Dataset Information

A Phase 0 Trial of Ribociclib in Recurrent Glioblastoma Patients Incorporating a Tumor Pharmacodynamic- and Pharmacokinetic-Guided Expansion Cohort.

ABSTRACT: PURPOSE:CDK4/6-dependent cell-cycle regulation is disrupted in most glioblastomas. This study assesses the central nervous system (CNS) pharmacokinetics and tumor pharmacodynamics of ribociclib, a highly selective CDK4/6 inhibitor, in patients with recurrent glioblastoma. PATIENTS AND METHODS:Patients with recurrent glioblastoma with intact retinoblastoma protein (RB) expression and CDKN2A deletion or CDK4/6 amplification were treated with ribociclib daily (900 mg) for 5 days before tumor resection. Blood, tumor, and cerebrospinal fluid (CSF) samples were collected, and total and unbound ribociclib concentrations were determined. Pharmacodynamic effects, assessed by RB and FOXM1 phosphorylation, were compared with matched archival tissue. Patients with positive pharmacokinetic and pharmacodynamic effects were enrolled into the expansion cohort for preliminary assessment of progression-free survival (PFS). RESULTS:Twelve patients were enrolled. The mean unbound ribociclib concentrations in CSF, nonenhancing, and enhancing tumor regions were 0.374 ?mol/L, 0.560, and 2.152 ?mol/kg, respectively, which were more than 5-fold the in vitro IC50 for inhibition of CDK4/6 (0.04 ?mol/L). G1-to-S phase suppression was inferred by decreases in phosphorylation of RB (P < 0.01) and cellular proliferation (P < 0.05). Six of 12 patients were enrolled into the pharmacokinetic/pharmacodynamic-guided expansion cohort and demonstrated a median PFS of 9.7 weeks. Examination of recurrent tumors following monotherapy indicated upregulation of the PI3K/mTOR pathway. CONCLUSIONS:Ribociclib exhibited good CNS penetration, and target modulation was indicated by inhibition of RB phosphorylation and tumor proliferation. Ribociclib monotherapy showed limited clinical efficacy in patients with recurrent glioblastoma. Combination therapy with CDK4/6 and PI3K/mTOR inhibitors may be explored for treating recurrent glioblastoma.

SUBMITTER: Tien AC

PROVIDER: S-EPMC6863147 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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A Phase 0 Trial of Ribociclib in Recurrent Glioblastoma Patients Incorporating a Tumor Pharmacodynamic- and Pharmacokinetic-Guided Expansion Cohort.

Tien An-Chi AC Li Jing J Bao Xun X Derogatis Alanna A Kim Seongho S Mehta Shwetal S Sanai Nader N

Clinical cancer research : an official journal of the American Association for Cancer Research 20190708 19

<h4>Purpose</h4>CDK4/6-dependent cell-cycle regulation is disrupted in most glioblastomas. This study assesses the central nervous system (CNS) pharmacokinetics and tumor pharmacodynamics of ribociclib, a highly selective CDK4/6 inhibitor, in patients with recurrent glioblastoma.<h4>Patients and methods</h4>Patients with recurrent glioblastoma with intact retinoblastoma protein (RB) expression and <i>CDKN2A</i> deletion or <i>CDK4/6</i> amplification were treated with ribociclib daily (900 mg) f ...[more]

PMID: 31285369

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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: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:BackgroundThe combined use of a FGFR1 blocker and aromatase inhibitors is appealing for treating breast cancer patients with FGFR1 amplification. However, no pharmacodynamic studies have addressed the effects of this combined target modulation. We conducted a phase 0/I clinical trial in an adjuvant setting, with the goal of obtaining pharmacodynamic proof of the effects of combined aromatase and FGFR1 inhibition and to establish the RP2D for nintedanib combined with letrozole.Patients and methodsWomen with early-stage luminal breast cancer were eligible for enrollment in the study. Dose level 1 was nintedanib (150 mg/bid) plus letrozole (2.5 mg/day) administered for a single 28-day cycle (DLT assessment period), followed by a classic 3 + 3 schedule. FGF23 and 17-B-estradiol levels were determined on days 0 and 15; pharmacokinetic parameters were assessed on days 1 and 28. Patients were allowed to continue treatment for 6 cycles. The primary study endpoint was a demonstration of FGFR1 modulation (defined as a 25% increase in the plasma FGF23 level).ResultsA total of 19 patients were enrolled in the study (10 in the expansion cohort following dose escalation). At the RP2D (nintedanib 200 mg/bid plus letrozole 2.5 mg/day), we observed a 55% mean increase in the plasma FGF23 level, and 81.2% of the patients had no detectable level of 17-B-estradiol in their plasma (87.5% of the patients treated with letrozole alone). Nintedanib and letrozole displayed a pharmacokinetic interaction that led to three- and twofold increases in their respective plasma concentrations. Most G3 toxic events (5 out of 6: 2 diarrhea and 3 hypertransaminasemia) occurred subsequent to the DLT assessment period.ConclusionCombined treatment with nintedanib (200 mg/bid) plus letrozole (2.5 mg/day) effectively suppressed FGFR1 and aromatase activity, and these respective doses can be used as starting doses in any subsequent trials. However, drug-drug interactions may produce tolerability issues when these drugs are co-administered for an extended time period (e.g., 6 months). Patients enrolled in future trials with these drugs should be carefully monitored for their FGF23 levels and signs of toxicity, and those findings should guide individualized treatment decisions.Trial registrationThis trial was registered at www.clinicaltrials.gov under reg. # NCT02619162, on December 2, 2015.

Project description:Abstract BACKGROUND Drug development in recurrent glioblastoma multiforme (rGBM) is challenging. For randomized controlled trials (RCTs) short survival horizons and limited life-prolonging treatment options may delay accrual and introduce bias through differential dropout of control patients. Comparing results of a single-arm Phase 2b trial of intratumoral delivery of MDNA55 (an interleukin-4 receptor targeted fusion protein) to an external control arm, we sought early efficacy insights and consideration by the FDA of incorporating an ECA in a Phase 3 registrational trial. METHODS Using propensity score weighting, we compared rGBM patients from the Phase 2b trial (NCT02858895) (2017-2019) to patients from rGBM registries who had received standard of care therapies (2011-2019) and met eligibility requirements. Propensity scores were estimated using a logistic regression model with 11 covariates. We compared the propensity score weighted groups according to demographic and disease attributes before and after weighting and compared overall survival between the two groups. RESULTS Through propensity score weighting, 43 (98%, 43/44) MDNA55 patients and 40.80 weighted ECA patients (from 62 unweighted registry patients) were identified for comparison. MDNA55 and ECA patients were balanced on all baseline characteristics (i.e., standardized mean difference ≤ 0.15). Compared to ECA patients, MDNA55 patients had a 37% lower hazard of death (hazard ratio 0.63, 95% confidence interval: 0.39,1.02). CONCLUSION In advance of a Phase 3 trial, comparison of Phase 2b trial results to an ECA suggests that MDNA55 may be efficacious in rGBM. In view of the known challenges associated with drug development for rGBM, these results provided a proof-of-concept for the design of a novel hybrid Phase 3 trial. This planned Phase 3 trial incorporates propensity score weighting to create a composite hybrid randomized and external control arm, an approach preferred by the FDA over full replacement of a randomized control with an external control.

Dataset Information

A Phase 0 Trial of Ribociclib in Recurrent Glioblastoma Patients Incorporating a Tumor Pharmacodynamic- and Pharmacokinetic-Guided Expansion Cohort.

Publications

A Phase 0 Trial of Ribociclib in Recurrent Glioblastoma Patients Incorporating a Tumor Pharmacodynamic- and Pharmacokinetic-Guided Expansion Cohort.

Similar Datasets

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