First-in-Human Study of FOR46 in Men With Metastatic Castration Resistant Prostate Cancer (mCRPC) – Rahul Aggarwal

October 3, 2021

Rahul Aggarwal joins Alicia Morgans describing this first-in-human study of the safety and preliminary efficacy of FOR46 in metastatic castration-resistant disease (mCRPC) patients. FOR46 is a vc-MMAE antibody-drug conjugate that recognizes a tumor-selective epitope of Cluster of differentiation 46 (CD46). FOR46 binds to CD46 with high affinity and demonstrates anti-tumor activity in prostate cancer xenografts. FOR46 is currently being evaluated in 2 mCRPC expansion cohorts: adenocarcinoma and treatment-emergent small-cell neuroendocrine prostate cancer (t-SCNC).  

Biographies:

Rahul Aggarwal, MD Assistant Professor of Hematology/Oncology, Director of STAND Clinic, UCSF Helen Diller Family Comprehensive Cancer Center

Alicia Morgans, MD, MPH Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts


Read the Full Video Transcript

Alicia Morgans: Hi, my name is Alicia Morgans, and I am a GU Medical Oncologist at Dana Farber Cancer Institute, and I'm so excited to have here with me today Dr. Rahul Aggarwal, who is an Associate Professor of Medicine and a GU Medical Oncologist at UCSF in San Francisco in California. Thank you so much for being here with me today, Rahul.

Rahul Aggarwal: Thank you, Alicia, for having me. It's my pleasure.

Alicia Morgans: Wonderful. So I wanted to talk to you a little bit about your presentation at ESMO, really thinking about FOR46 and this application of a novel therapeutic in patients with metastatic CRPC. Can you tell me a little bit about it?

Rahul Aggarwal: Yeah, I'd be happy to. We are pretty excited about this trial. This target for this drug CD46 is a specific spot on the CD46 protein that actually one of our scientists at UCSF, Bin Liu, discovered a number of years ago, and we are excited that a company has taken this drug forward into clinical development. So the drug is basically binding to CD46, and then it's an antibody-drug conjugate. So the antibody portion binds the CD46, the drug gets internalized, and then it releases its payload within the cancer cell. So I like to think of it as targeted chemotherapy rather than generalized chemotherapy.

So the clinical trial that we are presenting the interim results at ESMO is really a phase I, first-in-human trial that is actually specifically in metastatic CRPC patients. So rather than an all-comers type phase I trial, it is really honing in specifically in metastatic CRPC, because we see that the CD46 target is very, very highly upregulated in prostate cancer, much more so than other cancers, and it has a lot of specificities. We don't see this target really expressed in other parts of the body. And so this trial has been ongoing through the Prostate Cancer Clinical Trials Consortium. We have a number of great collaborators at OHSU and other sites that have been participating and have been very excited with the results that we've seen so far.

Alicia Morgans: Great. So can you tell me a little bit about what you've seen in terms of responses?

Rahul Aggarwal: Yeah, so we did a first dose-escalation portion of the study to really find what is the right dose. And from those initial dose-escalation data, we have the dose in a schedule. The drug is given IV once every three weeks. It is based on patients' adjusted body weight, and we think the tolerability is quite good. You mainly see sort of transient decreases in white blood cell counts that are quite recoverable. We have not seen a high degree of infections or fevers related to that. And then some mild amount of cumulative neuropathy or numbness, tingling fingers or toes but otherwise has been very well tolerated.

And in terms of the effectiveness at dose levels that are predicted to be in the therapeutic range, we've seen a PSA 50 response rate of nearly 50%, I think around 45%, including patients in the dose-escalation portion of the study, which I think is quite impressive for a first-in-human compound where we are sort of treating patients at different dose levels. So we are quite excited about that, and then we've also seen some, I think three or four, objective responses where we are seeing tumor shrinkage on the scan.

So it's still pretty early. We just entered the dose-expansion or sort of mini phase II portion of the study, but the efficacy rates have been encouraging so far.

Alicia Morgans: That's fantastic. So if you had to characterize the AEs, what would be the things to look out for this particular agent?

Rahul Aggarwal: Yeah, I think that about a week after the infusion is when you can see a decrease in white blood cell count, and so that's one of the AEs to watch for. We do use a growth factor, GCSF, to support white blood cell count if needed, if patients have low white count with a previous cycle of treatment, and some patients have needed that. Occasionally you can get a little bit of a mild infusion reaction with the first dose, so some fevers, chills, sometimes a rash. We use pre-medication with Benadryl and a few other things. That seems to decrease the risk of that.

And then from a cumulative standpoint, probably a little bit of neuropathy sort of expected with this agent, so numbness, tingling in the fingers, toes. This tends to accumulate, but it's been pretty low grade, grade I, grade II thus far.

Alicia Morgans: That all makes sense. So if you had to sort of sum up your summary from the findings from this early stage trial, what would it be?

Rahul Aggarwal: Yeah, I think we've seen promising effectiveness for a new drug target in prostate cancer, and one that we are excited about both in regular adenocarcinoma but also in neuroendocrine prostate cancer where this CD46 target is also highly expressed. So we think, unlike PSMA, which is sort of more lineage-dependent and not as expressed in the neuroendocrine type, this target may be more broadly expressed. So we are excited about it and have this drug entering dose-expansion where we hope to learn more about it.

Alicia Morgans: Fantastic. So thank you so much for sharing your expertise. We are sincerely appreciative of your work pushing the boundaries and thank you for your time.

Rahul Aggarwal: Thank you so much for having me. My pleasure.
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