FDA Awards Orphan Drug Designation to Cambritaxestat for Pancreatic Cancer

The FDA has granted orphan drug designation to cambritaxestat (IOA-289) for use as a potential therapeutic option in patients with pancreatic cancer, according to an announcement from the drug developer iOnctura.¹

The oral agent inhibits the extracellular enzyme autotaxin (ATX), which converts lysophosphatidylcholine to lysophosphatidic acid (LPA), a bioactive phospholipid that fuels the proliferation, migration, and survival of cells that are involved in several diseases.^2,3 ATX levels are known to directly correlate with stage and grade in human cancers. Preclinical data have indicated that cambritaxestat can hinder cancer cell growth and proliferation, boost the ability of immune cells to enter into tumors and help prevent the development of fibrosis.

The safety and tolerability of the ATX inhibitor alone and in combination with gemcitabine and nab-paclitaxel (Abraxane) is under exploration in patients with metastatic pancreatic cancer as part of a phase 1/2 study (NCT05586516). The trial is currently recruiting.⁴

“There is an urgent need to develop new therapies for pancreatic cancer which is currently the third largest cause of death by cancer in the United States, and the fourth in Europe,” Catherine Pickering, chief executive officer of iOnctura, stated in a press release.1 “Although survival of patients with pancreatic cancer has improved in recent years, it still stands at just 13% after 5 years. This orphan drug designation will support our goal to accelerate cambritaxestat through the clinic to provide a new treatment to patients with limited options.”

In a study recently published in the Journal of Experimental & Clinical Cancer Research, investigators set out to evaluate cambritaxestat in different gastrointestinal (GI) tract tumor cell lines to gain insight into the effect of the agent on cell viability and motility.3 The agent was able to inhibit the growth and migration of the GI tract tumor cell lines in 2D and 3D in vitro models. Moreover, the effect was found to be dose dependent, with the highest efficacy achieved in the FBS-free culture medium. Treatment with the agent was also found to result in higher expression of several proapoptotic proteins in all tested cell lines.

The open-label, dose-escalation, phase 1b study is enrolling patients with histologically or cytologically confirmed metastatic unresectable pancreatic adenocarcinoma who are at least 18 years of age, have measurable disease by RECIST v1.1 criteria, and an ECOG performance status of 0 or 1.⁴ Those who previously received systemic therapy for their disease are not eligible.

Key exclusion criteria include having known active central nervous system metastases and/or carcinomatous meningitis, a history or presence of abnormal electrocardiogram determined to be clinically meaningful by a study investigator, or another known malignancy that is progressing or needs active treatment.

Cambritaxestat will be given orally, twice daily, beginning on day 1 of cycle 0. Gemcitabine and nab-paclitaxel will be administered intravenously, weekly for 3 weeks of a 4-week cycle that begins on day 1 of cycle 1.

The primary outcome measure of the research is to examine treatment-emergent adverse effects. Key secondary outcome measures include examining the agent’s peak plasma concentration, minimum observed plasma concentration, terminal elimination half-life, time of maximum observed plasma concentration, and area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration or extrapolated to infinity.

Investigators are also evaluating changes in CA19-9 levels vs baseline, pharmacodynamics, and preliminary efficacy in the form of overall response rate, disease control rate, duration of response, progression-free survival, and overall survival.

The estimated enrollment for the trial is 24 patients and the estimated primary completion is December 2024.

References

1. US FDA grants orphan drug designation for iOnctura’s first-in-class autotaxin cancer therapy. News release. iOnctura. March 7, 2024. Accessed March 8, 2024. https://www.ionctura.com/admin/resources/odd-for-cambritaxestat-final.pdf
2. Pipeline & Science. iOnctura. Accessed March 8, 2024. https://www.ionctura.com/pipeline-and-science/
3. Centonze M, Di Conza G, Lahn M, et al. Autotaxin inhibitor IOA-289 reduces gastrointestinal cancer progression in preclinical models. J Exp Clin Cancer Res. 2023;42(1):197. doi:10.1186/s13046-023-02780-4
4. A study to assess an ATX inhibitor (IOA-289) in patients with metastatic pancreatic cancer. ClinicalTrials.gov. Updated March 5, 2024. Accessed March 8, 2024. https://clinicaltrials.gov/study/NCT05586516