racemetyrosine (SM-88) / Eagle Pharma, Syros - LARVOL DELTA

Precision Promise: A Multi-center Trial to Evaluate Multiple Regimens in Metastatic Pancreatic Cancer (clinicaltrials.gov) - P3 | N=502 | Completed | Sponsor: Pancreatic Cancer Action Network | Active, not recruiting ➔ Completed | N=825 ➔ 502 | Trial completion date: Jun 2027 ➔ Feb 2025 | Trial primary completion date: Jun 2027 ➔ Feb 2025

Enrollment change • Trial completion • Trial completion date • Trial primary completion date • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

HopES: SM-88 Maintenance Therapy for Advanced Ewing's Sarcoma and as Salvage Therapy for Sarcoma (clinicaltrials.gov) - P2 | N=31 | Active, not recruiting | Sponsor: Sarcoma Oncology Research Center, LLC | Trial completion date: Mar 2025 ➔ Mar 2028 | Trial primary completion date: Dec 2024 ➔ Dec 2027

Trial completion date • Trial primary completion date • Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor

Tyme-88-Panct: A Randomized Phase 2/3 Multi-Center Study of SM-88 in Participants With Metastatic Pancreatic Cancer (clinicaltrials.gov) - P2/3 | N=130 | Terminated | Sponsor: Tyme, Inc | Completed ➔ Terminated; Sponsor's decision

Metastases • Trial termination • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

HopES: SM-88 Maintenance Therapy for Advanced Ewing's Sarcoma and as Salvage Therapy for Sarcoma (clinicaltrials.gov) - P2 | N=31 | Active, not recruiting | Sponsor: Sarcoma Oncology Research Center, LLC | Trial completion date: Oct 2023 ➔ Mar 2025 | Trial primary completion date: Jan 2023 ➔ Dec 2024

Metastases • Trial completion date • Trial primary completion date • Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor

Precision Promise (PrP) Bayesian platform trial for metastatic pancreatic cancer (mPDAC): Results of the first experimental arm, SM-88 as second line therapy. (ASCO-GI 2024) - P3 | "Methoxsalen, phenytoin and sirolimus are added to SM-88 to potentially enhance oxidative stress, and form a 4-drug oral regimen...Pooled controls for SM-88 were gemcitabine/nab-paclitaxel and mFOLFIRINOX at standard doses, since neither therapy was a backbone for SM-88... Leveraging small sample sizes of SM-88 and controls, PrP efficiently and compellingly concluded SM-88 futility in 2nd line mPDAC. PrP continues to assess other therapies, utilizing time-adjusted, as well as concurrently randomized, controls. Clinical trial information: NCT04229004."

Clinical • Metastases • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor

OASIS: Oral SM-88 in Patients With Metastatic HR+/HER2- Breast Cancer (clinicaltrials.gov) - P2 | N=11 | Terminated | Sponsor: Georgetown University | N=50 ➔ 11 | Trial completion date: May 2025 ➔ Feb 2023 | Active, not recruiting ➔ Terminated | Trial primary completion date: May 2024 ➔ Feb 2023; Lack of efficacy

Enrollment change • Metastases • Trial completion date • Trial primary completion date • Trial termination • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CD4 • ER • HER-2 • PGR

A Multi-center Trial to Evaluate Multiple Regimens in Metastatic Pancreatic Cancer (clinicaltrials.gov) - P3 | N=825 | Active, not recruiting | Sponsor: Pancreatic Cancer Action Network | Trial completion date: May 2026 ➔ Jun 2027 | Trial primary completion date: May 2024 ➔ Jun 2027

Metastases • Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

A Multi-center Trial to Evaluate Multiple Regimens in Metastatic Pancreatic Cancer (clinicaltrials.gov) - P3 | N=825 | Active, not recruiting | Sponsor: Pancreatic Cancer Action Network | Recruiting ➔ Active, not recruiting

Enrollment closed • Metastases • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Histologic Spectrum, Immunohistochemical, and Molecular Profiling of Squamoid Morules ("Microcarcinoid") Associated with Gastrointestinal Neoplasia (USCAP 2023) - "Nuclear beta-catenin was highly expressed among all groups (SM 88% vs. NCH 100% vs. MC/NET 71%)... Incidental lesional cell nests associated with GI neoplasia can be sub-classified based on morphology and immunoprofile. Those cell nests demonstrate frequent nuclear beta-catenin expression and less oncogenic mutations compared to background neoplasia, suggesting stem cell phenotype which may drive divergent differentiation (squamous vs. NE) in particular cases."

Colorectal Cancer • Endocrine Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Neuroendocrine Tumor • Oncology • APC • BRAF • CTNNB1 • EGFR • KRAS • PIK3CA • SYP • TP63

Phase II trial of SM88 in non-metastatic biochemical recurrent prostate cancer (ESMO 2017) - "We propose that hormonal castration is not necessary for nmPC disease control based on a preliminary assessment of both Phase Ib and II data of SM88. CTCs and N::L were improved while maintaining normal T. These early biomarker indicators are consistent with the observed 100% radiographic progression free survival and avoidance of additional toxic therapy. A phase III RCT is planned for confirmation of these results."

Biomarker • Clinical • Combination therapy • P2 data • Prostate Cancer

Typical hormone deprivation side effects compared to SM-88 therapy for rising PSA. (ASCO-GU 2019) - P1b/2; "SM-88 may be useful in delaying the start of HT. While on SM88 subjects did not report any T or therapy related AEs >G2. SM88 may be useful in prostate cancer patients who are more sensitive or vulnerable to HT related toxicity while maintaining stable PSA values."

Adverse events

Evaluating non-hormonal therapy in a phase II trial of SM-88 for rising PSA prostate cancer. (ASCO-GU 2019) - P1b/2; "Since September 2016, 31 subjects enrolled with 17 on study for > 12 weeks. Mean age 68.9; BMI 28.7; 38% black and 62% post RT. Mean T increased 61 mg/dl from baseline 319 mg/dl (p=0.19)."

P2 data

Designing clinical trials in 3L+ pancreatic cancer. (ASCO-GI 2019) - P2; "... Initiated as a retrospective evaluation of consenting patients screened for a prospective 2L+ pancreatic cancer Phase II trial with SM-88... Rapid enrollment from 3L+ patients demonstrated significant interest among this patient segment. The screen failure rate was within reasonable expectations, implying a majority of the patients were within standard inc/exc criteria. The high level of unrelated SAEs during the consent period and initial enrollment period indicate this may not be a suitable population to properly assess drug safety."

Clinical

A Phase II pharmacokinetics of oral SM-88 in heavily pretreated advanced pancreatic ductal adenocarcinoma (PC). (ASCO-GI 2019) - P2; "Single dose C1 and C2 TI PKs are consistent with preclinical predictions (ESMO 2016. Ann Oncol (2016) 27 (supp_6): 1605P) and those previously reported in a healthier population of cancer patients (JCO 2018 36: TPS 4156). Based on these results and PK ones from the repurposed drugs, additional data is being collected in order to define the ongoing phase II expansion cohort dose."

P2 data • PK/PD data

Feasibility of SM-88 in PC after multiple prior lines and ECOG < 2 (NCT03512756). (ASCO-GI 2019) - P2; "This prospective SM88 trial suggests that heavily pretreated PC patients with criteria that includes less than ideal ECOG can participate and gain access to novel therapies. This trial plans to enroll 99 additional subjects in under a year. Although ECOG 2 was allowed none have been consented to date and may reflect investigator bias on enrollment or PS assessment."

Phase II trial of SM-88 in patients with metastatic pancreatic cancer: Preliminary results of the first stage. (ASCO-GI 2019) - P2; "SM-88 has demonstrated unconfirmed monotherapy efficacy signals with no meaningful toxicity in a preliminary assessment of this ongoing trial. With additional follow up a dose will be selected for expansion"

Clinical • P2 data

SM-88, D/L-alpha-metyrosine, is a novel anti-cancer agent in estrogen receptor positive breast cancer (AACR 2022) - P2 | "Since drug resistant cancer cells often have deregulated metabolic pathways, we tested the efficacy of a novel dysfunctional tyrosine, SM-88 (D,L-alpha-metyrosine; racemetyrosine), alone or in combination with sub-toxic doses of conditioning agents, methoxsalen, phenytoin, and sirolimus (MPS) in resistant cell models of ER+ breast cancer. Ongoing work is focused on further defining the biochemical pathways in drug sensitive and resistant cells that will further support the current clinical use of SM-88 in advanced ER+ breast cancer (ClinicalTrials.gov Identifier: NCT04720664). Collectively, we show that SM-88 is potentially a novel anti-cancer agent in drug resistant ER+ breast cancer."

Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Lung Cancer • Oncology • Solid Tumor • ER • SLC3A2 • SLC7A5 • TP53

OASIS: Oral SM-88 in Patients With Metastatic HR+/HER2- Breast Cancer (clinicaltrials.gov) - P2 | N=50 | Active, not recruiting | Sponsor: Georgetown University | Recruiting ➔ Active, not recruiting

Enrollment closed • Metastases • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CD4 • ER • HER-2 • PGR

HopES: SM-88 Maintenance Therapy for Advanced Ewing's Sarcoma and as Salvage Therapy for Sarcoma (clinicaltrials.gov) - P2 | N=31 | Active, not recruiting | Sponsor: Sarcoma Oncology Research Center, LLC | Recruiting ➔ Active, not recruiting

Enrollment closed • Metastases • Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor

Oral SM-88 plus MPS, an effective yet less toxic treatment option in second-line advanced pancreatic cancer? Final phase II/III study results. (ASCO-GI 2022) - P2/3, P3 | "SM-88 Regimen, which comprises oral SM-88 (racemetyrosine, TYME Inc) plus 10mg methoxsalen, 50mg phenytoin, and 0.5mg sirolimus (MPS), has previously shown clinical activity in mPDAC...Twenty pts (54.1%) had received FOLFIRINOX in the first line and 16 pts (43.2%), a gemcitabine-based regimen... This final analysis confirmed that SM-88 Regimen was well tolerated, with pts attaining an overall DCR of 27%. Of note, for the small subset of pts treated in the second line, the mOS and mPFS were on par with results achieved in other published randomized PhIII second-line trials for mPDAC. Moreover, SM-88 Regimen exhibited far fewer Grade 3 and 4 AEs than other commonly used cytotoxic regimens in the second line."

Clinical • P2/3 data • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CTCs

Precision Promise (PrP): An adaptive, multi-arm registration trial in metastatic pancreatic ductal adenocarcinoma (PDAC). (ASCO 2022) - P3 | "Focused on 1st and 2nd line treatment of mPDAC, PrP uses an adaptive platform design with randomization to one of 2 control arms (gemcitabine + nab-paclitaxel (GA) or mFOLFIRINOX, 30% of pts) or experimental therapy (70% of pts)...Current experimental arms include: (i) GA + Pamrevlumab, an anti-CTGF Ab, (ii) Racemetyrosine monotherapy, a cancer metabolism-based therapy (for follow-up of patients) and (iii) an immuno-oncology arm in activation...Compared to traditional designs, PrP offers several advantages: multiple investigational treatments evaluated in parallel over time; ̃175 pts per experimental arm required to initiate a regulatory registration; and continuous learning from every patient, resulting in significant savings of time and resources. PrP has created an entirely new learning environment for accelerating drug development in PDAC."

Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Sarcopenia • CTGF

A Multi-center Trial to Evaluate Multiple Regimens in Metastatic Pancreatic Cancer (clinicaltrials.gov) - P3 | N=825 | Recruiting | Sponsor: Pancreatic Cancer Action Network | Trial completion date: Feb 2024 ➔ May 2026 | Trial primary completion date: Jan 2024 ➔ May 2024

Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Ghrelin Receptor (GHSR 1a ) Functional Selectivity As A Novel Pharmacotherapeutic Strategy To Normalize Dysfunctional Metabolic Homeostasis) (ENDO 2022) - "We discovered a GHSR 1a -selective, G protein-biased agonist — N8279 (NCATS-SM8864) — based on a novel chemotype...Critically, N8279 is readily brain penetrant in mice, exhibits advantageous pharmacokinetics, and attenuates aberrant dopaminergic behaviors in both genetic and pharmacological mouse models of hyperdopaminergia. Our findings together provide important insights into mechanisms governing GPCR signaling and illustrate how functional selectivity might be leveraged to develop GHSR 1a pharmacotherapeutics to normalize pathological disruptions of metabolic homeostasis."

Late-breaking abstract • Cardiovascular • CNS Disorders • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

Study of SM-88 in Advanced Cancers (clinicaltrials.gov) - P1/2 | N=0 | Withdrawn | Sponsor: Tyme, Inc | N=50 ➔ 0 | Not yet recruiting ➔ Withdrawn

Enrollment change • Trial withdrawal • Breast Cancer • Oncology • Solid Tumor

Tyme-88-Panct: A Randomized Phase 2/3 Multi-Center Study of SM-88 in Patients With Metastatic Pancreatic Cancer (clinicaltrials.gov) - P2/3 | N=132 | Completed | Sponsor: Tyme, Inc | Active, not recruiting ➔ Completed | N=250 ➔ 132 | Trial completion date: Dec 2021 ➔ Apr 2022 | Trial primary completion date: Dec 2021 ➔ Apr 2022

Enrollment change • Trial completion • Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor