Investigation into a novel oncolytic adenovirus as a treatment option for patients with colorectal cancer and other cancers with liver metastasis is underway. The biotech company, DNAtrix, recently announced the treatment of the first patient enrolled to a phase 1 dose-escalation and dose-expansion study of DNX-2440 (NCT04714983) in patients with resectable liver metastasis.

DNX-2240 is a replication competent, potent, oncolytic adenovirus expressing human OX40 ligand. Expression of OX40 ligand on the surface of tumor cells is expected to enhance antitumor immune responses by providing costimulatory signals to T cells within the tumor microenvironment.

“[DNX-2440] will infect, replicate, and kill cells,” Brett Ewald, senior vice president of development for DNAtrix explained in an interview with 

 “As it does [this], DNX-2440 will release inflammatory cytokines and viral and tumor-associated antigens which will trigger both an innate and adaptive immune response. We know from our preclinical and clinical work across all of our programs that this helps drive durable clinical activity.”

DNX-2440 demonstrated an effect on both injected and noninjected tumors in preclinical models, including those that are distanced, Ewald explained. The agent also facilitated immune memory, displaying an impact in mice that were rechallenged with new tumors.

In the phase 1 study, DNX-2240 will be evaluated in approximately 24 to 30 patients with resectable multifocal liver metastasis, who are scheduled to have liver resection with curative-intent. The primary end point of the study is to establish safety and identify a maximum tolerated dose. Secondary end points include evaluating tumor cell killing of injected and uninjected tumors, determining viral replication in the injected tumor, and measuring local and systemic anti-tumor immune responses.

“In this study, patients will mostly have more than 1 lesion and we’ll inject 1 lesion but not inject the other lesions with DNX-2440, 2 times, 2 weeks apart,” Ewald said. “Then, they’ll have their scheduled surgery. That will allow us to remove the treated tumors, the nontreated tumors, and healthy tissue and really evaluate the mechanism of DNX-2440 from a detailed standpoint. The idea is that you give exposure to this powerful immunotherapy the month before surgery, allow the immune system to kick into gear, and, after the tumors are removed, that will have an impact on the tumor coming back.”

Ewald said that DNX-2440 has the potential to fulfill an unmet need in this disease setting because many of these tumors have not previously had typical responses to other immunotherapies, such as checkpoint inhibitors.

“We think that this unique immunotherapy might provide that kind of immune spark, that stimulation, needed to really have an impact in these tumors,” Ewald said. “We’re really just adding on to the standard of care. Patients are already getting scheduled surgery to remove these tumors, if you can add on a dose or 2 of DNX-2440 before that scheduled surgery and that impacts the disease in a positive manner, you can see why that would be very beneficial for the patients and their families.”

If the phase 1 study is successful, the agent will be tested in other patient populations in the neoadjuvant and other settings. DNX-2440 would also be evaluated in combination with checkpoint inhibitors and other agents.

“I think the design of this trial is what’s especially exciting,” Ewald concluded. “It’s really focused on a patient population with a need, but it is also focused on scientifically understanding more about the drug and its mechanism within the tumors themselves. I think we’re going to learn a lot, get a lot of bang for our buck, in a fairly small study.”

DNAtrix announces first patient dosed in clinical study of DNX-2440, an OX40 ligand expressing immunotherapy, in colorectal cancer and other cancers with liver metastasis. News release. DNAtrix. March 4, 2021. Accessed March 12, 2021. 

https://www.dnatrix.com/view.cfm/140/2021-press-release

DNX-2440 for resectable colorectal liver metastasis. Updated March 10, 2021. Accessed March 12, 2021. 

https://clinicaltrials.gov/ct2/show/NCT04714983?term=DNX-2440&draw=2&rank=2

Articles

Investigation into a novel oncolytic adenovirus as a treatment option for patients with colorectal cancer and other cancers with liver metastasis is underway. 

DNX-2440 Shows Promise in CRC and Other Cancers With Liver Metastasis as Phase 1 Trial Begins

The first-in-class N-terminal domain (NTD) androgen receptor (AR) inhibitor EPI-7386 is being examined in combination with enzalutamide (Xtandi) in patients with metastatic castration-resistant prostate cancer (mCRPC) as part of a phase 1/2 trial, according to an announcement from ESSA Pharma Inc.

The study is the product of a clinical collaboration forged between ESSA Pharma Inc., a clinical-stage pharmaceutical company focused on developing novel therapies for the treatment of patients with prostate cancer and manufacturer of EPI-7386, and Astellas Pharma Inc. As part of the terms of their supply agreement, ESSA Pharma Inc. will sponsor the trial and retain all rights to EPI-7386, while Astellas Pharma Inc. will supply enzalutamide for the research.

The clinical trial will specifically examine the combination in patients with mCRPC who have not received prior treatment with second-generation antiandrogen therapies; it is slated to begin enrollment in 2021.

"We are delighted to collaborate with Astellas to explore the potential clinical role of EPI-7386 in combination with Astellas' enzalutamide in patients with mCRPC, who have progressed on androgen deprivation therapy," David R. Parkinson, MD, chief executive officer of ESSA Pharma Inc., stated in a press release. "Combining our 2 therapies will simultaneously target both ends of the AR. In preclinical models, we have seen that combining EPI-7386 with current antiandrogens can lead to deeper and broader inhibition of androgen biology. We look forward to investigating the combination of these therapies and their potential role together in the treatment of [patients with] prostate cancer."

Most patients with mCRPC experience progression with a rising prostate-specific antigen, underlying a persistent dependence on the AR pathway.

 Although standard-of-care options target the AR axis, resistance eventually develops to antiandrogens and this can involve mechanisms such as AR gene amplification, ligand-binding domain (LBD) mutations, and expression of constitutively active AR splice variants that are missing the LBD. Inhibition of the NTD of the AR can hinder its transcriptional activity, even in the presence of resistance driven by LBD. 

Investigators evaluated the potency of EPI-7386 through the use of reporter cellular models or viability assays several cell lines that either expressed AR or did not. Investigators determined pharmacodynamic markers of activity in AR full length or AR-V7–driven models through the use of quantitative polymerase chain reaction or RNA sequencing. Using screening and functional assays, investigators learned more about the stability and selectivity of the molecule.

Results from the research indicated that EPI-7386 has an IC50 of 421 nM in LNCaP reporter assays, which is a range that is comparable to most LBD inhibitors; however, this agent differs from known agents in that its antitumor activity was maintained in CRPC models that expressed AR-V7. As anticipated, no activity with the agent was reported in non-AR–driven models. The agent was able to successfully inhibit the expression of AR full length driven genes like PSA, FKBP5, and STEAP4, while also modulating the expression of genes driven by AR V7. The investigative agent was also found to have impressive in vivo activity in several models, including a CRC patient-derived xenograft that was enzalutamide resistant.

Additionally, RNA sequencing revealed that the agent had on-target activity, although it had a transcriptomic profile that differed from that of enzalutamide. Investigators surmised that this finding meant that the combination of both LBD inhibition and NTD AR inhibition could potentially result in more robust hindrance of the AR pathway. The enhanced activity of the combination was confirmed in vivo when investigators utilized a CRPC model VCaP.

“The second-generation aniten compound EPI-7386 is more active and metabolically stable than EPI-506,” the investigators had concluded. “It has a favorable safety profile and ADME profile, with predicted long half-life in humans, supporting [a] once-daily dose. In vivo, EPI-7386 demonstrated potential as a single agent in overcoming antiandrogen clinical resistance as well as in combination therapy.”

the FDA granted fast track designation to EPI-7386 for the treatment of adult patients with mCRPC

 who are resistant to standard-of-care options. This investigational, highly-selective, oral small molecule inhibitor is currently under investigation in a first-in-human phase 1 trial (NCT04421222).

 Here, investigators set out to examine the safety of the agent and to determine a dose that can be administered without intolerable adverse effects. Investigators also seek to characterize the pharmacokinetic, biological, and antitumor effects of EPI-7386.

ESSA Pharma announces clinical collaboration with Astellas to evaluate the combination of EPI-7386 and enzalutamide for patients with metastatic castration-resistant prostate cancer. News release. ESSA Pharma Inc. February 25, 2021. Accessed March 15, 2021. 

Hong NH. Le Moigne R, Banuelos CA, et al. Pre-clinical development of the second-generation N-terminal domain androgen receptor inhibitor, EPI-7386, for the treatment of prostate cancer. 

. 2020;80(16). doi:10.1158/1538-7445.AM2020-1953

ESSA Pharma announces fast track designation granted by the FDA to EPI-7386 for the treatment of metastatic castration-resistant prostate cancer. News release. ESSA Pharma Inc. September 14, 2020. Accessed March 15, 2021. 

Oral EPI-7386 in patients with metastatic castration-resistant prostate cancer (EPI-7386). ClinicalTrials.gov. Updated July 29, 2020. Accessed March 15, 2021. 

https://clinicaltrials.gov/ct2/show/NCT04421222

The first-in-class N-terminal domain androgen receptor inhibitor EPI-7386 is being examined in combination with enzalutamide in patients with metastatic castration-resistant prostate cancer as part of a phase 1/2 trial. 

Novel NTD Inhibitor EPI-7386 Plus Enzalutamide Under Evaluation in mCRPC 

A phase 2 clinical trial (NCT04436029) has been initiated to evaluate Descartes-11, an mRNA CAR T-cell therapy, as a consolidative therapy in patients with newly diagnosed, high-risk multiple myeloma who have residual disease after induction therapy.

To date, Descartes-11 is the first RNA-engineered cellular therapy to enter clinical development for the frontline treatment of cancer, according to Cartesian Therapeutics, the engineer of the product.

“Patients [who are] newly diagnosed with high-risk multiple myeloma seldom achieve deep, durable responses after frontline therapy,” said Kenneth C. Anderson, MD, the Kraft Family Professor of Medicine at Harvard Medical School and program director of the Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics at Dana-Farber Cancer Institute, a 2014 Giant of Cancer Care® winner in Multiple Myeloma. “Integrating a CAR T-cell therapy into our standard of care, without using lymphodepleting chemotherapy, would be a welcome addition to our toolkit for treating this currently incurable disease.”

Multiple myeloma represents the second most common hematologic malignancy in the world and remains difficult to treat despite numerous therapeutic advances and drug approvals. Patients continue to experience multiple relapses and complications from the disease, affecting many areas of the body, such as the bones, kidneys, and immune system.

Descartes-11 is part of Cartesian Therapeutics RNA Armory

, a cellular therapy platform that “enables mRNA-engineering any cell, to target to any tissue, any combination of therapies.”

 The platform utilizes autologous and allogeneic approaches to engineer products that optimize each therapy to different cell types. Moreover, the “army” of cells that is engineered deliver precision-targeted treatment directly to the myeloma cells with a defined half-life, which allows for repeat dosing and outpatient administration of some therapies.

The investigational Descartes-11 product is manufactured to express CAR molecules transiently rather than permanently, which could reduce some of the short- and long-term risks associated with traditional autologous CAR T-cell therapies.

Notably, the full therapeutic dose of Descartes-11 can be administered with each infusion as billions of cells are mRNA-engineered with the CAR molecule. Moreover, this eliminates the need for preconditioning, lymphodepleting chemotherapy that current CAR T-cell therapies require.

Phase 1 data showed no evidence of cytokine release syndrome or neurotoxicity with Decartes-11 in patients with advanced multiple myeloma. Currently, the emergence of these adverse effects remains a key challenge faced with CAR T-cell therapies in hematologic malignancies.

The open-label, phase 2 trial has a planned enrollment of approximately 30 patients with newly diagnosed multiple myeloma who remain minimal residual disease positive after completing a pre-transplant, anti-myeloma combination regimen comprised of a minimum of 2 drugs. Eligible patients must be 18 years or older at the time of enrollment.

Those who are pregnant or lactating or those with active and uncontrolled infections are ineligible for enrollment.

The primary end point will be the 2-year stringent complete response rate.

The estimated primary completion date is set for April 2022, with an estimated study completion date set for April 2025.

Cartesian Therapeutics initiates phase 2 clinical trial of first RNA-engineered cell therapy for frontline cancer. Cartesian Therapeutics. News release. Published February 22, 2021. Accessed February 25, 2021. 

RNA Armory. Cartesian Therapeutics. 2021. Accessed February 25, 2021. 

https://www.cartesiantherapeutics.com/rna-armory/

Descartes-11 consolidation treatment in patients with high-risk multiple myeloma who have residual disease after induction therapy. ClinicalTrials.gov. Posted June 17, 2020. Updated February 10, 2021. Accessed February 25, 2021. 

https://clinicaltrials.gov/ct2/show/NCT04436029

A phase 2 clinical trial has been initiated to evaluate Descartes-11, an mRNA CAR T-cell therapy, as a consolidative therapy in patients with newly diagnosed, high-risk multiple myeloma who have residual disease after induction therapy.

mRNA-Based CAR T-Cell Therapy Descartes-11 Moves Into Phase 2 Trial in Myeloma

Pipeline Report: March 2021

Kenneth C. Anderson, MD, program director of the Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics at Dana-Farber Cancer Institute, as well as Kraft Family Professor of Medicine at Harvard Medical School, discusses potentially addressing unmet needs in patients with multiple myeloma through the use of the mRNA-based CAR T-cell therapy Descartes-11.

The field of CAR T-cell therapy is still quite early in its development, according to Anderson. Most clinical trials include DNA-based CAR T cells that are used in patients with advanced relapsed/refractory myeloma who have received multiple lines of prior therapy. Although results, even in the advanced setting, have shown rapid and deep responses with this modality, the durability of response still needs to be expanded, Anderson explains.

Moving DNA- and mRNA-based CAR T-cell therapies like Descartes-11 earlier on in the disease course will definitively improve outcomes in patients who are less heavily pretreated, according to Anderson. The high-risk patient population currently represents an unmet need in multiple myeloma, Anderson adds. By utilizing novel CAR T products such as Descartes-11, this unmet need could potentially be addressed, concludes Anderson.

Videos

Kenneth C. Anderson, MD, discusses potentially addressing unmet needs in patients with multiple myeloma through the use of the mRNA-based CAR T-cell therapy Descartes-11.

Pipeline Report: March 2021

Articles

DNX-2440 Shows Promise in CRC and Other Cancers With Liver Metastasis as Phase 1 Trial Begins

Novel NTD Inhibitor EPI-7386 Plus Enzalutamide Under Evaluation in mCRPC

Videos

Dr. Anderson on Addressing Unmet Needs in Myeloma With Descartes-11