SBIR-STTR Award

Paclitaxel (Taxol) has shown significant activity in human cancers. However, clinical utility of Paclitaxel is limited by its insolubility in water and toxic side effects. We developed a water-soluble poly (L-glutamic acid)-Paclitaxel conjugate (PG-TXL) that has shown striking anti-tumor effects yet has low toxicity. A single intravenous injection of PG-TXL at its maximum tolerated dose resulted in complete disappearance of well-established breast and ovarian tumors in vivo. Based on its outstanding anti-tumor efficacy, PG-TXL is considered a promising anticancer agent for future clinical trials. The objective of the proposed studies is to investigate in detail the pre-clinical anti-tumor efficacy and relevant pharmacology/toxicology of PG-TXL and to address those aspects which will most likely influence the therapeutic efficacy and safety of PG-TXL in subsequent Phase I/II clinical trials. The specific aims are: 1. To define the dose-time sequence which would maximize the anti-tumor effects of PG-TXL. 2. To determine the pre-clinical toxicity of PG-TXL and define the starting dose for a clinical trial for breast and ovarian cancer patients. 3. To develop an analytical assay for determination of the time-dependent concentration changes of PG-TXL. The applicant's goal is expressed in the following sentence: "It is expected that PG-TXL will be less toxic and more effective than Taxol and that commercialization of PG-TXL in cancer patients will have significant impact on the management and treatment of breast cancer and ovarian cancer." PROPOSED COMMERCIAL APPLICATION: As a anti cancer agent.

Thesaurus Terms:
antineoplastic, drug administration rate /duration, drug screening /evaluation, glutamate, neoplasm /cancer chemotherapy, nonhuman therapy evaluation, paclitaxel breast neoplasm, chemical conjugate, dosage, ovary neoplasm, pharmacokinetics athymic mouse, chemical synthesis, dog, laboratory mouse

Chemoradiation improves survival for patients with locally advanced non-small cell lung cancer (NSCLC) over radiotherapy (R) alone. Les than 20% of patients have complete pathologic response to combination therapy. Paclitaxel (TXL) is effective as an anti-tumor agent and a radiosensitizer. Peripheral neurotoxicity and granulocytopenia limit its dosage; acute effects from TXL's infusion include nausea, hypotension, and cardiac arrhythmias related to Cremophor and ethanol. Conjugating TXL with poly-L-glutamate (PG-TXL/CT-2103) makes it water-soluble, allowing infusion of twice the amount of free TXL and higher intratumoral drug concentrations, which was confirmed by preclinical testing. Combining PG-TXL with radiation demonstrated synergistic radiation enhancement higher than that seen with other taxane or nucleoside analog. A phase I clinical trial of CT-2103 as single agent salvage therapy for patients with advanced solid tumors demonstrated safety and tolerability in dose up to 266 mg equivalent paclitaxel/m2 without significant alopecia. This Phase II STTR proposes a Phase I/II clinical trial of CT-213 given concurrently with chest RT in patients with unresectable Stage III or medically inoperable Stage II NSCLC. This study will determine MTD, DLT, pharmacokinetics, assess toxicity, and document patient costs. We expect this combination RT and CT-2103 to improve patient survival and response to treatment. PROPOSED COMMERCIAL APPLICATIONS: At M.D. Anderson Cancer Center, the combination of Taxol and cisplatin given concurrently with radiation therapy is the treatment of choice for lung cancer patients. In animal studies, CT-2103 is water soluble, infectable intravenously in 10 minutes without pre-medication, more effective (2-3X) and less toxic than Taxol. CT-2103 could possibly replace Taxol.

Thesaurus Terms:
chemical conjugate, combination cancer therapy, human therapy evaluation, lung neoplasm, neoplasm /cancer chemotherapy, neoplasm /cancer radiation therapy, nonhuman therapy evaluation, paclitaxel, polyglutamate antineoplastic, clinical trial phase I, clinical trial phase II /III /IV, pharmacokinetics clinical research, human subject, patient oriented research, positron emission tomography