Research And Grants

CONNECT2109A - $705,764

Dr. Margot Lazow
Grant Amount



September 2021

Research Type


Cancer Type


CONNECT2109A: A molecularly-guided phase II study of ribociclib and everolimus in children and young adults with newly diagnosed diffuse intrinsic pontine glioma (DIPG) and high-grade glioma (HGG)


Given that a sizable portion of pediatric high-grade gliomas and DIPG tumors have genetic alterations in the cell cycle and PI3K/mTOR pathways, there is great interest in studying ribociclib (a CDK4/6 inhibitor, which blocks overactive cell cycle pathways in tumors) and everolimus (a mTOR inhibitor, which blocks overactive PI3K/mTOR pathways in tumors). Our CONNECT team recently completed a phase I study of ribociclib and everolimus in children with newly diagnosed DIPG and high-grade glioma (CONNECT1701). Results of this study showed that this combination can be safely given to pediatric patients with DIPG and high-grade glioma post-radiation, with little side effects. Findings additionally suggest a preliminary success signal of this combination in this small cohort of children with DIPG and HGG; continued investigation of ribociclib and everolimus in a larger phase II trial designed to evaluate effectiveness of this treatment is warranted. In the phase I study, median overall survival of 15 patients with DIPG treated with ribociclib and everolimus was 13.9 months, with 12-, 24-, and 36-month OS of 53%, 39%, and 39%, respectively. Although interpretation is limited by the small sample size, these outcomes (especially at 24- and 36-months) are greater than DIPG historical control data pooled from >1000 patients in the European and International DIPG registries (12-, 24-, and 36-month OS of 42%, 9.6%, 4.3%). Furthermore, among the subset of patients with tumor genomic profiling results available, two of the longer survivors in the cohort (with overall survival of 20 and >37 months) had evidence of cell cycle upregulation with CDKN2A/B deletion and CDK4 overexpression identified, respectively, motivating the present molecularly-guided phase II concept.


Study design/goals:

The current proposal will build on our phase I experience to conduct a Phase II study of ribociclib and everolimus in patients with newly diagnosed DIPG and high-grade glioma (following radiation) whose tumors have confirmed genetic alterations of cell cycle or PI3K/mTOR pathways identified through detailed molecular profiling. The primary endpoints will be overall survival (in patients with DIPG) and progression-free survival in patients with high-grade glioma.


Importantly, this study will represent one of several targeted therapy arms in the planned CONNECT molecularly-guided phase II umbrella trial, TARGET (CONNECT2109), shown in the figure below. Specifically, TARGET is a multi-arm clinical trial offering a precision medicine approach to treat children, adolescents, and young adults newly diagnosed with high-grade gliomas, including DIPG. Detailed genetic sequencing using advanced technology will be performed on tumor tissue from all patients upfront, with return of results within 3 weeks. Patients will then be assigned to one of several unique molecularly-targeted treatment arms based on (and directly targeting) the genetic alterations identified in their tumor. There are also treatment arms available for patients whose tumors do not have the specific genetic alterations evaluated to offer them new therapies that have shown potential for success in pre-clinical and clinical models of pediatric high-grade gliomas. Therefore, all high-grade glioma and DIPG patients who enroll on this trial will be offered novel therapy, guided by the distinct genetic profile of their tumors, and based on evidence from emerging scientific research, including this ribociclib and everolimus arm.


Furthermore, in addition to studying the genetic alterations present in tumor tissue prior to treatment, we will collect blood samples as well as cerebrospinal fluid (CSF) and/or future tumor tissue (if a second surgery is performed or at autopsy) throughout the study. Genomic and immune profiling analyses will be performed on these specimens over time to identify biomarkers (“liquid biopsy” tools) that can predict early response or recurrence to treatment and improve the understanding of why some tumors become resistant to therapy. Additionally, detailed imaging will be performed and reviewed to determine strategies to assess response and progression by MRI (and other advanced imaging techniques) that predict outcomes in these patients.


Our proposal (both the TARGET study overall and the ribociclib and everolimus arm specifically) seeks to (1) transform the treatment paradigm of children, adolescents, and young adults with HGGs through detailed molecular profiling and subsequent therapy assignment based on identified targets, (2) expand treatment options, reduce therapy toxicity, and improve survival for children, adolescents, and young adults with brain tumors, and (3) develop minimally-invasive biomarkers to predict response, resistance, and recurrence.