Results from a o recent Phase 0 clinical trial of ribociclib (Kisqali®)*, an inhibitor of cyclin D1/CDK4 and CDK6 developed Novartis and Astex Pharmaceuticals used for the treatment of certain kinds of breast cancer, confirmed that this agent may also benefit patients with other drug-resistant cancers, including recurrent glioblastoma.
The study results were published in Clinical Cancer Research, a journal published by the American Association of Cancer Research (AACR).
Ribociclib was recently approved by the U.S. Food and Drug Administration (FDA) for advanced breast cancer. The drug is part of a newly-discovered class of targeted therapy undermining cancer cell division and could form the backbone of a new drug cocktail for patients with malignant brain tumors like glioblastoma.
“Glioblastoma presents singular, complex challenges as compared to other types of cancer,” said Nader Sanai, MD, an internationally-recognized neurosurgical oncologist with clinical and research expertise in the treatment of all brain tumors and director of the Ivy Brain Tumor Center in Phoenix, Arizona.
The center was established in 2018 through a US $ 50 million grant from the Ben & Catherine Ivy Foundation, the largest-ever award dedicated to brain cancer research, and emphasizes early-phase clinical trials in drug development to identify promising new strategies within an accelerated timeline for hard to treat cancers like glioblastoma.
“You are not dealing with a single entity, but rather a collection of genetic variants that differ from patient to patient. This Phase 0 clinical trial used a precision medicine approach to uncover which sub-types of glioblastoma may respond to ribociclib and how our patients’ tumors developed resistance to the new therapy,” Sanai added.
Results from the trial show that ribociclib is uniquely capable of breaking through the blood-brain barrier, a critical obstacle that for years has stalled drug development in brain tumor patients. As a result, the drug effectively hits its molecular target in cancer cells.
The experimental Phase 0 clinical trial design also identifies a potential mechanism of drug resistance, which the Ivy Brain Tumor Center clinical trials team is exploiting as part of an ongoing drug cocktail trial for recurrent glioblastoma patients.
“This comprehensive study has helped us to identify a potent combined-drug regimen to undermine a glioblastoma resistance mechanism to ribociclib. In less than a year, we have made tremendous progress in moving towards creating a new drug cocktail, which is significant given how precious time is for both patients and physicians fighting this disease,” Sanai concluded.
Phase 0 trial design
The Phase 0 clinical trial design used in this study is expected to streamline the process of drug development. It requires fewer preclinical studies than are usually required for a Phase I trial and participating volunteers receive less than 1% of the therapeutic dose of an investigational drug. Such a microdose allows drug developers to manufacturer smaller batches.
In addition, a Phase 0 trial generally takes no more than seven days and, in most cases, the greatly reduced dose ensure the absence of toxic effects. Furthermore, this approach quickly weed out ineffective drugs, because it provides drug developers faster answers about whether to move forward with regular clinical trials if the investigational drug shows a clinical benefit, or decide to not proceed if this is not the case.
* Ribociclib is a kinase inhibitor indicated in combination with an aromatase inhibitor for the treatment of pre/perimenopausal or postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer, as initial endocrine-based therapy; or fulvestrant for the treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer, as initial endocrine-based therapy or following disease progression on endocrine therapy.
 Tien AC, Li J, Bao X, DeRogatis A, Kim S, Mehta S, Sanai N. A Phase 0 Trial of Ribociclib in Recurrent Glioblastoma Patients Incorporating a Tumor Pharmacodynamic- and Pharmacokinetic-Guided Expansion Cohort. Clin Cancer Res. 2019 Jul 8. pii: clincanres.0133.2019. doi: 10.1158/1078-0432.CCR-19-0133. [Pubmed][Artikel]
 Fromer MJ.FDA Introduces New Phase 0 for Clinical Trials: Some Enthusiastic, Some Skeptical. Oncology Times: August 10th, 2006 – Volume 28 – Issue 15 – p 18–19 doi: 10.1097/01.COT.0000293387.34124.a8