Zelenirstat Shows Evidence of Clinical Benefit Across Advanced Cancers

Randeep Sangha, MD

Zelenirstat (PCLX-001), an investigational NMT inhibitor, has shown clinical benefit across a variety of relapsed/refractory (R/R) solid tumors and hematologic cancers, according to findings from a phase 1 study.^1,2

Most recently at the 2024 Gastrointestinal Cancers Symposium,1 results from the dose-escalation portion of the phase 1 study were promising in regard to safety and tolerability among patients with colorectal and appendiceal cancers. In addition to the encouraging findings, a recommended phase 2 dose (RP2D) for the study was established at 210 mg/day.

The study was conducted in 29 heavily pretreated patients with solid tumors or lymphomas. Patients received an average of 4 prior lines of therapy, and were R/R. Among these patients, 8 had colorectal cancer, 2 had pancreatic cancer, and 1 had appendiceal cancer.

Findings showed that zelenirstat led to longer rates of progression-free and overall survival in phase 1 among the patients with solid tumors receiving the RP2D. Five (30%) of the 17 evaluable patients had stable disease as best response, including 1 patient with advanced refractory colon cancer who received 6 cycles of therapy with zelenirstat at a dose of 140 mg daily prior to progressive disease.

For safety, the most common treatment-related adverse events were gastrointestinal (GI), including diarrhea, nausea, and vomiting. They were mostly grade 1-2, self-limiting, and occurred in a minority of patients. There was no myelosuppression, neuropathy, or QT prolongation observed among any of the patients enrolled in the study.

In an interview with Targeted Oncology^TM, Randeep Sangha, MD, medical oncologist at the Cross Cancer Institute, further discussed the background of the phase 1 study and the rationale for studying zelenirstat for the treatment of solid tumors and hematologic malignancies.

Targeted Oncology: Can you discuss the mechanism of action of zelenirstat and its potential role in cancer treatment?

Sangha: I think the first thing we need ask is: What is myristoylation? Myristoylation is the N- terminal modification of proteins with the fatty acid myristate. This is critical for cell signaling since it regulates multiple signal transduction pathways. We know in cancer cells there is an abnormality of myristoylation and the enzymes which catalyze this are NMT1 and NMT2, which make it an intriguing target. Zelenirstat is a potent NMT1 and NMT2 inhibitor and preclinical data shows it can abrogate myristoylation and cause apoptosis in cancer cells at concentrations lower than required to kill normal cells.

Can you discuss the clinical trial that is currently evaluating zelenirstat?

This is a new mechanism of action we are targeting. I think this is why it is particularly exciting, because we are studying a new drug, a new target, and a new strategy. As far as I am aware, this is the first trial being done in this class of compound.

What are the methods and design of this study?

This is a first-in-human phase 1 clinical trial using a standard dose escalation strategy. The dose escalation cohorts ranged from 20 mg to 280 mg daily. We discovered zelenirstat was well-tolerated with only minimal grade 1 or grade 2 GI toxicities. We were able to determine that the maximum tolerated dose (MTD) was 210 mg taken oral once daily. The dose-limiting toxicities seen at the 280 mg dose were predominantly gastrointestinal.

The 210 mg oral dose will also be the recommended phase II dose since it is safe and tolerable. It is also showing signs of anti-cancer activity which we are particularly excited about.

Based on these data, what types of cancers seem most responsive?

This trial has been done across advanced solid tumors and B-cell lymphomas. The preclinical data suggests activity in select solid tumors, B-cell lymphoma, and even AML. In the dose escalation portion of the trial, there seemed to be activity in colorectal cancers, ovarian cancers, appendiceal cancers, and non-small cell lung cancer. We have also seen activity in lymphoma. In an ongoing dose-expansion cohort, a relapsed B-cell NHL patient currently has stable disease on treatment. Interestingly, there is a broad spectrum activity of this agent.

Compared with existing treatment options, what are the potential advantages and disadvantages of using zelenirstat?

I think this drug is particularly appealing because it is an oral agent that can be taken once daily with minimal toxicity. It is rapidly absorbed as the pharmacokinetic data has shown. Also, there is anti-cancer activity. When we looked at our MTD cohort, 210 mg daily, we saw these patients were heavily treated, some up to 7 lines of therapy. While on zelenirstat, some of the patients have had durable stability of disease. I think those are the key advantages. Any new drug which is being developed and check off those boxes has the potential to be a home run and needs further study.

What are the known adverse effects associated with zelenirstat and how are they managed?

Most are grade 1 or grade 2 adverse event and predominantly GI such as mild nausea or vomiting. If needed, these would be managed with antiemetics.

How might this agent be incorporated into treatment plans based on individual patient characteristics?

This would be the next phase of investigation. We would like to expand these cohorts of patients in a phase 2a setting. We would like to learn which patients are deriving the most benefit. One of the exploratory endpoints was a correlative science component where we could potentially analyze for biomarkers.

Are there any ongoing or planned clinical trials that one should be aware of?

Our next step is to expand cohorts in advanced solid tumors where we thoughtfully pre-select the tumor types we think would be the best for this agent. We already have an expansion cohort for B-cell lymphomas. The goal will be to develop this drug further to determine its efficacy.

What should a community oncologist know about this research?

This is a new agent with a novel mechanism of action. It is an agent that is oral, taken once daily, with not a lot of toxicities. It is preliminary data, but we are seeing signs of activity. Sometimes this is difficult to see in phase 1 trials but when we get all those components together, I think it can be quite promising.

REFERENCES:

1. Spratlin J, Sangha R, Jamal R, et al. A firs-in-human, open-label, phase 1 trial of daily oral zelenirstat, an NMT inhibitor, in patients with relapsed/refractory advanced cancers. Presented at the 2024 Gastrointestinal Cancers Symposium; San Francisco, CA, January 18-20, 2024. Abstract 129.

2. Pacylex Pharmaceuticals reports phase 1 safety and efficacy results for zelenirstat in colorectal and other cancers. News release. Pacylex Pharmaceuticals Inc. January 16, 2024. Accessed January 22, 2024. http://tinyurl.com/mte362jb