tumor suppression and disease free survival in 90% of animals. (ii) DTX-loaded INCeRT spacers show sustained synergistic radiosensitization. (iii) For combined LCRT, sustained DTX release prolongs the tumor suppression in irradiated mice. (iv) Toxicity as assessed by gross weight, and visual observation, is greatly reduced compared with IV administration of equivalent doses of DTX. These results have demonstrated the validity and feasibility of LCRT using INCeRT spacers. The Phase I STTR project demonstrated the feasibility of a solvent free hot-melt extrusion process of fabrication of InCeRT DTX spacers thus providing proof-of-principle of reproducible scale-up of manufacturing of INCeRT spacers. The HME spacers fabricated possessed all the desired material and drug characteristics, as well as in vitro release, PrCa model efficacy and toxicity profiles, achieving all the aims of the project. The Phase I project met and exceeded all its aims. In this Phase II STTR project Theranano will partner with outstanding collaborators to carry out IND-enabling GLP level manufacture and pre-clinical animal studies through the following aims: Specific Aim 1: Fabricate GLP quality InCeRT-DTX brachytherapy spacer implants GLP level manufacture of InCeRT-DTX implants will be carried out. The GLP implants will be thoroughly characterized for their physico-chemical properties. Specific Aim 2: Non-GLP therapeutic efficacy of INCeRT spacers in clinically relevant PCa mice models. The implant spacers fabricated in SA1 will be tested for release and therapeutic efficacy in PC3 cells and tumor models to ensure their bioactivity. Specific Aim 3: IND-enabling GLP pharmacokinetics and toxicity evaluation of INCeRT implants with brachytherapy in canine models. GLP level animal studies in canine models will be carried out for demonstrating the safety of the InCeRT-DTX implants in conjunction with I125 brachytherapy seeds. Specific Aim 4: Submission of FDA IND application An FDA IND application will be submitted and planning for a Phase I clinical trial will be initiated.

Public Health Relevance Statement:
PROJECTNARRATIVE TITLE: Drug-eluting Brachytherapy Implants for Chemo-radiation Therapy This STTR phase II project seeks to translate drug-eluting brachytherapy implants for Local Chemo-Radiation Therapy (LCRT) as a new modality of prostate cancer treatment. LCRT combines radiation therapy with chemotherapy delivered locally to the prostate, utilizing drug releasing spacers similar to those currently used in brachytherapy, to boost the overall treatment efficiency while greatly reducing toxic side effects. The treatment has the potential to improve the lives of all of the thousands of men with localized prostate cancer who are treated each year with radiation therapy.

NIH Spending Category:
Cancer; Prostate Cancer; Radiation Oncology; Urologic Diseases

Project Terms:
Alternative Therapies; American; Animals; base; Biocompatible Materials; Brachytherapy; Brachytherapy Seeds; Cancer Etiology; Cancer Patient; cancer recurrence; Canis familiaris; Cells; Cessation of life; Characteristics; chemoradiation; chemotherapy; Clinic; Clinical; clinically relevant; cohort; Collaborations; combinatorial; commercialization; curative treatments; Dana-Farber Cancer Institute; Development; Disease; Disease-Free Survival; docetaxel; Dose; Drug Kinetics; Drug Utilization; Ensure; Evaluation; Fostering; Foundations; Head and Neck Cancer; Hospitals; I125 isotope; Implant; improved; In Vitro; innovation; International; Lead; Licensing; Local Therapy; Low Dose Radiation; Malignant neoplasm of prostate; Malignant Neoplasms; manufacturing scale-up; Medical center; melting; men; Modality; Modeling; mouse model; Mus; Operative Surgical Procedures; Patients; PC3 cell line; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; pre-clinical; Process; Property; Prostate; Prostate Cancer therapy; Radiation; Radiation therapy; Radiation Toxicity; Radiation-Sensitizing Agents; Radiosensitization; radiosensitizing; rectal; Reproducibility; response; Risk; Safety; Science; side effect; Site; Small Business Technology Transfer Research; Solvents; Structure; success; Technology; Testing; Therapeutic; Therapeutic Effect; Toxic effect; Translating; Translations; Treatment Efficacy; treatment strategy; tumor; Tumor Suppression; Universities; Visual; Weight; Woman