Liu, Xiaowei

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.

Abstract Background: Inhibition of the WEE1 kinase by AZD1775 potentiates replicative stress induced by oncogenes or chemotherapy, and demonstrated anti-tumor activity in preclinical models of pediatric cancer. A pediatric phase I dose escalation study of AZD1775 in combination with irinotecan was completed within the COG DVL consortium. Methods: Patients age 1-21 years with relapsed/refractory solid or CNS tumors were eligible. Both agents were administered orally once daily on days 1-5 of a 21-day cycle with a step-wise inter-patient dose escalation of both agents. AZD1775 dose levels (DL) were 50 mg/m2 (DL1), 65 mg/m2 (DL 2 and 3), 85 mg/m2 (DL4) and 110 mg/m2 (DL5). Irinotecan, 70 mg/m2 day (DL 1-2), or 90 mg/m2/day (DL3-5), was administered with cefixime for diarrheal prophylaxis. Toxicity was graded according to CTCAE v4.0. Results: Thirty-one eligible patients, median age 14 years (range 5-20) were enrolled; 29 (93%) received prior chemotherapy (median 3 regimens) and 25 (81%) received prior radiation therapy. Sixteen patients had a primary CNS malignancy: malignant glioma (9), ependymoma (4), medulloblastoma (2) and CNS Ewings sarcoma (1). Fifteen patients had extracranial solid tumors: soft tissue sarcoma (6), neuroblastoma (2), carcinoma (4), osteosarcoma (2) and Wilms’ Tumor (1). The most common toxicities were hematologic and gastrointestinal (nausea, vomiting, diarrhea). Two patients experienced dose limiting toxicity, grade 3 diarrhea and dehydration at DL5 (AZD1775 110 mg/m2 and irinotecan 90 mg/m2). Conclusion: This is the first pediatric clinical trial of AZD1775 in combination with chemotherapy. The maximum tolerated dose in children and adolescents with solid tumors was AZD1775 85 mg/m2/day in combination with irinotecan 90 mg/m2/day for five days every 21 days. Accrual is ongoing for a pediatric PK expansion, PD analysis and Phase 2 expansion in patients with neuroblastoma or medulloblastoma / CNS PNET. Clinical trial information: NCT02095132 Citation Format: Kristina A. Cole, Joel M. Reid, Xiaowei Liu, Charles G. Minard, John M. Maris, Elizabeth Fox, Brenda J. Weigel. Pediatric phase I trial of the WEE1 inhibitor AZD1775 and irinotecan in patients with refractory solid and CNS malignancies; A Children’s Oncology Group Study (ADVL1312) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT144. doi:10.1158/1538-7445.AM2017-CT144

Abstract Purpose: Trebananib is a first-in-class antiangiogenic peptibody (peptide–Fc fusion protein) that inhibits Angiopoietin 1 and 2. A pediatric phase 1 trial was performed to define trebananib dose-limiting toxicities (DLT), recommended phase 2 dose (RP2D), and pharmacokinetics (PK). Experimental Design: Trebananib was administered by weekly infusion. Three dose levels (10, 15, or 30 mg/kg/dose) were evaluated using a rolling-six design. Part 2 evaluated a cohort of subjects with primary central nervous system (CNS) tumors. Pharmacokinetic sampling and analysis of peripheral blood biomarkers was performed during the first 4 weeks. Response was evaluated after 8 weeks. Correlative studies included angiogenic protein expression and DCE-MRI. Results: Thirty-seven subjects were enrolled (31 evaluable for toxicity) with median age 12 years (range, 2 to 21). Two of 19 evaluable non-CNS subjects developed DLT at the 30 mg/kg dose level, including venous thrombosis and pleural effusion. In the CNS cohort, 3/12 subjects developed DLT, including decreased platelet count, transient ischemic attack, and cerebral edema with headache and hydrocephalus. Other grade 3 or 4 toxicities included lymphopenia (n = 4), anemia, thrombocytopenia, neutropenia, vomiting, and hypertension (n = 1 each). Response included stable disease in 7 subjects, no partial or complete responses. Two subjects continued study treatment with prolonged stable disease for 18 cycles (neuroblastoma) and 26 cycles (anaplastic astrocytoma). Pharmacokinetics appeared linear over 3 dose levels. Correlative studies demonstrated increased PlGF and sVCAM-1, but no change in endoglin or perfusion by DCE-MRI. Conclusions: Trebananib was well tolerated in pediatric patients with recurrent or refractory solid or CNS tumors. RP2D is 30 mg/kg. Clin Cancer Res; 23(20); 6062–9. ©2017 AACR.

AbstractBackgroundThe c‐Met receptor tyrosine kinase is dysregulated in many pediatric cancers. Tivantinib is an oral small molecule that inhibits the c‐Met receptor tyrosine kinase. A phase 1 and pharmacokinetic (PK) trial evaluating tivantinib was conducted in children with relapsed/refractory solid tumors.MethodsOral tivantinib capsules were administered twice daily with food, continuously in 28‐day cycles. Dose levels 170, 200, and 240 mg/m2/dose were evaluated using a rolling‐six design (Part A). In Part B, subjects received tivantinib powder sprinkled on food at the recommended phase 2 dose (RP2D) from Part A. PK, CYP2C19 genotyping, and baseline tumor tissue c‐Met expression were analyzed.ResultsThirty‐six patients were enrolled: 20 in Part A, 6 in a PK expansion cohort, and 10 in Part B. Fifteen patients had primary central nervous system tumors and 21 had solid tumors. In Part A, there were no dose‐limiting toxicities. One grade 4 intracranial hemorrhage occurred in a patient with a progressive brain tumor in the expanded PK cohort (240 mg/m2). PK analysis showed marked interpatient variability (20‐fold) in the Cmax and AUC0‐8h across all dose levels. Sprinkling tivantinib powder over food did not alter exposure. Membranous and total c‐Met expression was moderate (2), low (4), or not detected (26). Two patients had stable disease as the best response.ConclusionsThe RP2D of tivantinib given with food in children with refractory solid tumors is 240 mg/m2/dose. PK of tivantinib in children demonstrated high variability. Objective responses were not observed in this phase 1 trial.