DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

The Prostate Cancer Clinical Trials Consortium: Clinical Research Site Application

Principal Investigator: AGGARWAL, RAHUL
Institution Receiving Award: CALIFORNIA, UNIVERSITY OF, SAN FRANCISCO
Program: PCRP
Proposal Number: PC170139
Award Number: W81XWH-18-2-0039
Funding Mechanism: Clinical Consortium Award - Clinical Research Site
Partnering Awards:
Award Amount: $822,000.00


TECHNICAL ABSTRACT

Background: The mission of the University of California, San Francisco (UCSF), Prostate Cancer Program is to advance patient care through discovery, innovation, and education. While retaining commitment to several legacy areas of expertise, the UCSF GUMOP has recently added new competencies and is poised to serve as a productive and creative participant in the Department of Defense Prostate Cancer Research Program Clinical Consortium (PCCTC) by virtue of (1) integration and interaction of outstanding basic, translational, and clinical research programs led by national and international opinion leaders; (2) a robust and mature research infrastructure; (3) an institutional commitment to this research; (4) extensive experience in conducting creative, thematic, translational clinical trials; (5) a strong pipeline of novel agents; and (6) extensive collaborations in many multi-center PCCTC-coordinated studies.

Objective: Leveraging the expertise of clinical and translational investigators at UCSF and the infrastructure of the PCCTC, the UCSF Prostate Cancer Program seeks to develop novel therapies for men with advanced prostate cancer, with concomitant focus on biomarker development and cancer survivorship. UCSF has a strong track record of success in fostering the development of novel therapies in prostate cancer, including past efforts leading early-phase clinical trials of abiraterone and sipuleucel-T, to support the feasibility of this objective.

Specific Aims:

1. To develop novel approaches to targeting DNA damage response pathway in advanced prostate cancer

2. To foster robust study and integration of prostate cancer survivorship strategies

3. To link therapy, imaging, and genomics in aggressive phenotypic prostate cancer

4. To develop and validate novel immunotherapies and biomarkers of response

Study Design: The UCSF Prostate Cancer Program has multiple active, planned, and potential clinical trials utilizing the PCCTC infrastructure to support completion of the proposed aims.

Specific Aim 1: Dr. Ryan (Principal Investigator [PI]) leads multiple investigator-initiated and industry-sponsored trials targeting the DNA repair pathway in patients with advanced prostate cancer, including (1) TRITON III, a randomized phase 3 study of rucaparib versus best standard care (docetaxel, abiraterone, or enzalutamide) in patients with BRCA1, BRCA2, or ATM mutations; (2) RUDDER, a UCSF-led investigator-initiated phase 2 study for patients with homologous recombination defects (HRD) other than those in TRITON III; and (3) CLEAVER, a phase 2 investigator-initiated study testing the hypothesis that taxane chemotherapy or radium-223 can clear reversion mutations, an increasingly recognized resistance mechanism to agents targeting the DNA repair pathway.

Specific Aim 2: Dr. Ryan and Dr. Aggarwal (Co-PIs) are leading multiple clinical and translational studies to improve the quality of life for men with prostate cancer, including (1) STAND (Supportive Therapy in Androgen Deprivation Therapy), a clinic led by Dr. Aggarwal that is focused on improving outcomes for men receiving ADT via multi-disciplinary individualized patient counseling; (2) detailed investigations of the impact of ADT on cognition (e.g., SEARCH, DaroCare, COGCAP studies); (3) prospective evaluation of the impact of supervised high-intensity exercise training on cancer outcomes, including the phase 3 Movember-funded CHAMP study led by Dr. Ryan and UCSF; and (4) investigating potent, intermittent androgen deprivation therapy as a means to prolong treatment-free intervals, including ongoing phase 2 and upcoming phase 3 studies in biochemically recurrent prostate cancer (AFT-19).

Specific Aim 3: Leveraging the expertise and infrastructure of the Stand Up 2 Cancer/PCF-funded West Coast Dream Team led by UCSF and Dr. Small (see letter of support), we have uncovered the transition to a neuroendocrine aggressive phenotype in up to 20% of all mCRPC patients. UCSF has developed a robust clinical trial pipeline designed to improve outcomes for these high-risk patients, including (1) novel antibody-drug conjugates targeting DLL3 and CD46 (rovalpituzumab tesirine and FOR46, respectively); (2) a novel MYC pathway targeting treatment, including BET bromodomain inhibitor ZEN-003694 and CDK 4/6 inhibitor ribociclib; and (3) novel imaging modalities, including transferrin-based PET imaging.

Specific Aim 4: Led by Dr. Fong (see letter of support), UCSF continues to be a leader in the development of novel immunotherapies and biomarkers in advanced prostate cancer, including (1) novel biomarker development of T cell receptor clonotyping and repertoire predictive of immune-related toxicities and sustained response and (2) clinical trials of multiple novel therapies, including neoadjuvant PROSTVAC + ipilimumab, TLR 7/8 agonist SD-101 in combination with brachytherapy and pembrolizumab, a randomized phase 2 study of sipuleucel-T followed by ipilimumab, and novel bi-specific antibodies ES414 and MGD-009.

Impact: The proposed areas of focus are predicted to have a major impact on changing the standard of care for treatment and survivorship for men with advanced prostate cancer. Participation in the PCCTC significantly enhances the chance of therapeutic success and clinical development of these novel treatment strategies.