Updated Interim Efficacy and Safety Results from a Phase I/IIa Trial HPN424 in Metastatic Castration-Resistant Prostate Cancer (mCRPC) - Tomasz Beer

June 16, 2021

HPN424 is a prostate-specific membrane antigen (PSMA)-targeting T cell engager designed to redirect T cells to kill PSMA-expressing prostate cancer cells. It is engineered with three binding domains: anti-PSMA for tumor cell engagement, anti-albumin for half-life extension, and anti-CD3 for T cell engagement. Furthermore, HPN424 is optimized for small size and increased stability compared to other bispecific platforms. This Ph1/2a study is evaluating HPN424 in mCRPC patients who have received > 2 prior systemic therapies. The primary endpoints are safety, tolerability, and determination of maximum tolerated dose and the recommended phase 2 dose. Secondary objectives include pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary anti-tumor activity. HPN424 is administered IV once weekly, and tumor assessments include PSA, CT, and bone scans every 9-weeks. In this conversation with Charles Ryan, MD, Tomasz Beer, MD, medical oncologist highlight the updated interim results of the ongoing phase 1/2a HPN424-1001 trial assessing HPN424 in metastatic castration-resistant prostate cancer (mCRPC) that were presented at the ASCO 2021 annual meeting.  Dr. Beer reports HPN424 is active and generally well tolerated when administered once weekly and assessment of optimal target dose and patient population is in the expansion phase of the ongoing trial.  Cytokine release syndrome (CRS) has been transient and manageable with 4% of patients experiencing Grade 3 CRS and CRS and transaminitis events observed most often in Cycle 1, with diminished frequency and severity in subsequent cycles.

Clinical Trial Information: NCT03577028

Biographies:

Tomasz M. Beer, MD, FACP, Professor of Medicine, Division of Hematology/Medical Oncology, School of Medicine.  Grover C. Bagby Chair of Prostate Cancer Research OHSU Knight Cancer Institute Deputy Director, OHSU Knight Cancer Institute, School of Medicine.  Chief Medical Officer, CEDAR, OHSU Knight Cancer Institute, School of Medicine. Cancer Biology Graduate Program, School of Medicine

Charles J. Ryan, MD, The B.J. Kennedy Chair in Clinical Medical Oncology at the University of Minnesota and Director of the Division of Hematology, Oncology and Transplantation.


Read the Full Video Transcript

Charles Ryan: Hello from ASCO 2021. Chuck Ryan here from the University of Minnesota. I'm joined by colleague Tom Beer from Oregon Health Sciences University, where he is a Professor of medicine and the Grover Bagby Chair of Prostate Cancer Research. Dr. Beer was part of a team and presented abstract 5013 results of an ongoing phase 1/2A, doses escalation study of HPN424. A Tri-Specific half-life extended PSMA-targeting T-cell engager therapy from Harpoon. Tom, thanks for joining us. Congratulations on this abstract. Tell us about tri-specific therapies and what they may mean for prostate cancer.

Tomasz Beer: Sure. Thank you for that question. So what these therapies are attempting to do is by using a synthetic antibody construct, bring prostate cancer cells and immune effector cells, T-cells specifically, into physical close proximity. Activate the T-cells and elicit an immune response against prostate cancer without a toxic payload, no radioactive or cytotoxic agents that pure immune strategy that tries specific part refers to a linker to albumin, which extends the half-life of this drug.

Charles Ryan:  And that's really been one of the big challenges with T-cell engager therapies. Hasn't it is that, the early iterations had short half-lives requiring prolonged infusions and creating potential toxicity problems. So this is a pretty significant advance simply in regards to the pharmacokinetics, correct?

Tomasz Beer: Yes, I would characterize the challenges with this class of drugs as two different things. One is the half-life and I think, this construct is illustrates that that can be overcome. And the other is Cytokine Release Syndrome, which I suspect we'll talk about a common side effect of these class of drugs. Those are the two drug development challenges for bi-specifics.

Charles Ryan:  So tell us about Cytokine Release Syndrome and what you saw with this and how this might or might not compare or be similar to some of the other agents out there being tested.

Tomasz Beer: So, Cytokine Release Syndrome is an expected toxicity of this drug that indicates an acute activation of an immune response with release of cytokines and can present with, with Fever Tech, Cardiac hypotension, Liver function abnormalities. And it's typically transient, but can be severe. And what we saw in this study is that, it was reasonably manageable. We didn't see any great four or five CRS. It was self-limited and did not result in any significant enduring consequences, but I will point out that in this study as is common for this class of drugs, at least the first two doses for each patient were administered in an inpatient setting. So patients could be observed and taken care of in the event of CRS.

Charles Ryan:  Right, so this is a new way of delivering a solid Tumor therapies, Cellular therapies. How long were the patients in the hospital for that?

Tomasz Beer: Usually Just 24 hours.

Charles Ryan:  And the CRS typically occurs during the infusion, right? It says, almost an immediate thing that occurs correct?

Tomasz Beer: During Or within the next several hours is what we typically observed.

Charles Ryan:  And so you were able to get to what you call a clinical action, clinically active dose. There were some signs that there were some anti-tumor effects ongoing in a certain proportion of the patients. What was that? What was the experience there?

Tomasz Beer: We had six patients with confirmed PSA declines. We had some measurable disease responses. We had a subset of patients that had a prolonged course of treatment indicating disease, stability, and probably a relevant anticancer effect that enabled that. I think in a phase 1 study setting where patients are heavily pretreated, have very aggressive cancers. This is a study that enrolled folks who typically did not have any other remaining viable treatment options. Anti-tumor activity is not something you expect to see a lot of, but it was gratifying to see that an immune agent alone was able to elicit antitumor responses.

Charles Ryan:  Right, and I would agree. And you saw reductions in circulating tumor cells in a majority of patients with measurable CTCs at baseline. And some of these PSA declines by with all your caveats were reasonably sustained. So it suggests that this approach is something that probably merits further testing. And what is the future for this particular agent?

Tomasz Beer: Well, In the study that we presented continues, we are still working out the optimal dose strategy, whether it should be stepped dosing or straight up dosing. So we're still in the phase 1/2A process for this trial. I can't comment on the next trial, but I know obviously, once we identify a dose that we're comfortable with, we'll be thinking about either a larger phase 2 studies or moving something bigger than that.

Charles Ryan:  And of course, this is a PSMA targeted therapy. There was another major advance and PSMA targeted therapies at ASCO this year. Was this a coupled to identification of PSMA on the tumor cells through imaging or other analysis?

Tomasz Beer: Yeah, So this study did not require unlike the VISION trial did not require PSMA pet imaging for studying the entry now. We learned from the VISION trial of course that, nearly 87% of patients who are screened for eligibility with a scan qualified for treatment. So we do expect data a substantial majority, a large majority of folks express PSMA.

Charles Ryan:  Right, Well, it's really gratifying to see these moving forward to get to a point where, I think we're getting beyond sort of the major question of CRS where we now, as you point out can identify, we'd have a strategy for treating it across multiple tumor types. And you're seeing clinically active doses here in this T-cell engager. So, one of the concepts that's emerging is that T-cell based therapies may have a role in prostate cancer. The challenge is actually getting the T-cells to the tumor and that's where the bi-specific or a tri-specific agent like this would be promising I presume.

Tomasz Beer: I couldn't agree more. I think, when I think about the checkpoint inhibitors that are now in widespread use. As a non-immunologist, I think about them pretty simple terms. And I think by and large, they unlock a preexisting, but an inadequate immune response. And we do see responses in prostate cancer to immune checkpoint inhibitors, but they're unfortunately quite infrequent indicating that we need something else. And I think that, these strategies that essentially enforce an immune response to prostate cancer by bringing the T-cells to the tumor hold a lot of promise. And there's a number of ways to do this. The CD3 PSMA strategy is far from the only one.

Charles Ryan:  Right, I agree so well, it's a great step forward and congratulations on this to you and the entire team and Harpoon Therapeutics, for HPM 424 this phase 1/2 data that was presented at ASCO 2021. And thank you Tom, for joining us.

Tomasz Beer: Chuck, thanks so much for the chance to speak with you today.