EpicentRx presents new data at AACR Annual Meeting 2017
EpicentRx presents new and promising Phase 2 trial data for RRx-001 at the American Association for Cancer Research Annual Meeting held April 1-5th 2017 in Washington DC. Click on poster for further information.
See the poster, click here
EpicentRx Announces Publication of Phase 1 Trial Results for the Anti-Cancer Agent, RRx-001, in Lancet Oncology
To read the press release, click here To read about the phase 1 trial results in the Lancet Oncology, click here. Upon publishing the RRx-001 Phase 1 trial results, the Lancet Oncology published an accompanying comment. This comment, a companion analysis of the RRx-001 Phase 1 trial, takes a broad view of epigenetics and puts the study in a wider context with a discussion about “episensitization”. Click here to read the Lancet Oncology comment article.
Epigenetic Targeted Agent May Combat Resistance in Many CancersPublished in Targeted Oncology September 4th 2015
The phase I results of RRx-001, which has multiple epigenetic targets, have been published in Lancet Oncology.1 The drug is of interest because epigenetic alterations are associated with resistance to chemotherapy. Drugs that target these alterations are a promising avenue for research.
RRx-001 had antitumor properties in several tumor types and, preliminary evidence was obtained that it can chemosensitize and resensitize tumors to subsequent therapies. Thus, it may have a role in overcoming acquired resistance.
“The ability to provide resensitization to previous chemotherapy would be a change in [the] treatment framework, allowing for repetitive reintroduction of existing lines of therapy, interspersed at designated intervals with the priming or episensitizing drug,” wrote Reid et al.1
RRX-001 is a member of a new class of compounds, the dinitroazetidines, and sourced from the defense and aerospace industry. RRx-001 binds to hemoglobin and alters the properties of a subpopulation of erythrocytes. These erythrocytes then adhere to the tumor endothelium, blocking tumor microvasculature. This creates hypoxic conditions leading to the production of reactive oxygen and nitrogen species, which can epigenetically modulate DNA methylation, histone deacetylation and lysine demethylation. Preclinical studies on cell lines showed that it inhibits proliferation, and the generation of reactive oxygen and nitrogen species, causes DNA damage, and triggers caspase-independent apoptosis. It has been shown to inhibit tumor growth and affect tumor vasculature in animal models.1-4
The primary objective of the phase I open label study was to evaluate the safety tolerability and dose-limiting adverse events (AEs) of multiple increasing doses of intravenously delivered RRx-001, in order to quantify single-dose pharmacokinetics and discover a suitable dose for a phase II trial. Determining any antitumor activity of the drug by RECIST assessment was a secondary objective.1
The study enrolled 25 patients with advanced malignant incurable tumors that were rapidly progressing. The majority of the patients were male (60%), and the most common tumor type was colorectal cancer (CRC; 44%), followed by head and neck (16%), and pancreatic (12%). Other tumor types included lung, ovarian, cholangiocarcinoma, melanoma and oligodendroglioma. There were six dose cohorts, ranging from 16.7 mg/m2 to 83 mg/m2, and patients were treated once or twice a week for a minimum of 4 weeks.
More than 44% of patients had received >3 previous regimens, while others had previously recieved 1 to 3 previous treatments. Ninety-two percent of patients had former treatment with chemotherapy, 80% surgery, and 48% radiation therapy. Tumor size was measured at baseline (<2 weeks before treatment began) and then every 4 or 8 weeks until progression using CT, PET-CT or MRI.
Safety of RRx-001
The majority of AEs were grade 1 and 2; the most common being treatment-related injection site pain and forearm vasodilation, which in most cases resolved in a few minutes when infusion was stopped. To reduce the pain, patients were infused over a duration of 8 hours, and at the highest dose, some patients were infused twice weekly. Analgesics, nonsteroidal antiinflammatory drugs or corticosteroids were prescribed as needed. The authors reported no treatment-related deaths and no dose limiting toxicities in any dose cohort. Also, the maximum tolerated dose was not reached. Treatment compliance was described as very good.1
Antitumor Activity of RRx-001
Patients’ responses to treatment (21 evaluable) at 8 weeks are shown in the figure. Disease control was evident at first assessment in 71% of patients. Stable disease was experienced for more than 4 months in 28% of patients, and this was independent of the dose received.1
Median overall survival (OS) for all patients was 8.2 months (95% CI, 4.7-18.8), and median follow-up was 4.2 months. During effective treatment, there were no new metastatic foci, and tumors exhibited pseudo enlargement and central necrosis. Tumor density dropped by more than 10% in 36% of 22 lesions, without a change in tumor measurement. The authors state that this reduction suggests a “cytolytic rather than cytostatic response.” 1
It was expected that as an epigenetic therapy, RRx-001 would sensitize the tumors to subsequent therapy. Ten out of 12 patients from all dose cohorts went on to radiotherapy and chemotherapy and responded well with a median survival of 20.8 months (95% CI, 15.6 – not reached).1
Evidence that RRx-001 induced resensitization was obtained in four patients, who were resistant to chemotherapy and for whom there were no further treatment options. These patients were rechallenged with previously effective chemotherapies (3 CRC with FOLFIRI, 1 lung cancer with gemcitabine). These patients responded to the treatments, and their median OS was 17.8 months (95% CI, 10.0-not reached). 1
RRx-001 and the Future
The favorable safety profile of RRx-001, evidence of antitumor activity and importantly of chemo sensitization, and resensitization predict clinical utility of this drug. It is being further investigated in a phase II open-label randomized trial versus regorafenib in subjects with metastatic CRC (NCT 02096354); the primary outcome measure is OS. One of the secondary outcome measures is the response of the patients to subsequent therapies, to test for resensitization.1
Concluding their discussion, the authors stated that, “Additionally because epigenetic agents can affect immunological mechanisms, RRX-001 has the potential to enhance the activity of immune checkpoint inhibitors in combination,” and added that, “The priming potential of RRx-001 both as a single drug and in combination with radiation, immunotherapy, and chemotherapy will be explored in future studies.”1
1. Reid T, Oronsky B, Scicinski J, et al. Safety and activity of RRx-001 in patients with advanced cancer: a first-in-human, open-label, dose-escalationphase 1 study. Lancet Oncol. 2015 Aug 18. pii: S1470-2045(15)00089-3. doi:10.1016/S1470-2045(15)00089-3. [Epub ahead of print]
2. Ning S, Bednarski M, Oronsky B, et al. Dinitroazetidines are a novel class of anticancer agents and hypoxia-activated radiation sensitizers developed from highly energetic materials. Cancer Res. 2012;72:2600-2608.
3. Cabrales P, Reid T, Oronsky B et al. RRx-001 an EXO-based epigenetic anti-cancer agent in phase 2 clinical trials. ISEV2014 Educational Event; San Diego, CA, USA; Oct 26, 2014
4. Hongjuan Zhao, Shoucheng Ning, Jan Scicinski et al. RRx-001: A double action systemically non-toxic epigenetic agent for cancer therapy. American Association for Cancer Research annual meeting Philadelphia 2015. Abstract 3515
New Agent Targeting Epigenetic Modifications Shows Activity in Advanced Cancer
In a dose-escalation phase I study reported in The Lancet Oncology, Reid et al found that RRx-001, a representative of a new class of compounds called dinitroazetidines (sourced from the aerospace industry) that act on the tumor microenvironment, had activity in advanced cancers and a promising safety profile. RRx-001 is activated by hypoxia and induces generation of reactive oxygen and nitrogen species that can epigenetically modulate DNA methylation, histone deacetylation, and lysine demethylation.
In the study, 25 patients with advanced, malignant, incurable solid tumors from the University of California, San Diego, and Sarah Cannon Research Institute received intravenous infusions of RRx-001 at increasing doses of 10 mg/m², 16.7 mg/m², 24.6 mg/m², 33 mg/m², 55 mg/m², and 83 mg/m² once or twice weekly for ≥ 4 weeks.
Toxicity and Responses
The most common drug-related adverse event of any grade was pain at the injection site, with other common events including arm swelling or edema (32%) and vein hardening (28%). No dose-limiting toxicities were observed. However, time constraints for management of infusion pain resulted in a maximally feasible dose of 83 mg/m². Of 21 evaluable patients, 1 (5%) had a partial response, 14 (67%) had stable disease, and 6 (29%) had progressive disease at 8 weeks. After RRx-001 treatment, 4 patients were rechallenged with a treatment to which they had become refractory, with all 4 achieving response. The investigators concluded: “RRx-001 is a well-tolerated novel compound without clinically significant toxic effects at the tested doses. Preliminary evidence of activity is promising and, on the basis of all findings, a dose of 16.7 mg/m² was recommended as the targeted dose for phase 2 trials.”
Tony Reid, MD, of the University of California, San Diego, is the corresponding author of The Lancet Oncology article.
The study was funded by EpicentRx (formerly RadioRx). For full disclosures of the study authors, visit The Lancet.
- In patients with advanced solid tumors who received a new compound called RRx-001, partial response occurred in 5% and stable disease occurred in 67%.
- Four patients had response to rechallenge with previously effective treatment.
Click here for an in depth background on the clinical and scientific ‘buzz’ regarding the application of epigenetic therapies in cancer, which this article terms an “epigenetic frenzy” at the prestigious Kimmel Cancer Center at Johns Hopkins in Baltimore, Maryland
The Currently Incurable Scientist: RRx-001 and the Impact of One CRC Patient-Chemist
My most recent The Currently Incurable Scientist column published this week on the Fight Colorectal Cancer website. It explains in layman’s terms the mechanism of action & the very unique and promising preliminary clinical profile of an experimental drug called “RRx-001” in early clinical trials including a randomized Phase 2 trial (NCT02096354) for metastatic colorectal cancer (CRC).
As usual, I wanted to use my personal blog not to simply repeat the information in The Currently Incurable Scientist column (for all of that very interesting information, read the column!). Instead I wanted to use my personal blog to offer a “Director’s Cut” focused more on the fascinating human interest story behind RRx-001’s discovery and development, as well as drug discovery in general. Let’s just say it is neither a typical drug molecule nor a typical drug discovery/development story – and some aspects of the story are both very surprising and inspirational.
A Short Recap on Why I Think RRx-001 is Such an Interesting Experimental Drug
“Epigenetics” is like software running on top of your DNA genetic code which turns genes on & off. Cancer cells & tumors use epigenetics for a number of reasons including for example:
- Turning genes on which tell a cancer cell to grow when it shouldn’t be growing
- Turning genes off which normally would tell a cancer cell to stop growing or die
- Turning genes off/on which help the tumor evade the immune system
- Turning genes off/on which cause tumors to become resistant to chemotherapy
RRx-001 uniquely impacts a number of epigenetic pathways with intriguing end results, at least in preliminary clinical trial data. RRx-001 appears to resensitize tumors in multiple CRC patients to previously failed FOLFIRI chemotherapy – and it appears to do this with a very benign side effect profile.
Its Phase 1 clinical trial data was recently published in the journal Lancet Oncology, along with an accompanying commentary. In addition to the Lancet Oncology Phase 1 trial publication, two case reports on CRC patients from this trial have also been published. Most recently, preliminary Phase 2 data has also been publicly presented. RRx-001 appears to continue to show a similar profile in the early days of its current randomized Phase 2 CRC clinical trial, potentially confirming the Phase 1 trial observations.
Possibly even more exciting, as an untested (yet!) scientific hypothesis, I am very curious how many cycles of FOLFIRI –> RRx-001 –> FOLFIRI –> RRx-001… could potentially be done in a continuous loop fashion. If that kind of “continuous loop” treatment protocol worked in a significant number of patients, it could potentially transform standard of care for Stage IV CRC patients and significantly extend survival. At this point it is only a scientific hypothesis but I am crossing fingers it might work in eventual clinical testing!
Serendipity, Intuition, Persistence and the Impact of One CRC Patient-Chemist
The back story of where RRx-001 came from and its path to development for CRC (and now multiple other types of cancer) is one of the most unique I have personally heard in modern drug discovery. A longer version of the story is on the developing company’s website. My goal is to present some of the information from that source and use it to illustrate some common aspects of drug discovery: 1.) Serendipity 2.) Intuition 3.) Persistence 4.) the impact of a scientist serving as a molecule’s champion – in this case a CRC patient-chemist.
RRx-001’s Origins – Serendipity and a VERY Intuitive Open Mind
Prof. Mark Bednarski was initially a Chemistry professor at a top University, the University of California at Berkeley. He also was diagnosed with early-onset CRC shortly after his 33rd birthday. His CRC diagnosis transformed his life and afterwards Prof. Bednarski went to Medical School at another top University (Stanford) and eventually he became a professor of Radiology there.
RRx-001, in terms of becoming a potential cancer drug, was born in all places, on the ski slopes of Utah. By chance, Prof. Bednarski met another chemist on the ski slopes, a chemist from ATK Thiokol, a defense and aerospace contractor which designs and manufactures e.g. rocket fuel and military-grade explosives. As often happens when two chemists meet, even if they work in different chemistry sub-fields, chatting about research ensued. As they chatted, structures related to RRx-001 were drawn in the snow and Prof. Bednarski was intrigued… Yes they were meant to be explosives but his nimble scientific mind and intuition also envisioned that their very unique chemical structures could potentially have medicinal value as well.
The structures were so unique that most drug discovery medicinal chemists (including me) would not have made that potential therapeutic mental leap. That is actually saying it too mildly – at least speaking for me, I would have run away as fast as possible if it were proposed to me as a drug. I tend to run away from things that look like chemicals from the explosives/rocket fuel industry!
How Unique Were the Chemical Structures?
Keep in mind, these chemicals were designed by a maker of explosives and rocket fuels… they were not originally intended to be potential medicines. And their structures show that design background. For my chemist readers, I pasted the structure of RRx-001 below.
For this blog’s audience, I won’t go into the chemistry details of why a compound like RRx-001 does not look like a traditional medicine but I will say that no structure like it is usually allowed in pharmaceutical & biotech compound testing collections. Why? For the basic logical reason that as I mentioned… it looks like chemicals from the explosives/rocket fuel industry! Chemists also would not be fans of that bromine (the “Br”) atom sticking off the end – but I’ll save you from hearing a chemistry lecture today why… By the way once again, serendipity rears its head… this kind of chemical structure would cause worries of toxicity – but thus far based upon early testing, RRx-001 appears to have an abnormally benign clinical toxicity profile compared to most cancer drugs! No nausea. No hair-loss. No fatigue. No low blood counts. Nothing similar to standard chemotherapy or prior epigenetic drugs’ side effects.
An important note: RRx-001, although chemically related to explosive and rocket fuels – is itself non-explosive. So don’t worry… no cancer patients are exploding when it is being dosed! The chemistry term for it is a “synthetic intermediate” which means a chemical that is generated on the path towards synthesizing a desired design goal. That is what makes Prof. Bednarski’s intuition so incredible – and it also shows the power of a scientist from outside of drug discovery looking at potential medicines with fresh eyes.
Initially, Prof. Bednarski observed the potential of a chemical like RRx-001 to possibly be useful to selectively damage cancer cells during radiation therapy. Along those lines he collaborated with his colleague and company co-founder Dr. Susan Knox, a practicing radiation oncologist. Upon subsequent testing over the years by an ever growing group of fellow scientists, the unique structure of RRx-001 was found to also impact epigenetic pathways, as mentioned at the top of this post, which opened up its potential use to a much broader cancer patient population than ever originally intended!
Persistence and Being a Molecules Champion
Drug discovery is hard. Very hard. I was quoted in Ken Burn’s adaption of the Emperor of All Maladies as saying something along the lines of “Chemists need to be eternal optimists, because 99.99 percent of what you do fails.” Your chemistry often fails to make your target compound. If that works, the compound fails in in vitro testing. If that works, the compound fails to adequately enter & survive in the blood stream after being dosed to an animal. If that works, the compound fails to show efficacy in an animal model. If that works, the compound fails to pass toxicity testing. If that works, the compound fails to adequately enter & survive in the blood stream when dosed to a human. If that works, the compound fails to be safe in humans. If that works, the compound fails to have efficacy in patients in clinical trials. Believe it or not, that is actually an over-simplification of all the ways that a potential drug can fail before it can become a medicine! Drug discovery is one of the hardest endeavors attempted by humans – but the potential end result of really making a difference against unmet medical needs in real people’s lives also make it one of the most rewarding possible!
With all the possible ways to fail lined up against it – a potential drug needs at least one “champion” who believes in it and pushes it forward against the headwind of all that potential failure – as long as data indicates that it can possibly still make it to the finish line and become a medicine! That job, of being a champion, is very tough to do in the best of circumstances. To push forward a strange drug molecule, sourced from an explosives manufacture no less, takes the strongest molecular champion possible. Prof. Mark Bednarski was that first champion for what is now a molecule being tested against multiple tumor types (including CRC with preliminary signs of success) in five parallel clinical trials.
Prof. Mark Bednarski passed away on February 18, 2006 after a 14 year battle with CRC. He was only 47 years old.
Many scientists and others have worked on the development of RRx-001. Quoting the Lancet Oncology commentary “RRx-001 is a member of a new class of panepigenetic modifying drugs called dinitroazetidines that look exceptionally promising in early clinical development”. There are still a lot of unknowns as it undergoes additional clinical testing to attempt to confirm the early safety and efficacy profile. If it successfully becomes an approved drug for Stage IV CRC patients, RRx-001 would be the best example I personally have seen of serendipity, intuition, persistence and the impact of one Patient-Chemist. Thanks to a member of the CRC patient community itself, Prof. Mark Bednarski.