Prostate-Specific Membrane Antigen (PSMA) is an ideal tumor biomarker as it is expressed on >90% of all prostate cancers and expression increases as the cancer progresses. Cancer Targeted Technology (CTT) has developed a unique phosphoramidate-based scaffold that binds irreversibly to PSMA leading to > 90% rapid internalization and selective accumulation in tumor cells. With previous SBIR grant support, CTT created an 18F- labeled PET diagnostic imaging agent, CTT1057, and in Aug 2017 completed a Phase I clinical trial in patients with metastatic prostate cancer. CTT1057 demonstrated significant uptake in PSMA-avid bone and visceral lesions with far greater specificity and sensitivity than standard of care scans. In Jan 2018, CTT licensed this PET imaging agent to Advanced Accelerator Applications/Novartis. Prostate cancer is radiosensitive, but only Radium-223, which is neither specific nor selective, has been commercialized as a radiotherapeutic for advanced stage disease. Under an additional SBIR Phase I/II fast track contract, CTT modified the original CTT1057 PSMA-binding scaffold to develop a specific and potent companion therapeutic, CTT1403, radiolabeled with 177Lu. CTT1403, unlike other PSMA-targeting agents under development, is highly innovative in that it binds irreversibly to PSMA and uses an albumin-binding motif to dramatically slow clearance, resulting in an unprecedented tumor uptake of >80% injected dose/g of tumor tissue and a significant survival advantage in animal models. Under the SBIR Phase II contract, GMP-manufacturing, radiolabeling and IND- enabling pharmacology, dosimetry and initial animal safety studies were completed. An FDA pre-IND meeting was held, and the IND will be filed Q4 2018. The objective of this SBIR Phase IIB application is to support the first in human Phase 1 clinical trial of CTT1403 and to position the drug for further clinical development and rapid commercialization.
Specific aims :
AIM 1 : Phase 1 clinical trial of CTT1403 in metastatic castration-resistant prostate cancer (mCRPC), assessing safety and initial efficacy: CTT will conduct an accelerated dose escalation/expansion trial in patients with mCRPC. Increased uptake of the albumin-binding, PSMA-targeted, 177Lu-labeled CTT1403 drug is hypothesized to translate into a meaningful survival advantage.
AIM 2 : Assess GLP late radiation safety: CTT will evaluate long term tolerance of repeat-dose CTT1403 in dogs to meet FDA late radiation safety recommendations prior to start of Phase 2 trials.
AIM 3 : Process development in support of further clinical development: CTT will develop and scale CTT1403 manufacturing methods in support of multiple dose trials. This innovative work harnesses the ideal performance of a cell-penetrating irreversible small-molecule PSMA-targeted drug that uses albumin binding to increase circulation half-life and tumor targeting and decrease renal toxicity. CTT1403 should have considerable significance for metastatic prostate cancer therapy by reducing toxic side effects in a patient population with a substantial unmet need.

Public Health Relevance

This grant proposes the development and characterization of an innovative Prostate Specific Membrane Antigen (PSMA)-targeted peptidomimetic 177Lu-radiotherapy, CTT1403, that can be specifically delivered to tumor cells and released over time as a result of an albumin-binding moiety. The work will assess the safety and initial efficacy of CTT1403 in a first in human Phase 1 study in late stage castration-resistant prostate cancer, and will further set the groundwork for subsequent clinical studies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
Project #
2R44CA239461-04
Application #
9763920
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Narayanan, Deepa
Project Start
2019-07-02
Project End
2022-06-30
Budget Start
2019-07-02
Budget End
2020-06-30
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Cancer Targeted Technology, LLC
Department
Type
DUNS #
829368690
City
Woodinville
State
WA
Country
United States
Zip Code
98072