Reid, Joel M.

Abstract Ramucirumab (RAM) is a high affinity, humanized, monoclonal antibody that binds to the extra-cellular domain of the vascular endothelial growth factor receptor (VEGFR). RAM prevents the binding of VEGF ligands with VEGFR-2, the most potent receptor of the VEGF tumor angiogenesis pathway. RAM is FDA approved for adults with NSCLC, as well as for gastric and colorectal adenocarcinoma where higher exposure was associated with better outcomes. Based on population pharmacokinetic (PK) analysis of the adult data, a minimum steady state concentration (Cmin ss) of ≥ 50 µg/ml of RAM was considered the target concentration for pediatrics. The Children's Oncology Group (COG) conducted a phase 1 study using a rolling six design to define the maximum tolerated dose (MTD) and /or a recommended phase 2 dose (RP2D), evaluate toxicities and explore circulating angiogenic cells as a biomarker for RAM monotherapy in children with recurrent/refractory solid tumors. The starting dose of 8 mg/kg IV q2 weeks (DL1) was chosen based on the adult safety profile and effective Cmin ss. Since adult data suggested that lower body weight was associated with lower Cmin ss, dose escalation to 12 mg/kg IV q2 weeks (DL2) was planned provided the MTD was not exceeded in DL1 and up to 16 mg/kg IV q2 weeks (DL3) if Cmin ss was < 50 µg/ml in 1 of 6 subjects on DL2 without exceeding the MTD. An expansion cohort was planned at the lowest dose where at least 5 of 6 subjects exceeded the target in order to generate PK data in at least 6 additional subjects < 12 years of age. In the absence of an MTD, the RP2D was defined as the dose achieving Cmin ss ≥ 50 µg/ml on day 42 ± 2, after 3 doses of RAM administered IV every 2 weeks, in at least 10 of 12 subjects. Sixteen subjects (15 eligible; 7 females), median age of 14 years (3-21 yrs.) have been enrolled. Of the 7 subjects on DL1, two had insufficient PK sampling to establish Cmin ss, including 1 who experienced grade 2 proteinuria (DLT). In the remaining 5, the median (range) Cmin ss was 66 (40-136) µg/ml; 2/5 did not achieve the target of ≥ 50 µg/ml. Of the 8 subjects on DL2, two had insufficient PK sampling, including 1 with grade 2 proteinuria (DLT). In the remaining 6, the median (range) Cmin ss was 64 (51-101) µg/ml, all ≥ 50 µg/ml; thus 12mg/kg IV q2 weeks was identified for the expansion cohort. The most common RAM related non-DLT toxicities were grade 1/2 headache in 6 subjects, grade 1/2 elevation in aspartate aminotransferase in 7 subjects and grade 2/3 hypertension in 2 subjects. Due to low participation, circulating angiogenic cells could not be analyzed. This is the first COG study in which dose escalation and RP2D for a targeted agent incorporated a primary PK endpoint (Cmin ss) based upon efficacy data from adult studies and paves the way for similar study design for future phase-1 studies. Citation Format: Kamnesh Pradhan, Stacey L. Berg, Xiaowei Liu, Charles G. Minard, James Croop, Joel M. Reid, Elizabeth Fox, Brenda J. Weigel. A dose escalation and toxicity study using pre-determined target concentration of Ramucirumab, a novel anti-angiogenic agent in children with recurrent / refractory solid tumors: A report from the children's oncology group phase I/ pilot consortium (ADVL1416) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT054.

Abstract Purpose: In phase I testing, alisertib tablets with irinotecan and temozolomide showed significant antitumor activity in patients with neuroblastoma. This study sought to confirm activity of this regimen; evaluate an alisertib oral solution; and evaluate biomarkers of clinical outcomes. Patients and Methods: We conducted a two-stage phase II trial of alisertib tablets (60 mg/m2/dose × 7 days), irinotecan (50 mg/m2/dose i.v. × 5 days), and temozolomide (100 mg/m2/dose orally × 5 days) in patients with relapsed or refractory neuroblastoma. The primary endpoint was best objective response. A separate cohort was treated with alisertib at 45 mg/m2 using oral solution instead of tablets. Exploratory analyses sought to identify predictors of toxicity, response, and progression-free survival (PFS) using pooled data from phase I, phase II, and oral solution cohorts. Results: Twenty and 12 eligible patients were treated in the phase II and oral solution cohorts, respectively. Hematologic toxicities were the most common adverse events. In phase II, partial responses were observed in 19 evaluable patients (21%). The estimated PFS at 1 year was 34%. In the oral solution cohort, 3 patients (25%) had first cycle dose-limiting toxicity (DLT). Alisertib oral solution at 45 mg/m2 had significantly higher median Cmax and exposure compared with tablets at 60 mg/m2. Higher alisertib trough concentration was associated with first cycle DLT, whereas MYCN amplification was associated with inferior PFS. Conclusions: This combination shows antitumor activity, particularly in patients with MYCN nonamplified tumors. Data on an alisertib oral solution expand the population able to be treated with this agent.

Abstract Background Eribulin mesylate is a novel anticancer agent that inhibits microtubule growth, without effects on shortening, and promotes nonproductive tubulin aggregate formation. We performed a phase 1 trial to determine the dose‐limiting toxicities (DLTs), maximum tolerated or recommended phase 2 dose (MTD/RP2D), and pharmacokinetics (PK) of eribulin in children with refractory or recurrent solid (excluding central nervous system) tumors. Methods Eribulin was administered intravenously on days 1 and 8 in 21‐day cycles. Three dose levels (1.1, 1.4, and 1.8 mg/m 2 /dose) were evaluated using the rolling six design with additional patients enrolled into a PK expansion cohort at the MTD. PK samples were obtained following the day 1, cycle 1 dose. Results Twenty‐three patients, ages 3–17 (median 14) years were enrolled; 20 were evaluable for toxicity. DLTs occurred in 0/6 and 1/6 subjects at the 1.1 and 1.4 mg/m 2 /dose, respectively. One subject at the 1.4 mg/m 2 /dose had grade 4 neutropenia and grade 3 fatigue. At the 1.8 mg/m 2 /dose, 2/5 subjects experienced dose‐limiting (grade 4) neutropenia. Grade 3/4 non‐DLTs included lymphopenia and hypokalemia, while low‐grade toxicities included anorexia and nausea. No episodes of grade > 2 corrected QT interval prolongation or peripheral neuropathy were reported. Eribulin pharmacokinetic parameters were highly variable; the median elimination half‐life was 39.6 (range 24.2–96.4) hr. A partial response was observed in one patient (Ewing sarcoma). Conclusions Eribulin was well tolerated in children with refractory or recurrent solid tumors with neutropenia identified as the primary DLT. The RP2D of eribulin is 1.4 mg/m 2 /dose on days 1 and 8 of a 21‐day cycle.

Abstract Background We conducted a phase 1 trial to determine the maximum tolerated dose (MTD), toxicity profile, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary activity of cabozantinib in children with refractory or relapsed solid tumors. Methods Patients received cabozantinib tablets on a continuous dosing schedule in a rolling‐six escalating phase 1 trial design. PK and PD studies were performed. Results Forty‐one patients, median (range) age 13 (4–18) years, received cabozantinib to achieve a weekly cumulative dose equivalent to 30 (n = 6), 40 (n = 23). or 55 (n = 12) mg/m 2 /day. At 40 mg/m 2 /d, dose‐limiting toxicities (DLTs) were palmar‐plantar erythrodysesthesia syndrome, mucositis, and elevated alanine aminotransferase, lipase, and bilirubin. At 55 mg/m 2 /d, hypertension, reversible posterior leukoencephalopathy syndrome, headache, fatigue, and proteinuria were DLTs. Frequent non‐DLTs included diarrhea, hypothyroidism, fatigue, nausea, vomiting, elevated hepatic transaminases, and proteinuria. In subsequent cycles, DLTs occurred at all dose levels. Across all dose levels, the steady‐state exposure and peak cabozantinib concentrations were similar. Four patients experienced a confirmed partial response: medullary thyroid cancer (MTC; n = 2), Wilms tumor, and clear cell sarcoma. Stable disease (>6 cycles) was seen in seven patients (MTC [n = 2], Ewing sarcoma, synovial sarcoma, alveolar soft part sarcoma, paraganglioma, and ependymoma). Conclusions A protocol‐defined MTD was not reached; DLTs and dose reductions for toxicity occurred in the first and subsequent cycles at all dose levels. Based on the toxicity profile, pharmacokinetics, and responses, the recommended dose of cabozantinib in pediatric patients with refractory solid tumors is 40 mg/m 2 /day. A phase 2 study of cabozantinib is being conducted.

AbstractBackgroundVorinostat combined with retinoids produces additive antitumor effects in preclinical studies of neuroblastoma. Higher systemic exposures of vorinostat than achieved in pediatric phase I trials with continuous daily dosing are necessary for in vivo increased histone acetylation and cytotoxic activity. We conducted a phase I trial in children with relapsed/refractory neuroblastoma to determine the maximum tolerated dose (MTD) of vorinostat on an interrupted schedule, escalating beyond the previously identified pediatric MTD.MethodsIsotretinoin (cis‐13‐retinoic acid) 80 mg/m2/dose was administered by mouth twice daily on days 1–14 in combination with escalating doses of daily vorinostat up to 430 mg/m2/dose (days 1–4; 8–11) in each 28‐day cycle using the standard 3 + 3 design. Vorinostat pharmacokinetic testing and histone acetylation assays were performed.ResultsTwenty‐nine patients with refractory or relapsed neuroblastoma were enrolled and 28 were evaluable for dose escalation decisions. Median number of cycles completed was two (range 1–15); 11 patients received four or more cycles. Three patients experienced cycle 1 dose‐limiting toxicities. A total of 18 patients experienced grade 3/4 toxicities related to study therapy. The maximum intended dose of vorinostat (430 mg/m2/day, days 1–4; 8–11) was tolerable and led to increased histone acetylation in surrogate tissues when compared to lower doses of vorinostat (P = 0.009). No objective responses were seen.ConclusionsIncreased dose vorinostat (430 mg/m2/day) on an interrupted schedule is tolerable in combination with isotretinoin. This dose led to increased vorinostat exposures and demonstrated increased histone acetylation. Prolonged stable disease in patients with minimal residual disease warrants further investigation.

Background. Cervical interlaminar epidural steroid injections (ESIs) are commonly performed procedures to treat painful cervical radiculopathy, but little is known about the systemic absorption and serum levels of steroids following injection. The primary objective of this study was to investigate the pharmacokinetics of fluoroscopy-guided cervical epidural-administered triamcinolone acetonide in a cohort of patients with cervical radicular pain seeking treatment in a pain medicine clinic.Methods. The study cohort included eight patients undergoing a fluoroscopically guided C7-T1 interlaminar ESI at a pain medicine specialty clinic. Blood was collected prior to the ESI and on days 1, 2, 4, 6, 8, 14, 21, 28, 35, and 42 following the injection. The sample extract was analyzed by tandem mass spectrometry.Results. The terminal elimination half-life of cervical epidural-administered triamcinolone in a noncompartmental analysis was 219 hours. In the noncompartmental analysis, peak triamcinolone concentrations of 5.4 ng/mL were detected within 22.1 hours after administration.Conclusions. The pharmacokinetics of cervical epidural-administered triamcinolone is consistent with our previous study of lumbar ESI, demonstrating that the elimination half-life is longer than that which has been reported following intravenous triamcinolone. The elimination half-life was shorter following cervical ESI than that which has been reported following lumbar ESI.

AbstractBackgroundFacet joint steroid injections are used to treat chronic low back pain. However, little is known about the systemic absorption and serum levels of steroids following intra‐articular facet joint injections. The primary objective of this preliminary study was to investigate the pharmacokinetics of triamcinolone acetonide following fluoroscopically guided intra‐articular lumbar facet joint injections in a cohort of patients with chronic low back pain. A secondary aim was to investigate the effects of triamcinolone on serum cortisol levels following lumbar facet joint injections.MethodsThe study cohort included 5 patients undergoing fluoroscopically guided intra‐articular lumbar facet joint injections at a pain medicine specialty clinic. Blood was collected prior to the injections and on days 1, 2, 4, 6, 8, 14, 21, 28, 35, and 42 following the injections.ResultsThe terminal elimination half‐life of triamcinolone in a noncompartmental analysis was 213 hours. The peak median triamcinolone concentration of 3.6 ng/mL was detected within 24 hours after the injections. Serum cortisol levels were < 30 ng/mL for an average of 4.4 days. The maximum effect of triamcinolone on cortisol suppression was observed with triamcinolone serum levels of > 1.9 ng/mL.ConclusionsThe peak serum concentration of triamcinolone following intra‐articular facet joint injections occurred within 24 hours. The median terminal elimination half‐life was 213 hours, but baseline cortisol levels were suppressed for an average of 4.4 days. Clinically, the prolonged half‐life and endocrine effects of triamcinolone could increase the risk for serious drug–drug interactions in patients taking medications that inhibit corticosteroid metabolism.

AbstractBackgroundOntuxizumab is a humanized IgG monoclonal antibody that targets the cell‐surface glycoprotein endosialin (tumor endothelial marker‐1[TEM‐1]/CD248) found on activated mesenchymal cells and certain tumors. Ontuxizumab binding to endosialin may interfere with platelet‐derived growth factor signaling, prevent tumor stroma organization, and prevent new vessel formation.MethodsOntuxizumab was administered intravenously on days 1, 8, 15, and 22 of a 28‐day cycle at three dose levels (4, 8, and 12 mg/kg). Further dose escalation to 16 mg/kg was planned if the maximum tolerated dose (MTD) was not reached and the ontuxizumab systemic clearance was ≥30% higher in children compared to adults. Following determination of the MTD/recommended phase 2 dose, an additional cohort of six patients (<12 years) was enrolled for further pharmacokinetics (PK) evaluation.ResultsTwenty‐seven eligible patients (17 male, median age 15 years, range 3–21 years) were enrolled. Twenty‐two patients (neuroblastoma [5], Ewing sarcoma [4], rhabdomyosarcoma [4], and other tumors [9]) were fully evaluable for toxicity. Five patients did not complete cycle 1 due to tumor progression. Two of 10 patients experienced dose‐limiting toxicity of bacteremia (n = 1) and hyponatremia (n = 1) at 12 mg/kg. Grade ≤2 fever or infusion‐related reactions occurred in 10 patients. Clearance was dose dependent and within 30% of adult value at 12 mg/kg.ConclusionOntuxizumab administered weekly at 12 mg/kg appears to be well tolerated in children with relapsed or refractory solid tumors. The PK of ontuxizumab does not appear to be significantly different in children compared to adults.