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Tumor pharmacokinetics and pharmacodynamics of the CDK4/6 inhibitor ribociclib in patients with recurrent glioblastoma.

ABSTRACT: INTRODUCTION:We conducted a phase Ib study (NCT02345824) to determine whether ribociclib, an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), penetrates tumor tissue and modulates downstream signaling pathways including retinoblastoma protein (Rb) in patients with recurrent glioblastoma (GBM). METHODS:Study participants received ribociclib (600 mg QD) for 8-21 days before surgical resection of their recurrent GBM. Total and unbound concentrations of ribociclib were measured in samples of tumor tissue, plasma, and cerebrospinal fluid (CSF). We analyzed tumor specimens obtained from the first (initial/pre-study) and second (recurrent/on-study) surgery by immunohistochemistry for Rb status and downstream signaling of CDK4/6 inhibition. Participants with Rb-positive recurrent tumors continued ribociclib treatment on a 21-day-on, 7-day-off schedule after surgery, and were monitored for toxicity and disease progression. RESULTS:Three participants with recurrent Rb-positive GBM participated in this study. Mean unbound (pharmacologically active) ribociclib concentrations in plasma, CSF, MRI-enhancing, MRI-non-enhancing, and tumor core regions were 0.337 ?M, 0.632 ?M, 1.242 nmol/g, 0.484 nmol/g, and 1.526 nmol/g, respectively, which exceeded the in vitro IC50 (0.04 ?M) for inhibition of CDK4/6 in cell-free assay. Modulation of pharmacodynamic markers of ribociclib CDK 4/6 inhibition in tumor tissues were inconsistent between study participants. No participants experienced serious adverse events, but all experienced early disease progression. CONCLUSIONS:This study suggests that ribociclib penetrated recurrent GBM tissue at concentrations predicted to be therapeutically beneficial. Our study was unable to demonstrate tumor pharmacodynamic correlates of drug activity. Although well tolerated, ribociclib monotherapy seemed ineffective for the treatment of recurrent GBM.

SUBMITTER: Miller TW

PROVIDER: S-EPMC6863163 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Tumor pharmacokinetics and pharmacodynamics of the CDK4/6 inhibitor ribociclib in patients with recurrent glioblastoma.

Miller Todd W TW Traphagen Nicole A NA Li Jing J Lewis Lionel D LD Lopes Beatriz B Asthagiri Ashok A Loomba Johanna J De Jong Jenny J Schiff David D Patel Sohil H SH Purow Benjamin W BW Fadul Camilo E CE

Journal of neuro-oncology 20190809 3

<h4>Introduction</h4>We conducted a phase Ib study (NCT02345824) to determine whether ribociclib, an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), penetrates tumor tissue and modulates downstream signaling pathways including retinoblastoma protein (Rb) in patients with recurrent glioblastoma (GBM).<h4>Methods</h4>Study participants received ribociclib (600 mg QD) for 8-21 days before surgical resection of their recurrent GBM. Total and unbound concentrations of ribociclib were measured ...[more]

PMID: 31399936

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Project description:Abstract BACKGROUND CDK4/6-dependent cell-cycle regulation is disrupted in 78% of glioblastoma (GBM) patients and novel CDK4/6 inhibitors have shown anti-tumor activity in animal models. To explore the utility of ribociclib, a selective CDK4/6-inhibitor, in treating recurrent GBM patients, we conducted a phase 0/II clinical trial (NCT02933736) to examine plasma and tumor pharmacokinetics (PK) and pharmacodynamics (PD). METHODS Recurrent GBM patients enrolled in the phase 0 component were treated with daily oral ribociclib (900 mg) for 5 days prior to planned resection of their tumor. Patient selection was based on intact Rb expression and CDKN2A deletion or CDK4/6 amplification. Plasma, tumor, and CSF samples were collected at predefined time points, and drug concentrations in these samples were determined by validated LC-MS/MS methods. PD effects, including RB phosphorylation and FoxM1 expression, were compared to matched archival tissue. Patients with positive PK and PD outcomes were enrolled into the phase II component to evaluate clinical efficacy with a primary endpoint of progression-free survival. RESULT To date, 10 recurrent GBM patients have been screened and 5 patients enrolled into the phase 0 component, each undergoing surgery 2–4 hours after their final dose. No drug-related adverse events have been observed. Ribociclib showed better penetration into contrast-enhancing tumor regions than non-enhancing regions, with median tumor concentrations of 48.4 vs. 12.7 nmol/g, respectively, and median tumor-to-plasma partition ratios of 10.2 and 3.5, respectively. Ribociclib CSF concentrations (potentially pharmacologically-active, unbound drug) ranged from 0.32 – 0.68 nmol/mL (median, 0.58 nmol/mL), exceeding the in vitro IC50 for inhibition of CDK4/6 (<0.04 nmol/mL). 60% of phase 0 patients exhibited PD effects and were enrolled into the phase II component. CONCLUSION Preliminary PK data suggests ribociclib achieves pharmacologically-active, and potentially therapeutic, concentrations in human GBM. Further studies to validate drug tumor penetration, tumor pharmacodynamic effects, and clinical efficacy are underway.

Project description:Abstract BACKGROUND CDK4/6-dependent cell-cycle regulation is disrupted in 78% of glioblastoma patients. We conducted a Phase 0/2 clinical trial (NCT02933736) of ribociclib, a selective CDK4/6-inhibitor, to examine the plasma and tumor pharmacokinetics (PK) and pharmacodynamics (PD) of recurrent glioblastoma. METHODS Eligible patients with intact RB expression and CDKN2A deletion or CDK4/6 amplification were enrolled into the Phase 0 component to receive ribociclib (900mg daily) for 5 days prior to tumor resection. Plasma, tumor, and CSF samples were collected to determine drug concentrations using validated LC-MS/MS methods. PD effects, including RB and FoxM1 phosphorylation, were compared to archival tissue. Patients with favorable PK and PD outcomes were transitioned into the Phase 2 component. RESULTS Twelve patients were enrolled into three presurgical time-escalation groups (2-hours, 8-hours, 24-hours). Ribociclib penetrated both enhancing and non-enhancing regions of the tumor. In non-enhancing tissue, median unbound brain-to-plasma ratio was 1.78 and median ribociclib concentration was 0.54 nmol/mL, exceeding the in vitro IC50 for CDK4/6 (0.04 nmol/mL). Suppression of G1-to-S phase was inferred by a decrease in RB phosphorylation (p<0.01) and cell proliferation (p<0.05). Six patients (50%) were graduated to the Phase 2 component and demonstrated a median progression-free survival of 9.7 weeks (95% CI, 6.3 to 40 weeks). Tissue samples from re-resection following Phase 2 study identified mTOR pathway upregulation as a candidate resistance mechanism to ribociclib monotherapy. CONCLUSION: Ribociclib penetrates the tumor-brain barrier, achieving pharmacologically-active concentrations in human glioblastoma and suppressing tumor proliferation. Phase 2 study results suggest ribociclib is ineffective as a monotherapy, but analysis of ribociclib-resistant tumors identified the addition of an mTOR inhibitor as a dual-drug strategy for recurrent glioblastoma.

Project description:INTRODUCTION:Despite the development of new therapies for advanced prostate cancer, it remains the most common cause of cancer and the second leading cause of cancer death in men. It is critical to develop novel agents for the treatment of prostate cancer, particularly those that target aspects of androgen receptor (AR) signalling or prostate biology other than inhibition of androgen synthesis or AR binding. Neoadjuvant pharmacodynamic studies allow for a rational approach to the decisions regarding which targeted therapies should progress to phase II/III trials. CDK4/6 inhibitors have evidence of efficacy in breast cancer, and have been shown to have activity in preclinical models of hormone sensitive and castrate resistant prostate cancer. The LEEP trial aims to assess the pharmacodynamic effects of LEE011 (ribociclib), an orally bioavailable and highly selective CDK4/6 inhibitor, in men undergoing radical prostatectomy for high-risk, localised prostate cancer. METHODS AND ANALYSIS:The multicentre randomised, controlled 4:1 two-arm, phase II, open label pharmacodynamic study will recruit 47 men with high risk, localised prostate cancer who are planned to undergo radical prostatectomy. Participants who are randomised to receive the study treatment will be treated with LEE011 400?mg daily for 21 days for one cycle. The primary endpoint is the frequency of a 50% reduction in Ki-67 proliferation index from the pretreatment prostate biopsy compared to that present in prostate cancer tissue from radical prostatectomy. Secondary and tertiary endpoints include pharmacodynamic assessment of CDK4/6?cell cycle progression via E2F levels, apoptotic cell death by cleaved caspase-3, changes in serum and tumour levels of Prostate Specific Antigen (PSA), pathological regression, safety via incidence of adverse events and exploratory biomarker analysis. ETHICS AND DISSEMINATION:The protocol was approved by a central ethics review committee (St Vincent's Hospital HREC) for all participating sites (HREC/17/SVH/294). Results will be disseminated in peer-reviewed journals and at scientific conferences. DRUG SUPPLY:Novartis. PROTOCOL VERSION:2.0, 30 May 2019 TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN12618000354280).

Dataset Information

Tumor pharmacokinetics and pharmacodynamics of the CDK4/6 inhibitor ribociclib in patients with recurrent glioblastoma.

Publications

Tumor pharmacokinetics and pharmacodynamics of the CDK4/6 inhibitor ribociclib in patients with recurrent glioblastoma.

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