Abstract
Background: Axitinib is an oral small molecule that inhibits receptor tyrosine kinases vascular endothelial growth factor receptors 1 to 3. A phase 1 and pharmacokinetic (PK) trial evaluating axitinib was conducted in children with refractory solid tumors. Methods: Axitinib was administered orally twice daily in continuous 28-day cycles. Dose levels (2.4 mg/m2/dose and 3.2 mg/m2/dose) were evaluated using a rolling 6 design. Serial PKs (cycle 1, days 1 and 8) and exploratory biomarkers were analyzed. Results: A total of 19 patients were enrolled; 1 patient was ineligible due to inadequate time having elapsed from prior therapy. The median age of the patients was 13.5 years (range, 5-17 years). Two of 5 patients who were treated at dose level 2 experienced dose-limiting toxicities (palmar-plantar erythryodysesthesia syndrome in 1 patient and intratumoral hemorrhage in 1 patient). Frequent (>20%) grade 1 to 2 toxicities during cycle 1 included anemia, anorexia, fatigue, diarrhea, nausea, and hypertension. Nonhematological toxicities of grade ≥3 in subsequent cycles included hypertension and elevated serum lipase. PK analysis demonstrated variability in axitinib exposure, the median time to peak plasma concentration was 2 hours, and the half-life ranged from 0.7 to 5.2 hours. Exposure and dose were not found to be significantly associated with hypertension. Five patients achieved stable disease for ≥6 cycles as their best response, including patients with malignant peripheral nerve sheath tumor (1 patient), Ewing sarcoma (1 patient), hepatocellular carcinoma (1 patient), and osteosarcoma (2 patients). One patient with alveolar soft part sarcoma achieved a partial response. Kidney injury biomarkers were found to be elevated at baseline; no trends were identified. Conclusions: In children with refractory solid tumors, the maximum tolerated and recommended dose of axitinib appears to be 2.4 mg/m2/dose, which provides PK exposures similar to those of adults.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 4548-4555 |
| Number of pages | 8 |
| Journal | Cancer |
| Volume | 124 |
| Issue number | 23 |
| DOIs | |
| State | Published - Dec 1 2018 |
Bibliographical note
Funding Information:Supported by the National Cancer Institute of the National Institutes of Health under award number UM1 CA097452, Mayo Clinic Comprehensive Cancer Center grant P30 CA15083-43, the Cookies for Kids’ Cancer Foundation, Champions FORE Children, and the Children’s Oncology Group Foundation.
Funding Information:
Supported by the National Cancer Institute of the National Institutes of Health under award number UM1 CA097452, Mayo Clinic Comprehensive Cancer Center grant P30 CA15083-43, the Cookies for Kids’ Cancer Foundation, Champions FORE Children, and the Children’s Oncology Group Foundation. VEGF has been demonstrated to be overexpressed or biologically active in pediatric cancers, including Wilms tumor, hepatocellular carcinoma, hepatoblastoma, nonrhabdomyosarcoma soft-tissue sarcoma, rhabdomyosarcoma, Ewing sarcoma, osteosarcoma, and neuroblastoma. Targeting VEGF in pediatric solid tumors has been of interest to the pediatric oncology community. We established the RP2D of axitinib (2.4 mg/m2/dose orally twice daily) for patients aged >12 months and <18 years. This dose is approximately 80% of the adult recommended starting dose. The toxicity and PK profiles in children and adolescents are similar to those reported in adults. The most common grade 1 and 2 toxicities were gastrointestinal symptoms (nausea and diarrhea), fatigue, anorexia, anemia, and hypertension. Grade 3 and 4 toxicities were rare. Two DLTs at dose level 2 (3.2 mg/m2/dose, equivalent to the adult dose of 5.5 mg orally twice daily) were palmar-plantar erythrodysesthesia and intratumoral hemorrhage. Intratumoral hemorrhage may not be dose related, but we defined this event as a DLT to err on the side of patient safety. Similar to those in adults, PK parameters were variable, and there was no correlation noted between hypertension or response and axitinib exposure. In adults, dose titration is used to maximize potential clinical benefit. Adults treated with axitinib at a dose of 5 mg orally twice daily, without the occurrence of adverse events of grade >2 for consecutive 2-week periods and with a blood pressure ≤150/90 mm Hg, are permitted to increase their dose to 7 mg twice daily, then to a maximum of 10 mg twice daily. We did not permit intrapatient dose titration in the current study, but it is possible that some patients would have tolerated higher doses using similar criteria. We observed preliminary evidence of efficacy: 1 patient with alveolar soft part sarcoma experienced a partial response and 5 patients had stable disease for ≥6 cycles. In future studies, intrapatient dose titration might increase the likelihood of disease response. Recently, the combination of antiangiogenic therapy with immune checkpoint inhibitor therapy has been evaluated in adults with renal cell carcinoma (RCC). Nivolumab in combination with sunitinib with each agent administered at full dose has been reported to be tolerable and demonstrated antitumor activity and a manageable safety profile. Axitinib in combination with pembrolizumab was tolerable when each agent was administered at its MTD/RP2D. Translocation-associated RCC (tRCC) accounts for approximately 48% of all pediatric RCC cases, and both children and adults with tRCC have achieved objective responses and durable complete remissions with VEGF RTK inhibitors. The Children’s Oncology Group, along with other National Cancer Institute–affiliated cooperative groups, plans to conduct a 3-arm randomized trial to evaluate axitinib versus axitinib in combination with nivolumab versus nivolumab in patients with tRCC across all age groups. The current study has established the recommended starting dose of axitinib for children for the upcoming trial. Future exploration of strategies to permit intrapatient dose titration of axitinib in children who do not experience toxicity at the starting doses is warranted. A total of 16 patients were evaluable for the assessment of DLTs. Two patients were not evaluable because they did not receive approximately 85% of the prescribed study drug and did not experience a DLT. Toxicities are summarized in Table and Table. No DLTs were noted to occur in 11 evaluable patients (6 in the dose escalation cohort and 5 in the PK expansion cohort) at dose level 1 (2.4 mg/m2/dose). At dose level 2 (3.2 mg/m2/dose), 5 patients were evaluable and 2 DLTs occurred: grade 2 palmar-plantar erythrodysesthesia syndrome in 1 patient and grade 3 intratumoral hemorrhage in 1 patient, a 10-year-old girl with a thoracic malignant peripheral nerve cell tumor (MPNST). A second patient on the study with an MPNST did not have hemorrhage. Thus, dose level 1 was defined as the MTD. There were 2 grade 3 toxicities (increased hemoglobin, hypertension, and increased lipase) and no grade 4 toxicities reported (Table). Grade 1 to 2 nonhematologic toxicities that were reported to occur in ≥20% of patients during cycle 1 included anorexia, diarrhea, fatigue, nausea, and hypertension. Abbreviations: A, treatment cohort; DLT, dose-limiting toxicity; PK, pharmacokinetic cohort. DLTs included moderate palmar-plantar erythrodysesthesia syndrome (1 patient) and severe intratumoral hemorrhage (1 patient). Abbreviation: DLT, dose-limiting toxicity. Nonhematologic toxicities occurring in >10% of evaluable patients. Toxicities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0). A total of 14 of the 18 patients studied (78%) had open growth plates at baseline; 12 patients were assessed in subsequent cycles. No growth plate abnormalities were observed, and all growth plates remained open throughout the course of the study. Systolic and diastolic blood pressure did not significantly change over subsequent cycles. On average, systolic blood pressure increased by 0.67 mm Hg per cycle (95% confidence interval, −0.17 to 1.52 mm Hg) and diastolic blood pressure decreased by 0.34 mm Hg per cycle (95% confidence interval, −1.00 to 0.33 mm Hg). A total of 19 patients were enrolled; 1 patient was ineligible due to inadequate time having elapsed from prior therapy. Patient characteristics are summarized in Table. All patients enrolled had received at least 1 prior therapy including chemotherapy, radiotherapy, or both. A total of 16 patients were evaluable for the assessment of DLTs. Two patients were not evaluable because they did not receive approximately 85% of the prescribed study drug and did not experience a DLT. Toxicities are summarized in Table and Table. No DLTs were noted to occur in 11 evaluable patients (6 in the dose escalation cohort and 5 in the PK expansion cohort) at dose level 1 (2.4 mg/m2/dose). At dose level 2 (3.2 mg/m2/dose), 5 patients were evaluable and 2 DLTs occurred: grade 2 palmar-plantar erythrodysesthesia syndrome in 1 patient and grade 3 intratumoral hemorrhage in 1 patient, a 10-year-old girl with a thoracic malignant peripheral nerve cell tumor (MPNST). A second patient on the study with an MPNST did not have hemorrhage. Thus, dose level 1 was defined as the MTD. There were 2 grade 3 toxicities (increased hemoglobin, hypertension, and increased lipase) and no grade 4 toxicities reported (Table). Grade 1 to 2 nonhematologic toxicities that were reported to occur in ≥20% of patients during cycle 1 included anorexia, diarrhea, fatigue, nausea, and hypertension. Abbreviations: A, treatment cohort; DLT, dose-limiting toxicity; PK, pharmacokinetic cohort. DLTs included moderate palmar-plantar erythrodysesthesia syndrome (1 patient) and severe intratumoral hemorrhage (1 patient). Abbreviation: DLT, dose-limiting toxicity. Nonhematologic toxicities occurring in >10% of evaluable patients. Toxicities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0). A total of 14 of the 18 patients studied (78%) had open growth plates at baseline; 12 patients were assessed in subsequent cycles. No growth plate abnormalities were observed, and all growth plates remained open throughout the course of the study. Systolic and diastolic blood pressure did not significantly change over subsequent cycles. On average, systolic blood pressure increased by 0.67 mm Hg per cycle (95% confidence interval, −0.17 to 1.52 mm Hg) and diastolic blood pressure decreased by 0.34 mm Hg per cycle (95% confidence interval, −1.00 to 0.33 mm Hg). PK samples were obtained on day 1 and day 8 after the first dose (Table). Peak plasma concentrations (Cmax) were achieved at a median of approximately 2 hours (range, 0-4 hours). Cmax and exposure (AUC) were highly variable and did not appear to differ between the dose levels on day 1 (P=.10 and P=.34, respectively) or day 8 (P=.88 and P=1.00, respectively) (Table) (Fig.). The correlation between Cmax (correlation coefficient [r]day 1=0.36 [P=.14] and rday 8=0.15 [P=.57]) or AUC0-8h (rday 1=0.20 [P=.43] and rday 8=0.10 [P=.71]) and dose was not found to be statistically significant. On day 1, the median oral clearance was found to be similar in males and females (CL/F of 24.2 L/hour/m2 and 19.7 L/hour/m2, respectively [P=.36]) and did not differ in children aged <12 years compared with children aged ≥12 years (CL/F of 28.6 L/hour/m2 and 19.7 L/hour/m2, respectively [P=.36]). The median half-life of axitinib was 2.4 hours (day 1) and 2.5 hours (day 8). The median accumulation ratio based on comparison of day 8 AUC0-8h versus day 1 AUC0-8h was 1.8 (range, 0.3-4.7). Abbreviations: AUC, area under the concentration versus time curve; Cl/F, oral clearance; Cl/m2, clearance per square meter; Cmax, peak plasma concentration; PK, pharmacokinetic; Tmax, amount of time that a drug is present at the maximum concentration in serum; V/F, volume of distribution, where F is oral bioavailability; V/m2, volume per square meter. Shown as the median (range). The relationship between axitinib exposure and hypertension was assessed. A cutoff AUClast value of 130 hour•ng/mL was selected based on the adult cutoff value of AUC0-12h 200 hour•ng/mL, a terminal elimination rate constant, and differences in the sample collection interval of 0 to 8 hours used in the current trial versus the collection interval of 0 to 12 hours used in the adult trial. There appeared to be no association between hypertension and PK parameters (day 1 Cmax [P=.43], day 8 AUClast [P=.16], or day 8 AUClast ≥130 hour•ng/mL [P=.30]). The urine UPC ratio did not significantly change during axitinib therapy, and was found to increase by 4% per cycle (P=.30), even after adjusting for baseline values (P=.10). Biomarkers of AKI are presented in Supporting Table 1. The normal ranges for urine AKI biomarkers in healthy children are dependent on sex and age. At baseline, urine KIM-1 (median, 4 ng/mL [range, 0.2-14.4 ng/mL]) and IL-18 (median, 88 ng/mL [range, 5-445 ng/mL]) were elevated compared with normal ranges for healthy children (KIM-1: median, 0.41 ng/mL [range, 0.226-0.703 ng/mL]; IL-18: median, 0.0216 ng/mL [range, 0.0136-0.0329 ng/mL); and NGAL: median, 6.6 ng/mL [range, 2.8-17 ng/mL]), thereby indicating possible kidney dysfunction prior to enrollment on the study. During axitinib therapy, AKI biomarkers were found to be highly variable and no trends were identified during cycle 1 or between dose levels. A total of 16 patients were evaluable for response; 15 patients had sufficient evaluations to report a response (1 patient did not have all required evaluations). One patient with alveolar soft part sarcoma had a confirmed partial response that was durable for 6 months prior to clinical progression of disease and discontinuation of protocol therapy. Five patients achieved stable disease for ≥6 cycles including 2 patients with osteosarcoma and 1 patient each with MPNST, Ewing sarcoma, and hepatocellular carcinoma. A rolling 6 design was used for dose escalation: twice-daily administrations of 2.4 mg/m2/dose (starting dose, equivalent to 4 mg in adults), 3.2 mg/m2/dose (equivalent to 5.5 mg in adults), and 4.2 mg/m2/dose (equivalent to 7.2 mg in adults) were planned. Intrapatient dose escalation or dose titration were not permitted. For patients experiencing dose-limiting axitinib-related toxicity, their dose was decreased by 1 dose level or, for patients receiving dose level 1, a reduction to 1.8 mg/m2/dose (equivalent to 3 mg in adults). A dosing nomogram was used to prescribe doses based on body surface area at each dose level (see Supporting Table 1). Axitinib as 1-mg and 5-mg capsules was supplied by Pfizer Inc. Abbreviation: NOS, not otherwise specified. Toxicities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0). A hematologic DLT was defined as grade 4 thrombocytopenia (platelet count <25,000/mm3) or grade 4 neutropenia not due to malignant infiltration. Grade 3 or 4 fever of <5 days’ duration with or without grade 1 to 3 neutropenia was not considered to be a DLT. Any grade 2 arterial thromboembolic events, any venous thromboembolic events of grade ≥3, any thrombotic events requiring systemic anticoagulation, and any grade ≥2 hemorrhages were considered to be DLTs. Any grade 3 or 4 nonhematologic toxicity that was attributable to axitinib was considered to be a DLT with the exclusion of grade 3 proteinuria (urine protein/creatinine [UPC] ratio >1.9) unless confirmed within 72 hours, grade 3 rapidly reversible hepatic function tests and asymptomatic lipase elevation that did not recur upon rechallenge of axitinib, grade 3 electrolyte abnormalities that were responsive to oral supplementation, grade 3 diarrhea or nausea and vomiting of ≤3 days’ duration, and grade 3 infection of <5 days’ duration. Any grade 2 nonhematologic toxicity that persisted for ≥7 days and was sufficiently medically significant or intolerable to the patient that it required treatment interruption was considered to be a DLT. The MTD was defined as the dose level at which <33% of the patients experienced a DLT in cycle 1. Once the MTD was defined, up to 6 additional patients could be enrolled to obtain tolerability and PK data regarding at least 3 patients aged <12 years. The RP2D would be the MTD or, in the absence of a DLT, the highest dose level evaluated. Patients aged >12 months and <18 years with a minimum body surface area of 0.53 m2 and measurable or evaluable refractory/recurrent solid tumors, excluding primary brain tumors, were eligible. Patients were permitted to have received prior anti-VEGF–targeting antibodies or blocking tyrosine kinase inhibitors but may not have received axitinib. Patients must have recovered fully from the acute toxic effects of prior therapy. A performance status of at least 50% (Karnofsky for patients aged >16 years and Lansky for patients aged ≤16 years) was required. Organ function requirements included an absolute neutrophil count ≥1000/mm3, a platelet count ≥100,000/mm3, hemoglobin ≥8 gm/dL, creatinine clearance or radioisotope glomerular filtration rate ≥70 mL/minute/1.73 m2 or age-appropriate serum creatinine, bilirubin ≤1.5 times the upper limit of normal for age, alanine aminotransferase ≤110 U/L, aspartate aminotransferase ≤125 U/L, serum albumin ≥2 g/dL, lipase ≤1.5 times the upper limit of normal, and a shortening fraction ≥27% by echocardiogram or ejection fraction ≥50% by gated radionuclide study. Blood pressure ≤95th percentile for age, height, and sex was required. Patients were required to swallow intact tablets. Institutional review board approval was obtained prior to patient enrollment and written informed consent was obtained; assent was obtained according to institutional guidelines. The current study is registered at ClinicalTrials.gov (ClinicalTrials.gov identifier NCT02164838). A rolling 6 design was used for dose escalation: twice-daily administrations of 2.4 mg/m2/dose (starting dose, equivalent to 4 mg in adults), 3.2 mg/m2/dose (equivalent to 5.5 mg in adults), and 4.2 mg/m2/dose (equivalent to 7.2 mg in adults) were planned. Intrapatient dose escalation or dose titration were not permitted. For patients experiencing dose-limiting axitinib-related toxicity, their dose was decreased by 1 dose level or, for patients receiving dose level 1, a reduction to 1.8 mg/m2/dose (equivalent to 3 mg in adults). A dosing nomogram was used to prescribe doses based on body surface area at each dose level (see Supporting Table 1). Axitinib as 1-mg and 5-mg capsules was supplied by Pfizer Inc. Abbreviation: NOS, not otherwise specified. Toxicities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0). A hematologic DLT was defined as grade 4 thrombocytopenia (platelet count <25,000/mm3) or grade 4 neutropenia not due to malignant infiltration. Grade 3 or 4 fever of <5 days’ duration with or without grade 1 to 3 neutropenia was not considered to be a DLT. Any grade 2 arterial thromboembolic events, any venous thromboembolic events of grade ≥3, any thrombotic events requiring systemic anticoagulation, and any grade ≥2 hemorrhages were considered to be DLTs. Any grade 3 or 4 nonhematologic toxicity that was attributable to axitinib was considered to be a DLT with the exclusion of grade 3 proteinuria (urine protein/creatinine [UPC] ratio >1.9) unless confirmed within 72 hours, grade 3 rapidly reversible hepatic function tests and asymptomatic lipase elevation that did not recur upon rechallenge of axitinib, grade 3 electrolyte abnormalities that were responsive to oral supplementation, grade 3 diarrhea or nausea and vomiting of ≤3 days’ duration, and grade 3 infection of <5 days’ duration. Any grade 2 nonhematologic toxicity that persisted for ≥7 days and was sufficiently medically significant or intolerable to the patient that it required treatment interruption was considered to be a DLT. The MTD was defined as the dose level at which <33% of the patients experienced a DLT in cycle 1. Once the MTD was defined, up to 6 additional patients could be enrolled to obtain tolerability and PK data regarding at least 3 patients aged <12 years. The RP2D would be the MTD or, in the absence of a DLT, the highest dose level evaluated. Clinical history, physical examination, and vital signs including protocol-specific blood pressure measurement and laboratory assessment were required. A plain radiograph of the tibia growth plate was required at the end of cycle 1, prior to cycle 5, and every 6 months thereafter during receipt of study therapy. An algorithm for the management of axitinib-associated hypertension was provided. Blood samples for PK analyses were collected during cycle 1, on days 1 and 8 (predose and at 1, 2, 4, 6, and 8 hours after the morning dose). Plasma concentrations of axitinib were measured by a validated liquid chromatography–mass spectrometry assay as previously described. PK parameters were calculated using standard noncompartmental analysis (Phoenix WinNonlin 6.4; Pharsight Corporation, Mountain View, California). Biomarkers of AKI included kidney injury molecule 1 (KIM-1), which measures proximal tubular damage; neutrophil gelatinase–associated lipocalin (NGAL), which discriminates prerenal from intrinsic AKI; and interleukin 18 (IL-18), which is a mediator of ischemic tubular necrosis. Blood and urine were collected during cycle 1, prior to the first dose and 2 to 4 hours after the morning dose on days 1, 8, 15, and 22. AKI biomarkers were processed and assayed as previously described. Response based on revised Response Evaluation Criteria In Solid Tumors (RECIST; version 1.1) was assessed prior to cycles 2, 4, and 6, and every third cycle thereafter. Radiographic objective responses (complete response or partial response) or stable disease of >6 months’ duration were reviewed centrally. Descriptive statistics were used to summarize patient characteristics, toxicities, and PK and correlative studies. PK parameters were compared between age groups (age <12 years vs age ≥12 years), dose levels, and sex using the Wilcoxon rank sum test. The Wilcoxon rank sum test also was used to compare PK parameters between patients with and without hypertension. Generalized linear mixed models were used to estimate the change in urinary biomarkers over time. The models included fixed effects for course number, and the matrix of correlated error terms assumed a first-order autoregressive structure to model repeated measures within the same subject. The UPC ratio was log-transformed (natural logarithm) for the analysis. The regression models for the change in biomarkers over time also were adjusted for baseline values. Statistical significance was assessed at the.05 level for all hypotheses tested. Angiogenesis plays a critical role in the growth and metastases of cancer. Vascular endothelial growth factor (VEGF) is a proangiogenic factor that is important for the formation of tumor blood vessels and modulating vascular permeability. VEGF activity is mediated by its receptors (VEGFRs): VEGFR-1, VEGFR-2, and VEGFR-3. Inhibition of the VEGF receptor tyrosine kinases (RTKs) has emerged as an anticancer strategy in adults with renal and hepatic carcinomas as well as soft-tissue sarcomas. When evaluated in the National Cancer Institute pediatric preclinical testing program solid tumor panel, VEGF RTK inhibitors demonstrated tumor growth delay. Axitinib (Inlyta; Pfizer Inc, New York, New York), a potent and selective small molecule inhibitor of VEGFR-1 to VEGFR-3, binds to the inactive conformation of the catalytic domain of VEGF RTKs. Studies in adults have established a maximum tolerated dose (MTD) of 5 mg orally twice daily, and provided guidelines for intrapatient dose titration to a maximum of 10 mg orally twice daily. Common adverse effects include diarrhea, hypertension, fatigue, anorexia, nausea, weight loss, dysphonia, palmar-plantar erythrodysesthesia syndrome, proteinuria, and vomiting. Hypertension and diarrhea are the most common grade 3/4 events. In adults, the median time to the onset of axitinib-associated grade 1 to 2 and grade ≥3 hypertension is 16 days and 24 days, respectively. Axitinib-related hypertension was reported to result in dose interruptions in 12% of patients, dose modifications in 5% of patients, and treatment discontinuation in <1% of patients. Patients treated with axitinib who have a diastolic blood pressure >90 mm Hg or increased diastolic blood pressure ≥10 to 15 mm Hg from baseline had longer progression-free survival. Pharmacokinetic (PK) parameters in adults receiving axitinib at a dose of 5 mg orally twice daily were highly variable. Population PK analyses have indicated that patients with higher axitinib exposures (area under the concentration versus time curve [AUC]24h >200 h•ng/mL) may have a higher objective response rate and a trend toward improved progression-free survival. However, to the best of our knowledge, there are insufficient data to recommend the use of either PK parameters or blood pressure measurements as the exclusive guide to uptitration of the axitinib dose. In the current study, we conducted a phase 1 trial to estimate the MTD or recommended phase 2 dose (RP2D), described the toxicities, and characterized the PKs of axitinib administered orally twice daily in pediatric patients with refractory solid tumors. The secondary aims of the current study were to describe the antitumor activity of axitinib within the confines of a phase 1 study and to investigate biomarkers of acute kidney injury (AKI) and nephrotoxicity.
Publisher Copyright:
© 2018 American Cancer Society
Keywords
- Inlyta
- axitinib
- pediatric solid tumor
- phase 1
- vascular endothelial growth factor receptor (VEGFR)
