Jaymes Holland

A phase I study of cabozantinib (XL184) in patients with renal cell cancer

BACKGROUND Cabozantinib targets tyrosine kinases including the hepatocyte growth factor receptor (MET) and vascular endothelial growth factor (VEGF) receptor 2, which are important drug targets in renal cell carcinoma (RCC). PATIENTS AND METHODS This single-arm open-label phase I trial evaluated the safety and tolerability of cabozantinib in heavily pretreated patients with metastatic clear cell RCC. RESULTS The study enrolled 25 RCC patients for whom standard therapy had failed. Patients received a median of two prior systemic agents, and most patients had previously received at least one VEGF pathway inhibiting therapy (22 patients [88%]). Common adverse events included fatigue, diarrhea, nausea, proteinuria, appetite decreased, palmar-plantar erythrodysesthesia, and vomiting. Partial response was reported in seven patients (28%). Median progression-free survival was 12.9 months, and median overall survival was 15.0 months. CONCLUSION Cabozantinib demonstrates preliminary anti-tumor activity and a safety profile similar to that seen with other multitargeted VEGFR tyrosine kinase inhibitors in advanced RCC patients. Further evaluation of cabozantinib in RCC is warranted. ClinicalTrials.gov identifier: NCT01100619.

Activity of cabozantinib (XL184) in patients (pts) with metastatic, refractory renal cell carcinoma (RCC).

364 Background: Cabozantinib (cabo) is an oral, potent inhibitor of MET and VEGFR2 that is currently undergoing clinical efficacy evaluation in several oncology indications. Renal cell carcinoma (RCC) was chosen as an indication in this drug-drug interaction (DDI) study based on involvement of the MET and VEGFR signaling pathways in this disease. The primary objective of this study is to determine the effect of cabo on single dose PK of the CYP2C8 substrate rosiglitazone (rosi). The exploratory objective of this study is to evaluate the preliminary antitumor activity of cabo in pts with RCC. METHODS Eligible pts were required to have RCC with clear cell components with metastases, Karnofsky performance status of ≥70 and measurable disease by RECIST. Pts needed to have experienced PD following standard therapies. Method for DDI study: Day 1, 4 mg rosi; Days 2 - 22, cabo given daily at a dose of 175 mg; Day 22, 4 mg rosi to complete PK assessment for DDI. Cabo continued until PD. On Day 57 and every 8 weeks thereafter subjects underwent tumor assessments by mRECIST. RESULTS Enrollment is complete at 25 RCC pts with a median of 2 prior regimens; 17/25 (68%) RCC pts had received ≥ 2 lines of prior therapy and 13/25 (52%) with at least 1 VEGF pathway inhibitor and 1 mTOR inhibitor. All pts were intermediate (24/25) or poor (1/25) risk category per Heng et al prognostic strata (JCO 2009). Related AEs ≥ Grade 3 severity: hypophosphatemia 8 (32%), PE 3 (12%; all were incidental / resolved) and diarrhea 3 (12%). Preliminary PK data suggest that clinically relevant doses of cabo do not markedly alter the Cmax or AUC0-24h of rosi consistent with lack of inhibition of CYP2C8. RCC pts with confirmed PR by mRECIST: 6/25 (24%). Additionally, 1 pt had an unconfirmed PR. Disease control rate (PR + SD): 68% at 16 weeks; 18/21 (86%) pts with ≥1 post-baseline scan experienced tumor regression (range: 4 - 63% reduction in measurements). 14/25 (56%) remain on cabo with a median follow-up of 4 months. Median PFS and OS have not been reached. CONCLUSIONS Cabo demonstrates encouraging anti-tumor activity in heavily pretreated pts with RCC with a toxicity profile similar to that of other TKIs. Preliminary data suggest no DDI between cabo and rosi (CYP2C8 substrate).

A Phase I Study of Cabozantinib (XL184) in Patients with Differentiated Thyroid Cancer

BACKGROUND Cabozantinib targets tyrosine kinases including MET, vascular endothelial growth factor (VEGF) receptor 2, and rearranged during transfection (RET). Differentiated thyroid cancer (DTC) is a tumor type that may be sensitive to cabozantinib. Therefore, we evaluated cabozantinib in a cohort of heavily pretreated patients with metastatic DTC. METHODS This single-arm open-label phase I trial assessed the safety, tolerability, and antitumor activity of cabozantinib in DTC patients taking part in a drug-drug interaction study. Adult patients with histologically confirmed metastatic or surgically unresectable DTC (including papillary, follicular, or Hürthle cell) were enrolled. Patients received daily oral dosing of 140 mg cabozantinib. Safety was assessed by evaluation of adverse events (AEs), vital signs, electrocardiograms, laboratory tests, and concomitant medications. Tumor response by magnetic resonance imaging or computed tomography scan was investigator assessed using Response Evaluation Criteria In Solid Tumors (RECIST) v1.0. RESULTS The study enrolled 15 patients who had failed standard radioactive iodine therapy. Patients had received a median of two prior systemic agents, and 11 patients (73%) had previously received at least one VEGF pathway inhibiting therapy. Common AEs included diarrhea, nausea, fatigue, and decreased appetite. Partial response was reported in eight patients (53%). Median progression-free survival and median overall survival were not reached. CONCLUSIONS Cabozantinib demonstrates a safety profile similar to other multitargeted VEGFR inhibitors in advanced DTC patients. The antitumor activity observed in this study warrants further investigation of cabozantinib in patients with advanced DTC.

Pharmacokinetic (PK) drug interaction studies of cabozantinib: Effect of CYP3A inducer rifampin and inhibitor ketoconazole on cabozantinib plasma PK and effect of cabozantinib on CYP2C8 probe substrate rosiglitazone plasma PK

Cabozantinib is a small‐molecule tyrosine kinase inhibitor that has been approved for the treatment of patients with progressive, metastatic medullary thyroid cancer. In vitro data indicate that (1) cytochrome P450 (CYP) 3A4 is the primary CYP isoenzyme involved in the metabolism of cabozantinib, and (2) CYP2C8 is the CYP isoenzyme most potently inhibited by cabozantinib with potential for in vivo inhibition at clinically relevant plasma exposures. Pharmacokinetic (PK) drug–drug interactions (DDIs) were evaluated clinically between cabozantinib and (1) a CYP3A inducer (rifampin) in healthy volunteers, (2) a CYP3A inhibitor (ketoconazole) in healthy volunteers, and (3) a CYP2C8 substrate (rosiglitazone) in patients with solid tumors. Compared with cabozantinib given alone, coadministration with rifampin resulted in a 4.3‐fold higher plasma clearance (CL/F) of cabozantinib and a 77% decrease in cabozantinib plasma AUC0–inf, whereas coadministration with ketoconazole decreased cabozantinib CL/F by 29% and increased cabozantinib AUC0–inf by 38%. Chronic coadministration with cabozantinib resulted in no significant effect on rosiglitazone plasma Cmax, AUC0–24, or AUC0–inf. In summary, chronic use of strong CYP3A inducers and inhibitors should be avoided when cabozantinib is administered, and cabozantinib at clinically relevant exposures is not anticipated to markedly affect the PK of concomitant medications via CYP enzyme inhibition.

Evaluation of the effect of food and gastric pH on the single-dose pharmacokinetics of cabozantinib in healthy adult subjects

Cabozantinib is a small molecule tyrosine kinase inhibitor that has been approved for the treatment of patients with progressive, metastatic medullary thyroid cancer. Cabozantinib exhibits a pH‐dependent solubility profile in vitro. Two phase 1 clinical pharmacology studies were conducted in healthy subjects to evaluate whether factors that may affect cabozantinib solubility and gastric pH could alter cabozantinib bioavailability: a food effect study (study 1) and a drug–drug interaction (DDI) study with the proton pump inhibitor (PPI) esomeprazole (study 2). Following a high‐fat meal (study 1), cabozantinib Cmax and AUC were increased (40.5% and 57%, respectively), and the median tmax was delayed by 2 hours. Cabozantinib should thus not be taken with food (patients should not eat for at least 2 hours before and at least 1 hour after administration). In the DDI study (study 2), the 90% confidence intervals (CIs) around the ratio of least‐squares means of cabozantinib with esomeprazole versus cabozantinib alone for AUC0–inf were within the 80%–125% limits; the upper 90%CI for Cmax was 125.1%. Because of the low apparent risk of a DDI, concomitant use of PPIs or weaker gastric pH‐altering agents with cabozantinib is not contraindicated.

Effect of Renal and Hepatic Impairment on the Pharmacokinetics of Cabozantinib

Cabozantinib is a tyrosine kinase inhibitor approved for the treatment of patients with progressive, metastatic medullary thyroid cancer. Two clinical pharmacology studies were conducted to characterize single‐dose pharmacokinetics (PK) of cabozantinib in renally or hepatically impaired subjects. Study 1 enrolled 10 subjects, each with mild or moderate impairment of renal function; 12 healthy subjects were matched to the moderate group for age, sex, and body mass index (BMI). Study 2 enrolled 8 males each with mild or moderate hepatic impairment; 10 healthy males were matched to the moderate group for age, BMI, and ethnicity. All subjects received one 60 mg cabozantinib oral capsule dose followed by PK sampling over 21 days. Plasma concentration and protein binding were determined by liquid chromatography tandem mass spectrometry and equilibrium dialysis, respectively. PK parameters were computed using noncompartmental methods. Geometric least squared mean (LSM) ratios for plasma cabozantinib AUC0‐∞ for impaired to normal organ function cohorts were (1) approximately 30% and 6% higher in subjects with mild and moderate renal impairment, respectively, and (2) approximately 81% and 63% higher in subjects with mild and moderate hepatic impairment, respectively. The percentage of unbound drug was slightly higher in both moderately impaired cohorts. No deaths or discontinuations due to adverse events occurred in either study. Cabozantinib should be used with caution in subjects with mild or moderate renal impairment. Subjects with mild or moderate hepatic impairment administered cabozantinib should be monitored closely for potential treatment‐emergent drug toxicity that may necessitate a dose hold or reduction.

Phase II study of cabozantinib in patients with progressive glioblastoma: Subset analysis of patients naive to antiangiogenic therapy

Abstract Background Cabozantinib is a tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptor 2 (VEGFR2) and MET that has demonstrated clinical activity in advanced solid tumors. This open-label, phase II trial evaluated cabozantinib in patients with recurrent or refractory glioblastoma (GBM). Methods Patients were initially enrolled at a starting dose of 140 mg/day, but the starting dose was amended to 100 mg/day because of toxicity. Treatment continued until disease progression or unacceptable toxicity. The primary endpoint was objective response rate assessed by an independent radiology facility using modified Response Assessment in Neuro-Oncology criteria. Additional endpoints included duration of response, 6-month and median progression-free survival, overall survival, and safety. Results Among 152 patients naive to prior antiangiogenic therapy, the objective response rate was 17.6% and 14.5% in the 140 mg/day and 100 mg/day groups, respectively, which did not meet the predefined statistical target for success. The proportions of patients alive and progression free at 6 months were 22.3% and 27.8%, respectively. Median progression-free survival was 3.7 months in both groups, and median overall survival was 7.7 months and 10.4 months, respectively. The incidence of grade 3/4 adverse events (AEs) was 79.4% and 84.7% in the 140 mg/day and 100 mg/day groups, respectively, and dose reductions due to AEs were experienced by 61.8% and 72.0%, respectively. Common grade 3/4 AEs included fatigue, diarrhea, and palmar-plantar erythrodysesthesia syndrome. Conclusions Cabozantinib showed evidence of clinical activity in patients with recurrent GBM naive to antiangiogenic therapy, although the predefined statistical target for success was not met. At the starting doses assessed, AEs were frequently managed with dose reductions. Clinical Trials Registration Number NCT00704288 (https://www.clinicaltrials.gov/ct2/show/NCT00704288)

Volumetric response quantified using T1 subtraction predicts long-term survival benefit from cabozantinib monotherapy in recurrent glioblastoma

Background To overcome challenges with traditional response assessment in anti-angiogenic agents, the current study uses T1 subtraction maps to quantify volumetric radiographic response in monotherapy with cabozantinib, an orally bioavailable tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptor 2 (VEGFR2), hepatocyte growth factor receptor (MET), and AXL, in an open-label, phase II trial in patients with recurrent glioblastoma (GBM) (NCT00704288). Methods A total of 108 patients with adequate imaging data and confirmed recurrent GBM were included in this retrospective study from a phase II multicenter trial of cabozantinib monotherapy (XL184-201) at either 100 mg (N = 87) or 140 mg (N = 21) per day. Contrast enhanced T1-weighted digital subtraction maps were used to define volume of contrast-enhancing tumor at baseline and subsequent follow-up time points. Volumetric radiographic response (>65% reduction in contrast-enhancing tumor volume from pretreatment baseline tumor volume sustained for more than 4 wk) was tested as an independent predictor of overall survival (OS). Results Volumetric response rate for all therapeutic doses was 38.9% (41.4% and 28.6% for 100 mg and 140 mg doses, respectively). A log-linear association between baseline tumor volume and OS (P = 0.0006) and a linear correlation between initial change in tumor volume and OS (P = 0.0256) were observed. A significant difference in OS was observed between responders (median OS = 20.6 mo) and nonresponders (median OS = 8.0 mo) (hazard ratio [HR] = 0.3050, P < 0.0001). Multivariable analyses showed that continuous measures of baseline tumor volume (HR = 1.0233, P < 0.0001) and volumetric response (HR = 0.2240, P < 0.0001) were independent predictors of OS. Conclusions T1 subtraction maps provide value in determining response in recurrent GBM treated with cabozantinib and correlated with survival benefit.