On November 21, 2023 Kazia Therapeutics Limited (NASDAQ: KZIA), an oncology-focused drug development company, reported key highlights of the clinical and preclinical paxalisib related presentations given by key thought leaders at the Society of Neuro-Oncology 2023 Annual Meeting (Press release, Kazia Therapeutics, NOV 21, 2023, View Source [SID1234637916]). "The 2023 SNO Annual Meeting was another successful event with the latest advances in clinical trials, diagnosis and treatment of pediatric and adult patients with CNS malignancies," stated Dr. John Friend, CEO Kazia. "We are highly encouraged with the preliminary overall survival data from the PNOC022 clinical study that we believe will provide an alternative to the current therapies considered as standard of care."
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Key paxalisib highlights from the meeting:
Friday, November 17th
Combining ONC201 and paxalisib for the treatment of diffuse midline glioma (DMG); the preclinical results underpinning the international Phase II clinical trial (NCT05009992).
Presenter: Evangeline R. Jackson; University of Newcastle, NSW, Australia
The mechanism of action of both paxalisib and ONC201 were reviewed as well as the synergistic effects of their combination in DMG preclinical models
Specifically, the authors observed how ONC201 over activates the PI3K-AKT pathway, which is the target pathway for paxalisib
Consistent and statistically significant improvements were observed with the combination of paxalisb and ONC201 in DMG preclinical mouse models
Two patient case studies were discussed; each receiving the combination of paxalisib and ONC201 through compassionate access
16-year old female with advanced and relapsed diffuse intrinsic pontine glioma (DIPG) who demonstrated significant neurological improvements as well as rapid tumour regression after receiving the combination
Six-year old female with DIPG who received the combination of paxalisib and ONC201 after upfront radiation therapy. Tumor regression has been maintained for more than two years on paxalisib and ONC201
Exploiting the genetic dependency on PI3K/mTOR signaling for the treatment of H3-altered Diffuse Midline Glioma
Presenter: Ryan Duchatel, PhD; University of Newcastle, NSW, Australia
PI3K pathway activation is observed in >80% of all DMGs and was shown to be required for DMG cell growth
The authors stated that the success of a monotherapy in DMG is highly unlikely; therefore they explored several combinations [of other therapies] with paxalisib with the aim of optimizing tolerability and efficacy of such combinations in preclinical mouse studies
Adding metformin to paxalisib was observed to improve hyperglycemia (elevated blood glucose) as well as extend the overall survival rate
The combination of paxalisib and enzastaurin (PKC inhibitor) was observed to further extend the overall survival when combined to radiation treatment
Authors concluded the triple combination of paxalisib, enzastaurin and metformin warranted further investigation in clinical trials
Phase I study of paxalisib and radiotherapy for CNS disease harboring PI3K pathway mutations: pilot analysis of circulating tumor DNA for patient eligibility confirmation and post-treatment response
Presenter: Brandon Imber, MD, Memorial Sloan Kettering Cancer Center, NYC, USA
This is a multi-institutional, Phase I trial of concurrent paxalisib and radiation therapy in patients with brain metastases with documented PI3K pathway mutations
Study has expanded after data from the initial stage identified the maximal tolerated dose (45mg once daily) along with observed signals of clinical activity (100% response rate)
The authors observed that plasma circulating tumor DNA (ctDNA) was able to accurately confirm the tumor’s genetic mutations at baseline and can potentially be used as a biomarker to assess patient treatment response
The authors presented a representative case from the ongoing Phase I study:
70-year-old woman with metastatic breast cancer with tumor harboring PIK3CA mutation received radiation therapy in combination with paxalisib for brain metastases
Her baseline plasma ctDNA test before starting treatment detected the same PIK3CA mutation as her tumor
MRI scan three months after treatment demonstrated radiographic response. In addition, a 99% reduction in the amount of ctDNA with PIK3CA mutation compared to baseline was detected, indicating ctDNA can potentially be used as an accurate method to monitor response after radiation therapy in combination with paxalisib
This is the first time in this patient population to demonstrate a link between MRI findings and a blood-based measure of tumor burden (ctDNA)
Sunday, November 19
PNOC022: a combination therapy trial using an adaptive platform design for patients with diffuse midline gliomas (DMGs) at initial diagnosis, post-radiation therapy and at time of therapy
Presenter: Sabine Mueller, MD, UCSF, San Francisco, USA
30 sites open to enrollment in North America, Europe and Australia
Total enrollment to date: 137 patients
Cohort 1 (newly diagnosed) = 37 patients
Cohort 2 (post radiation therapy) = 69 patients (one patient was replaced due to physician preference)
Cohort 3 (at the time of recurrence) = 31 patients
Cohort 2 preliminary analyses (median follow-up time was approximately 9 months)
Median Overall Survival rate was 16.5 months
Median Progression Free Survival (PFS) was 9.9 months (central review is ongoing)
Analysis of preliminary data from all cohorts is still ongoing and the protocol is subject to amendment to refine dosing with the aim of improving tolerability and efficacy at which time the enrollment of new patients will start
Additional data includes ctDNA, microbiome and quality of life measures