SBIR-STTR Award

In 2007, lung cancer will be the number one cancer killer in the US with the identification of an estimated 213,380 new lung cancer cases. Roughly one-quarter of these patients will be considered candidates for potentially curative surgical resection. The extent of tissue removed during surgical resection of the tumor is minimized to preserve as much lung function as possible and reduce morbidity. Unfortunately, local recurrence following limited resection is significantly increased, and doubles to 16% even in patients with early stage lung cancer. While radiation and chemotherapy are commonly utilized as adjuvant therapies for more advanced primary cancers, use as a preventative therapy to decrease recurrence is administered only in selected cases. This is a consequence of the often severe side-effects associated with these treatments and the inability to accurately predict in which patients the benefits would warrant the additional morbidity. In this phase 1 proposal, FIFth Base proposes to develop and evaluate paclitaxel-loaded polyester-carbonate copolymer films for localized delivery of anticancer agents for preventing local recurrence in an in vivo model of lung cancer. The three Specific Aims are: SPECIFIC AIM 1: Prepare and characterize paclitaxel-loaded poly(ester-co-carbonate) films and their anti-proliferative response in vitro. SPECIFIC AIM 2: Obtain safety data on the poly(carbonate-co-ester) scaffold necessary for the submission of an Investigational Device Exemption with the FDA, required for human use. SPECIFIC AIM 3: Evaluate anti-cancer activity of paclitaxel-loaded films in subcutaneous and recurrence tumor models in vivo. Successful completion of these Aims will produce a prototype delivery device that: (1) delivers drug in a sustained and controlled manner directly to the site of disease (i.e. site of resection); (2) that maintains mechanical integrity throughout its functional life; (3) that minimizes the side effects associated with intravenously-administered chemotherapy; (4) that is compatible with current surgical techniques; (5) that allows for sufficient healing of the tissue at/near the resection margins, and (6) that elicits minimal or no antigenic response.

Public Health Relevance:
In 2007, lung cancer will be the number one cancer killer in the US with the identification of an estimated 213,380 new lung cancer cases. Roughly one-quarter of these patients will be considered candidates for potentially curative surgical resection. The extent of tissue removed during surgical resection of the tumor is minimized to preserve as much lung function as possible and reduce morbidity. Unfortunately, local recurrence following limited resection is significantly increased, and doubles to 16% even in patients with early stage lung cancer. While radiation and chemotherapy are commonly utilized as adjuvant therapies for more advanced primary cancers, use as a preventative therapy to decrease recurrence is administered only in selected cases. This is a consequence of the often severe side-effects associated with these treatments and the inability to accurately predict in which patients the benefits would warrant the additional morbidity. We are developing a drug delivery device that can be fixated along resection margins for the prevention of local recurrence. The ability to inhibit recurrence of malignant disease through local delivery while minimizing systemic exposure to toxic anticancer agents will ultimately lead to the first standard of care for prevention of recurrence in early stage lung cancer patients.

Public Health Relevance:
This Public Health Relevance is not available.

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In 2009, there were 219,000 new lung cancer cases reported. Roughly one-quarter of these patients will be considered candidates for ""curative"" surgical resection, where the preservation of lung function must be balanced against the extent of tissue removed. As a result, patients requiring these limited resection procedures suffer a high risk of developing local tumor recurrence, including early stage patients (16% local recurrence rate), due to the increased presence of microscopic tumors cells remaining at or near the resection margin. Recurrent lung cancer is resected if possible, but the extent of disease or inadequate pulmonary function often limits treatment to palliative chemotherapy or external radiation therapy. There is currently no established standard of care for preventing locoregional tumor recurrence following resection. Fifth Base has developed a unique, and simple to use, drug eluting implant that reduces the incidence of locoregional cancer recurrence by locally delivering therapeutic levels of drug to the site of highest risk of recurrence for over several months. The local delivery of chemotherapeutic drugs to the resection margins would reduce the significant side effects associated with systemic administration, change the paradigm to ""see and treat"" at the time of surgery, allow the surgeon to excise a smaller margin while treating the residual tumor burden effectively and locally, reducing the tumor recurrence while preserving lung function. Fifth Base proposes to advance our technology down the path of commercialization by the completion of the following Phase II proposed aims: 1) scale-up of monomer synthesis, 2) cGMP large scale synthesis of polymer with in-process validations, 3) performance of chemistry, manufacturing, and controls validations required for drug-eluting devices, 4) performance of FDA-required ISO-compliant biocompatibility studies including in vivo chronic toxicity, and 5) investigation of pharmacokinetic, distribution, and excretion of paclitaxel following orthotopic implantation of the drug-loaded polymer implant in a large animal lung model. With the successful completion of the key technological objectives in this Phase II SBIR proposal, along with work currently being performed in parallel, we will produce a batch of cGMP manufactured and packaged devices and performed nearly the complete battery of preclinical safety and toxicity testing required by the FDA for regulatory approval sufficient to initiate clinical trials. Phase III will consist of a large animal safety study, obtainment of IDE/IRB clinical site approval, followed by the Phase I first-in-human clinical safety trial.

Public Health Relevance:
Fifth Base has developed a unique, and simple to use, drug-eluting implant that reduces the incidence of locoregional lung cancer recurrence by locally delivering therapeutic levels of drug to the site of disease for over several months. Locoregional tumor recurrence after a surgical lung resection is a significant clinical problem in the management of early stage lung cancer patients. Our device will be implanted at the time of surgery using standard procedures and surgical tools and enables a new paradigm of low toxicity, preventative treatment at the site of highest risk of tumor recurrence.

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