Publications by authors named "Jan H Beumer"

137 Publications

Neratinib-Plus-Cetuximab in Quadruple-WT () Metastatic Colorectal Cancer Resistant to Cetuximab or Panitumumab: NSABP FC-7, A Phase Ib Study.

Clin Cancer Res 2021 Mar 17;27(6):1612-1622. Epub 2020 Nov 17.

NSABP Foundation, Inc., Pittsburgh, Pennsylvania.

Purpose: In metastatic colorectal cancer (mCRC), () gene amplification is implicated in anti-EGFR therapy resistance. We sought to determine the recommended phase II dose (RP2D) and efficacy of neratinib, a pan-ERBB kinase inhibitor, combined with cetuximab, in patients with progressive disease (PD) on anti-EGFR treatment.

Patients And Methods: Twenty-one patients with quadruple-wild-type, refractory mCRC enrolled in this 3+3 phase Ib study. Standard dosage cetuximab was administered with neratinib at 120 mg, 160 mg, 200 mg, and 240 mg/day orally in 28-day cycles. Samples were collected for molecular and pharmacokinetic studies.

Results: Sixteen patients were evaluable for dose-limiting toxicity (DLT). 240 mg was determined to be the RP2D wherein a single DLT occurred (1/7 patients). Treatment-related DLTs were not seen at lower doses. Best response was stable disease (SD) in 7 of 16 (44%) patients. amplification (chromogenic IHC) was detected in 2 of 21 (9.5%) treatment-naïve tumors and 4 of 16 (25%) biopsies upon trial enrollment (post-anti-EGFR treatment and progression). Compared with matched enrollment biopsies, 6 of 8 (75%) blood samples showed concordance for CNV in circulating cell-free DNA. Five SD patients had amplification in either treatment-naïve or enrollment biopsies. Examination of gene-expression, total protein, and protein phosphorylation levels showed relative upregulation of ≥2 members of the HER-family receptors or ligands upon enrollment versus matched treatment-naïve samples.

Conclusions: The RP2D of neratinib in this combination was 240 mg/day, which was well tolerated with low incidence of G3 AEs. There were no objective responses; SD was seen at all neratinib doses. amplification, detectable in both tissue and blood, was more frequent post-anti-EGFR therapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1831DOI Listing
March 2021

Improved chemosensitivity following mucolytic therapy in patient-derived models of mucinous appendix cancer.

Transl Res 2021 Mar 22;229:100-114. Epub 2020 Oct 22.

Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania. Electronic address:

Abundant intraperitoneal (IP) accumulation of extracellular mucus in patients with appendiceal mucinous carcinoma peritonei (MCP) causes compressive organ dysfunction and prevents delivery of chemotherapeutic drugs to cancer cells. We hypothesized that reducing extracellular mucus would decrease tumor-related symptoms and improve chemotherapeutic effect in patient-derived models of MCP. Mucolysis was achieved using a combination of bromelain (BRO) and N-acetylcysteine (NAC). Ex vivo experiments of mucolysis and chemotherapeutic drug delivery/effect were conducted with MCP and non-MCP tissue explants. In vivo experiments were performed in mouse and rat patient-derived xenograft (PDX) models of early and late (advanced) MCP. MCP tumor explants were less chemosensitive than non-MCP explants. Chronic IP administration of BRO + NAC in a mouse PDX model of early MCP and a rat PDX model of late (advanced) MCP converted solid mucinous tumors into mucinous ascites (mucolysis) that could be drained via a percutaneous catheter (rat model only), significantly reduced solid mucinous tumor growth and improved the efficacy of chemotherapeutic drugs. Combination of BRO + NAC efficiently lyses extracellular mucus in clinically relevant models of MCP. Conversion of solid mucinous tumors into mucinous ascites decreases tumor bulk and allows for minimally invasive drainage of liquified tumors. Lysis of extracellular mucus removes the protective mucinous coating surrounding cancer cells and improves chemotherapeutic drug delivery/efficacy in cancer cells. Our data provide a preclinical rationale for the clinical evaluation of BRO + NAC as a therapeutic strategy for MCP.
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http://dx.doi.org/10.1016/j.trsl.2020.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867596PMC
March 2021

In vitro evaluation of the metabolic enzymes and drug interaction potential of triapine.

Cancer Chemother Pharmacol 2020 Nov 28;86(5):633-640. Epub 2020 Sep 28.

Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA.

Purpose: To investigate the metabolic pathways of triapine in primary cultures of human hepatocytes and human hepatic subcellular fractions; to investigate interactions of triapine with tenofovir and emtricitabine; and to evaluate triapine as a perpetrator of drug interactions. The results will better inform future clinical studies of triapine, a radiation sensitizer currently being studied in a phase III study.

Methods: Triapine was incubated with human hepatocytes and subcellular fractions in the presence of a number of inhibitors of drug metabolizing enzymes. Triapine depletion was monitored by LC-MS/MS. Tenofovir and emtricitabine were co-incubated with triapine in primary cultures of human hepatocytes. Triapine was incubated with a CYP probe cocktail and human liver microsomes, followed by LC-MS/MS monitoring of CYP specific metabolite formation.

Results: Triapine was not metabolized by FMO, AO/XO, MAO-A/B, or NAT-1/2, but was metabolized by CYP450s. CYP1A2 accounted for most of the depletion of triapine. Tenofovir and emtricitabine did not alter triapine depletion. Triapine reduced CYP1A2 activity and increased CYP2C19 activity.

Conclusion: CYP1A2 metabolism is the major metabolic pathway for triapine. Triapine may be evaluated in cancer patients in the setting of HIV with emtricitabine or tenofovir treatment. Confirmatory clinical trials may further define the in vivo triapine metabolic fate and quantify any drug-drug interactions.
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http://dx.doi.org/10.1007/s00280-020-04154-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906094PMC
November 2020

Evaluation of the pharmacokinetic drug-drug interaction potential of iohexol, a renal filtration marker.

Cancer Chemother Pharmacol 2020 Oct 18;86(4):535-545. Epub 2020 Sep 18.

Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA.

Purpose: Carboplatin dose is calculated based on kidney function, commonly estimated with imperfect creatinine-based formulae. Iohexol is used to measure glomerular filtration rate (GFR) and allows calculation of a more appropriate carboplatin dose. To address potential concerns that iohexol administered during a course of chemotherapy impacts that therapy, we performed in vitro and in vivo pharmacokinetic drug-drug interaction evaluations of iohexol.

Methods: Carboplatin was administered IV to female mice at 60 mg/kg with or without iohexol at 300 mg/kg. Plasma ultrafiltrate, kidney and bone marrow platinum was quantitated by atomic absorption spectrophotometry. Paclitaxel microsomal and gemcitabine cytosolic metabolism as well as metabolism of CYP and UGT probes was assessed with and without iohexol at 300 µg/mL by LC-MS/MS.

Results: In vivo carboplatin exposure was not significantly affected by iohexol co-administration (platinum AUC combination vs alone: plasma ultrafiltrate 1,791 vs 1920 µg/mL min; kidney 8367 vs 9757 µg/g min; bone marrow 12.7 vs 12.7 µg/mg-protein min). Paclitaxel microsomal metabolism was not impacted (combination vs alone: 6-α-OH-paclitaxel 38.3 versus 39.4 ng/mL/60 min; 3-p-OH-paclitaxel 26.2 versus 27.7 ng/mL/60 min). Gemcitabine human cytosolic elimination was not impacted (AUC combination vs gemcitabine alone: dFdU 24.1 versus 23.7 µg/mL/30 min). Iohexol displayed no relevant inhibition of the CYP and UGT enzymes in human liver microsomes.

Conclusions: Iohexol is unlikely to affect the clinical pharmacokinetics of carboplatin, paclitaxel, gemcitabine, or other agents used in combination with carboplatin treatment. Measuring GFR with iohexol to better dose carboplatin is unlikely to alter the safety or efficacy of chemotherapy through pharmacokinetic drug-drug interactions.
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http://dx.doi.org/10.1007/s00280-020-04145-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521612PMC
October 2020

Quantitation of iohexol, a glomerular filtration marker, in human plasma by LC-MS/MS.

J Pharm Biomed Anal 2020 Sep 7;189:113464. Epub 2020 Jul 7.

Cancer Therapeutics Program, UPMC Hillman Cancer Center, Pittsburgh, PA, United States; Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, United States; Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States. Electronic address:

We developed a high-performance liquid chromatography mass spectrometry method for quantitating iohexol in 50 μL human plasma. After acetonitrile protein precipitation, chromatographic separation was achieved with a Shodex Asahipak NH2P-50 2D (5 μm, 2 × 150 mm) column and a gradient of 0.1 % formic acid in acetonitrile and 0.1 % formic acid in water over a 10 min run time. Mass spectrometric detection was performed on a Micromass Quatromicro triple-stage bench-top mass spectrometer with electrospray, positive-mode ionization. The assay was linear from 1 to 500 μg/mL for iohexol, proved to be accurate (101.3-102.1 %) and precise (<3.4 %CV), and fulfilled Food and Drug Administration (FDA) criteria for bioanalytical method validation. Recovery from plasma was 53.1-64.2 % and matrix effect was trivial (-3.4 to -1.3 %). Plasma freeze thaw stability (97.4-99.4 %), stability for 5 months at -80 °C (95.5-103.3 %), and stability for 4 h at room temperature (100.6-103.3 %) were all acceptable. This validated assay using a deuterated internal standard will be an important tool in measuring iohexol clearance and determining glomerular filtration rate (GFR) in patients.
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http://dx.doi.org/10.1016/j.jpba.2020.113464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484441PMC
September 2020

Phase I clinical trial of temozolomide and methoxyamine (TRC-102), an inhibitor of base excision repair, in patients with advanced solid tumors.

Invest New Drugs 2021 Feb 17;39(1):142-151. Epub 2020 Jun 17.

Case Comprehensive Cancer Center, Case Western Reserve University, University Hospitals Seidman Cancer Center, 11100 Euclid Avenue, Lakeside 1200, Cleveland, OH, 44106, USA.

Temozolomide (TMZ) generates DNA adducts that are repaired by direct DNA and base excision repair mechanisms. Methoxyamine (MX, TRC-102) potentiates TMZ activity by binding to apurinic and apyrimidinic (AP) sites after removal of N-methyladenine and N-methylguanine, inhibiting site recognition of AP endonuclease. We conducted a phase I trial to determine the maximum tolerated dose and dose-limiting toxicities (DLTs) of intravenous MX when given with oral TMZ. Patients with advanced solid tumors and progression on standard treatment were enrolled to a standard 3 + 3 dose escalation trial assessing escalating doses of TMZ and MX. Tumor response was assessed per RECIST and adverse events (AEs) by CTCAEv3. Pharmacokinetics (PK) of MX and COMET assays on peripheral blood mononuclear cells were performed. 38 patients were enrolled-median age 59.5 years (38-76), mean number of cycles 2.9 [1-13]. No DLTs were observed. Cycle 1 grade 3 AEs included fatigue, lymphopenia, anemia, INR, leukopenia, neutropenia, allergic reaction, constipation, psychosis and paranoia. Cycle 2-13 grade 4 AEs included thrombocytopenia and confusion. A partial response was seen in 1 patient with a pancreatic neuroendocrine tumor (PNET) and six additional patients, each with different tumor types, demonstrated prolonged stable disease. MX PK was linear with dose and was not affected by concomitant TMZ. TMZ 200 mg/m daily × 5 may be safely administered with MX 150 mg/m intravenously once on day 1 with minimal toxicity. Further studies assessing this drug combination in select tumor types where temozolomide has activity may be warranted.
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http://dx.doi.org/10.1007/s10637-020-00962-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744386PMC
February 2021

Intravenous 5-fluoro-2'-deoxycytidine administered with tetrahydrouridine increases the proportion of p16-expressing circulating tumor cells in patients with advanced solid tumors.

Cancer Chemother Pharmacol 2020 05 20;85(5):979-993. Epub 2020 Apr 20.

Division of Cancer Treatment and Diagnosis, National Cancer Institute, 31 Center Drive, Bldg. 31 Room 3A-44, Bethesda, MD, 20892, USA.

Purpose: Following promising responses to the DNA methyltransferase (DNMT) inhibitor 5-fluoro-2'-deoxycytidine (FdCyd) combined with tetrahydrouridine (THU) in phase 1 testing, we initiated a non-randomized phase 2 study to assess response to this combination in patients with advanced solid tumor types for which tumor suppressor gene methylation is potentially prognostic. To obtain pharmacodynamic evidence for DNMT inhibition by FdCyd, we developed a novel method for detecting expression of tumor suppressor protein p16/INK4A in circulating tumor cells (CTCs).

Methods: Patients in histology-specific strata (breast, head and neck [H&N], or non-small cell lung cancers [NSCLC] or urothelial transitional cell carcinoma) were administered FdCyd (100 mg/m) and THU (350 mg/m) intravenously 5 days/week for 2 weeks, in 28-day cycles, and progression-free survival (PFS) rate and objective response rate (ORR) were evaluated. Blood specimens were collected for CTC analysis.

Results: Ninety-three eligible patients were enrolled (29 breast, 21 H&N, 25 NSCLC, and 18 urothelial). There were three partial responses. All strata were terminated early due to insufficient responses (H&N, NSCLC) or slow accrual (breast, urothelial). However, the preliminary 4-month PFS rate (42%) in the urothelial stratum exceeded the predefined goal-though the ORR (5.6%) did not. An increase in the proportion of p16-expressing cytokeratin-positive CTCs was detected in 69% of patients evaluable for clinical and CTC response, but was not significantly associated with clinical response.

Conclusion: Further study of FdCyd + THU is potentially warranted in urothelial carcinoma but not NSCLC or breast or H&N cancer. Increase in the proportion of p16-expressing cytokeratin-positive CTCs is a pharmacodynamic marker of FdCyd target engagement.
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http://dx.doi.org/10.1007/s00280-020-04073-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188725PMC
May 2020

Phase I and pharmacokinetic study of veliparib, a PARP inhibitor, and pegylated liposomal doxorubicin (PLD) in recurrent gynecologic cancer and triple negative breast cancer with long-term follow-up.

Cancer Chemother Pharmacol 2020 04 13;85(4):741-751. Epub 2020 Feb 13.

NYU Langone Health, Division of Gynecologic Oncology, New York University School of Medicine, 240 East 38th street, 19th floor, New York, NY, USA.

Objective: Poly(ADP-ribosyl) polymerases (PARPs) are nuclear enzymes with roles in DNA damage recognition and repair. PARP1 inhibition enhances the effects of DNA-damaging agents like doxorubicin. We sought to determine the recommended phase two dose (RP2D) of veliparib with pegylated liposomal doxorubicin (PLD) in breast and recurrent gynecologic cancer patients.

Methods: Veliparib and PLD were administered in a standard phase 1, 3 + 3 dose-escalation design starting at 50 mg veliparib BID on days 1-14 with PLD 40 mg/mg on day 1 of a 28-day cycle. Dose escalation proceeded in two strata: A (prior PLD exposure) and B (no prior PLD exposure). Patients underwent limited pharmacokinetic (PK) sampling; an expansion PK cohort was added.

Results: 44 patients with recurrent ovarian or triple negative breast cancer were enrolled. Median age 56 years; 23 patients BRCA mutation carriers; median prior regimens four. Patients received a median of four cycles of veliparib/PLD. Grade 3/4 toxicities were observed in 10% of patients. Antitumor activity was observed in both sporadic and BRCA-deficient cancers. Two BRCA mutation carriers had complete responses. Two BRCA patients developed oral squamous cell cancers after completing this regimen. PLD exposure was observed to be higher when veliparib doses were > 200 mg BID.

Conclusions: The RP2D is 200 mg veliparib BID on days 1-14 with 40 mg/m PLD on day 1 of a 28-day cycle. Anti-tumor activity was seen in both strata. However, given development of long-term squamous cell cancers and the PK interaction observed, efforts should focus on other targeted combinations to improve efficacy.
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http://dx.doi.org/10.1007/s00280-020-04030-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845144PMC
April 2020

Triple drugs co-delivered by a small gemcitabine-based carrier for pancreatic cancer immunochemotherapy.

Acta Biomater 2020 04 28;106:289-300. Epub 2020 Jan 28.

Center for Pharmacogenetics, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA; Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address:

Poor tumor penetration and highly immunosuppressive tumor microenvironment are two major factors that limit the therapeutic efficacy for the treatment of pancreatic ductal adenocarcinoma (PDA). In this work, a redox-responsive gemcitabine (GEM)-conjugated polymer, PGEM, was employed as a tumor penetrating nanocarrier to co-load an immunomodulating agent (NLG919, an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1) and a chemotherapeutic drug (paclitaxel (PTX)) for immunochemo combination therapy. The NLG919/PTX co-loaded micelles showed very small size of ~15 nm. In vivo tumor imaging study indicated that PGEM was much more effective than the relatively large-sized POEG-co-PVD nanoparticles (~160 nm) in deep tumor penetration and could reach the core of the pancreatic tumor. PTX formulated in the PGEM carrier showed improved tumor inhibition effect compared with PGEM alone. Incorporation of NLG919 in the formulation led to a more immunoactive tumor microenvironment with significantly decreased percentage of Treg cells, and increased percentages of CD4 IFNγ T and CD8 IFNγ T cells. PGEM micelles co-loaded with PTX and NLG919 showed the best anti-tumor activity in pancreatic (PANC02) as well as two other tumor models compared to PGEM micelles loaded with PTX or NLG919 alone, suggesting that codelivery of NLG919 and PTX via PGEM may represent an effective strategy for immunochemotherapy of PDA as well as other types of cancers. STATEMENT OF SIGNIFICANCE: In order to effectively accumulate and penetrate the PDA that is poorly vascularized and enriched with dense fibrotic stroma, the size of nanomedicine has to be well controlled. Here, we reported an immunochemotherapy regimen based on co-delivery of GEM, PTX and IDO1 inhibitor NLG919 through an ultra-small sized GEM-based nanocarrier (PGEM). We demonstrated that the PGEM carrier was effective in accumulating and penetrating into PDA tumors. Besides, PGEM co-loaded with PTX and NLG9 induced an improved anti-tumor immune response and was highly efficacious in inhibiting tumor growth as well as in prolonging the survival rate in PANC02 xenograft model. Our work represents a potential strategy for enhancing PDA tumor penetration and immunochemotherapy.
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http://dx.doi.org/10.1016/j.actbio.2020.01.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183357PMC
April 2020

Editorial.

Authors:
Jan H Beumer

Cancer Chemother Pharmacol 2020 01;85(1)

Cancer Therapeutics Program, UPMC Hillman Cancer Center, Room G27E, Hillman Research Pavilion, 5117 Centre Avenue, Pittsburgh, PA, 15213-1863, USA.

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http://dx.doi.org/10.1007/s00280-020-04032-0DOI Listing
January 2020

Phase 1 study of the Aurora kinase A inhibitor alisertib (MLN8237) combined with the histone deacetylase inhibitor vorinostat in lymphoid malignancies.

Leuk Lymphoma 2020 02 16;61(2):309-317. Epub 2019 Oct 16.

Department of Medical Oncology, Division of Molecular Pharmacology, City of Hope, Duarte, CA, USA.

Alisertib, an Aurora kinase A inhibitor, was evaluated in a Phase 1 study in combination with the histone deacetylase inhibitor vorinostat, in patients with relapsed/refractory lymphoid malignancies ( = 34; NCT01567709). Patients received alisertib plus vorinostat in 21-day treatment cycles with escalating doses of alisertib following a continuous or an intermittent schedule. All dose-limiting toxicities (DLTs) were hematologic and there were no study-related deaths. The recommended phase 2 dose (RP2D) of the combination was 20 mg bid of alisertib and 200 mg bid of vorinostat on the intermittent schedule. A 13-patient expansion cohort was treated for a total of 18 patients at the RP2D. There were no DLTs at the RP2D, and toxicities were mainly hematologic. Two patients with DLBCL achieved a durable complete response, and two patients with HL achieved partial response. Alisertib plus vorinostat showed encouraging clinical activity with a manageable safety profile in heavily pretreated patients with advanced disease.
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http://dx.doi.org/10.1080/10428194.2019.1672052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6982547PMC
February 2020

Phase 1 study of veliparib (ABT-888), a poly (ADP-ribose) polymerase inhibitor, with carboplatin and paclitaxel in advanced solid malignancies.

Cancer Chemother Pharmacol 2019 12 23;84(6):1289-1301. Epub 2019 Sep 23.

Winship Cancer Institute, Emory University, Atlanta, GA, USA.

Purpose: Veliparib is an oral inhibitor of poly (ADP-ribose) polymerase (PARP)-1 and -2. PARP-1 expression may be increased in cancer, and this increase confers resistance to cytotoxic agents. We aimed to determine the recommended phase 2 dose (RP2D), maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics (PK) of veliparib combined with paclitaxel and carboplatin.

Methods: Eligibility criteria included patients with advanced solid tumors treated with ≤ 3 prior regimens. Paclitaxel and carboplatin were administered on day 3 of a 21-day cycle. Veliparib was given PO BID days 1-7, except for cycle 1 in the first 46 patients to serve as control for toxicity and PK. A standard "3 + 3" design started veliparib at 10 mg BID, paclitaxel at 150 mg/m, and carboplatin AUC 6. The pharmacokinetic (PK) disposition of veliparib, paclitaxel, and carboplatin was determined by LC-MS/MS and AAS during cycles 1 and 2.

Results: Seventy-three patients were enrolled. Toxicities were as expected with carboplatin/paclitaxel chemotherapy, including neutropenia, thrombocytopenia, and peripheral neuropathy. DLTs were seen in two of seven evaluable patients at the maximum administered dose (MAD): veliparib 120 mg BID, paclitaxel 200 mg/m, and carboplatin AUC 6 (febrile neutropenia, hyponatremia). The MTD and RP2D were determined to be veliparib 100 mg BID, paclitaxel 200 mg/m, and carboplatin AUC 6. Median number of cycles of the three-agent combination was 4 (1-16). We observed 22 partial and 5 complete responses. Veliparib did not affect paclitaxel or carboplatin PK disposition.

Conclusion: Veliparib, paclitaxel, and carboplatin were well tolerated and demonstrated promising antitumor activity.
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http://dx.doi.org/10.1007/s00280-019-03960-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825275PMC
December 2019

Phase I trial of belinostat in combination with 13-cis-retinoic acid in advanced solid tumor malignancies: a California Cancer Consortium NCI/CTEP sponsored trial.

Cancer Chemother Pharmacol 2019 12 14;84(6):1201-1208. Epub 2019 Sep 14.

Beckman Research Institute City of Hope, Duarte, CA, 91010, USA.

Purpose: The reported maximum tolerated dose (MTD) of single-agent belinostat is 1000 mg/m given days 1-5, every 21 days. Pre-clinical evidence suggests histone deacetylase inhibitors enhance retinoic acid signaling in a variety of solid tumors. We conducted a phase I study of belinostat combined with 50-100 mg/m/day 13-cis-retinoic acid (13-cRA) in patients with advanced solid tumors.

Methods: Belinostat was administered days 1-5 and 13-cRA days 1-14, every 21 days. Dose-limiting toxicity (DLT) was defined as cycle 1 hematologic toxicity grade ≥ 3 not resolving to grade ≤ 1 within 1 week or non-hematologic toxicity grade ≥ 3 (except controlled nausea and vomiting and transient liver function abnormalities) attributable to belinostat.

Results: Among 51 patients, two DLTs were observed: grade 3 hypersensitivity with dizziness and hypoxia at 1700 mg/m/day belinostat with 100 mg/m/day 13-cRA, and grade 3 allergic reaction at 2000 mg/m/day belinostat with 100 mg/m/day 13-cRA. The MTD was not reached. Pharmacokinetics of belinostat may be non-linear at high doses. Ten patients had stable disease, including one with neuroendocrine pancreatic cancer for 56 cycles, one with breast cancer for 12 cycles, and one with lung cancer for 8 cycles. Partial responses included a patient with keratinizing squamous cell carcinoma of the tonsils, and a patient with lung cancer.

Conclusions: The combination of belinostat 2000 mg/m days 1-5 and 13-cRA 100 mg/m days 1-14, every 21 days, was well-tolerated and an MTD was not reached despite doubling the established single-agent MTD of belinostat.
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http://dx.doi.org/10.1007/s00280-019-03955-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821594PMC
December 2019

Safety and Efficacy of T-DM1 Plus Neratinib in Patients With Metastatic HER2-Positive Breast Cancer: NSABP Foundation Trial FB-10.

J Clin Oncol 2019 10 23;37(29):2601-2609. Epub 2019 Aug 23.

NSABP Foundation, Pittsburgh, PA.

Purpose: Patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer eventually develop resistance to dual-antibody therapy with trastuzumab plus pertuzumab. Mechanisms of resistance have not been well elucidated. We evaluated the safety, tolerability, and efficacy of ado-trastuzumab emtansine (T-DM1) plus neratinib in patients who progressed on trastuzumab plus pertuzumab.

Patients And Methods: In this 3 + 3 dose-escalation study, patients with metastatic breast cancer who progressed on trastuzumab, pertuzumab, and a taxane were treated with T-DM1 at 3.6 mg/kg intravenously every 3 weeks and dose-escalating neratinib at 120, 160, 200, or 240 mg/d orally.

Results: Twenty-seven patients were treated across four dose-levels of neratinib. Dose-limiting toxicity in cycle 1 was grade 3 diarrhea in six patients and grade 3 nausea in one; no patient experienced grade 4 diarrhea, and there were no grade 5 toxicities. Other grade 3 to 4 toxicities included nausea (11%), dehydration (11%), electrolyte abnormality (19%), thrombocytopenia (15%), elevated transaminase levels (7%), and fatigue (7%). Twelve (63%) of 19 evaluable patients had an objective response. Responses occurred at all neratinib doses. Plasma cell-free DNA at baseline showed (HER2) amplification in 10 of 27 patients. Deep and more durable responses occurred in patients with cell-free DNA amplification. Two complete responders had high expression of total HER2 and p95HER2 in baseline tissue.

Conclusion: We report the recommended phase II dose of T-DM1 3.6 mg/kg and neratinib 160 mg/d for this combination. Possible resistance mechanisms to HER2 antibodies may be loss of the HER2 receptor and high expression of p95HER2. These data provide the basis for an ongoing phase II study to better define the activity of this regimen.
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http://dx.doi.org/10.1200/JCO.19.00858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784849PMC
October 2019

Combination Therapy with Disulfiram, Copper, and Doxorubicin for Osteosarcoma: Support for a Novel Drug Repurposing Strategy.

Sarcoma 2019 11;2019:1320201. Epub 2019 Jul 11.

Musculoskeletal Oncology Laboratory, Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA, USA.

Although many cancer cells have significantly higher copper concentrations compared with normal cells and tissues, the role of copper in cancer biology and metastatic disease remains poorly understood. Here, we study the importance of copper in osteosarcoma, which frequently metastasizes to the lungs and is often chemoresistant. K12 and K7M2 are murine OS cells with differing metastatic phenotypes: K7M2 is highly metastatic, whereas K12 is much less so. Intracellular copper levels were determined using atomic absorption. Copper transporters were quantified by qPCR. Cytotoxicity of doxorubicin, disulfiram, and copper(II) chloride was assessed with a cell viability fluorescence stain. Additionally, K7M2 viable cell counts were determined by trypan blue exclusion staining after 72 hours of treatment. Copper levels were found to be significantly higher in K12 OS cells than in K7M2 cells. qPCR showed that K12 cells upregulate the copper influx pump CTR1 and downregulate the copper efflux pump ATP7A compared to K7M2 OS cells. Combination treatment of copper chloride (50 nM) with disulfiram (80 nM) was only cytotoxic to K12 cells. Triple treatment with doxorubicin, disulfiram, and copper displayed potent and durable cytotoxicity of highly metastatic K7M2 cells. We demonstrate here that murine OS cell lines differing in metastatic potential also vary in endogenous copper levels and regulation. Additionally, these differences in copper regulation may contribute to selective cytotoxicity of K12 cells by extremely low doses of copper-potentiated disulfiram. The combination of doxorubicin, disulfiram, and copper should be explored as a therapeutic strategy against OS metastases.
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http://dx.doi.org/10.1155/2019/1320201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6657614PMC
July 2019

A phase I pharmacokinetic study of belinostat in patients with advanced cancers and varying degrees of liver dysfunction.

Br J Clin Pharmacol 2019 11 4;85(11):2499-2511. Epub 2019 Sep 4.

Early Clinical Trials Development Program, Developmental Therapeutics Clinic, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA.

Aims: The histone deacetylase inhibitor belinostat has activity in various cancers. Because belinostat is metabolized by the liver, reduced hepatic clearance could lead to excessive drug accumulation and increased toxicity. Safety data in patients with liver dysfunction are needed for this drug to reach its full potential in the clinic.

Methods: We performed a phase 1 trial to determine the safety, maximum tolerated dose (MTD) and pharmacokinetics of belinostat in patients with advanced cancer and varying degrees of liver dysfunction.

Results: Seventy-two patients were enrolled and divided into cohorts based on liver function. In patients with mild dysfunction, the MTD was the same as the recommended phase 2 dose (1000 mg/m /day). Belinostat was well tolerated in patients with moderate and severe liver dysfunction, although the trial was closed before the MTD in these cohorts could be determined. The mean clearance of belinostat was 661 mL/min/m in patients with normal liver function, compared to 542, 505 and 444 mL/min/m in patients with mild, moderate and severe hepatic dysfunction. Although this trial was not designed to assess clinical activity, of the 47 patients evaluable for response, 13 patients (28%) experienced stable disease.

Conclusion: While a statistically significant difference in clearance indicates increased belinostat exposure with worsening liver function, no relationship was observed between belinostat exposure and toxicity. An assessment of belinostat metabolites revealed significant differences in metabolic pathway capability in patients with differing levels of liver dysfunction. Further studies are needed to establish formal dosing guidelines in this patient population.
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http://dx.doi.org/10.1111/bcp.14054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6848909PMC
November 2019

Quantitation of paclitaxel, and its 6-alpha-OH and 3-para-OH metabolites in human plasma by LC-MS/MS.

J Pharm Biomed Anal 2019 Aug 15;172:26-32. Epub 2019 Apr 15.

Cancer Therapeutics Program, UPMC Hillman Cancer Center, Pittsburgh, PA, United States; Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States; Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, United States. Electronic address:

We have developed a high performance liquid chromatography mass spectrometry method for quantitating paclitaxel and its 6-alpha-OH and 3-para-OH metabolites in 0.1 mL human plasma. After MTBE liquid-liquid extraction, chromatographic separation was achieved with a Phenomenex synergy polar reverse phase (4 μm, 2 mm × 50 mm) column and a gradient of 0.1% formic acid in acetonitrile and water over an 8 min run time. Mass spectrometric detection was performed on an ABI SCIEX 4000Q with electrospray, positive-mode ionization. The assay was linear from 10-10,000 ng/mL for paclitaxel and 1-1000 ng/mL for both metabolites and proved to be accurate (94.3-110.4%) and precise (<11.3%CV). Recovery from plasma was 59.3-91.3% and matrix effect was negligible (-3.5 to 6.2%). Plasma freeze thaw stability (90.2-107.0%), stability for 37 months at -80 °C (89.4-112.6%), and stability for 4 h at room temperature (87.7-100.0%) were all acceptable. This assay will be an essential tool to further define the metabolism and pharmacology of paclitaxel and metabolites in the clinical setting. The assay may be utilized for therapeutic drug monitoring of paclitaxel and may also reveal the CYP2C8 and CYP3A4 activity phenotype of patients.
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http://dx.doi.org/10.1016/j.jpba.2019.04.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548629PMC
August 2019

Estimation of Kidney Function in Oncology: Implications for Anticancer Drug Selection and Dosing.

Clin J Am Soc Nephrol 2019 04 19;14(4):587-595. Epub 2019 Mar 19.

Hematology/Oncology Division, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; and

Estimation of kidney function in patients with cancer directly affects drug dosing, agent selection, and eligibility for clinical trials of novel agents. Overestimation of kidney function may lead to overdosing or inappropriate agent selection and corresponding toxicity. Conversely, underestimation of kidney function may lead to underdosing or inappropriate agent exclusion and subsequent therapeutic failure. It would seem obvious that the most accurate estimates of kidney function should be used to reduce variability in decision making and ultimately, the therapeutic outcomes of toxicity and clinical benefit. However, clinical decision making is often more complex. The Cockcroft-Gault formula remains the most universally implemented estimator of kidney function in patients with cancer, despite its relative inaccuracy compared with the Chronic Kidney Disease Epidemiology Collaboration equation. The Chronic Kidney Disease Epidemiology Collaboration equation is a more precise estimator of kidney function; however, many currently used kidney function cutoff values were determined before the development of the Chronic Kidney Disease Epidemiology Collaboration equation and creatinine assay standardization using Cockcroft-Gault estimates. There is a need for additional studies investigating the validity of currently used estimates of kidney function in patients with cancer and the applicability of traditional anticancer dosing and eligibility guidelines to modern and more accurate estimates of kidney function. In this review, we consider contemporary calculation methods used to estimate kidney function in patients with cancer. We discuss the clinical implications of using these various methods, including the potential influence on drug dosing, drug selection, and clinical trial eligibility, using carboplatin and cisplatin as case studies.
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http://dx.doi.org/10.2215/CJN.11721018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450339PMC
April 2019

Oligoadenylate-Synthetase-Family Protein OASL Inhibits Activity of the DNA Sensor cGAS during DNA Virus Infection to Limit Interferon Production.

Immunity 2019 01 8;50(1):51-63.e5. Epub 2019 Jan 8.

Cancer Virology Program, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA 15219, USA. Electronic address:

Interferon-inducible human oligoadenylate synthetase-like (OASL) and its mouse ortholog, Oasl2, enhance RNA-sensor RIG-I-mediated type I interferon (IFN) induction and inhibit RNA virus replication. Here, we show that OASL and Oasl2 have the opposite effect in the context of DNA virus infection. In Oasl2 mice and OASL-deficient human cells, DNA viruses such as vaccinia, herpes simplex, and adenovirus induced increased IFN production, which resulted in reduced virus replication and pathology. Correspondingly, ectopic expression of OASL in human cells inhibited IFN induction through the cGAS-STING DNA-sensing pathway. cGAS was necessary for the reduced DNA virus replication observed in OASL-deficient cells. OASL directly and specifically bound to cGAS independently of double-stranded DNA, resulting in a non-competitive inhibition of the second messenger cyclic GMP-AMP production. Our findings define distinct mechanisms by which OASL differentially regulates host IFN responses during RNA and DNA virus infection and identify OASL as a negative-feedback regulator of cGAS.
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http://dx.doi.org/10.1016/j.immuni.2018.12.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342484PMC
January 2019

A window-of-opportunity clinical trial of dasatinib in women with newly diagnosed endometrial cancer.

Cancer Chemother Pharmacol 2019 03 8;83(3):473-482. Epub 2018 Dec 8.

Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA, USA.

Objective: To determine the extent of dasatinib uptake and effect on Src kinase activity in tumor, normal adjacent tissue, and blood in newly diagnosed endometrial cancer patients.

Methods: Dasatinib was dosed at 100 or 200 mg PO BID at 32 and 8 h preoperatively. Blood and tissue were collected pre-treatment and at surgery to assess active (pY419) and total Src protein (pharmacodynamics [PD]) and pharmacokinetics (PK). Plasma PK and PD were also analyzed at 2, 4 and 8 h following the second dose.

Results: Ten patients completed the study, 5 at each dose level (DL). Average (median, standard deviation, range) 2 h plasma concentration of drug was 119 (121, 80, 226) and 236 (162, 248, 633) ng/mL, for the 100 and 200 mg DL, respectively. Average ratio of 8 h normal and tumor tissue to plasma concentration overall was 3.6 (2.3, 3.4, 9.6) and 8.3 (3.2, 11.9, 38.7), respectively. Dasatinib concentration in tumor was higher than in plasma for both DL. Four patients displayed significant reductions in pTyr419Src at ≥ 1 time points in blood, and four patients satisfied the PD activity criteria in tissue, with reductions in pTyr419Src of ≥ 60%.

Conclusions: This is the first study to show PK and PD effects of dasatinib in tumor tissue, allowing evaluation of tissue PD markers as a function of tumor dasatinib concentration. Dasatinib tissue concentrations at 8 h after dosing were associated with modulation of pTyr419Src, total Src protein, and pTyr419Src/Src ratio. All patients had reduction in at least one Src parameter in either tissue or blood.
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http://dx.doi.org/10.1007/s00280-018-3749-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628688PMC
March 2019

Population pharmacokinetics and exposure-response assessment of veliparib co-administered with temozolomide in patients with myeloid leukemias.

Cancer Chemother Pharmacol 2019 02 20;83(2):319-328. Epub 2018 Nov 20.

UPMC Hillman Cancer Center, Pittsburgh, PA, USA.

Purpose: Veliparib is an oral inhibitor of poly(ADP-ribose) polymerase enzyme. Combination of veliparib and temozolomide was well-tolerated and demonstrated clinical activity in older patients with relapsed or refractory acute myeloid leukemia (AML) or AML arising from pre-existing myeloid malignancies. We aimed to perform quantitative assessments of pharmacokinetics, efficacy, and safety of veliparib in this patient population to inform future trial design.

Methods: Population pharmacokinetic analysis was performed using Phoenix NLME with pharmacokinetic data obtained from 37 subjects after oral administration of veliparib in a Phase I study with and without temozolomide. Effect of covariates (age, sex, BMI, creatinine clearance (CL), and co-administration of temozolomide) on the pharmacokinetics of veliparib were evaluated, as well as impact of veliparib exposure on mucositis (dose-limiting toxicity), objective response rate (ORR), and overall survival.

Results: A two-compartment model with first-order elimination and a first-order absorption with lag-time adequately described veliparib pharmacokinetics. CL and body weight were clinically significant covariates for veliparib disposition. The proportion of subjects with all grade mucositis increased with veliparib exposure (AUC). However, no trend in ORR and overall survival was observed with increasing exposure.

Conclusions: Veliparib with temozolomide presents a promising combination for older patients with myeloid leukemias. An exposure-safety relationship was established for this combination. Further clinical investigations aimed at elucidating the veliparib exposure-efficacy/safety relationship and optimizing dosing recommendations for maximizing benefit-risk in patients with advanced myeloid malignancies should study veliparib doses ranging up to 120 mg in combination with temozolomide.
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http://dx.doi.org/10.1007/s00280-018-3731-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6404524PMC
February 2019

NCI Comparative Oncology Program Testing of Non-Camptothecin Indenoisoquinoline Topoisomerase I Inhibitors in Naturally Occurring Canine Lymphoma.

Clin Cancer Res 2018 12 30;24(23):5830-5840. Epub 2018 Jul 30.

Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda.

Purpose: Only one chemical class of topoisomerase I (TOP1) inhibitors is FDA approved, the camptothecins with irinotecan and topotecan widely used. Because of their limitations (chemical instability, drug efflux-mediated resistance, and diarrhea), novel TOP1 inhibitors are warranted. Indenoisoquinoline non-camptothecin topoisomerase I (TOP1) inhibitors overcome chemical instability and drug resistance that limit camptothecin use. Three indenoisoquinolines, LMP400 (indotecan), LMP776 (indimitecan), and LMP744, were examined in a phase I study for lymphoma-bearing dogs to evaluate differential efficacy, pharmacodynamics, toxicology, and pharmacokinetics.

Experimental Design: Eighty-four client-owned dogs with lymphomas were enrolled in dose-escalation cohorts for each indenoisoquinoline, with an expansion phase for LMP744. Efficacy, tolerability, pharmacokinetics, and target engagement were determined.

Results: The MTDs were 17.5 mg/m for LMP 776 and 100 mg/m for LMP744; bone marrow toxicity was dose-limiting; up to 65 mg/m LMP400 was well-tolerated and MTD was not reached. None of the drugs induced notable diarrhea. Sustained tumor accumulation was observed for LMP744; γH2AX induction was demonstrated in tumors 2 and 6 hours after treatment; a decrease in TOP1 protein was observed in most lymphoma samples across all compounds and dose levels, which is consistent with the fact that tumor response was also observed at low doses LMP744. Objective responses were documented for all indenoisoquinolines; efficacy (13/19 dogs) was greatest for LMP744.

Conclusions: These results demonstrate proof-of-mechanism for indenoisoquinoline TOP1 inhibitors supporting their further clinical development. They also highlight the value of the NCI Comparative Oncology Program (https://ccr.cancer.gov/Comparative-Oncology-Program) for evaluating novel therapies in immunocompetent pets with cancers.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-1498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6312717PMC
December 2018

ATR kinase inhibitor AZD6738 potentiates CD8+ T cell-dependent antitumor activity following radiation.

J Clin Invest 2018 08 13;128(9):3926-3940. Epub 2018 Aug 13.

Department of Radiation Oncology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

DNA-damaging chemotherapy and radiation therapy are integrated into the treatment paradigm of the majority of cancer patients. Recently, immunotherapy that targets the immunosuppressive interaction between programmed death 1 (PD-1) and its ligand PD-L1 has been approved for malignancies including non-small cell lung cancer, melanoma, and head and neck squamous cell carcinoma. ATR is a DNA damage-signaling kinase activated at damaged replication forks, and ATR kinase inhibitors potentiate the cytotoxicity of DNA-damaging chemotherapies. We show here that the ATR kinase inhibitor AZD6738 combines with conformal radiation therapy to attenuate radiation-induced CD8+ T cell exhaustion and potentiate CD8+ T cell activity in mouse models of Kras-mutant cancer. Mechanistically, AZD6738 blocks radiation-induced PD-L1 upregulation on tumor cells and dramatically decreases the number of tumor-infiltrating Tregs. Remarkably, AZD6738 combines with conformal radiation therapy to generate immunologic memory in complete responder mice. Our work raises the possibility that a single pharmacologic agent may enhance the cytotoxic effects of radiation while concurrently potentiating radiation-induced antitumor immune responses.
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http://dx.doi.org/10.1172/JCI96519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6118586PMC
August 2018

Therapeutic Drug Monitoring in Oncology: International Association of Therapeutic Drug Monitoring and Clinical Toxicology Recommendations for 5-Fluorouracil Therapy.

Clin Pharmacol Ther 2019 03 11;105(3):598-613. Epub 2018 Sep 11.

Department of Medical Oncology & Hematology, Cantonal Hospital, St. Gallen, Switzerland.

5-Fluorouracil (5-FU) is dosed by body surface area, a practice unable to reduce the interindividual variability in exposure. Endorsed by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT), we evaluated clinical evidence and strongly recommend TDM for the management of 5-FU therapy in patients with colorectal or head-and-neck cancer receiving common 5-FU regimens. Our systematic methodology provides a framework to evaluate published evidence in support of TDM recommendations in oncology.
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http://dx.doi.org/10.1002/cpt.1124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309286PMC
March 2019

Evaluation of Biodistribution of Sulforaphane after Administration of Oral Broccoli Sprout Extract in Melanoma Patients with Multiple Atypical Nevi.

Cancer Prev Res (Phila) 2018 07 24;11(7):429-438. Epub 2018 Apr 24.

UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania.

Broccoli sprout extract containing sulforaphane (BSE-SFN) has been shown to inhibit ultraviolet radiation-induced damage and tumor progression in skin. This study evaluated the toxicity and potential effects of oral BSE-SFN at three dosages. Seventeen patients who each had at least 2 atypical nevi and a prior history of melanoma were randomly allocated to 50, 100, or 200 μmol oral BSE-SFN daily for 28 days. Atypical nevi were photographed on days 1 and 28, and plasma and nevus samples were taken on days 1, 2, and 28. Endpoints assessed were safety, plasma and skin sulforaphane levels, gross and histologic changes, IHC for phospho-STAT3(Y705), Ki-67, Bcl-2, HMOX1, and TUNEL, plasma cytokine levels, and tissue proteomics. All 17 patients completed 28 days with no dose-limiting toxicities. Plasma sulforaphane levels pooled for days 1, 2, and 28 showed median postadministration increases of 120 ng/mL for 50 μmol, 206 ng/mL for 100 μmol, and 655 ng/mL for 200 μmol. Median skin sulforaphane levels on day 28 were 0.0, 3.1, and 34.1 ng/g for 50, 100, and 200 μmol, respectively. Plasma levels of proinflammatory cytokines decreased from day 1 to 28. The tumor suppressor decorin was increased from day 1 to 28. Oral BSE-SFN is well tolerated at daily doses up to 200 μmol and achieves dose-dependent levels in plasma and skin. A larger efficacy evaluation of 200 μmol daily for longer intervals is now reasonable to better characterize clinical and biological effects of BSE-SFN as chemoprevention for melanoma. .
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http://dx.doi.org/10.1158/1940-6207.CAPR-17-0268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6030491PMC
July 2018

A phase-1 study of dasatinib plus all-trans retinoic acid in acute myeloid leukemia.

Leuk Lymphoma 2018 11 4;59(11):2595-2601. Epub 2018 Apr 4.

b Division of Hematology-Oncology, Department of Medicine , University of Pittsburgh School of Medicine , Pittsburgh , PA , USA.

Src family kinases (SFKs) are hyperactivated in acute myeloid leukemia (AML). SFKs impede the retinoic acid receptor, and SFK inhibitors enhance all-trans retinoic acid (ATRA)-mediated cellular differentiation in AML cell lines and primary blasts. To translate these findings into the clinic, we undertook a phase-I dose-escalation study of the combination of the SFK inhibitor dasatinib and ATRA in patients with high-risk myeloid neoplasms. Nine subjects were enrolled: six received 70 mg dasatinib plus 45 mg/m ATRA daily, and three received 100 mg dasatinib plus 45 mg/m ATRA daily for 28 days. Headache and QTc prolongations were the only two grade 3 adverse events observed. No significant clinical responses were observed. We conclude that the combination of 70 mg dasatinib and 45 mg/m ATRA daily is safe with acceptable toxicity. Our results provide the safety profile for further investigations into the clinical efficacy of this combination therapy in myeloid malignancies.
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http://dx.doi.org/10.1080/10428194.2018.1443330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6201295PMC
November 2018

Targeting p53-dependent stem cell loss for intestinal chemoprotection.

Sci Transl Med 2018 02;10(427)

Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.

The gastrointestinal (GI) epithelium is the fastest renewing adult tissue and is maintained by tissue-specific stem cells. Treatment-induced GI side effects are a major dose-limiting factor for chemotherapy and abdominal radiotherapy and can decrease the quality of life in cancer patients and survivors. p53 is a key regulator of the DNA damage response, and its activation results in stimulus- and cell type-specific outcomes via distinct effectors. We demonstrate that p53-dependent PUMA induction mediates chemotherapy-induced intestinal injury in mice. Genetic ablation of , but not of , protects against chemotherapy-induced lethal GI injury. Blocking chemotherapy-induced loss of LGR5 stem cells by KO or a small-molecule PUMA inhibitor (PUMAi) prevents perturbation of the stem cell niche, rapid activation of WNT and NOTCH signaling, and stem cell exhaustion during repeated exposures. PUMAi also protects human and mouse colonic organoids against chemotherapy-induced apoptosis and damage but does not protect cancer cells in vitro or in vivo. Therefore, targeting PUMA is a promising strategy for normal intestinal chemoprotection because it selectively blocks p53-dependent stem cell loss but leaves p53-dependent protective effects intact.
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http://dx.doi.org/10.1126/scitranslmed.aam7610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5827930PMC
February 2018

Development and Validation of a Bioanalytical Method to Quantitate Enzalutamide and its Active Metabolite N-Desmethylenzalutamide in Human Plasma: Application to Clinical Management of Patients With Metastatic Castration-Resistant Prostate Cancer.

Ther Drug Monit 2018 04;40(2):222-229

Department of Pharmacy, Radboud University Medical Center, Radboud Institute for Health Sciences.

Background: Enzalutamide is a potent androgen-signaling receptor inhibitor and is licensed for the treatment of metastatic castration-resistant prostate cancer. N-desmethylenzalutamide is the active metabolite of enzalutamide. A method to quantitate enzalutamide and its active metabolite was developed and validated according to the European Medicine Agency guidelines.

Methods: Enzalutamide and N-desmethylenzalutamide were extracted by protein precipitation, separated on a C18 column with gradient elution and analyzed with tandem quadrupole mass spectrometry in positive ion mode. A stable deuterated isotope (D6-enzalutamide) was used as an internal standard. The method was tested and stability was studied in real-life patients with metastatic castration-resistant prostate cancer patients treated with enzalutamide.

Results: The calibration curve covered the range of 500-50,000 ng/mL. Within- and between-day precisions were <8% and accuracies were within 108% for both enzalutamide and N-desmethylenzalutamide. Precisions for lower limit of quantification level were <10% and accuracies within 116% for enzalutamide and N-desmethylenzalutamide. Enzalutamide and N-desmethylenzalutamide stability was proven for 24 hours for whole blood at ambient temperature and 23 days for plasma at both ambient temperature and 2-8°C. Long-term patient plasma stability was shown for 14 months at -40°C.

Conclusions: This bioanalytical method was successfully validated and applied to determine plasma concentrations of enzalutamide and N-desmethylenzalutamide in clinical studies and in routine patient care.
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http://dx.doi.org/10.1097/FTD.0000000000000484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6085835PMC
April 2018

Liquid chromatography-tandem mass spectrometric assay for the quantitation of the novel radiation protective agent and radiation mitigator JP4-039 in murine plasma.

J Pharm Biomed Anal 2018 Feb 12;150:169-175. Epub 2017 Dec 12.

Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA; Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.

JP4-039 radio-protects prior to, and radio-mitigates after ionizing radiation by neutralizing reactive oxygen species. We developed and validated an LC-MS/MS assay for the quantitation of JP4-039 in murine plasma. Methanol protein precipitation of 50μL plasma was followed by isocratic reverse phase chromatography for a 6min run time, and electrospray positive mode ionization mass spectrometric detection. The plasma assay was linear from 1 to 1000ng/mL with appropriate accuracy (97.1-107.6%) and precision (3.7-12.5%CV), and fulfilled FDA guidance criteria. Recovery was 77.2-136.1% with moderate ionization enhancement (10.9-39.5%). Plasma freeze-thaw stability (98.8-104.2%), stability for 13.5 months at -80°C (93.1-105.6%), and stability for 4h at room temperature (94.2-97.6%) were all acceptable. Limited cross-validation to tissue homogenates suggested that these could also be analyzed for JP4-039 accurately. This assay has been directly applied to determine the pharmacokinetics of JP4-039 in C57BL/6 male mice after IV administration of 20mg/kg JP4-039 and will be extended to other studies of this agent.
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http://dx.doi.org/10.1016/j.jpba.2017.12.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5767136PMC
February 2018

Improving Carboplatin Dosing Based on Estimated GFR.

Am J Kidney Dis 2018 02 6;71(2):163-165. Epub 2017 Dec 6.

Division of Nephrology, Tufts Medical Center, Boston, MA. Electronic address:

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http://dx.doi.org/10.1053/j.ajkd.2017.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6317965PMC
February 2018