Kazia Therapeutics Ltd (ASX:KZA, NASDAQ:KZIA)'s ongoing Phase 1 clinical trial tackling brain metastases, using paxalisib in combination with radiotherapy, will be showcased at the upcoming 2022 Annual Conference on CNS (central nervous system) Clinical Trials and Brain Metastases.
The conference is jointly organised by the Society for Neuro-Oncology (SNO) and the American Society for Clinical Oncology (ASCO), and will be held in Toronto, Canada, from August 12-13. The trial is sponsored by the Memorial Sloan Kettering Cancer Center in New York.
Overall response rate of 100%
Interim data from the first stage of the study reports that all nine evaluable patients experienced complete or partial response, representing an overall response rate (ORR) of 100%.
By contrast, a typical ORR following whole brain radiotherapy alone commonly ranges from 20 to 45% in published studies.
Nine of 12 patients in the initial stage were evaluable for efficacy, and all nine patients exhibited complete or partial response, according to RANO-BM criteria, representing an ORR of 100%.
The patients had a range of primary tumours, with breast cancer the most common, representing one third of patients.
The safety profile of paxalisib in combination was broadly consistent with monotherapy experience in other clinical trials, and the trial has established a daily maximum tolerated dose of 45 milligrams in combination with radiotherapy.
Trial design
The trial is designed in two stages: an initial exploratory stage and a confirmatory expansion stage.
The first stage of the study is intended to establish the maximum tolerated dose of paxalisib in combination with whole-brain radiotherapy (WBRT) and to characterise safety and tolerability.
The second stage is intended to elicit confirmatory signals of efficacy, with the intent to recruit a further 12 patients.
Recruitment to this second or expansion stage has already commenced.
Brain metastases in cancer patients
It is estimated that as many as 20% of all patients with cancer will develop brain metastases – secondary tumours in the central nervous system.
The most common primary tumours that spread to the brain include lung, breast, colorectal, melanoma, and renal cell carcinoma.
Median overall survival for patients diagnosed with brain metastases ranges from 2.3 to 7.7 months.
Brain metastases are typically very challenging to treat and associated with poor prognosis. Radiotherapy is the current mainstay of clinical management.
Each year, around 200,000 cancer patients in the US develop brain metastases.
Dr. Jonathan Yang, director of metastatic disease at the Memorial Sloan Kettering Cancer Center’s Department of Radiation Oncology, is the principal investigator of the clinical trial.
Kazia CEO Dr. James Garner said: “We are encouraged by this data and by the potential benefit it may indicate to this substantial and high-need group of patients.
“Radiotherapy is a ubiquitous component of the treatment paradigm for brain metastases, but resistance is common.
“Dr Yang’s study has shown a very promising signal that paxalisib may help to potentiate the effect of radiotherapy.
“We also learned recently that the ongoing Alliance study in brain metastases had graduated to an expansion stage in the breast cancer cohort, so this now represents the second positive signal for paxalisib in brain metastases, which we increasingly believe represents a very promising opportunity for the product candidate.”
Pathway discovery
Dr Yang and others have shown that activation of the PI3K pathway is common in brain metastases, even in some cases where it is not present in the primary tumour. Moreover, PI3K pathway activation appears to be induced by radiotherapy, and to confer upon the tumour resistance to radiotherapy.
These observations provide a strong rationale for testing the combination of a brain-penetrant PI3K inhibitor with radiotherapy.
This Phase 1 study is a single-arm prospective trial comprising patients with brain metastases or leptomeningeal metastases from any primary tumour.
The primary objective is safety and tolerability. All patients have PI3K pathway mutations at baseline.
Next steps
Enrolment to the second stage of the study is already underway and the company estimates that preliminary data from the second part of the Phase 1 trial will be available in 2023.
Kazia expects to discuss emerging data from this study, along with other research in brain metastases, with its scientific advisors and regulatory consultants in due course, with potential FDA consultation at a future date.