Publications by authors named "Lee S Rosen"

70 Publications

Tolerability and antitumor activity of cemiplimab, a human monoclonal anti-PD-1, as monotherapy in patients with pretreated non-small cell lung cancer (NSCLC): Data from the Phase 1 NSCLC expansion cohort.

Lung Cancer 2021 May 4;155:151-155. Epub 2021 Mar 4.

Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA.

Objectives: Blockade of programmed cell death-1 (PD-1) and its ligand (PD-L1) has transformed the treatment of NSCLC. In a first-in-human, Phase 1, dose escalation and cohort expansion study, cemiplimab, a monoclonal antibody directed against PD-1, was evaluated for the treatment of patients with advanced solid tumors (NCT02383212). Here, we report results in patients with advanced NSCLC from the dose expansion cohort.

Materials And Methods: Immune-checkpoint inhibitor naive patients with advanced NSCLC (stage III/IV), irrespective of PD-L1 status, who had progressed after, or were refractory to first- or later-line therapy were enrolled and received cemiplimab 200 mg every 2 weeks intravenously for up to 48 weeks. Primary study objectives were to assess safety and tolerability, and to evaluate clinical activity of cemiplimab.

Results: Twenty patients with NSCLC were enrolled. Median age was 64.0 years (range: 50-82); 65.0 % were male; 80.0 % had an ECOG performance status of 1; 60.0 % had a histology of adenocarcinoma. Median number of prior lines of systemic therapy was 2 (range: 1-4). Median duration of follow-up was 7.0 months (range: 1.0-18.2). All patients experienced ≥1 treatment-emergent adverse event (TEAE) of any grade. Most common TEAEs were arthralgia, asthenia, cough, and dyspnea (each 4/20; 20.0 %). Grade ≥3 TEAEs occurred in 60.0 % (12/20) of patients. Of patients with measurable disease per independent central review (ICR), five had partial response (PR), four had stable disease (SD) and 10 had progressive disease. Objective response rate (ORR; complete response + PR) was 25.0 % (95 % CI: 8.7-49.1 %). Duration of response exceeded 8 months in four of the five responding patients at the time of data cut-off (April 30, 2019). The disease control rate per ICR (ORR + SD) was 50.0 % (95 % CI: 27.2-72.8 %).

Conclusion: Cemiplimab showed an acceptable safety profile and demonstrated antitumor activity in pretreated patients with NSCLC.
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http://dx.doi.org/10.1016/j.lungcan.2021.02.034DOI Listing
May 2021

First-In-Human Study of Cemiplimab Alone or In Combination with Radiotherapy and/or Low-dose Cyclophosphamide in Patients with Advanced Malignancies.

Clin Cancer Res 2020 03 3;26(5):1025-1033. Epub 2019 Dec 3.

Earle A. Chiles Research Institute and The Oregon Clinic, Portland, Oregon.

Purpose: This first-in-human study assessed the safety, tolerability, dose-limiting toxicities (DLT), antitumor activity, and pharmacokinetics of cemiplimab, a monoclonal anti-programmed cell death-1 (PD-1), as monotherapy and in combination with hypofractionated radiotherapy (hfRT) and/or cyclophosphamide (CPA) in patients with advanced solid tumors.

Patients And Methods: Patients were enrolled in 1 of 10 dose escalation cohorts and received cemiplimab 1, 3, or 10 mg/kg every 2 weeks intravenously for up to 48 weeks. Depending on the cohort, patients received hfRT and/or low-dose (200 mg/m) CPA. Safety was evaluated. Antitumor activity was assessed by Response Evaluation Criteria in Solid Tumors version 1.1.

Results: Sixty patients were enrolled. The median duration of follow-up was 19.3 weeks (range, 2.3-84.3). There were no DLTs. The most common treatment-emergent adverse events (TEAEs) of any grade were fatigue (45.0%), nausea (36.7%), and vomiting (25.0%). The most common immune-related adverse events (irAEs) of any grade were arthralgia (10.0%), hypothyroidism (8.3%), and maculopapular rash (8.3%). Cemiplimab pharmacokinetic parameters increased in a close to dose-proportional manner and were similar regardless of combination therapy regimen. Two patients (one with cutaneous squamous cell carcinoma and one with cervical cancer) experienced a complete response; 7 had a partial response. Observed duration of response was ≥12 months in 6 patients.

Conclusions: The safety profile of cemiplimab was comparable with other anti-PD-1 agents. Addition of hfRT and/or CPA did not appear to increase grade ≥3 irAEs, suggesting that cemiplimab can be safely administered with hfRT and/or CPA. Cemiplimab exhibited encouraging antitumor activity with 2 complete responses and 7 partial responses observed; responses were also durable.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2609DOI Listing
March 2020

A phase I, dose-escalation study of PF-06650808, an anti-Notch3 antibody-drug conjugate, in patients with breast cancer and other advanced solid tumors.

Invest New Drugs 2020 02 18;38(1):120-130. Epub 2019 Mar 18.

START Center for Cancer Care, 4383 Medical Dr., San Antonio, TX, 78229, USA.

Background PF-06650808 is a novel anti-Notch3 antibody-drug conjugate (ADC) able to deliver an auristatin-based cytotoxic payload to target cells. In this first-in-human, dose-finding, phase I study (NCT02129205), we investigated safety, pharmacokinetics, immunogenicity, and preliminary antitumor activity of single-agent PF-06650808 in 40 patients with advanced breast cancer (BC) and other solid tumors unselected for Notch3 expression. Primary endpoint was dose-limiting toxicity (DLT). PF-06650808 was administered intravenously every 3 weeks at a starting dose of 0.2 mg/kg, escalated up to 6.4 mg/kg following the modified continual reassessment method. An additional dose level, 2.0 mg/kg, was evaluated in patients with advanced, estrogen receptor-positive (ER) BC. Results The majority of patients had advanced BC (60%) and almost all (90%) had received ≥3 prior lines of anticancer therapy. Treatment with PF-06650808 was generally well tolerated at dose levels ≤2.0 mg/kg with no DLTs. The maximum tolerated dose (MTD) was estimated to be 2.4 mg/kg. The most common treatment-related AEs in all patients were fatigue (40.0%), decreased appetite (37.5%), nausea (35.0%), alopecia (32.5%), abdominal pain (25.0%), pruritus (25.0%), and vomiting (25.0%). Five patients achieved a partial response (PR), including 2 unconfirmed PRs; 4 of the responders had ER/PR/HER2 BC. Sixteen (51.6%) patients achieved stable disease, including 8 (57.1%) of 14 patients with ER BC. Tumor samples from all responders tested positive for NOTCH3 expression in a retrospective, exploratory analysis. Conclusions The anti-Notch3 ADC PF-06650808 has demonstrated a manageable safety profile and early signs of antitumor activity in patients with advanced BC.
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http://dx.doi.org/10.1007/s10637-019-00754-yDOI Listing
February 2020

Phase I study of the anti-α5β1 monoclonal antibody MINT1526A with or without bevacizumab in patients with advanced solid tumors.

Cancer Chemother Pharmacol 2018 08 15;82(2):339-351. Epub 2018 Jun 15.

California Cancer Associates for Research & Excellence, Encinitas, CA, USA.

Purpose: MINT1526A is a monoclonal antibody that blocks the interaction of integrin alpha 5 beta 1 (α5β1) with its extracellular matrix ligands. This phase I study evaluated the safety and pharmacokinetics of MINT1526A with or without bevacizumab in patients with advanced solid tumors.

Methods: MINT1526A was administered every 3 weeks (Q3W) as monotherapy (arm 1) or in combination with bevacizumab 15 mg/kg, Q3W (arm 2). Each arm included a 3 + 3 dose-escalation stage and a dose-expansion stage.

Results: Twenty-four patients were enrolled in arm 1 (dose range 2-30 mg/kg) and 30 patients were enrolled in arm 2 (dose range 3-15 mg/kg). Monocyte α5β1 receptor occupancy was saturated at a dose of 15 mg/kg. No dose-limiting toxicities were observed, and the maximum tolerated dose was not reached in either arm. The most common adverse events, regardless of causality, included abdominal pain (25%), diarrhea (25%), nausea (21%), vomiting (21%), and fatigue (21%) in arm 1 and nausea (40%), fatigue (33%), vomiting (30%), dehydration (30%), headache (30%), and hypertension (30%) in arm 2. No grade ≥ 3 bleeding events were observed in either arm. No confirmed partial responses (PR) were observed in arm 1. In arm 2, one patient with thymic carcinoma experienced a confirmed PR and two patients with hepatocellular carcinoma (HCC) experienced durable minor radiographic responses.

Conclusions: MINT1526A, with or without bevacizumab, was well-tolerated. Preliminary evidence of combination efficacy, including in patients with HCC, was observed, but cannot be distinguished from bevacizumab monotherapy in this phase I study.
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http://dx.doi.org/10.1007/s00280-018-3622-8DOI Listing
August 2018

Phase 1 and pharmacokinetic study of LY3007113, a p38 MAPK inhibitor, in patients with advanced cancer.

Invest New Drugs 2018 08 1;36(4):629-637. Epub 2017 Dec 1.

South Texas Accelerated Research Therapeutics, San Antonio, TX, USA.

Background The signaling protein p38 mitogen-activated protein kinase (MAPK) regulates the tumor cell microenvironment, modulating cell survival, migration, and invasion. This phase 1 study evaluated the safety of p38 MAPK inhibitor LY3007113 in patients with advanced cancer to establish a recommended phase 2 dose. Methods In part A (dose escalation), LY3007113 was administered orally every 12 h (Q12H) at doses ranging from 20 mg to 200 mg daily on a 28-day cycle until the maximum tolerated dose (MTD) was reached. In part B (dose confirmation), patients received MTD. Safety, pharmacokinetics, pharmacodynamics, and tumor response data were evaluated. Results MTD was 30 mg Q12H. The most frequent treatment-related adverse events (>10%) were tremor, rash, stomatitis, increased blood creatine phosphokinase, and fatigue. Grade ≥ 3 treatment-related adverse events included upper gastrointestinal haemorrhage and increased hepatic enzyme, both occurring at 40 mg Q12H and considered dose-limiting toxicities. LY3007113 exhibited an approximately dose-proportional increase in exposure and time-independent pharmacokinetics after repeated dosing. Maximal inhibition (80%) of primary biomarker MAPK-activated protein kinase 2 in peripheral blood mononuclear cells was not reached, and sustained minimal inhibition (60%) was not maintained for 6 h after dosing to achieve a biologically effective dose (BED). The best overall response in part B was stable disease in 3 of 27 patients. Conclusions The recommended phase 2 dosage of LY3007113 was 30 mg Q12H. Three patients continued treatment after the first radiographic assessment, and the BED was not achieved. Further clinical development of this compound is not planned as toxicity precluded achieving a biologically effective dose.
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http://dx.doi.org/10.1007/s10637-017-0532-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6061137PMC
August 2018

Phase 1 trials of PEGylated recombinant human hyaluronidase PH20 in patients with advanced solid tumours.

Br J Cancer 2018 01 26;118(2):153-161. Epub 2017 Sep 26.

Mayo Clinic, 13400 E. Shea Boulevard, Scottsdale, AZ 85259, USA.

Background: Hyaluronan accumulation in tumour stroma is associated with reduced survival in preclinical cancer models. PEGPH20 degrades hyaluronan to facilitate tumour access for cancer therapies. Our objective was to assess safety and antitumour activity of PEGPH20 in patients with advanced solid tumours.

Methods: In HALO-109-101 (N=14), PEGPH20 was administered intravenously once or twice weekly (0.5 or 50 μg kg) or once every 3 weeks (0.5-1.5 μg kg). In HALO-109-102 (N=27), PEGPH20 was administered once or twice weekly (0.5-5.0 μg kg), with dexamethasone predose and postdose.

Results: Dose-limiting toxicities included grade ⩾3 myalgia, arthralgia, and muscle spasms; the maximum tolerated dose was 3.0 μg kg twice weekly. Plasma hyaluronan increased in a dose-dependent manner, achieving steady state by Day 8 in multidose studies. A decrease in tumour hyaluronan level was observed in 5 of the 6 patients with pretreatment and posttreatment tumour biopsies. Exploratory imaging showed changes in tumour perfusion and decreased tumour metabolic activity, consistent with observations in animal models.

Conclusions: The tumour stroma has emerging importance in the development of cancer therapeutics. PEGPH20 3.0 μg kg administered twice weekly is feasible in patients with advanced cancers; exploratory analyses indicate antitumour activity supporting further evaluation of PEGPH20 in solid tumours.
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http://dx.doi.org/10.1038/bjc.2017.327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5785735PMC
January 2018

Bevacizumab in Colorectal Cancer: Current Role in Treatment and the Potential of Biosimilars.

Target Oncol 2017 Oct;12(5):599-610

Mount Sinai Hospital, Joseph and Wolf Lebovic Health Complex, 600 University Avenue, Toronto, ON, M5G 1X5, Canada.

Colorectal cancer (CRC) is a leading cause of tumor-related morbidity and mortality worldwide, with mortality most often attributable to metastatic disease. Bevacizumab, a humanized monoclonal antibody targeting vascular endothelial growth factor, has a significant role in the treatment of metastatic CRC (mCRC). However, patient access to bevacizumab may be limited in some regions or circumstances, owing to factors related to insurance coverage, reimbursement, patient out-of-pocket costs, or availability. As a result, outcomes for patients with mCRC may be worsened. Additionally, counterfeit bevacizumab has infiltrated legitimate supply chains, exposing patients to risk. Oncologists may also be affected detrimentally, since resolving access issues can be time-consuming and demoralizing. The imminent expiry of patents protecting bevacizumab provides other manufacturers with the opportunity to produce highly similar versions known as biosimilars. High-quality, safe, and effective biosimilars have the potential to expand access to bevacizumab. Most of the bevacizumab biosimilars currently in development are in clinical trials in patients with non-small-cell lung cancer, and future authorization for mCRC indications will, therefore, be based on extrapolation. This article reviews the current role of bevacizumab in the management of mCRC, the possible barriers associated with diminished access to bevacizumab, and the potential bevacizumab biosimilars in development. How biosimilars may impact the treatment of mCRC is also discussed.
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http://dx.doi.org/10.1007/s11523-017-0518-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5610666PMC
October 2017

A phase 1 study of the pharmacokinetics of nucleoside analog trifluridine and thymidine phosphorylase inhibitor tipiracil (components of TAS-102) vs trifluridine alone.

Invest New Drugs 2017 04 23;35(2):189-197. Epub 2017 Jan 23.

University of Pittsburgh Cancer Institute/UPMC, 5150 Centre Avenue, Fifth Floor, Pittsburgh, PA, 15232, USA.

Background Trifluridine, a thymidine-based chemotherapeutic, has limited bioavailability after clinical administration as it is rapidly degraded via thymidine phosphorylase. An oral combination tablet combines trifluridine with a potent thymidine phosphorylase inhibitor, tipiracil hydrochloride. This study's objective was to evaluate whether trifluridine/tipiracil (TAS-102) administration increases trifluridine exposure vs trifluridine alone. Methods This open-label pharmacokinetic study randomly assigned patients with advanced solid tumors into two groups. On the morning of day 1, one group received a single 35 mg/m dose of trifluridine/tipiracil and the other group received a single 35-mg/m dose of trifluridine. Both groups received trifluridine/tipiracil 35 mg/m on the evening of day 1, then twice daily on days 2-5 and 8-12 in a 28-day cycle. Results Twenty patients received an initial one-time dose of trifluridine alone and 19 other patients received an initial dose of trifluridine/tipiracil. Trifluridine area under the curve (AUC) and maximum observed plasma concentrations (C) were approximately 37- and 22-fold higher, respectively, with trifluridine/tipiracil vs trifluridine alone. Plasma concentrations of the major metabolite of trifluridine were lower following the administration of trifluridine/tipiracil vs trifluridine alone. Conclusion Tipiracil administered in combination with trifluridine significantly increased exposure to trifluridine compared with trifluridine alone.
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http://dx.doi.org/10.1007/s10637-016-0409-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5352756PMC
April 2017

A First-in-Human Phase I Study of a Bivalent MET Antibody, Emibetuzumab (LY2875358), as Monotherapy and in Combination with Erlotinib in Advanced Cancer.

Clin Cancer Res 2017 04 10;23(8):1910-1919. Epub 2016 Oct 10.

Mayo Clinic Rochester, Rochester, Minnesota.

The MET/HGF pathway regulates cell proliferation and survival and is dysregulated in multiple tumors. Emibetuzumab (LY2875358) is a bivalent antibody that inhibits HGF-dependent and HGF-independent MET signaling. Here, we report dose escalation results from the first-in-human phase I trial of emibetuzumab. The study comprised a 3+3 dose escalation for emibetuzumab monotherapy (Part A) and in combination with erlotinib (Part A2). Emibetuzumab was administered i.v. every 2 weeks (Q2W) using a flat dosing scheme. The primary objective was to determine a recommended phase II dose (RPTD) range; secondary endpoints included tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity. Twenty-three patients with solid tumors received emibetuzumab monotherapy at 20, 70, 210, 700, 1,400, and 2,000 mg and 14 non-small cell lung cancer (NSCLC) patients at 700, 1,400, and 2,000 mg in combination with erlotinib 150 mg daily. No dose-limiting toxicities and related serious or ≥ grade 3 adverse events were observed. The most common emibetuzumab-related adverse events included mild diarrhea, nausea, and vomiting, and mild to moderate fatigue, anorexia, and hypocalcemia in combination with erlotinib. Emibetuzumab showed linear PK at doses >210 mg. Three durable partial responses were observed, one for emibetuzumab (700 mg) and two for emibetuzumab + erlotinib (700 mg and 2,000 mg). Both of the responders to emibetuzumab + erlotinib had progressed to prior erlotinib and were positive for MET protein tumor expression. Based on tolerability, PK/PD analysis, and preliminary clinical activity, the RPTD range for emibetuzumab single agent and in combination with erlotinib is 700 to 2,000 mg i.v. Q2W. .
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http://dx.doi.org/10.1158/1078-0432.CCR-16-1418DOI Listing
April 2017

A first-in-human phase I study to evaluate the MEK1/2 inhibitor, cobimetinib, administered daily in patients with advanced solid tumors.

Invest New Drugs 2016 10 16;34(5):604-13. Epub 2016 Jul 16.

Stanford University, Stanford, CA, USA.

Objective Cobimetinib, a MEK1/2 inhibitor, was administered to patients with advanced solid tumors to assess safety, pharmacokinetics, pharmacodynamics, and anti-tumor activity. Methods For dose-escalation, a 3 + 3 design was used. Oral cobimetinib was administered once daily on a 21-day on/7-day off (21/7) or a 14-day on/14-day off (14/14) schedule. Serial plasma samples were collected for pharmacokinetic (PK) analysis on Day 1 and at steady state. In expansion stages, patients with RAS or RAF mutant tumors were treated at the maximum tolerated dose (MTD) of the 21/7 or 14/14 schedule. Results Ninety-seven patients received cobimetinib. In the 21/7 dose escalation, 36 patients enrolled in 8 cohorts (0.05 mg/kg-80 mg). Dose-limiting toxicities (DLTs) were Grade 4 hepatic encephalopathy, Grade 3 diarrhea, and Grade 3 rash. In the 14/14 dose escalation, 20 patients enrolled in 4 cohorts (60-125 mg). DLTs were Grade 3 rash and Grade 3 blurred vision associated with presence of reversible subretinal fluid. The MTD was 60 mg on 21/7 schedule and 100 mg on 14/14 schedule. Cobimetinib PK showed dose-proportional increases in exposure. The most frequent adverse events attributed to cobimetinib were diarrhea, rash, fatigue, edema, nausea, and vomiting. In patients treated at the 60-mg (21/7) or 100-mg (14/14) dose, one unconfirmed complete response and 6 confirmed partial responses were observed. All responses occurred in melanoma patients; 6 harbored the BRAF(V600E) mutation. Conclusions Cobimetinib is generally well tolerated and durable responses were observed in BRAF(V600E) mutant melanoma patients. Evaluation of cobimetinib in combination with other therapies is ongoing.
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http://dx.doi.org/10.1007/s10637-016-0374-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863157PMC
October 2016

Efficacy and Safety of Abemaciclib, an Inhibitor of CDK4 and CDK6, for Patients with Breast Cancer, Non-Small Cell Lung Cancer, and Other Solid Tumors.

Cancer Discov 2016 07 23;6(7):740-53. Epub 2016 May 23.

Dana-Farber Cancer Institute, Boston, Massachusetts.

Unlabelled: We evaluated the safety, pharmacokinetic profile, pharmacodynamic effects, and antitumor activity of abemaciclib, an orally bioavailable inhibitor of cyclin-dependent kinases (CDK) 4 and 6, in a multicenter study including phase I dose escalation followed by tumor-specific cohorts for breast cancer, non-small cell lung cancer (NSCLC), glioblastoma, melanoma, and colorectal cancer. A total of 225 patients were enrolled: 33 in dose escalation and 192 in tumor-specific cohorts. Dose-limiting toxicity was grade 3 fatigue. The maximum tolerated dose was 200 mg every 12 hours. The most common possibly related treatment-emergent adverse events involved fatigue and the gastrointestinal, renal, or hematopoietic systems. Plasma concentrations increased with dose, and pharmacodynamic effects were observed in proliferating keratinocytes and tumors. Radiographic responses were achieved in previously treated patients with breast cancer, NSCLC, and melanoma. For hormone receptor-positive breast cancer, the overall response rate was 31%; moreover, 61% of patients achieved either response or stable disease lasting ≥6 months.

Significance: Abemaciclib represents the first selective inhibitor of CDK4 and CDK6 with a safety profile allowing continuous dosing to achieve sustained target inhibition. This first-in-human experience demonstrates single-agent activity for patients with advanced breast cancer, NSCLC, and other solid tumors. Cancer Discov; 6(7); 740-53. ©2016 AACR.See related commentary by Lim et al., p. 697This article is highlighted in the In This Issue feature, p. 681.
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http://dx.doi.org/10.1158/2159-8290.CD-16-0095DOI Listing
July 2016

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

Magn Reson Med 2017 02 26;77(2):814-825. Epub 2016 Feb 26.

Clinical Imaging Group, Genentech, Inc., South San Francisco, California, USA.

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.

Results: R and R2* relaxation rates were still significantly elevated in tumors and liver 48 h after ferumoxytol injection; liver values returned to baseline by week 2. Q was relatively insensitive to changes in ΔR2*, indicating lack of dependence on contrast agent concentration. Variability in Q was higher among human tumors compared with xenografts and was mostly driven by ΔR . Relative VVFs were higher in human tumors compared with xenografts, while values in muscle were similar between species.

Conclusion: Clinical ferumoxytol-based VSI is feasible using standard MRI techniques in a multicenter study of patients with lesions outside of the brain. Ferumoxytol accumulation in the liver does not preclude measurement of VSI parameters in liver metastases. Magn Reson Med 77:814-825, 2017. © 2016 International Society for Magnetic Resonance in Medicine.
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http://dx.doi.org/10.1002/mrm.26167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5677523PMC
February 2017

Effect of Food on the Pharmacokinetics of the Investigational Aurora A Kinase Inhibitor Alisertib (MLN8237) in Patients with Advanced Solid Tumors.

Drugs R D 2016 Mar;16(1):45-52

Institute for Drug Development, Cancer Therapy and Research Center at University of Texas Health Science Center, San Antonio, TX, USA.

Objective: This study was conducted to characterize the effects of food on single-dose pharmacokinetics (PK) of the investigational Aurora A kinase inhibitor alisertib (MLN8237) in patients with advanced solid tumors.

Methods: Following overnight fasting for 10 h, a single 50 mg enteric-coated tablet (ECT) of alisertib was administered under either fasted (alisertib with 240 mL of water) or fed (high-fat meal consumed 30 min before receiving alisertib with 240 mL of water) conditions using a two-cycle, two-way crossover design. Patients on both arms were not allowed food for 4 h post-dose. Water was allowed as desired, except for 1 h before and after alisertib administration.

Results: Twenty-four patients were enrolled and 14 patients were PK-evaluable (ten patients were not PK-evaluable due to insufficient data). Following a single oral dose of alisertib, median t max was 6 h and 3 h under fed and fasted conditions, respectively. The geometric mean ratio of AUCinf (fed- vs. fasted-state dosing) was 0.94 [90% confidence interval (CI) 0.68-1.32]. The geometric mean C max under fed conditions was 84% of that under fasted conditions (90% CI 66-106). Alisertib was generally well-tolerated; most common drug-related grade 3/4 adverse events included neutropenia (50%), leukopenia (38%), and thrombocytopenia (21%).

Conclusions: Systemic exposures achieved following a single 50 mg dose of alisertib administered as an ECT formulation after a high-fat meal are similar to those observed in the fasted state. Alisertib 50 mg ECT can be administered without regard for food. CLINICALTRIALS.

Gov Identifier: NCT00962091.
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http://dx.doi.org/10.1007/s40268-015-0114-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767718PMC
March 2016

Safety, efficacy, and pharmacokinetics of navitoclax (ABT-263) in combination with irinotecan: results of an open-label, phase 1 study.

Cancer Chemother Pharmacol 2015 Nov 1;76(5):1041-9. Epub 2015 Oct 1.

UCLA Division of Hematology-Oncology, Santa Monica, CA, USA.

Purpose: The oral Bcl-2 inhibitor navitoclax demonstrated activity in solid and hematologic malignancies as monotherapy and in combination with other cytotoxic agents in preclinical and early clinical studies. We evaluated the safety, pharmacokinetics (PK), and antitumor activity of navitoclax plus irinotecan.

Methods: In this multicenter, open-label, phase 1 dose escalation study, adults with advanced solid tumors received navitoclax (starting dose 150 mg/day) in combination with 1 of 2 irinotecan schedules during a 21-day cycle: a once-every-3-week regimen (Q3W 180, 250, or 350 mg/m(2)) or a once-weekly regimen (QW 75 or 100 mg/m(2)). Enrollment occurred until a maximum tolerated dose (MTD) and/or recommended phase 2 dose (RPTD) was reached.

Results: All patients (Q3W, n = 14; QW, n = 17) were evaluable for safety, PK, and efficacy. The most common adverse event in both groups was diarrhea (Q3W 92.9 %; QW 76.5 %), which was the most frequent grade 3/grade 4 adverse event (Q3W 42.9 %; QW 29.4 %). The study was amended to exclude 4 UGT1A1*28 7/7 homozygous patients due to frequent irinotecan-related grade 3/grade 4 diarrhea and/or febrile neutropenia. No apparent PK interactions between navitoclax and irinotecan were observed. The MTD of the combination was exceeded in the Q3W group at the lowest dose administered. In the QW group, the MTD and RPTD for navitoclax were 150 mg when combined with irinotecan 75 mg/m(2). One patient in each group achieved a partial response.

Conclusion: The RPTD of navitoclax in combination with irinotecan 75 mg/m(2) QW during a 21-day cycle was 150 mg in these heavily pretreated patients.
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http://dx.doi.org/10.1007/s00280-015-2882-9DOI Listing
November 2015

Safety, efficacy, and pharmacokinetics of navitoclax (ABT-263) in combination with erlotinib in patients with advanced solid tumors.

Cancer Chemother Pharmacol 2015 Nov 29;76(5):1025-32. Epub 2015 Sep 29.

Division of Hematology-Oncology, University of California Los Angeles, 2020 Santa Monica Blvd, Suite 600, Santa Monica, CA, 90404, USA.

Purpose: Navitoclax (ABT-263), a novel, oral Bcl-2 inhibitor, enhances the antitumor effects of chemotherapy in vitro by lowering the apoptotic threshold. This phase I study (NCT01009073) evaluated the safety, pharmacokinetics, and preliminary antitumor activity of navitoclax combined with erlotinib in patients with advanced solid tumors.

Patients And Methods: An open-label dose escalation study included an arm evaluating navitoclax combined with erlotinib, which included a dose escalation cohort and a planned safety expansion cohort. Patients with documented cancers for whom erlotinib therapy was appropriate received erlotinib 150 mg orally once daily plus navitoclax 150 mg orally once daily, with navitoclax dose escalation via a continuous reassessment method model.

Results: Eleven patients were enrolled, including six patients with nonsmall cell lung cancer. Dose-limiting toxicities, most commonly diarrhea, were observed in 4 patients. Navitoclax dosing remained at 150 mg/day because the maximum tolerated dose was exceeded at this starting dose. The planned dose escalation did not occur; no recommended phase II dose (RPTD) was identified, and there was no safety expansion cohort. The most common treatment-related adverse events were diarrhea, nausea, vomiting, and decreased appetite. Pharmacokinetic analysis showed no apparent interactions between co-administered navitoclax and erlotinib. No objective responses were observed; the disease control rate was 27 % (95 % CI, 6-61 %).

Conclusion: At the erlotinib and navitoclax doses administered, RPTD was not reached, but the safety profile of the combination was consistent with data from monotherapy studies. There were no apparent pharmacokinetic interactions between erlotinib and navitoclax. Three patients had stable disease.
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http://dx.doi.org/10.1007/s00280-015-2883-8DOI Listing
November 2015

Phase 1 study of oral TAS-102 in patients with refractory metastatic colorectal cancer.

Cancer Chemother Pharmacol 2015 Nov 14;76(5):925-32. Epub 2015 Sep 14.

Sarah Cannon Research Institute/Florida Cancer Specialists, 600 N. Cattlemen Road, Suite 200, Sarasota, FL, 34232, USA.

Purpose: To evaluate safety of TAS-102 administered twice daily (bid) on days 1-5 and 8-12 of a 4-week cycle, confirm feasibility of the Japanese recommended dose (RD), 35 mg/m(2), in Western patients with metastatic colorectal cancer (mCRC) refractory to standard chemotherapies, and describe preliminary antitumor activity.

Methods: This open-label, dose-escalation phase 1 study was conducted at four US centers. Patients were enrolled into two sequential cohorts [30 (cohort 1) or 35 mg/m(2)/dose bid (cohort 2)]; dose-limiting toxicities (DLT) were evaluated during cycle 1 in dose-escalation cohorts. At RD, 15 additional patients were enrolled in an expansion cohort.

Results: Patients (N = 27) with refractory mCRC received TAS-102; 74 % had received ≥4 prior regimens. DLT was not observed in three patients in cohort 1, and was in one out of nine patients in cohort 2 (grade 3 febrile neutropenia). Therefore, RD was identified as 35 mg/m(2) bid. At RD, fatigue (63 %), gastrointestinal disturbances and nausea (46 %), vomiting (46 %), and diarrhea (42 %) were common but rarely grade 3/4. Grade 3/4 nausea, vomiting, and diarrhea occurred at 4 % each. Grade 3/4 toxicity was predominantly hematologic [neutropenia (71 %), anemia (25 %)]; febrile neutropenia was observed in two patients. Stable disease lasting ≥6 weeks was achieved by 16 evaluable patients (70 %); median progression-free survival and overall survival were 5.3 and 7.5 months, respectively.

Conclusions: TAS-102 has an acceptable safety profile and preliminary evidence of disease stabilization in Western patients with refractory mCRC. Results from a randomized phase 3 study have shown survival benefit with disease stabilization evidence in this population.
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http://dx.doi.org/10.1007/s00280-015-2850-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4612319PMC
November 2015

Relative bioavailability of a prototype oral solution of the Aurora A kinase inhibitor alisertib (MLN8237) in patients with advanced solid tumors.

Int J Clin Pharmacol Ther 2015 Jul;53(7):563-72

Objectives: Alisertib (MLN8237) is an investigational, oral, small-molecule, selective inhibitor of Aurora A kinase. Phase I/II studies of powder-in-capsule (PIC) and enteric-coated tablet formulations of alisertib have determined the recommended phase II dose and have demonstrated anti-tumor activity. This phase I relative bioavailability study characterized the pharmacokinetics of a prototype oral solution (OS) of alisertib (developed for patients unable to swallow solid dosage forms) in reference to the PIC formulation in adult cancer patients.

Materials And Methods: A safety evaluation was undertaken first following a 3+3 design (OS starting dose, 15 mg). The relative bioavailability of alisertib OS vs. PIC was then evaluated following single dose administration of alisertib OS 25 mg and PIC 50 mg, using a 2-way crossover study design.

Results: The relative bioavailability (geometric mean dose-normalized AUCinf ratio) of alisertib OS vs. PIC formulation was 1.26 (90% confidence interval (CI): 1.09-1.47 (OS, n=17; PIC, n=18 evaluable patients)). These results support a distinguishable difference in bioavailability of alisertib between the two formulations (lower bound of 90% CI>1), with an estimated 26% higher total systemic exposure with alisertib OS vs. PIC. Alisertib absorption from OS was faster than from PIC, with a shorter median tmax (OS, 1 hour; PIC, 2 hours) and a geometric mean dose-normalized Cmax ratio (OS vs. PIC) of 1.90 (90% CI: 1.52 - 2.37).

Conclusions: These findings inform the starting dose of alisertib OS to support further clinical evaluation of alisertib in patients unable to swallow solid dosage forms.
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http://dx.doi.org/10.5414/CP202359DOI Listing
July 2015

Clinical outcomes of patients with advanced gastrointestinal stromal tumors: safety and efficacy in a worldwide treatment-use trial of sunitinib.

Cancer 2015 05 13;121(9):1405-13. Epub 2015 Jan 13.

Department of Interdisciplinary Oncology, HELIOS Clinic Berlin-Buch, Berlin, Germany.

Background: The objectives of this study were to provide sunitinib to patients with gastrointestinal stromal tumor (GIST) who were otherwise unable to obtain it and to collect broad safety and efficacy data from a large population of patients with advanced GIST after imatinib failure. (ClinicalTrials.gov identifier NCT00094029).

Methods: Imatinib-resistant/intolerant patients with advanced GIST received sunitinib on an initial dosing schedule of 50 mg daily in 6-week cycles (4 weeks on treatment, 2 weeks off treatment). Tumor assessment frequency was according to local practice, and response was assessed by investigators according to Response Evaluation Criteria in Solid Tumors version 1.0. Overall survival (OS) and safety were assessed regularly. Post hoc analyses evaluated different patterns of treatment management.

Results: At final data cutoff, 1124 patients comprised the intent-to-treat population, and 15% of these patients had a baseline Eastern Cooperative Oncology Group performance status ≥2. The median treatment duration was 7.0 months. The median time to tumor progression was 8.3 months (95% confidence interval [CI], 8.0-9.4 months), the median OS was 16.6 months (95% CI, 14.9-18.0 months), and 36% of patients were alive at the time of analysis. Patients for whom the initial dosing schedule was modified exhibited longer median OS (23.5 months) than those who were treated strictly according to the initial dosing schedule (11.1 months). The most common treatment-related grade 3 and 4 adverse events were hand-foot syndrome (11%), fatigue (9%), neutropenia (8%), hypertension (7%), and thrombocytopenia (6%). Treatment-related adverse events associated with cardiac function (eg, congestive heart failure and myocardial infarction) were reported at frequencies of ≤1% each.

Conclusions: This treatment-use study confirms the long-term safety and efficacy of sunitinib in a large international population of patients with advanced GIST after imatinib failure.
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http://dx.doi.org/10.1002/cncr.29220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4442000PMC
May 2015

Phase I dose-escalation trial of checkpoint kinase 1 inhibitor MK-8776 as monotherapy and in combination with gemcitabine in patients with advanced solid tumors.

J Clin Oncol 2015 Mar 20;33(9):1060-6. Epub 2015 Jan 20.

Adil I. Daud, Michelle T. Ashworth, Alan P. Venook, Jennifer A. Grabowsky, and Pamela N. Munster, University of California, San Francisco, San Francisco; Jonathan W. Goldman and Lee S. Rosen, University of California, Los Angeles, Santa Monica, CA; Jonathan Strosberg and Gregory Springett, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; David Mendelson, Pinnacle Oncology Hematology, Scottsdale, AZ; and Sabine Loechner, Frances Shanahan, David Parry, Stuart Shumway, Tomoko Freshwater, Christopher Sorge, Soonmo Peter Kang, and Randi Isaacs, Merck, Whitehouse Station, NJ.

Purpose: We determined the safety, pharmacokinetics, pharmacodynamics, and recommended phase II dose of MK-8776 (SCH 900776), a potent, selective checkpoint kinase 1 (Chk1) inhibitor, as monotherapy and in combination with gemcitabine in a first-in-human phase I clinical trial in patients with advanced solid tumor malignancies.

Patients And Methods: Forty-three patients were treated by intravenous infusion with MK-8776 at seven dose levels ranging from 10 to 150 mg/m(2) as monotherapy and then in combination with gemcitabine 800 mg/m(2) (part A, n = 26) or gemcitabine 1,000 mg/m(2) (part B, n = 17). Forty percent of patients had three or more prior treatment regimens, and one third of patients had previously received gemcitabine.

Results: As monotherapy, MK-8776 was well tolerated, with QTc prolongation (19%), nausea (16%), fatigue (14%), and constipation (14%) as the most frequent adverse effects. Combination therapy demonstrated a higher frequency of adverse effects, predominantly fatigue (63%), nausea (44%), decreased appetite (37%), thrombocytopenia (32%), and neutropenia (24%), as well as dose-related, transient QTc prolongation (17%). The median number of doses of MK-8776 administered was five doses, with relative dose-intensity of 0.96. Bioactivity was assessed by γ-H2AX ex vivo assay. Of 30 patients evaluable for response, two showed partial response, and 13 exhibited stable disease.

Conclusion: MK-8776 was well tolerated as monotherapy and in combination with gemcitabine. Early evidence of clinical efficacy was observed. The recommended phase II dose is MK-8776 200 mg plus gemcitabine 1,000 mg/m(2) on days 1 and 8 of a 21-day cycle.
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http://dx.doi.org/10.1200/JCO.2014.57.5027DOI Listing
March 2015

A phase 1b, open-label study of trebananib plus bevacizumab or motesanib in patients with solid tumours.

Oncotarget 2014 Nov;5(22):11154-67

Department of Medicine, Division of Hematology and Oncology, UCLA, Santa Monica, CA 90404, USA.

Background: To examine the angiopoietin pathway inhibitor trebananib IV plus the anti-VEGF agents bevacizumab or motesanib in advanced solid tumours.

Methods: In this open-label phase 1b study, patients received IV trebananib 3 mg kg-1 QW plus bevacizumab 15 mg kg-1 Q3W (cohort 1) or motesanib orally 75 mg (cohort 2); or trebananib 10 mg kg-1 plus bevacizumab 15 mg kg-1 (cohort 3) or motesanib 125 mg (cohort 4). If <33% of patients had dose-limiting toxicities (DLTs), dose escalation occurred. Endpoints were treatment-related adverse events (AEs) incidence and pharmacokinetics (primary); anti-trebananib antibodies, biomarkers, and tumour response (secondary).

Results: Thirty-six patients received ≥ 1 dose of trebananib (cohorts 1, 2, 3, 4; n = 6, 8, 19, 3). DLT of G3 intestinal perforation and G3 tumor haemorrhage occurred in cohorts 2 and 3, respectively (both n = 1). Across both trebananib plus bevacizumab cohorts, the most common AEs included fatigue (n = 8), diarrhoea (n =4), constipation (n = 3), nausea (n = 3), and epistaxis (n = 3). Three patients across those cohorts had grade ≥ 3 AEs. Across the trebananib plus motesanib cohorts, the most common AEs included hypertension (n = 4), diarrhoea (n = 4), nausea (n = 3), fatigue (n = 3), vomiting (n = 2), and decreased appetite (n = 2). Two patients had grade ≥ 3 AEs. Trebananib did not markedly affect motesanib pharmacokinetics. Across the trebananib plus bevacizumab cohorts, two patients had a partial response; 11 patients had stable disease lasting >6 months. Across the trebananib plus motesanib cohorts, one patient had a partial response; five patients had stable disease lasting >6 months.

Conclusion: Trebananib IV 3 mg kg-1 or 10 mg kg-1 plus bevacizumab or motesanib in advanced solid tumours may be associated with less severe toxicities relative to those emerging when combining two anti-VEGF agents.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4294348PMC
http://dx.doi.org/10.18632/oncotarget.2568DOI Listing
November 2014

Phase I dose-escalation trial of the oral investigational Hedgehog signaling pathway inhibitor TAK-441 in patients with advanced solid tumors.

Clin Cancer Res 2015 Mar 12;21(5):1002-9. Epub 2014 Dec 12.

University of Colorado Cancer Center, Aurora, Colorado.

Purpose: This first-in-human study assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary clinical activity of single and multiple doses of TAK-441, an investigational inhibitor of the Hedgehog signaling pathway.

Experimental Design: Patients with advanced, solid tumors received daily oral TAK-441 (50-1,600 mg/day); daily dose was doubled in each subsequent cohort until the maximum tolerated/feasible dose (MTD/MFD) was reached. Blood was collected to evaluate TAK-441 plasma concentrations. Skin biopsies were obtained to evaluate suppression of the Hedgehog-regulated gene Gli1.

Results: Thirty-four patients were enrolled (median age 59). The most common diagnoses were colorectal cancer (26%), basal cell carcinoma (BCC, 21%), and pancreatic cancer (9%). The MFD of 1,600 mg/day (based on tablet size and strength) was considered the MTD. Dose-limiting toxicities included muscle spasms and fatigue. Grade ≥3 treatment-emergent adverse events, regardless of causality, occurred in 15 patients (44%), of which hyponatremia (n = 4) and fatigue (n = 3) were most common. Oral absorption was fairly rapid; median Tmax was 2.0 to 4.0 hours after a single dose. Mean elimination half-life was 13.5 to 22.6 hours. Systemic exposure of TAK-441 based on the area under the plasma concentration-time curve was linear across the dose range. Gli1 expression in skin biopsies was strongly inhibited at all dose levels. Best response was partial response (1 patient with BCC) and stable disease (7 patients with various solid tumors).

Conclusions: TAK-441 was generally well tolerated up to MFD of 1,600 mg/day, with preliminary antitumor activity. Further study of TAK-441 may be appropriate in populations selected for tumors with ligand-dependent or independent Hedgehog signaling.
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http://dx.doi.org/10.1158/1078-0432.CCR-14-1234DOI Listing
March 2015

An open-label phase Ib dose-escalation study of TRC105 (anti-endoglin antibody) with bevacizumab in patients with advanced cancer.

Clin Cancer Res 2014 Dec 26;20(23):5918-26. Epub 2014 Sep 26.

UCLA Department of Medicine, Los Angeles, California.

Purpose: Endoglin, an endothelial cell membrane receptor expressed on angiogenic tumor vessels, is essential for angiogenesis and upregulated in the setting of VEGF inhibition. TRC105 is an anti-endoglin IgG1 monoclonal antibody that potentiates VEGF inhibitors in preclinical models. This study assessed safety, pharmacokinetics, and antitumor activity of TRC105 in combination with bevacizumab.

Experimental Design: Patients (n = 38) with advanced solid tumors, Eastern Cooperative Group performance status 0-1, and normal organ function were treated with escalating doses of TRC105 plus bevacizumab until disease progression or unacceptable toxicity using a standard 3 + 3 phase I design.

Results: TRC105 and bevacizumab were well tolerated at their recommended single-agent doses (10 mg/kg) when the initial dose of TRC105 was delayed by one week and divided over 2 days to limit the frequency of headache. The concurrent administration of bevacizumab and TRC105 did not otherwise potentiate known toxicities of TRC105 or bevacizumab. Hypertension and proteinuria were observed, though not at rates expected for single-agent bevacizumab. Several patients who had previously progressed on bevacizumab or VEGF receptor tyrosine kinase inhibitor (VEGFR TKI) treatment experienced reductions in tumor volume, including two partial responses by RECIST, and 6 remained without progression for longer periods than during their prior VEGF inhibitor therapy.

Conclusions: TRC105 was well tolerated with bevacizumab and clinical activity was observed in a VEGF inhibitor-refractory population. Ongoing clinical trials are testing TRC105 in combination with bevacizumab in glioblastoma and with VEGFR TKIs in renal cell carcinoma, hepatocellular carcinoma, and soft tissue sarcoma.
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http://dx.doi.org/10.1158/1078-0432.CCR-14-1143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4570619PMC
December 2014

A phase 1 study to evaluate effect of food on veliparib pharmacokinetics and relative bioavailability in subjects with solid tumors.

Cancer Chemother Pharmacol 2014 Sep 23;74(3):583-91. Epub 2014 Jul 23.

Research and Development, AbbVie Inc., One N. Waukegan Road, North Chicago, IL, 60064, USA,

Purpose: A phase 1 study was conducted to evaluate the bioavailability and food effect of a new veliparib formulation in subjects with solid tumors.

Methods: Subjects (planned: Stage I, N = 20; Stage II, N = 16) received four regimens of a single oral dose of veliparib utilizing a group-sequential design. Subjects were administered single doses of 40 mg veliparib supplied as four 10 mg current formulation, four 10 mg new formulation and one 40 mg new formulation under fasting conditions and under non-fasting conditions. Serial blood samples were collected for the determination of veliparib pharmacokinetics. At the end of Stage I, the relative bioavailability between each pair of regimens was assessed by a two one-sided tests procedure from the analyses of the natural logarithms of C(max) and AUC. A 92.7 % confidence interval within the 0.80-1.25 range between each regimen pair determined bioequivalence.

Results: Four 10 mg current formulation capsules, four 10 mg new formulation and one 40 mg new formulation were bioequivalent with respect to C(max) and AUC under fasting conditions. The administration of a high-fat meal did not have a significant effect on AUC and only caused a slight decrease in veliparib C(max) (17 %) and a delay of approximately 1 h in T(max).

Conclusions: The 40 mg new capsule was bioequivalent to currently used formulation. Food had no effect on the extent of veliparib absorption and only a small (17 %) decrease in peak exposure of veliparib.
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http://dx.doi.org/10.1007/s00280-014-2529-2DOI Listing
September 2014

Endoglin for targeted cancer treatment.

Curr Oncol Rep 2014 Feb;16(2):365

Hematology-Oncology, UCLA Medical Center Santa Monica, 2020 Santa Monica Blvd, Ste 600, Santa Monica, CA, 90404, USA,

Endoglin is a homodimeric cell membrane glycoprotein receptor for transforming growth factor β and bone morphogenetic proteins. Endoglin is essential for angiogenesis, being densely expressed on proliferating endothelial cells and upregulated during hypoxia. Its expression is implicated in development of resistance to vascular endothelial growth factor (VEGF) inhibition. TRC105 is an antibody that binds endoglin and prevents endothelial cell activation. Targeting endoglin and the VEGF pathway concurrently improves treatment in vitro and appears to reverse resistance to bevacizumab in some refractory cancer patients. Randomized trials are under way to assess the clinical benefit of adding TRC105 therapy to bevacizumab therapy. Further trials are under way to assess the activity of TRC105 with small-molecule inhibitors of the VEGF pathway in renal cell carcinoma, hepatocellular carcinoma, and soft tissue sarcoma. Stratification of soft tissue sarcomas based on endoglin expression levels is proposed to identify patients most likely to benefit from TRC105 treatment. The development of a TRC105 antibody-drug conjugate is also described.
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http://dx.doi.org/10.1007/s11912-013-0365-xDOI Listing
February 2014

A phase I trial of LY2584702 tosylate, a p70 S6 kinase inhibitor, in patients with advanced solid tumours.

Eur J Cancer 2014 Mar 15;50(5):867-75. Epub 2014 Jan 15.

UCLA Division of Hematology & Oncology, Santa Monica, CA, USA. Electronic address:

Background: LY2584702 tosylate (hereafter referred to as LY2584702) is a potent, highly selective adenosine triphosphate (ATP) competitive inhibitor against p70 S6 kinase, a downstream component of the phosphatidylinositol-3-kinase signalling pathway which regulates cell proliferation and survival. LY2584702 exhibited anti-tumour activity in preclinical analysis.

Methods: Patients with advanced solid tumours were treated with LY2584702 orally on a 28-day cycle until the criteria for maximum tolerated dose (MTD) were met. Skin biopsies were collected for pharmacodynamic analysis, and levels of phospho-S6 protein were examined. The primary objective was to determine a phase II dose and schedule with secondary objectives of observing safety and tolerability. Dose escalation was based upon Common Terminology Criteria for Adverse Events Version 3.0.

Results: Thirty-four patients were enrolled onto this phase I study and treated with LY2584702 on a QD (once-daily) or BID (twice-daily) dosing schedule. Part A dose escalation (n=22) began with 300 mg BID (n=2). Due to toxicity, this was scaled back to doses of 25mg (n=3), 50 mg (n=8), 100mg (n=3), and 200 mg (n=6) QD. Part B dose escalation (n=12) included 50 mg (n=3), 75 mg (n=3), and 100 mg (n=6) BID. Seven patients experienced dose-limiting toxicity (DLT). All DLTs were Grade 3 and included vomiting, increased lipase, nausea, hypophosphataemia, fatigue and pancreatitis.

Conclusion: The MTD was determined to be 75 mg BID or 100mg QD. No responses were observed at these levels. Pharmacokinetic analysis revealed substantial variability in exposure and determined that LY2584702 treatment was not dose proportional with increasing dose.
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http://dx.doi.org/10.1016/j.ejca.2013.11.039DOI Listing
March 2014

A phase I study of the HSP90 inhibitor retaspimycin hydrochloride (IPI-504) in patients with gastrointestinal stromal tumors or soft-tissue sarcomas.

Clin Cancer Res 2013 Nov 17;19(21):6020-9. Epub 2013 Sep 17.

Authors' Affiliations: Dana-Farber Cancer Institute and Harvard Medical School; Ludwig Center at Dana-Farber/Harvard Cancer Center, Boston, Massachusetts; University of Michigan, Ann Arbor, Michigan; UCLA Division of Hematology-Oncology, Santa Monica, California; Pinnacle Oncology, Scottsdale, Arizona; and Infinity Pharmaceuticals, Inc., Cambridge, Massachusetts.

Purpose: Heat shock protein 90 (HSP90) is required for the proper folding, function, and stability of various client proteins, two of which (KIT and PDGFRα) are critical in the pathogenesis and progression of gastrointestinal stromal tumors (GIST). This phase I study investigated the safety and maximum tolerated dose (MTD) of retaspimycin hydrochloride (IPI-504), a novel potent and selective HSP90 inhibitor, in patients with metastatic and/or unresectable GIST or other soft-tissue sarcomas (STS).

Experimental Design: IPI-504 was administered intravenously at doses ranging from 90 to 500 mg/m(2) twice weekly for 2 weeks on/1 week off. Safety, pharmacokinetic, and pharmacodynamic profiles were determined. Response was assessed by Response Evaluation Criteria for Solid Tumors (RECIST) 1.0 and optionally via 18-fluorodeoxyglucose positron emission tomography (18-FDG-PET) imaging.

Results: Fifty-four patients received IPI-504; 37 with GIST and 17 with other STS. The MTD was 400 mg/m(2) twice weekly for 2 weeks on/1 week off. Common related adverse events were fatigue (59%), headache (44%), and nausea (43%). Exposure to IPI-504, 17-AAG, and 17-AG increased with IPI-504 dose. Stable disease (SD) was observed in 70% (26 of 37) of patients with GIST and 59% (10 of 17) of patients with STS. There was one confirmed partial response (PR) in a patient with GIST and one PR in a patient with liposarcoma. Metabolic partial responses occurred in 11 of 29 (38%) patients with GIST.

Conclusions: In this study of advanced GIST or other STS, IPI-504 was generally well-tolerated with some evidence of antitumor activity, serving as a clinical proof-of-concept that HSP90 inhibition remains a promising strategy.
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http://dx.doi.org/10.1158/1078-0432.CCR-13-0953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4330562PMC
November 2013

Phase I study of BIIB028, a selective heat shock protein 90 inhibitor, in patients with refractory metastatic or locally advanced solid tumors.

Clin Cancer Res 2013 Sep 19;19(17):4824-31. Epub 2013 Jul 19.

Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.

Purpose: Heat shot protein 90 (Hsp90) is a ubiquitous molecular chaperone involved in protein folding, activation, and assembly, including key mediators of signal transduction, cell-cycle control, and transcriptional regulation. We conducted a phase I dose-finding and pharmacokinetic/pharmacodynamic study of BIIB028, a prodrug designed to inhibit Hsp90 activity.

Experimental Design: Patients with advanced solid tumors were enrolled and received escalating doses of BIIB028 intravenously twice a week in 21-day cycles (3+3 design). Response was evaluated after two cycles.

Results: Forty-one patients received doses of 6 to 192 mg/m2. The maximum tolerated dose was 144 mg/m2. Dose-limiting toxicities were syncope (n=1) and fatigue (n=1). Common toxicities at least possibly related to drug were grades 1 to 2, including fatigue (46%), diarrhea (44%), nausea (44%), vomiting (29%), hot flushes (29%), and abnormal dreams (17%). The concentration-time curves for day 1 and day 18 for both prodrug and active metabolite (CF2772) showed a negligible difference. There was a dose-dependent increase in plasma exposure for BIIB028 (CF3647) and CF2772 with plasma half-life of 0.5 and 2.1 hours, respectively. Pharmacodynamic analyses showed significant increases in Hsp70 in peripheral blood mononuclear cells and significantly decreased circulating human EGF receptor-2 extracellular domain in all patients who received BIIB028 at dose levels of 48 mg/m2 or more. Stable disease for at least eight cycles (24 weeks) was achieved in 5 (12%) patients (for durations of 6, 6, 8, 12.5, and 19 months).

Conclusion: BIIB028 is a well-tolerated molecule that showed target impact and was associated with prolonged stable disease in two patients.
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http://dx.doi.org/10.1158/1078-0432.CCR-13-0477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3935614PMC
September 2013