Phase 1/2, Multi-center, Open Label, Dose Escalation, Safety, Efficacy and PK Study of PRLX 93936 Administered IV 3 Days a Week for 3 Weeks Followed by a 9 Day Rest Period in Patients With Relapsed or Relapsed/Refractory Multiple Myeloma

To determine the maximum tolerated dose of, and response to, PRLX 93936 as treatment for patients with relapsed or relapsed/refractory multiple myeloma.

Start Date01 Mar 2012

Sponsor / Collaborator

Prolexys Pharmaceuticals, Inc.

NCT00528047 / CompletedPhase 1

A Phase I, Multi-center, Open-Label, Dose-Escalation, Safety, Pharmacodynamic and Pharmacokinetic Study of PRLX 93936 Administered Intravenously Daily for Five Days Followed by a 23-Day Rest Period in Patients With Advanced Solid Tumors

The purpose of this study is to test the safety of PRLX 93936 and see what kind of effect it has on patients and their cancer. This study will also determine the highest dose of PRLX 93936 that can be given without causing adverse side effects and the dose of PRLX 93936 that should be used in future studies.

Start Date01 Aug 2007

Sponsor / Collaborator

Prolexys Pharmaceuticals, Inc.

100 Clinical Results associated with Prolexys Pharmaceuticals, Inc.

0 Patents (Medical) associated with Prolexys Pharmaceuticals, Inc.

Literatures (Medical) associated with Prolexys Pharmaceuticals, Inc.

06 Dec 2014·Blood

An Open-Label, Dose Escalation, Multi-Center Phase 1 Study of PRLX 93936, an Agent Synthetically Active Against the Activated Ras Pathway, in the Treatment of Relapsed or Relapsed and Refractory Multiple Myeloma

Author: Anderson, Kenneth C. ; Mitsiades, Constantine S ; Richardson, Paul G. ; Voorhees, Peter M ; Jacobstein, Douglas A ; Gasparetto, Cristina J ; Berdeja, Jesus G. ; Laubach, Jacob P. ; Schlossman, Robert L. ; Morris, John

AbstractIntroduction: Overall survival for patients with multiple myeloma (MM) has improved, but most patients relapse and eventually succumb to complications of the disease. The development of new therapeutic agents to treat relapsed and relapsed/refractory MM is therefore vital. Proteins of the Ras family are frequently mutated in human cancers, including MM. However, direct, selective, potent inhibitors of mutant Ras proteins are not clinically available. Extensive efforts have been made to identify agents which are "synthetically active" against the activated Ras pathway which may not inhibit the Ras protein itself, but target other molecules selectively important for cells with, but not those without, Ras mutation. PRLX 93936, 3-(2-ethoxyphenyl)-2-[(1-piperazinyl)methyl]-4(3H)-quinazolinone, is an analog of such a "synthetically active" compound against the activated Ras pathway. The compound has demonstrated promising efficacy in preclinical laboratory studies and mouse models of MM with an improvement in survival and 30% suppression in tumor growth at the lowest tested dose. A phase 1, multi-center, open-label, dose escalation trial was conducted to determine the maximum tolerated dose (MTD), assess toxicities, and evaluate response to treatment with monotherapy of PRLX 93936 in patients with relapsed or relapsed/refractory MM.Methods: Patients (Pts) with relapsed or relapsed/refractory MM in whom at least two prior anti-myeloma regimens had failed (including a proteasome inhibitor and/or immunomodulatory drug) were considered. PRLX 93936 as a single agent was given intravenously 3 days/week for 3 weeks followed by a 9 day rest period constituting a 28-day treatment cycle. Sequential cohorts of at least three pts were treated with escalating doses of PRLX 93936 beginning at 10 mg/m2 and increasing the dose in increments of 5mg/m2 until the MTD was established. Pts received a minimum of 2 cycles of treatment at their assigned dose level for evaluation of anti-myeloma activity of PRLX 93936 and could receive up to 8 cycles followed by an option of maintenance therapy. Dexamethasone at a dose of 20 mg provided on each day of PRLX 93936 infusion could be added at the investigator’s discretion after a minimum of 2 cycles or after cycle 1 for patients with progressive disease. Adverse events were assessed according to version 4.0 of the CTC, and response per the International Myeloma Working Group uniform response criteria, incorporating the modified EBMT response criteria, were assessed with each cycle. Correlative studies from peripheral blood and bone marrow were collected.Results: To date, 14 pts (4 women, 10 men) enrolled in the trial and 13 have completed therapy. Mean age was 61 years (range, 48-81). Prior to enrollment, pts had received an average of 5 lines of therapy (median 4, range 2-9) including 6 who received stem cell transplantation (4 autologous, 2 allogeneic). The median time since diagnosis was 5 years (range 2-11.5). Of the 13 pts whom completed treatment, 11 completed at least one full 28 day cycle (range 1-15). This includes 3 pts at the 10mg/m2 dose, 3 pts at the 15mg/m2 dose, 5 pts at the 20 mg/m2 dose, and 2 pts at the 25mg/m2 dose. Of the 13 pts who completed study therapy, 7 experienced at least one serious adverse event (SAE). The most frequently reported SAEs (2 each) included sepsis and cellulitis. Four SAEs were considered related to PRLX 93936 by the investigator (thrombocytopenia, neutropenia, nausea, and vomiting). The MTD was determined to be 20 mg/m2. Dose limiting toxicities that occurred at the next higher level of 25mg/m2 included nausea, vomiting, and neutropenia (both pts) and thrombocytopenia, weakness, elevated AST, and elevated creatinine (1 pt). The best response among 11 evaluable pts was minimal response (MR) in 2 pts (18%). Stable disease (n=4) and progressive disease (n=5) was observed in the remaining pts. Analysis of the impact of dexamethasone is on-going, but no significant additive toxicity has been seen.Conclusions: PRLX 93936, a “synthetically active” compound against the activated Ras pathway, has demonstrated activity as a single agent in relapsed and refractory MM patients with MR in 18% of patients to date. Toxicity has proven manageable and the MTD has been defined at 20 mg/m2. Additional studies, including those involving PRLX 93936 as part of combination therapy and correlative studies to determine those pts most likely to benefit, are warranted.DisclosuresVoorhees: Millennium: The Takeda Oncology Company : Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees. Off Label Use: PRLX 93936 is a non-FDA approved drug currently in phase 1 development in multiple myeloma. Gasparetto:Millenium: Honoraria; Celgene: Consultancy, Honoraria. Jacobstein:Prolexys Pharmaceuticals, Inc: Employment. Anderson:BMS: Consultancy; Sanofi Aventis: Consultancy; Gilead: Consultancy; Onyx: Consultancy; Millenium: Consultancy; Celgene: Consultancy; Oncopep/Acetylon: Equity Ownership. Mitsiades:Millennium: A Takeda Oncology Company: Consultancy; Celgene: Consultancy; Johnson & Johnson: Research Funding; Amgen: Research Funding. Laubach:Celgene: Research Funding; Novartis: Research Funding; Millennium: A Takeda Oncology Company: Research Funding; Onyx: Research Funding. Richardson:Janssen: Membership on an entity's Board of Directors or advisory committees; Millennium: The Takeda Oncology Co.: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

15 Apr 2010·Cancer Research

Abstract 2543: PRLX 93936, is a potent, novel, tumor-selective, small molecule with a unique mechanism of action

Author: Gauntlett, Ann ; Robbins, Paul B. ; Sahasrabudhe, Sudhir R. ; Clemens, Christopher ; Bell, Russell ; Pierce, Michael ; Venkat, Raj Gopal

AbstractCurrently in Phase I testing, PRLX 93936 was developed and characterized at Prolexys Pharmaceuticals. It is a potent small molecule drug that shows robust and selective anti-cancer activity in a wide array of solid tumors including those with mutations that activate the RAS pathway. PRLX 93936 was chosen as a clinical lead as a result of extensive medicinal chemistry efforts and pharmacological profiling of over 400 novel small molecules. These compounds were designed to cover the chemical space originating from a molecule, Erastin, identified in a screen against isogenic cell lines differentially expressing genes such as those that activate the RAS pathway (Dolma et. al, Cancer Cell 3: 285-296, 2003). Cells that are sensitive to PRLX 93936 undergo caspase dependent apoptosis, necrosis, cell cycle arrest, ion flux and cell shrinkage leading to death and tumor growth inhibition. Characterization of drug treated cells shows that selective activation of RAS and JNK pathway members correlates with compound sensitivity. Research to elucidate the precise mechanism(s) and target(s) through which these biological responses are achieved has revealed that PRLX 93936's mechanism of action is unique. Several key lines of evidence support this conclusion including: 1. COMPARE analysis of PRLX 93936 activity in the NCI 60 panel of cell lines which showed that it is functionally distinct among the agents tested, 2. Profiling studies which examined PRLX 93936 binding or inhibition of enzyme activity against CYP450 enzymes, cell surface receptors and action potential mediating cardiac ion channels revealed only Cyp 3A4 and hERG as potential targets, 3. Kinase profiling of PRLX 93936 against evolutionarily diverse enzymes which identified no significant inhibitory activity, and 4. Genotyping and gene expression profiling studies which have yet to reveal a clear target profile correlation. Since the most common target classes were eliminated as potential suspects, additional non-traditional enzyme targets were screened for relevance to PRLX 93936 activity. Proteomics experiments identified the mitochondrial protein VDAC (Voltage Dependent Anion Channel) as a specific binding protein and potential molecular target of PRLX 93936 (Yagoda et al., Nature. 447: 865-869, 2007). More recent findings indicate that PRLX 93936 is a potent, selective inhibitor of several RAS pathway proteins including key enzymes which regulate the phosphorylation and activity of proteins involved in the RAS/JNK pathway. RNAi based validation studies and synergistic anti-cancer activity observed in combination with specific targeted drugs support these findings. PRLX 93936 may therefore represent a novel class of cancer therapeutics that target the majority of tumors characterized by RAS pathway activation.Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2543.

16 Nov 2007·Blood

In Vitro and In Vivo Anti-Myeloma Activity of PRLX, an Orally-Bioavailable Agent Against Cells with Constitutive Activation of Ras or Its Downstream Pathway.

Author: Mitsiades, Nicholas ; Mitsiades, Constantine S. ; Sahasrabudhe, Sudhir ; Selliah, R. ; Anderson, Kenneth C. ; Richardson, Paul G. ; Rooney, Melissa ; Negri, Joseph M. ; Robbins, P. ; McMillin, Douglas W. ; Jenkins, Lauren ; Schlossman, Robert ; Klippel, Steffen ; Tesmenitsky, Yevgenia ; Delmore, Jake ; Jakubikova, Jana

AbstractRas mutations occur in 40–60% of multiple myeloma (MM) patients and are implicated in progression to advanced MM (including plasma cell leukemia/extramedullary lesions). The small molecule PRLX (Prolexys Pharmaceuticals) was identified in the context of “synthetic lethal” chemical screening for genotype-selective cytotoxicity against cells transformed with forced expression of mutant Ras (but not against isogenic normal cell counterparts) and was tested for anti-MM activity. In MTT survival assays, 34 of 46 human MM cell lines (74%) responded to 48hr treatment with sub-μM PRLX concentrations (achievable in preclinical pharmacokinetic studies). (24 MM lines had IC50 values <300nM). PRLX anti-MM activity compared favorably with its in vitro activity against cell lines from leukemias, lymphomas, and solid tumors. PRLX activity was not restricted to cells with known Ras mutations: it was also observed in cells with FGF-R3 overexpression and/or activating mutation, suggesting that PRLX may target cells with hyper-active signaling through either upstream receptors, Ras or its downstream effectors, rather than targeting Ras biochemical activity itself. PRLX was active against MM cells resistant to conventional (Dex, alkylators, anthracyclines) and/or novel (lenalidomide, CC-4047, bortezomib, multitargeted kinase inhibitors) anti-MM agents. No antagonism was observed when PRLX was combined in vitro with other anti-MM agents, including Dex, bortezomib or CC-4047. Co-culture with BMSCs did not protect MM cells against PRLX (at doses non-toxic to BMSCs). Cell death commitment assays revealed that a pharmacologically relevant 5hr pulse with 300nM PRLX is sufficient to commit OPM-2 MM cells to cell death. Gene expression profiles (with Affymetrix U133 2.0plus oligonucleotide microarrays) showed early (<2hr) PRLX-induced modulation of broad spectrum of genes involved in regulation of cellular bioenergetics. FACS analyses of PRLX-treated cells revealed decreased mitochondrial membrane potential followed by apoptotic and then necrotic features of cell death. Reducing agents, such as tocopherol, can protect MM cells against PRLX, suggesting that release of reactive oxidative species may be an ultimate downstream mediator of the mechanism of action of this agent. The in vivo anti-MM activity of PRLX was evaluated in 2 separate in vivo models of diffuse MM lesions in SCID-beige mice, generated by i.v.injections of OPM-2 and MM.1S cells, respectively. In both models, mice were sublethally irradiated, injected i.v. with 1x106 MM cells and then randomly assigned to receive by oral gavage either PRLX 100 mg/kg (n=14) or vehicle only (n=14) on cyclical schedule of 5 days-on/2 days-off treatment. In both models, >90% of PRLX-treated mice were alive at 140 and 64 days from treatment onset, in the OPM-2 and MM.1S model respectively. In contrast, median overall survival was 35 days (95% CI: 23–47) and 35 days (95%C.I.: 31–39) in the respective control groups (Kaplan-Meier analyses, p<0.0001 in both models, by log-rank test). PRLX represents a promising novel orally bioavailable agent that merits further evaluation for possible clinical trials in advanced MM.

100 Deals associated with Prolexys Pharmaceuticals, Inc.

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Drug(Targets)	Indications	Global Highest Phase

Erastin ( SLC7A11 x VDAC1 x VDAC2 x VDAC3 x p53 )	Mutation related cancer More	Preclinical
PRLX-93936 ( SYNGAP1 )	Solid tumor More	Pending
PRLX-8025 ( CTNNB1 )	Colonic Cancer More	Pending

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