Local delivery of mRNA-encoded cytokines promotes antitumor immunity and tumor eradication across multiple preclinical tumor models.

Local immunotherapy ideally stimulates immune responses against tumors while avoiding toxicities associated with systemic administration. Current strategies for tumor-targeted, gene-based delivery, however, are limited by adverse effects such as off-targeting or antivector immunity. We investigated the intratumoral administration of saline-formulated messenger (m)RNA encoding four cytokines that were identified as mediators of tumor regression across different tumor models: interleukin-12 (IL-12) single chain, interferon-α (IFN-α), granulocyte-macrophage colony-stimulating factor, and IL-15 sushi.

Phase I Trial of a Tablet Formulation of Pilaralisib, a Pan-Class I PI3K Inhibitor, in Patients with Advanced Solid Tumors.

Lessons Learned: A phase I study of the pan-class I phosphoinositide 3-kinase inhibitor pilaralisib (in capsule formulation) in advanced solid tumors established the maximum tolerated dose as 600 mg once daily.The current study investigated pilaralisib in tablet formulation.Pilaralisib tablets were associated with a favorable safety profile and preliminary antitumor activity.

Voxtalisib (XL765) in patients with relapsed or refractory non-Hodgkin lymphoma or chronic lymphocytic leukaemia: an open-label, phase 2 trial.

Background: Patients with relapsed or refractory lymphoma or chronic lymphocytic leukaemia have a poor prognosis. Therapies targeting more than one isoform of PI3K, as well as mTOR, might increase antitumour activity. We aimed to investigate the efficacy and safety of voxtalisib (also known as XL765 or SAR245409), a pan-PI3K/mTOR inhibitor, in patients with relapsed or refractory lymphoma, or chronic lymphocytic leukaemia/small lymphocytic lymphoma.

Janus kinase-2 inhibitor fedratinib in patients with myelofibrosis previously treated with ruxolitinib (JAKARTA-2): a single-arm, open-label, non-randomised, phase 2, multicentre study.

Background: Myelofibrosis is a chronic myeloproliferative neoplasm characterised by splenomegaly, cytopenias, bone marrow fibrosis, and debilitating symptoms including fatigue, weight loss, and bone pain. Mutations in Janus kinase-2 (JAK2) occur in approximately 50% of patients. The only approved JAK2 inhibitor for myelofibrosis is the dual JAK1 and JAK2 inhibitor, ruxolitinib.

A phase I dose-escalation study of the safety and pharmacokinetics of a tablet formulation of voxtalisib, a phosphoinositide 3-kinase inhibitor, in patients with solid tumors.

Background Voxtalisib, a PI3K/mTOR inhibitor, has shown antitumor activity in capsule formulation in patients with solid tumors. This Phase I study assessed safety and pharmacokinetics of voxtalisib administered as immediate-release tablets in patients with solid tumors (NCT01596270). Methods A "3 + 3" dose escalation design was used.

Phase I Dose-Escalation Study of Pilaralisib (SAR245408, XL147) in Combination with Paclitaxel and Carboplatin in Patients with Solid Tumors.

Lessons Learned: Despite involvement of PI3K pathway activation in tumorigenesis of solid tumors, single-agent PI3K inhibitors have shown modest clinical activity.Preclinical evidence suggests that combining PI3K pathway inhibitors and chemotherapy can enhance antitumor effects.In patients with solid tumors, the PI3K inhibitor pilaralisib had a favorable safety profile but did not enhance the antitumor activity of paclitaxel plus carboplatin.

Phase Ib Study of Safety and Pharmacokinetics of the PI3K Inhibitor SAR245408 with the HER3-Neutralizing Human Antibody SAR256212 in Patients with Solid Tumors.

This phase Ib study was designed to determine the MTD, safety, preliminary efficacy, and pharmacokinetics of the HER3 (ErbB3) mAb SAR256212 in combination with the oral PI3K inhibitor SAR245408 for patients with metastatic or locally advanced solid tumors. Patients received the combination of intravenous SAR256212 and oral SAR245408 in a 3 + 3 dose-escalation design until occurrence of disease progression or dose-limiting toxicity. Objective response rate, pharmacokinetics, pharmacodynamics, and mutational status were also evaluated.

Phase Ib trial of the PI3K/mTOR inhibitor voxtalisib (SAR245409) in combination with chemoimmunotherapy in patients with relapsed or refractory B-cell malignancies.

This phase Ib, dose-escalation study investigated the maximum tolerated dose (MTD), recommended phase II dose (RP2D), safety, pharmacokinetics (PK) and preliminary efficacy of the pan-class I phosphoinositide 3-kinase (PI3K) and mechanistic target of rapamycin (mTOR) inhibitor voxtalisib [30 or 50 mg twice daily (BID)], in combination with rituximab (voxtalisib+rituximab) or rituximab plus bendamustine (voxtalisib+rituximab+bendamustine), in relapsed or refractory indolent B-cell non-Hodgkin lymphoma (NHL), mantle cell lymphoma and chronic lymphocytic leukaemia (CLL). MTD and RP2D of voxtalisib were determined using a 3 + 3 dose-escalation design. Adverse events (AEs), plasma PK and disease response were recorded.

Phase I dose-escalation study of the PI3K/mTOR inhibitor voxtalisib (SAR245409, XL765) plus temozolomide with or without radiotherapy in patients with high-grade glioma.

Background: This phase I study aimed to evaluate safety, maximum tolerated dose, pharmacokinetics, pharmacodynamics, and preliminary efficacy of voxtalisib (SAR245409, XL765), a pan-class I phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor, in combination with temozolomide (TMZ), with or without radiation therapy (RT), in patients with high-grade glioma.

Methods: Patients received voxtalisib 30-90 mg once daily (q.d.

Phase I Trial of the Pan-PI3K Inhibitor Pilaralisib (SAR245408/XL147) in Patients with Chronic Lymphocytic Leukemia (CLL) or Relapsed/Refractory Lymphoma.

Purpose: This phase I expansion-cohort study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of the pan-PI3K inhibitor pilaralisib (SAR245408/XL147) in patients with chronic lymphocytic leukemia (CLL) or relapsed or refractory lymphoma.

Patients And Methods: Patients were treated with the maximum tolerated dose of pilaralisib previously determined in patients with solid tumors (600 mg capsules once daily). Adverse events (AE) and response were evaluated.

Phase I dose-escalation study of pilaralisib (SAR245408, XL147), a pan-class I PI3K inhibitor, in combination with erlotinib in patients with solid tumors.

Background: This phase I study evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics of pilaralisib (SAR245408), an oral pan-class I phosphoinositide 3-kinase (PI3K) inhibitor, in combination with erlotinib, an epidermal growth factor receptor (EGFR) inhibitor.

Methods: In a 3 + 3 dose-escalation study, patients with advanced solid tumors received pilaralisib capsules once daily (21 days per 28-day cycle; 50-600 mg) plus erlotinib tablets once daily (28 days per 28-day cycle; 100 or 150 mg). An MTD expansion cohort of patients with non-small cell lung cancer who had previously received treatment with an EGFR inhibitor was included.

Phase I study of pazopanib in combination with weekly paclitaxel in patients with advanced solid tumors.

Purpose: To evaluate the maximum tolerated regimen (MTR), dose-limiting toxicities, and pharmacokinetics of pazopanib, an oral small-molecule tyrosine kinase inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit, in combination with paclitaxel.

Patients And Methods: Pazopanib was given daily with weekly paclitaxel on days 1, 8, and 15 every 28 days. Dose levels of pazopanib (mg/day)/paclitaxel (mg/m(2)) were 400/15, 800/15, 800/50, and 800/80.

A phase I study of bevacizumab (B) in combination with everolimus (E) and erlotinib (E) in advanced cancer (BEE).

Purpose: VEGF, mTOR, and EGFR inhibitors have demonstrated anti-tumor and anti-angiogenic effects alone and in combination with each other. This study evaluated the safety, tolerability, and pharmacokinetics of bevacizumab, everolimus, and erlotinib combination.

Methods: Doublet therapy consisted of bevacizumab at 10 mg/kg every 14 days and everolimus 5 mg daily which escalated to 10 mg daily.

A Phase II, open-label study evaluating pazopanib in patients with recurrent ovarian cancer.

Objective: The progression-free and median survival of patients with advanced ovarian cancer has not appreciably improved over the last decade. Novel targeted therapies, particularly antiangiogenic agents, may potentially improve clinical outcomes in patients with ovarian cancer. This phase II, open-label study evaluated oral pazopanib monotherapy in patients with low-volume recurrent ovarian cancer.

Pooled analysis of phase II window studies in children with contemporary high-risk metastatic rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group.

Purpose: The Soft Tissue Sarcoma Committee of the Children's Oncology Group has conducted five upfront window trials in patients with newly diagnosed metastatic rhabdomyosarcoma to identify promising new treatment agents.

Patients And Methods: This pooled analysis identified a total of 420 patients (115 from Intergroup Rhabdomyosarcoma Study III [IRS-III] and 305 from the five window trials). We assessed window therapy response rate, failure-free survival (FFS), and overall survival (OS).