Investigation of the absolute bioavailability and human mass balance of navoximod, a novel IDO1 inhibitor.

Aims: Navoximod (GDC-0919, NLG-919) is a small molecule inhibitor of indoleamine-2,3-dioxygenase 1 (IDO1), developed to treat the acquired immune tolerance associated with cancer. The primary objectives of this study were to assess navoximod's absolute bioavailability (aBA), determine the mass balance and routes of elimination of [ C]-navoximod, and characterize navoximod's metabolite profile.

Methods: A phase 1, open-label, two-part study was conducted in healthy volunteers.

Phase I Study of the Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitor Navoximod (GDC-0919) Administered with PD-L1 Inhibitor (Atezolizumab) in Advanced Solid Tumors.

Purpose: IDO1 induces immune suppression in T cells through l-tryptophan (Trp) depletion and kynurenine (Kyn) accumulation in the local tumor microenvironment, suppressing effector T cells and hyperactivating regulatory T cells (Treg). Navoximod is an investigational small-molecule inhibitor of IDO1. This phase I study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of navoximod in combination with atezolizumab, a PD-L1 inhibitor, in patients with advanced cancer.

Association of Cancer Immunotherapy With Acute Macular Neuroretinopathy and Diffuse Retinal Venulitis.

Importance: Checkpoint inhibition in cancer immunotherapy related to T-cell-driven mechanisms of action associated with acute macular neuroretinopathy (AMN) and diffuse retinal venulitis, an adverse event not previously described, is reported here.

Objective: To describe 2 patients who developed ophthalmologic events after treatment with the programmed death 1 axis inhibitor, atezolizumab.

Design, Setting, And Participants: Retrospective review of 2 patients treated with atezolizumab for metastatic breast cancer and colon cancer, respectively, who presented with AMN and diffuse retinal venulitis conducted at 2 tertiary medical centers.

Phase Ia study of the indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor navoximod (GDC-0919) in patients with recurrent advanced solid tumors.

Background: Indoleamine-2,3-dioxygenase 1 (IDO1) catalyzes the oxidation of tryptophan into kynurenine and is partially responsible for acquired immune tolerance associated with cancer. The IDO1 small molecule inhibitor navoximod (GDC-0919, NLG-919) is active as a combination therapy in multiple tumor models.

Methods: This open-label Phase Ia study assessed safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary anti-tumor activity of navoximod in patients with recurrent/advanced solid tumors, administered as 50-800 mg BID on a 21/28 day and at 600 mg on a 28/28 day schedule.

Phase II Study of the Dual EGFR/HER3 Inhibitor Duligotuzumab (MEHD7945A) versus Cetuximab in Combination with FOLFIRI in Second-Line Wild-Type Metastatic Colorectal Cancer.

Duligotuzumab is a dual-action antibody directed against EGFR and HER3. Metastatic colorectal cancer (mCRC) patients with ex2 wild-type received duligotuzumab or cetuximab and FOLFIRI until progression or intolerable toxicity. Mandatory tumor samples underwent mutation and biomarker analysis.

A Phase Ib Dose-Escalation Study of the Safety, Tolerability, and Pharmacokinetics of Cobimetinib and Duligotuzumab in Patients with Previously Treated Locally Advanced or Metastatic Cancers with Mutant KRAS.

Lessons Learned: Cobimetinib and duligotuzumab were well tolerated as single agents and in combination with other agents.The cobimetinib and duligotuzumab combination was associated with increased toxicity, most notably gastrointestinal, and limited efficacy in the patient population tested.

Background: -mutant tumors possess abnormal mitogen-activated protein kinases (MAPK) pathway signaling, leading to dysregulated cell proliferation.

Randomized Phase II Study of Duligotuzumab (MEHD7945A) vs. Cetuximab in Squamous Cell Carcinoma of the Head and Neck (MEHGAN Study).

Background: Duligotuzumab, a novel dual-action humanized IgG1 antibody that blocks ligand binding to epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 3 (HER3), inhibits signaling from all ligand-dependent HER dimers, and can elicit antibody-dependent cell-mediated cytotoxicity. High tumor-expression of neuregulin 1 (NRG1), a ligand to HER3, may enhance sensitivity to duligotuzumab.

Methods: This multicenter, open-label, randomized phase II study (MEHGAN) evaluated drug efficacy in patients with recurrent/metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) progressive on/after chemotherapy and among patients with NRG1-high tumors.

Phase Ib study of duligotuzumab (MEHD7945A) plus cisplatin/5-fluorouracil or carboplatin/paclitaxel for first-line treatment of recurrent/metastatic squamous cell carcinoma of the head and neck.

Background: This open-label, multicenter, phase Ib study assessed the safety and preliminary activity of duligotuzumab, a dual-action antibody that blocks ligand binding to human epidermal growth factor receptor 3 (HER3) and epidermal growth factor receptor, in combination with chemotherapy, in the first-line treatment of patients with recurrent/metastatic squamous cell cancer of the head and neck.

Methods: On day 1, duligotuzumab at a dose of 1650 mg intravenously was combined with cisplatin at a dose of 100 mg/m and 5-fluorouracil at a dose of 1000 mg/m /day on days 1 to 4 in treatment arm A, or carboplatin (area under the curve, 6 mg/mL/min) and paclitaxel (at a dose of 200 mg/m ) in treatment arm B. Up to 6 cycles (21 days/cycle) were followed by duligotuzumab maintenance until disease progression or intolerable toxicity occurred.

Integrated genomic analysis of colorectal cancer progression reveals activation of EGFR through demethylation of the EREG promoter.

Key molecular drivers that underlie transformation of colonic epithelium into colorectal adenocarcinoma (CRC) are well described. However, the mechanisms through which clinically targeted pathways are activated during CRC progression have yet to be elucidated. Here, we used an integrative genomics approach to examine CRC progression.

Clinical translation of ferumoxytol-based vessel size imaging (VSI): Feasibility in a phase I oncology clinical trial population.

Purpose: To assess the feasibility of acquiring vessel size imaging (VSI) metrics using ferumoxytol injections and stock pulse sequences in a multicenter Phase I trial of a novel therapy in patients with advanced metastatic disease.

Methods: Scans were acquired before, immediately after, and 48 h after injection, at screening and after 2 weeks of treatment. ΔR , ΔR2*, vessel density (Q), and relative vascular volume fractions (VVF) were estimated in both normal tissue and tumor, and compared with model-derived theoretical and experimental estimates based on preclinical murine xenograft data.

Safety and Pharmacokinetics/Pharmacodynamics of the First-in-Class Dual Action HER3/EGFR Antibody MEHD7945A in Locally Advanced or Metastatic Epithelial Tumors.

Purpose: The novel dual-action humanized IgG1 antibody MEHD7945A targeting HER3 and EGFR inhibits ligand-dependent HER dimer signaling. This phase I study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of MEHD7945A.

Experimental Design: Patients with locally advanced or metastatic epithelial tumors received escalating doses of MEHD7945A (1-30 mg/kg) every 2 weeks (q2w) until disease progression or intolerable toxicity.

Pertuzumab and erlotinib in patients with relapsed non-small cell lung cancer: a phase II study using 18F-fluorodeoxyglucose positron emission tomography/computed tomography imaging.

Background: Combination blockade of human epidermal growth factor receptor (HER) family signaling may confer enhanced antitumor activity than single-agent blockade. We performed a single-arm study of pertuzumab, a monoclonal antibody that inhibits HER2 dimerization, and erlotinib in relapsed non-small cell lung cancer (NSCLC).

Methods: Patients received pertuzumab (840-mg loading dose and 420-mg maintenance intravenously every 3 weeks) and erlotinib (150-mg or 100-mg dose orally, daily).

High heregulin expression is associated with activated HER3 and may define an actionable biomarker in patients with squamous cell carcinomas of the head and neck.

Purpose: Tumors with oncogenic dependencies on the HER family of receptor tyrosine kinases (RTKs) often respond well to targeted inhibition. Our previous work suggested that many cell lines derived from squamous cell carcinomas of the head and neck (SCCHNs) depend on autocrine signaling driven by HER2/3 dimerization and high-level co-expression of HRG. Additionally, results from a Phase I trial of MEHD7495A, a dual-action antibody that blocks ligand binding to EGFR and HER3, suggest that high-level HRG expression was associated with clinical response in SCCHN patients.

Evaluation of circulating tumor cells and circulating tumor DNA in non-small cell lung cancer: association with clinical endpoints in a phase II clinical trial of pertuzumab and erlotinib.

Purpose: Elevated levels or increases in circulating tumor cells (CTC) portend poor prognosis in patients with epithelial cancers. Less is known about CTCs as surrogate endpoints or their use for predictive biomarker evaluation. This study investigated the utility of CTC enumeration and characterization using the CellSearch platform, as well as mutation detection in circulating tumor DNA (ctDNA), in patients with advanced non-small cell lung cancer (NSCLC).

Spatial characteristics of newly diagnosed grade 3 glioma assessed by magnetic resonance metabolic and diffusion tensor imaging.

The spatial heterogeneity in magnetic resonance (MR) metabolic and diffusion parameters and their relationship were studied for patients with treatment-naive grade 3 gliomas. MR data were evaluated from 51 patients with newly diagnosed grade 3 gliomas. Anatomic, diffusion, and metabolic imaging data were considered.

Changes in 18F-fluorodeoxyglucose and 18F-fluorodeoxythymidine positron emission tomography imaging in patients with non-small cell lung cancer treated with erlotinib.

Purpose: Assessing clinical activity of molecularly targeted anticancer agents, especially in the absence of tumor shrinkage, is challenging. To evaluate on-treatment 18F-fluorodeoxyglucose (FDG) and/or 18F-fluorodeoxythymidine (FLT) positron emission tomography (PET) for this purpose, we conducted a prospective multicenter trial assessing PET response rates and associations with progression-free (PFS) and overall survival (OS) in 2nd/3rd-line non-small-cell lung cancer patients treated with erlotinib.

Experimental Design: PET/computed tomography (CT) scans were conducted at baseline, day (d)14 and d56 after the first daily erlotinib dose, with diagnostic CT at baseline and d56 (all scans centrally reviewed).

Compliance with PET acquisition protocols for therapeutic monitoring of erlotinib therapy in an international trial for patients with non-small cell lung cancer.

Purpose: The Response Evaluation Criteria in Solid Tumors (RECIST) are widely used but have recognized limitations. Molecular imaging assessments, including changes in (18)F-deoxyglucose (FDG) or (18)F-deoxythymidine (FLT) uptake by positron emission tomography (PET), may provide earlier, more robust evaluation of treatment efficacy.

Methods: A prospective trial evaluated on-treatment changes in FDG and FLT PET imaging among patients with relapsed or recurrent non-small cell lung cancer treated with erlotinib to assess the relationship between PET-evaluated response and clinical outcomes.

Molecular biomarker analyses using circulating tumor cells.

Background: Evaluation of cancer biomarkers from blood could significantly enable biomarker assessment by providing a relatively non-invasive source of representative tumor material. Circulating Tumor Cells (CTCs) isolated from blood of metastatic cancer patients hold significant promise in this regard.

Methodology/principal Findings: Using spiked tumor-cells we evaluated CTC capture on different CTC technology platforms, including CellSearch and two biochip platforms, and used the isolated CTCs to develop and optimize assays for molecular characterization of CTCs.

Ex vivo MR spectroscopic measure differentiates tumor from treatment effects in GBM.

The motivation of this study was to address the urgent clinical problem related to the inability of magnetic resonance (MR) imaging measures to differentiate tumor progression from treatment effects in patients with glioblastoma multiforme (GBM). While contrast enhancement on MR imaging (MRI) is routinely used for assessment of tumor burden, therapy response, and progression-free survival in GBM, it is well known that changes in enhancement following treatment are nonspecific to tumor. To address this issue, the objective of this study was to investigate whether MR spectroscopy can provide improved biomarker surrogates for tumor following treatment.

Tumor regrowth between surgery and initiation of adjuvant therapy in patients with newly diagnosed glioblastoma.

To assess incidence and degree of regrowth in glioblastoma between surgery and radiation therapy (RT) and to correlate regrowth with presurgical imaging and survival, we examined images of 32 patients with newly diagnosed glioblastoma who underwent MR spectroscopic imaging (MRSI), perfusion-weighted imaging (PWI), and diffusion-weighted imaging (DWI) prior to surgery, after surgery, and prior to RT/temozolomide. Contrast enhancement (CE) in the pre-RT MR image was compared with postsurgical DWI to differentiate tumor growth from postsurgical infarct. MRSI and PWI parameters were analyzed prior to surgery and pre-RT.

Relationship of pre-surgery metabolic and physiological MR imaging parameters to survival for patients with untreated GBM.

Glioblastoma Multiforme (GBM) are heterogeneous lesions, both in terms of their appearance on anatomic images and their response to therapy. The goal of this study was to evaluate the prognostic value of parameters derived from physiological and metabolic images of these lesions. Fifty-six patients with GBM were scanned immediately before surgical resection using conventional anatomical MR imaging and, where possible, perfusion-weighted imaging, diffusion-weighted imaging, and proton MR spectroscopic imaging.

Evaluation of MR markers that predict survival in patients with newly diagnosed GBM prior to adjuvant therapy.

Purpose Glioblastoma Multiforme (GBM) is the most common and lethal primary brain tumor in adults. The goal of this study was to test the predictive value of MR parameters in relation to the survival of patients with newly diagnosed GBM who were scanned prior to receiving adjuvant radiation and chemotherapy. Methods The study population comprised 68 patients who had surgical resection and were to be treated with fractionated external beam radiation therapy and chemotherapy.

Potential value of MR spectroscopic imaging for the radiosurgical management of patients with recurrent high-grade gliomas.

Previous studies have shown that metabolic information provided by 3D Magnetic Resonance Spectroscopy Imaging (MRSI) could affect the definition of target volumes for radiation treatments (RT). This study aimed to (i) investigate the effect of incorporating spectroscopic volumes as determined by MRSI on target volume definition, patient selection eligibility, and dose prescription for stereotactic radiosurgery treatment planning; (ii) correlate the spatial extent of pre-SRS spectroscopic abnormality and treatment volumes with areas of focal recurrence as defined by changes in contrast enhancement; and (iii) examine the metabolic changes following SRS to assess treatment response. Twenty-six patients treated with Gamma Knife radiosurgery for recurrent glioblastoma multiforme (GBM) were retrospectively evaluated.

Patterns of recurrence analysis in newly diagnosed glioblastoma multiforme after three-dimensional conformal radiation therapy with respect to pre-radiation therapy magnetic resonance spectroscopic findings.

Purpose: To determine whether the combined magnetic resonance imaging (MRI) and magnetic resonance spectroscopy imaging (MRSI) before radiation therapy (RT) is valuable for RT target definition, and to evaluate the feasibility of replacing the current definition of uniform margins by custom-shaped margins based on the information from MRI and MRSI.

Methods And Materials: A total of 23 glioblastoma multiforme (GBM) patients underwent MRI and MRSI within 4 weeks after surgery but before the initiation of RT and at 2-month follow-up intervals thereafter. The MRSI data were quantified on the basis of a Choline-to-NAA Index (CNI) as a measure of spectroscopic abnormality.

Longitudinal multivoxel MR spectroscopy study of pediatric diffuse brainstem gliomas treated with radiotherapy.

Background And Purpose: After radiotherapy (RT), children with diffuse intrinsic pontine gliomas (DIPG) are followed with sequential magnetic resonance imaging (MRI). However, MRI changes do not necessarily reflect tumor progression, and therefore additional noninvasive tools are needed to improve the definition of progression vs. treatment-related changes.