Pralsetinib for patients with advanced or metastatic RET-altered thyroid cancer (ARROW): a multi-cohort, open-label, registrational, phase 1/2 study.

Background: Oncogenic alterations in RET represent important therapeutic targets in thyroid cancer. We aimed to assess the safety and antitumour activity of pralsetinib, a highly potent, selective RET inhibitor, in patients with RET-altered thyroid cancers.

Methods: ARROW, a phase 1/2, open-label study done in 13 countries across 71 sites in community and hospital settings, enrolled patients 18 years or older with RET-altered locally advanced or metastatic solid tumours, including RET-mutant medullary thyroid and RET fusion-positive thyroid cancers, and an Eastern Co-operative Oncology Group performance status of 0-2 (later limited to 0-1 in a protocol amendment).

Pralsetinib for RET fusion-positive non-small-cell lung cancer (ARROW): a multi-cohort, open-label, phase 1/2 study.

Background: Oncogenic alterations in RET have been identified in multiple tumour types, including 1-2% of non-small-cell lung cancers (NSCLCs). We aimed to assess the safety, tolerability, and antitumour activity of pralsetinib, a highly potent, oral, selective RET inhibitor, in patients with RET fusion-positive NSCLC.

Methods: ARROW is a multi-cohort, open-label, phase 1/2 study done at 71 sites (community and academic cancer centres) in 13 countries (Belgium, China, France, Germany, Hong Kong, Italy, Netherlands, Singapore, South Korea, Spain, Taiwan, the UK, and the USA).

Glembatumumab vedotin for patients with metastatic, gpNMB overexpressing, triple-negative breast cancer ("METRIC"): a randomized multicenter study.

The METRIC study (NCT#0199733) explored a novel antibody-drug conjugate, glembatumumab vedotin (GV), targeting gpNMB that is overexpressed in ~40% of patients with triple-negative breast cancer (TNBC) and associated with poor prognosis. The study was a randomized, open-label, phase 2b study that evaluated progression-free survival (PFS) of GV compared with capecitabine in gpNMB-overexpressing TNBC. Patients who had previously received anthracycline and taxane-based therapy were randomized 2:1 to receive, GV (1.

A Phase II Study of Glembatumumab Vedotin for Metastatic Uveal Melanoma.

Glembatumumab vedotin (CDX-011, GV) is a fully human Immunoglobulin G2 monoclonal antibody directed against glycoprotein NMB coupled via a peptide linker to monomethyl auristatin E (MMAE), a potent cytotoxic microtubule inhibitor. This phase II study evaluated the overall response rate and safety of GV, glycoprotein NMB (GPNMB) expression, and survival in patients with metastatic uveal melanoma. Eligible patients with metastatic uveal melanoma who had not previously been treated with chemotherapy received GV 1.

Rindopepimut with Bevacizumab for Patients with Relapsed EGFRvIII-Expressing Glioblastoma (ReACT): Results of a Double-Blind Randomized Phase II Trial.

Purpose: Rindopepimut is a vaccine targeting the tumor-specific EGF driver mutation, EGFRvIII. The ReACT study investigated whether the addition of rindopepimut to standard bevacizumab improved outcome for patients with relapsed, EGFRvIII-positive glioblastoma.

Patients And Methods: In this double-blind, randomized, phase II study (NCT01498328) conducted at 26 hospitals in the United States, bevacizumab-naïve patients with recurrent EGFRvIII-positive glioblastoma were randomized to receive rindopepimut or a control injection of keyhole limpet hemocyanin, each concurrent with bevacizumab.

A phase 2 study of glembatumumab vedotin, an antibody-drug conjugate targeting glycoprotein NMB, in patients with advanced melanoma.

Background: Glembatumumab vedotin is an antibody-drug conjugate that produced preliminary clinical activity against advanced melanoma in a phase 1 dose-escalation trial. The objective of the current study was to investigate further the antitumor activity of glembatumumab vedotin at the recommended phase 2 dose in heavily pretreated patients with melanoma.

Methods: This single-arm, phase 2 study enrolled patients with stage IV melanoma who were refractory to checkpoint inhibition and to B-raf proto-oncogene, serine/threonine kinase (BRAF)/mitogen-activated protein kinase kinase (MEK) inhibition (in the presence of a BRAF valine mutation at codon 600).

Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial.

Background: Rindopepimut (also known as CDX-110), a vaccine targeting the EGFR deletion mutation EGFRvIII, consists of an EGFRvIII-specific peptide conjugated to keyhole limpet haemocyanin. In the ACT IV study, we aimed to assess whether or not the addition of rindopepimut to standard chemotherapy is able to improve survival in patients with EGFRvIII-positive glioblastoma.

Methods: In this randomised, double-blind, phase 3 trial, we recruited patients aged 18 years and older with glioblastoma from 165 hospitals in 22 countries.

Evaluation of the effect of multiple doses of rifampin on the pharmacokinetics and safety of ponatinib in healthy subjects.

Ponatinib, an oral tyrosine kinase inhibitor with significant activity in heavily pretreated patients with chronic myeloid leukemia, is a CYP3A4 substrate. This open-label, nonrandomized, fixed-order crossover study evaluated the effect of multiple oral doses of rifampin, a strong CYP3A4 inducer, on the pharmacokinetics of ponatinib (45 mg, single dose). Twenty healthy adults received ponatinib on day 1, rifampin 600 mg alone on days 8-13, 15, and 16, and rifampin 600 mg with ponatinib on day 14.

Evaluation of the effect of multiple doses of lansoprazole on the pharmacokinetics and safety of ponatinib in healthy subjects.

Background: In vitro studies have demonstrated that the aqueous solubility of the tyrosine kinase inhibitor ponatinib decreases as pH increases.

Objectives: The primary aim of this study was to assess the effects of the gastric proton pump inhibitor lansoprazole on the pharmacokinetics of ponatinib. The single-dose safety profile of ponatinib with and without coadministration of lansoprazole was also characterized.

Evaluation of pharmacokinetics and safety of ponatinib in subjects with chronic hepatic impairment and matched healthy subjects.

Purpose: This study evaluated the effects of chronic hepatic impairment on the single-dose pharmacokinetics (PK) of the tyrosine kinase inhibitor ponatinib.

Methods: Subjects (n = 16) had Child-Pugh class A (mild, n = 6), B (moderate, n = 6), or C (severe, n = 4) hepatic impairment and were matched with healthy controls (n = 8). Each subject received a single oral dose of ponatinib 30 mg under fasting conditions, and PK parameters were assessed in blood samples collected through 96 h post-dose.

A phase II trial of a multi-agent oral antiangiogenic (metronomic) regimen in children with recurrent or progressive cancer.

Background: Preclinical models show that an antiangiogenic regimen at low-dose daily (metronomic) dosing may be effective against chemotherapy-resistant tumors. We undertook a prospective, open-label, single-arm, multi-institutional phase II study to evaluate the efficacy of a "5-drug" oral regimen in children with recurrent or progressive cancer.

Procedure: Patients ≤21 years old with recurrent or progressive tumors were eligible.

A multicenter, first-in-pediatrics, phase 1, pharmacokinetic and pharmacodynamic study of ridaforolimus in patients with refractory solid tumors.

Purpose: Ridaforolimus (MK-8669, AP23573) is a potent and selective mammalian target of rapamycin (mTOR) inhibitor. Preclinically, ridaforolimus displays antiproliferative activity against a variety of human tumors in vitro and tumor xenograft models in vivo, with additive or synergistic activity when combined with other anticancer agents. Antitumor activity has been confirmed in adults.

Analysis of the potential effect of ponatinib on the QTc interval in patients with refractory hematological malignancies.

Purpose: Cardiac dysfunction, particularly QT interval prolongation, has been observed with tyrosine kinase inhibitors approved to treat chronic myeloid leukemia. This study examines the effects of ponatinib on cardiac repolarization in patients with refractory hematological malignancies enrolled in a phase 1 trial.

Methods: Electrocardiograms (ECGs) were collected at 3 dose levels (30, 45, and 60 mg) at 6 time points.

Ponatinib in refractory Philadelphia chromosome-positive leukemias.

Background: Resistance to tyrosine kinase inhibitors in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) is frequently caused by mutations in the BCR-ABL kinase domain. Ponatinib (AP24534) is a potent oral tyrosine kinase inhibitor that blocks native and mutated BCR-ABL, including the gatekeeper mutant T315I, which is uniformly resistant to tyrosine kinase inhibitors.

Methods: In this phase 1 dose-escalation study, we enrolled 81 patients with resistant hematologic cancers, including 60 with CML and 5 with Ph-positive ALL.

Alleviating monoterpene toxicity using a two-phase extractive fermentation for the bioproduction of jet fuel mixtures in Saccharomyces cerevisiae.

Monoterpenes are a diverse class of compounds with applications as flavors and fragrances, pharmaceuticals and more recently, jet fuels. Engineering biosynthetic pathways for monoterpene production in microbial hosts has received increasing attention. However, monoterpenes are highly toxic to many microorganisms including Saccharomyces cerevisiae, a widely used industrial biocatalyst.

Ridaforolimus for patients with progressive or recurrent malignant glioma: a perisurgical, sequential, ascending-dose trial.

Purpose: This perisurgical phase 1 study evaluated the pharmacokinetics, pharmacodynamics, and safety of the mammalian target of rapamycin (mTOR) inhibitor ridaforolimus in patients (N = 10) with progressive or recurrent primary grade IV malignant glioma, who failed standard therapy. The primary objective of the study was to determine the maximum tolerated dose (MTD) of ridaforolimus.

Methods: Treatment was administered intravenously at doses of 12.

Late effects of therapy for pediatric brain tumor survivors.

Approximately 2 of every 3 of all pediatric patients with brain tumors will be long-term survivors. However, there is a steep cost for pediatric brain tumor survivors, and the group as a whole faces significantly more late effects than many other survivors of pediatric cancers. Most of these effects can be attributed to direct neurologic damage to the developing brain caused by the tumor and its removal, the long-term toxicity of chemotherapy, or the effects of irradiation on the central nervous system.

Medical, psychological, cognitive and educational late-effects in pediatric low-grade glioma survivors treated with surgery only.

Background: Surgical resection is often the only treatment necessary for pediatric low-grade gliomas (LGGs) and is thought to define a population with an excellent long-term prognosis. The goal of this study was to describe the multidimensional late-effects of pediatric LGG survivors treated exclusively with surgery.

Methods: A retrospective chart review of "surgery-only" LGG survivors followed at Dana-Farber/Children's Hospital Cancer Care was undertaken.

A novel TP53 germline mutation in a family with a history of multiple malignancies: case report and review of the literature.

Objective: Choroid plexus carcinoma (CPC) has been associated with TP53 germline mutations and Li-Fraumeni syndrome (LFS). We describe our finding of a novel germline mutation in the TP53 gene in a family with multiple malignancies and in association with a child presenting with CPC.

Method: An 8-month-old male presented with seizure-like activity; imaging disclosed a 1.

Intensive multimodality treatment for children with newly diagnosed CNS atypical teratoid rhabdoid tumor.

Purpose: Atypical teratoid rhabdoid tumor (ATRT) of the CNS is a highly malignant neoplasm primarily affecting young children, with a historic median survival ranging from 6 to 11 months. Based on a previous pilot series, a prospective multi-institutional trial was conducted for patients with newly diagnosed CNS ATRT.

Patients And Methods: Treatment was divided into five phases: preirradiation, chemoradiation, consolidation, maintenance, and continuation therapy.

Phase I trial of VNP40101M (Cloretazine) in children with recurrent brain tumors: a pediatric brain tumor consortium study.

Purpose: VNP40101M (Cloretazine), a novel DNA alkylating agent, was evaluated in a phase I study in children with recurrent brain tumors.

Experimental Design: VNP40101M was given i.v.