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ACTR-67. PLASMA AND TUMOR PHARMACOKINETICS OF RIBOCICLIB IN PATIENTS WITH RECURRENT GLIOBLASTOMA

ABSTRACT: 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.

SUBMITTER: Tien A

PROVIDER: S-EPMC5692032 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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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 Glioblastoma (GBM) is the most common and aggressive primary brain cancer. Current standard-of-care includes surgery followed by concurrent therapy with radiation and temozolomide (TMZ) and maintenance TMZ. Almost all GBM patients experience recurrent/progressive disease, and median survival after recurrence is 3–9 months. Effective therapies for recurrent GBM (rGBM) are lacking, representing a significant unmet medical need. Unmethylated promoter for O6-methylguanine-DNA-methyltransferase (MGMT) is a validated biomarker for TMZ-resistance and is correlated with a poor prognosis. Second-line treatment with the anti-angiogenic agent bevacizumab (BEV) has not improved survival, and 5-year survival is less than 3%. VAL-083 is a bi-functional DNA-targeting agent rapidly inducing interstrand cross-links at N7-guanine, leading to DNA double-strand breaks and cell-death. VAL-083s cytotoxicity is independent of MGMT status, and VAL-083 overcomes TMZ-resistance in GBM cell lines, GBM cancer stem cells, and in vivo GBM models. We completed a 3 + 3 dose-escalation trial of VAL-083 in TMZ- and BEV-refractory rGBM. 40mg/m2/day given on days 1,2,3 of a 21-day cycle was generally well-tolerated, and this dose was selected for further clinical evaluation in Phase 2 trials. The trial described here is an ongoing single-arm, biomarker-driven Phase 2 trial in MGMT-unmethylated BEV-naïve adult rGBM. In this trial, 48 patients will receive VAL-083 40mg/m2/day on days 1,2,3 of a 21-day cycle. Tumor response will be assessed by MRI approximately every 42 days, per RANO criteria. The primary objective of this study is to determine if VAL-083 improves median overall survival (mOS) for MGMT-unmethylated rGBM patients compared to a historical mOS of 7.1 months for such patients treated with lomustine (EORTC26101). Secondary efficacy endpoints include progression-free survival (PFS), overall response rate (ORR), duration of response (DOR), and quality-of-life (QOL) evaluation using the MD Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) self-reporting tool. Enrollment and safety data update will be provided at the meeting. Clinicaltrials.gov identifier: NCT02717962.

Project description:Abstract Current standard-of-care for glioblastoma (GBM) includes surgery followed by concurrent therapy with radiation and temozolomide (TMZ) followed by adjuvant TMZ (days 1–5 every 28 days. Almost all GBM patients experience recurrent/progressive disease, with a median survival after recurrence of 3–9 months. Second-line treatment for recurrent GBM with bevacizumab (BEV) has not improved survival, and effective therapies for GBM are lacking. Unmethylated promoter for O6-methylguanine-DNA-methyltransferase (MGMT) is a validated biomarker for TMZ-resistance and is correlated with poor patient prognosis. VAL-083 is a bi-functional DNA-targeting agent which rapidly induces interstrand DNA cross-links at N7-guanine, induces double-strand breaks and acts independent of MGMT DNA repair. The current ongoing trial is a biomarker-driven Phase 2 study in MGMT-unmethylated BEV-naïve adult GBM. The primary objective of this study is to determine the effect of VAL-083 on median overall survival (mOS) for MGMT-unmethylated GBM patients compared to historical control. Secondary efficacy endpoints include progression-free survival (PFS), overall response rate (ORR), duration of response (DOR), and quality-of-life. Thirty-five (35) subjects with recurrent GBM have received 40 mg/m2/day VAL-083 on days 1, 2, 3 of a 21-day cycle as the starting dose. Myelosuppression is the most common adverse event and a higher potential for this toxicity correlated with those patients who received a higher number of cycles of prior TMZ maintenance therapy, (>5 cycles vs. ?5 cycles, p< 0.05). To minimize the potential for hematological toxicity in rGBM, subsequent subjects initiated treatment at 30 mg/m2/d VAL-083 x 3 consecutive days every 21 days. In addition, since TMZ is of limited value in the MGMT-unmethylated setting, a second arm in newly diagnosed GBM has been included to explore whether substituting TMZ with VAL-083 offers clinical benefit and extends the time to recurrence. Enrollment, safety data and study updates will be presented at the meeting. Clinicaltrials.gov identifier: NCT02717962.

Project description:Abstract Stupp treatment protocol for patients with glioblastoma (GBM) has improved the median overall survival to 14.6 months. However, no investigations have defined effective strategies against recurrence and the prognosis of recurrent GBM patients remains poor. Personalized medicine with assay-guided treatment targeting chemotherapy resistant cancer stem cells (CSCs) alongside the bulk tumor cells is a new paradigm in cancer treatment that may result in improved patient’s outcome. We are using ChemoID, a CLIA and CAP certified CSC cytotoxicity assay for predicting response to chemotherapeutic agents. Our prospective analysis of 61 GBM patients demonstrated that ChemoID-guided treatment significantly improved tumor response. For every 5% increase in cell kill of CSCs by assay-guided chemotherapy, 12-month patient response (non-recurrence of cancer) increased 2.5-fold, OR=2.3 (p=0.01). We also found that median recurrence time was 20-months versus 3-months for patients with a positive (>40% cell kill) CSC test versus negative, whereas median recurrence time was 13-months versus 4-months for patients with a positive (>55% cell kill) bulk test versus negative. We are conducting a multi-institutional phase-III clinical trial (NCT03632135) to determine the clinical validity of the ChemoID assay as a predictor of clinical response in recurrent GBM. The study has been designed as a parallel group controlled clinical trial and the participants are randomized to either standard of care chemotherapy chosen by the physician or ChemoID-guided therapy. Response to therapy will be measured by MRI imaging using RANO criteria. Primary endpoint of median overall survival (OS) and secondary endpoints of OS at 6, 9, and 12 months, median progression free survival (PFS), PFS at 4, 6, 9, and 12 months, objective tumor response, time to recurrence, and quality of life will be measured. Trial is open and currently 22 subjects have been enrolled. Interim analysis of the trial will be conducted in approximately 12 months.

Project description:Abstract The standard of care for glioblastoma is neurosurgical resection followed by radiation therapy (RT) and temozolomide (TMZ) chemotherapy. Although RT is effective for glioblastoma, attempts to improve survival using RT dose escalation above 60 Gy have been largely unsuccessful. This may be because prior attempts have been targeted to resection cavity or enhancing tumor, which may not accurately predict areas at highest recurrence risk. To overcome the limitations of standard T1 and T2-weighted MRI in predicting tumor recurrence, we have shown that supplementation with 3D high-resolution spectroscopic MRI (sMRI) identifies actively proliferating tumor beyond areas of T1-enhancement by measuring endogenous metabolites and their ratios. Previously, we demonstrated that the choline to N-acetylaspartate ratio (Cho/NAA) best correlates with tumor cellularity in surgically resected tissue (?=0.82, p< 0.001) and, most importantly, areas of sMRI metabolic abnormalities predate disease recurrence in those same areas (Cordova et al, Neuro-Oncology 2016). Therefore, we seek to identify whether sMRI can be used by radiation oncologists to choose the optimal regions to target for RT dose escalation. To assess its feasibility and safety, we developed a web-based imaging platform designed specifically to incorporate sMRI into the RT planning clinical workflow and are using it in a multisite sMRI-guided dose escalation trial (NCT03137888; Emory, Johns Hopkins, U. Miami). Recently, we have completed full enrollment including 30 patients treated with sMRI-guided dose escalated RT across three institutions. We have demonstrated successful integration of sMRI into the RT planning workflow, and we have delivered sMRI-guided dose escalated RT plans to glioblastoma patients without severe adverse events to date. Follow-up data will be analyzed for overall and progression-free survival. Based on the feasibility and safety of this technique in the current trial, we plan to assess the efficacy of sMRI-guided dose-escalated RT on patient outcomes in a NCTN clinical trial.

Project description:Abstract BACKGROUND Depatuxizumab mafodotin (depatux-m, formerly ABT-414), is an antibody-drug conjugate comprised of an EGFR-targeted antibody, a non-cleavable linker maleimidocaproyl, and the microtubule inhibitor monomethylauristatin F. Promising antitumor activity of depatux-m was observed in patients with glioblastoma (GBM) in Phase 12 studies. Dosage of depatux-m is limited by ocular side effects (OSE), such as blurred vision, dry eye, and photophobia from corneal epitheliopathy, which are generally reversible after dose reduction or drug discontinuation. This Phase 3b study evaluates depatux-m-related OSE management strategies used in depatux-m clinical trials. METHODS This open-label study will enroll approximately 90 patients with newly diagnosed, histologically confirmed, grade IV GBM that is epidermal growth factor receptor (EGFR)-amplified. Patients will receive depatux-m during the chemoradiation phase (radiation and temozolomide [TMZ]), and during adjuvant therapy with TMZ. Patients are randomized to one of three prophylactic ocular treatments: standard steroids (SS), SS with vasoconstrictors and cold compress (VC), or enhanced steroids (ES) with VC. Primary objective is to evaluate these prophylactic strategies for their effect on the proportion of patients requiring a change in OSE management due to inadequate control of OSEs, defined as either a 3-line decline in visual acuity from baseline or Grade 3 OSE severity on the Corneal Epithelial Adverse Event (CEAE) activities of daily living-based scale. Inadequate control with initial prophylactic regimen will trigger a switch to the addition of bandage contact lenses (BCL). Secondary objective assesses change in OSE management due to inadequate control of OSEs by BCL, defined as percentage of patients with Grade 3 CEAE that will trigger transition of patient to investigator discretion regimen (depatux-m interruption/dose reduction, VC prophylaxis, or ES prophylaxis). ClinicalTrials.gov: NCT03419403.

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ACTR-67. PLASMA AND TUMOR PHARMACOKINETICS OF RIBOCICLIB IN PATIENTS WITH RECURRENT GLIOBLASTOMA

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