Phase II monotherapy efficacy of cancer metabolism targeting SM-88 in heavily pre-treated PDAC patients

Ocean, Allyson J.; Noel, Marcus Smith; Wang‐Gillam, Andrea; Chawla, Sant P.; Chung, Vincent; Pant, Shubham; Korn, Ronald I; Priore, G.l. De; Picozzi, Vincent J.

doi:10.1093/annonc/mdz247.046

Cited by 4 publications

(3 citation statements)

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“…In addition, a phase Ib/II, open-label, dose-escalation study of racemetyrosine was conducted in combination with methoxsalen, phenytoin, and sirolimus in patients with non-metastatic biochemically recurrent prostate cancer ( 126 ). Although the outcomes of these open-label studies appear encouraging (e.g., no serious adverse events) ( 127 , 128 ), more definitive conclusions await placebo-controlled randomized clinical trials.…”

Section: Metabolic Inhibitors In Clinical Trialsmentioning

confidence: 97%

Clinical development of metabolic inhibitors for oncology

Lemberg¹,

Gori²,

Tsukamoto³

et al. 2022

Journal of Clinical Investigation

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Metabolic inhibitors have been used in oncology for decades, dating back to antimetabolites developed in the 1940s. In the past 25 years, there has been increased recognition of metabolic derangements in tumor cells leading to a resurgence of interest in targeting metabolism. More recently there has been recognition that drugs targeting tumor metabolism also affect the often acidic, hypoxic, immunosuppressive tumor microenvironment (TME) and non-tumor cell populations within it, including immune cells. Here we review small-molecule metabolic inhibitors currently in clinical development for oncology applications. For each agent, we evaluate the preclinical studies demonstrating antitumor and TME effects and review ongoing clinical trials. The goal of this Review is to provide an overview of the landscape of metabolic inhibitors in clinical development for oncology.

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Section: Metabolic Inhibitors In Clinical Trialsmentioning

confidence: 97%

Clinical development of metabolic inhibitors for oncology

Lemberg¹,

Gori²,

Tsukamoto³

et al. 2022

Journal of Clinical Investigation

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“…The use of SM-88 is based on a growing body of literature showing the effects of targeting metabolic pathways that contribute to growth [6][7][8][9]. Specificity for cancer cells is high and off target toxicities few [10,11].…”

Section: Introductionmentioning

confidence: 99%

Phase II trial of SM-88, a cancer metabolism based therapy, in non-metastatic biochemical recurrent prostate cancer

Gartrell

Roach

Retter³

et al. 2020

Invest New Drugs

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Summary Background Androgen deprivation therapy (ADT) is a standard treatment for high-risk biochemically-recurrent, non-metastatic prostate cancer (BRPC) but is not curative and associated with toxicity. Racemetyrosine (SM-88) is an amino-acid analogue used with methoxsalen, phenytoin, and sirolimus (MPS) to enhance SM-88 activity. Method A phase 1b/2, open-label trial in BRPC and rising PSA. Patients were given daily SM-88 (230 mg BID), methoxsalen (10 mg), phenytoin (50 mg), and sirolimus (0.5 mg)). Outcome measures included changes in PSA, circulating tumor cells (CTCs) and imaging. Results 34 subjects were screened, 23 treated and 21 remained on study for ≥12 weeks. The median PSA was 6.4 ng/ml (range 1.7–80.1); doubling-time 6.2 months (range 1.4–36.6) and baseline testosterone 319.1 ng/ml (range 2.5–913.7). Median duration of therapy was 6.5 months (2.6–14.0). CTCs (median 48.5 cells/4 ml (range 15–268) at baseline) decreased a median of 65.3% in 18 of 19 patients. For patients who achieved an absolute CTC nadir count of <10 cells/4 ml (n = 10), disease control was 100% i.e. no metastases or PSA progression, while on trial (p = 0.005). PSA fell by ≥50% in 4.3% (1 subject). No patients developed metastatic disease while on treatment (metastases free survival =100%). There were no treatment-related adverse events (AEs) and quality of life was unchanged from baseline on the EORTC QLQ-C30 and QLQ-PR25. Testosterone levels rose slightly on SM-88 and were unrelated to efficacy or toxicity. Conclusions Use of SM-88 was associated with disease control while maintaining QOL. SM-88 may delay the need for ADT and the associated hormonal side effects. Larger trials are planned. Trial registration number, date of registration - NCT02796898, June 13, 2016

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“…Promising data are available for the combination of lenvatinib and pembrolizumab, which is tested within an open-label, Phase Ib study including 104 HCC-patients with BCLC stage B (not amenable for TACE) or BCLC C, Child-Pugh class A. At present, data from the first 67 patients enrolled by 31 December 2018 are available [33]. Serious adverse events occurred in 62.7% of all patients, ORR was 44.8%.…”

Section: Immunotherapymentioning

confidence: 99%

Systemic treatment of hepatocellular carcinoma: from sorafenib to combination therapies

et al. 2020

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For almost a decade, systemic therapy of advanced hepatocellular carcinoma (HCC) was limited to the tyrosine kinase inhibitor (TKI) sorafenib. Different agents including checkpoint inhibitors, TKIs and anti-VEGFR antibodies demonstrated efficacy in treatment. For the first time, the combination of atezolizumab and bevacizumab, a first-line treatment that is superior to the current standard was identified, potentially changing the way we treat HCC. In this review, we summarize current data on systemic treatment of patients with advanced HCC, focusing on combination therapies comprising immune checkpoint inhibitors, TKIs and locoregional therapies. We elucidate findings from recent trials and discuss such challenges as the lack of predictive biomarkers for identification of subgroups that will benefit from novel treatment strategies.

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Phase II monotherapy efficacy of cancer metabolism targeting SM-88 in heavily pre-treated PDAC patients

Cited by 4 publications

References 0 publications

Clinical development of metabolic inhibitors for oncology

Clinical development of metabolic inhibitors for oncology

Phase II trial of SM-88, a cancer metabolism based therapy, in non-metastatic biochemical recurrent prostate cancer

Systemic treatment of hepatocellular carcinoma: from sorafenib to combination therapies

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