Targeting Lipid Metabolism and Diet in Patients with Prostate Cancer - Ongoing Clinical Trials

We are thrilled to announce a significant milestone in our ongoing research at Loda's Lab. After dedicating years to in-depth investigations into lipogenesis and the crucial role of the Fatty Acid Synthase enzyme (FASN) in prostate cancer (PC), we are excited to start enrolling patients in two clinical trials.

Phase I, Open-Label, Dose-Finding Study of TVB-2640 Administered in Combination with Enzalutamide (enza) in Men with Metastatic Castration-Resistant Prostate Cancer (mCRPC) [NCT05743621]

Led by the distinguished Dr. David Nanus and Dr. Pier Vitale Nuzzo, this trial aims to contribute to developing a new treatment in mCRPC by targeting for the first time the intricate interplay between the Androgen Receptor (AR) pathway - which is the primary driver of lethal mCRPC - and the metabolic processes within cancer cells, particularly the FASN enzyme, its rate-limiting step.

This is an open-label, single-arm, Phase I dose-escalation study that enrolls pts with mCRPC who are candidates to receive enza. The primary objective is to determine the maximum tolerated dose  and recommended Phase II dose of TVB-2640 -  a FASN inhibitor developed by Sagimet Bioscience - in combination with enza. Secondary objectives include safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity. Exploratory objectives include the effects of FASN inhibition on metabolites, genetics, and lipids in human blood and tumor tissue, to identify potential predictive and prognostic markers of response.

Pts with a confirmed diagnosis of PC, evidence of metastatic PC on imaging, serum testosterone <50 ng/dl, who had progressed on androgen-depletion therapy,  with documented progressive mCRPC are eligible.

Enrolled pts will receive enza at a daily dose of 160 mg for 36 days to reach a steady state, followed by the addition of oral TVB-2640 starting at 100 mg/daily. The dose escalation will follow the Bayesian optimal interval (BOIN) design with additional dose levels of 150 mg, 200 mg, 250 mg, and 300 mg daily.

This is the first clinical trial to evaluate the targeting of the AR pathway through inhibition of lipid synthesis as a new approach to treating mCRPC. Enrollment of Cohort 1 began in August 2023. ClinicalTrials.gov ID NCT05743621. https://clinicaltrials.gov/study/NCT05743621?cond=prostate%20caner&term=tvb-2640&rank=1

Neoadjuvant FASN inhibitor TVB-2640 vs TVB-2640 plus Polyunsaturated (PUFA)-enriched limited-fat (PUFA-LF) diet in men with high-risk localized Prostate Cancer

Led by the distinguished Dr. David Nanus and Dr. Pier Vitale Nuzzo, this trial aims to assess the role of diet in PC, specifically how a PUFA-LF diet affects disease progression.

This is an open-label, randomized, phase II trial to compare the anti-tumor activity of a neoadjuvant dietary intervention with PUFA-enriched low-fat diet in addition to FASN inhibitor TVB-2640 vs TVB-2640 alone in men with a diagnosis of high-risk localized PC undergoing radical prostatectomy as primary treatment.

The study primary endpoint is the change in the proliferation rates, as measured by Ki-67, in tissue obtained pre- and post- neoadjuvant treatment. The secondary endpoint will be the rate of PSA decline and the expression of AR spice variants (AR-Vs) and pACC pre- and post- neoadjuvant treatment. Exploratory endpoints will include the ratio SFA/PUFA, level of Malonyl Carnitine and tripalmitin pre- and post-neoadjuvant treatment.

We will enroll 30 men with histologically confirmed clinically localized PC with NCCN high-risk characteristics who are willing to undergo radical prostatectomy as primary treatment: 15 participants will be randomized to a PUFA-enriched low-fat diet in combination with the FASN inhibitor TVB-2640 , while the remaining 15 will receive TVB-2640 alone. PUFA-LF diet will be prepared by the Nutrition and Metabolic Research Core of the Clinical & Translational Science Center (CTSC) of Weill Cornell Medicine and provided to subjects  for 4 weeks.

This is the first clinical trial to evaluate the effect of  PUFA-LF diet in combination with FASN inhibition

The trial will be conducted at two affiliated institutions, NYP-Brooklyn Methodist Hospital and NYP Queens, with the aim of not only increasing the number of PC pts but also including underrepresented populations, such as African Americans.