Publications by authors named "Patricia M LoRusso"

138 Publications

SARS-CoV-2 vaccination and phase 1 cancer clinical trials.

Lancet Oncol 2021 Feb 8. Epub 2021 Feb 8.

The Institute of Cancer Research, London, UK; Royal Marsden NHS Foundation Trust, London, UK.

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http://dx.doi.org/10.1016/S1470-2045(21)00017-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906739PMC
February 2021

Differential immunomodulatory effect of PARP inhibition in BRCA1 deficient and competent tumor cells.

Biochem Pharmacol 2021 Feb 4;184:114359. Epub 2020 Dec 4.

Department of Cellular and Molecular Medicine, University of Arizona Cancer Center College, Tucson, AZ, USA. Electronic address:

Poly-ADP-ribose polymerase (PARP) inhibitors are active against cells and tumors with defects in homology-directed repair as a result of synthetic lethality. PARP inhibitors (PARPi) have been suggested to act by either catalytic inhibition or by PARP localization in chromatin. In this study, we treat BRCA1 mutant cells derived from a patient with triple negative breast cancer and control cells for three weeks with veliparib, a PARPi, to determine if treatment with this drug induces increased levels of mutations and/or an inflammatory response. We show that long-term treatment with PARPi induces an inflammatory response in HCC1937 BRCA1 mutant cells. The levels of chromatin-bound PARP1 in the BRCA1 mutant cells correlate with significant upregulation of inflammatory genes and activation of the cyclic GMP-AMP synthase (cGAS)/signaling effector stimulator of interferon genes (STING pathway). In contrast, an increased mutational load is induced in BRCA1-complemented cells treated with a PARPi. Our results suggest that long-term PARP inhibitor treatment may prime both BRCA1 mutant and wild-type tumors for positive responses to immune checkpoint blockade, but by different underlying mechanisms.
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http://dx.doi.org/10.1016/j.bcp.2020.114359DOI Listing
February 2021

One Step at a Time - Clinical Evidence That KRAS Is Indeed Druggable.

N Engl J Med 2020 09 20;383(13):1277-1278. Epub 2020 Sep 20.

From Yale Cancer Center, New Haven, CT (P.M.L.); and the University of Michigan Rogel Cancer Center, Ann Arbor (J.S.S.-L.).

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http://dx.doi.org/10.1056/NEJMe2026372DOI Listing
September 2020

A Phase I Study of DLYE5953A, an Anti-LY6E Antibody Covalently Linked to Monomethyl Auristatin E, in Patients with Refractory Solid Tumors.

Clin Cancer Res 2020 Nov 21;26(21):5588-5597. Epub 2020 Jul 21.

Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: DLYE5953A is an antibody-drug conjugate consisting of an anti-LY6E antibody covalently linked to the cytotoxic agent monomethyl auristatin E. This study characterized the safety, pharmacokinetics, immunogenicity, potential biomarkers, and antitumor activity of DLYE5953A in patients with metastatic solid tumors.

Patients And Methods: This was a phase I, open-label, 3+3 dose-escalation, and dose-expansion study of DLYE5953A administered intravenously every 21 days (Q3W) in patients with locally advanced or metastatic solid malignancies.

Results: Sixty-eight patients received DLYE5953A (median, four cycles; range, 1-27). No dose-limiting toxicities were identified during dose escalation (0.2-2.4 mg/kg; = 20). The recommended phase II dose (RP2D) of 2.4 mg/kg Q3W was based on overall safety and tolerability. Dose-expansion cohorts for HER2-negative metastatic breast cancer (HER2-negative MBC; = 23) and non-small cell lung cancer (NSCLC; = 25) patients were enrolled at the RP2D. Among patients receiving DLYE5953A 2.4 mg/kg ( = 55), the most common (≥30%) related adverse events (AEs) included alopecia, fatigue, nausea, and peripheral neuropathy. Grade ≥3 related AEs occurred in 14 of 55 (26%) patients, with neutropenia being the most common (13%). DLYE5953A demonstrated linear total antibody pharmacokinetics at doses of ≥0.8 mg/kg with low unconjugated monomethyl auristatin E levels in blood. Partial response was confirmed in eight of 68 (12%) patients, including three of 29 patients with MBC (10%) and five of 25 patients with NSCLC (20%) at the RP2D. Stable disease was the best response for 37 of 68 (54%) patients.

Conclusions: DLYE5953A administered at 2.4 mg/kg has acceptable safety. Preliminary evidence of antitumor activity in patients with HER2-negative MBC and NSCLC supports further investigation of LY6E as a therapeutic target.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1067DOI Listing
November 2020

Novel Therapeutic Interventions Early in the Disease Trajectory: Drug Development Beyond the Refractory Setting.

Clin Cancer Res 2020 Sep 22;26(18):4743-4747. Epub 2020 Jun 22.

Yale Cancer Center, New Haven, Connecticut.

The 2019 Accelerating Anticancer Agent Development Workshop assembled a panel of experts for an in-depth discussion session to present "novel therapeutic interventions early in the disease trajectory." The panel reviewed the limitations of evaluating investigational cancer therapeutics solely in advanced metastatic and relapsed/refractory disease settings, and recommended strategies for drug evaluation earlier in the disease course, including in the first line in combination with standard chemotherapy, and in the maintenance and neoadjuvant disease settings. Advantages of earlier drug evaluation were discussed, including expanding the population of evaluable patients, earlier response assessment via surrogate endpoints, earlier clinical benefit in the disease course, tailoring of therapies based on response, and furthering our understanding of biomarker-driven therapies.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-4035DOI Listing
September 2020

An International Phase 2 Study of Pazopanib in Progressive and Metastatic Thyroglobulin Antibody Negative Radioactive Iodine Refractory Differentiated Thyroid Cancer.

Thyroid 2020 09 29;30(9):1254-1262. Epub 2020 Jul 29.

Division of Medical Oncology, Department of Oncology, Mayo Clinic, Rochester, Minnesota, USA.

Multikinase inhibitors have clinical activity in radioactive iodine refractory (RAIR) differentiated thyroid cancers (DTCs) but are not curative; optimal management and salvage therapies remain unclear. This study assessed clinical effects of pazopanib therapy in RAIR-DTC patients with progressive disease, examining in parallel biomarker that might forecast/precede therapeutic response. Assessment of responses and toxicities and of any association between thyroglobulin (Tg) changes cycle 1 and RECIST (response evaluation criteria in solid tumors) response to pazopanib therapy were prospectively undertaken in Tg antibody negative RAIR-DTC patients. RECIST progressive metastatic disease <6 months preceding enrollment was required. With a sample size of 68 (assuming 23 attaining partial response [PR]), there would be 90% chance of detecting a difference of >30% when the proportion of patients attaining PR whose Tg values decrease by >50% is >50% cycle 1 (one-sided  = 0.10, two sample test of proportions). Mean corpuscular volume (MCV) change or mutational status or pretreatment were also explored as early correlates of eventual RECIST response. From 2009 to 2011, 60 individuals were treated and evaluated; (one additional patient withdrew; another was found ineligible before therapy initiation); 91.7% had previous systemic therapy beyond RAI. Adverse events included one death (thromboembolic) deemed possibly pazopanib associated. Twenty-two confirmed RECIST PRs resulted (36.7%, confidence interval; CI [24.6-50.1]); mean administered 4-week cycles was 10. Among 44 fully accessible patients, the Tg nadir was greater among the 20 attaining PR (median: -86.8%; interquartile range [IQR]: -90.7% to -70.9%) compared with the 28 who did not (median: -69.0%; IQR: -78.1% to -27.7%, Wilcoxon rank-sum test:  = 0.002). However, the difference in the proportion of PRs among those whose Tg fell ≥50% after cycle 1 versus those that did not were not significantly correlated (-23.5% [CI: -55.3 to 8.3]; Fisher's exact test -value = 0.27). RECIST response was also not correlated with/predicted by early MCV change, receipt of prior therapy, or tumor mutational status. This trial prospectively confirmed pazopanib to have clinical activity and manageable toxicities in patients with progressive RAIR-DTC. Response to pazopanib, however, was not robustly forecast by early associated changes in Tg or MCV, by prior therapy, or by tumor mutational status. ClinicalTrials.gov NCT00625846.
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http://dx.doi.org/10.1089/thy.2019.0269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482116PMC
September 2020

Assessment of effects of repeated oral doses of fedratinib on inhibition of cytochrome P450 activities in patients with solid tumors using a cocktail approach.

Cancer Chemother Pharmacol 2020 07 14;86(1):87-95. Epub 2020 Jun 14.

Bristol Myers Squibb, Summit, NJ, USA.

Purpose: Fedratinib, an oral selective kinase inhibitor with activity against both wild type and mutationally activated Janus kinase 2, has been approved for the treatment of adult patients with intermediate-2 or high-risk myelofibrosis by the US Food and Drug Administration. In vitro studies indicated that fedratinib was an inhibitor of several cytochrome P450 (CYP) enzymes. The primary objective of this study was to evaluate the effects of repeated doses of fedratinib on the activity of CYP2D6, CYP2C19, and CYP3A4 in patients with solid tumors using a CYP probe cocktail.

Methods: An open-label, one-sequence, two-period, two-treatment crossover study was conducted. Patients were administered a single oral dose cocktail of metoprolol (100 mg), omeprazole (20 mg), and midazolam (2 mg) used as probe substrates for CYP2D6, CYP2C19, and CYP3A4 enzyme activities, respectively, without fedratinib on Day -1 or with fedratinib on Day 15.

Results: Coadministration of 500 mg once-daily doses of fedratinib for 15 days increased the mean area under the plasma concentration-time curve from time zero to infinity following a single-dose cocktail containing metoprolol (CYP2D6 substrate), omeprazole (CYP2C19 substrate), and midazolam (CYP3A4 substrate) by 1.77-fold (90% confidence interval [CI] 1.27-2.47) for metoprolol, 2.82-fold (90% CI 2.26-3.53) for omeprazole, and 3.84-fold (90% CI 2.62-5.63) for midazolam, respectively. The mean plasma Day 14/Day 1 ratio of 4β-hydroxycholesterol, an endogenous biomarker of CYP3A4 activity, was 0.59 (90% CI 0.54-0.66), suggesting a net inhibition of CYP3A4 by fedratinib.

Conclusion: Fedratinib is a weak inhibitor of CYP2D6, and a moderate inhibitor of CYP2C19 and CYP3A4. These results serve as the basis for dose modifications of these CYP substrate drugs when co-administered with fedratinib.
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http://dx.doi.org/10.1007/s00280-020-04102-3DOI Listing
July 2020

A Phase I Study of ASTX660, an Antagonist of Inhibitors of Apoptosis Proteins, in Adults with Advanced Cancers or Lymphoma.

Clin Cancer Res 2020 06 3;26(12):2819-2826. Epub 2020 Jan 3.

Clinical Research, South Texas Accelerated Research Therapeutics (START), San Antonio, Texas.

Purpose: This first-in-human, phase I study evaluated ASTX660, an oral, small-molecule antagonist of cellular/X-linked inhibitors of apoptosis proteins in patients with advanced solid tumors or lymphoma.

Patients And Methods: ASTX660 was administered orally once daily on a 7-day-on/7-day-off schedule in a 28-day cycle. Dose escalation followed a standard 3+3 design to determine the MTD and recommended phase II dose (RP2D). Dose expansion was conducted at the RP2D.

Results: Forty-five patients received ASTX660 (range 15-270 mg/day). Dose-limiting toxicity of grade 3 increased lipase with or without increased amylase occurred in 3 patients at 270 mg/day and 1 patient at 210 mg/day. The MTD was determined to be 210 mg/day and the RP2D 180 mg/day. Common treatment-related adverse events included fatigue (33%), vomiting (31%), and nausea (27%). Grade ≥3 treatment-related adverse events occurred in 7 patients, most commonly anemia (13%), increased lipase (11%), and lymphopenia (9%). ASTX660 was rapidly absorbed, with maximum concentration achieved at approximately 0.5-1.0 hour. An approximately 2-fold accumulation in AUC exposures was observed on day 7 versus 1. ASTX660 suppressed cellular inhibitor of apoptosis protein-1 in peripheral blood mononuclear cells, which was maintained into the second cycle beyond the off-therapy week at the 180-mg/day RP2D and above. Clinical activity was seen in a patient with cutaneous T-cell lymphoma.

Conclusions: ASTX660 demonstrated a manageable safety profile and exhibited evidence of pharmacodynamic and preliminary clinical activity at the 180-mg/day RP2D. The phase II part of the study is ongoing.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1430DOI Listing
June 2020

Targeted therapy and immunotherapy: Emerging biomarkers in metastatic melanoma.

Pigment Cell Melanoma Res 2020 05 15;33(3):390-402. Epub 2020 Mar 15.

Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical Center, Chicago, IL, USA.

Targeted therapy directed against oncogenic BRAF mutations and immune checkpoint inhibitors have transformed melanoma therapy over the past decade and prominently improved patient outcomes. However, not all patients will respond to targeted therapy or immunotherapy and many relapse after initially responding to treatment. This unmet need presents two major challenges. First, can we elucidate novel oncogenic drivers to provide new therapeutic targets? Second, can we identify patients who are most likely to respond to current therapeutic strategies in order to both more accurately select populations and avoid undue drug exposure in patients unlikely to respond? In an effort to evaluate the current state of the field with respect to these questions, we provide an overview of some common oncogenic mutations in patients with metastatic melanoma and ongoing efforts to therapeutically target these populations, as well as a discussion of biomarkers for response to immune checkpoint inhibitors-including tumor programmed death ligand 1 expression and the future use of neoantigens as a means of truly personalized therapy. This information is becoming important in treatment decision making and provides the framework for a treatment algorithm based on the current landscape in metastatic melanoma.
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http://dx.doi.org/10.1111/pcmr.12847DOI Listing
May 2020

Phase I trials as valid therapeutic options for patients with cancer.

Nat Rev Clin Oncol 2019 12 2;16(12):773-778. Epub 2019 Sep 2.

Center for Personalized Cancer Therapy, Department of Medicine, University of California San Diego Moores Cancer Center, La Jolla, CA, USA.

For many years, oncology phase I trials have been referred to as 'toxicity trials' and have been believed to have low clinical utility other than that of establishing the adverse event profile of novel therapeutic agents. The traditional distinction of clinical trials into three phases has been challenged in the past few years by the introduction of targeted therapies and immunotherapies into the routine management of patients with cancer. This transformation has especially affected early phase trials, leading to the current situation in which response rates are increasingly reported from phase I trials. In this Perspectives, we highlight key elements of phase I trials and discuss how each one of them contributes to a new paradigm whereby preliminary measurements of the clinical benefit from a novel treatment can be obtained in current phase I trials, which can therefore be considered to have a therapeutic intent.
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http://dx.doi.org/10.1038/s41571-019-0262-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868302PMC
December 2019

Challenges with Novel Clinical Trial Designs: Master Protocols.

Clin Cancer Res 2019 04 29;25(7):2049-2057. Epub 2019 Jan 29.

Yale Cancer Center, New Haven, Connecticut.

The 2018 Accelerating Anticancer Agent Development (AAADV) Workshop assembled a panel of experts for an in-depth discussion session to present "Challenges with Novel Clinical Trial Designs." This panel offered assessments of the challenges faced by industry, the FDA, investigators, institutional review boards, and patients. The panel focused on master protocols, which include umbrella trials, platform trials, and basket trials. Umbrella trials and platform trials share many commonalities, whereas basket trials are more distinct. Umbrella and platform trials are generally designed with multiple arms where patients of the same histology or other unifying characteristics are enrolled into different arms and multiple investigational agents are evaluated in a single protocol. In contrast, basket studies generally enroll patients with different tumor types based on the presence of a specific mutation or biomarker regardless of histology; these trials may include expansion cohorts. These novel designs offer the promise of expedited drug assessment and approval, but they also place new challenges on all the stakeholders involved in the drug development process. Only by identifying the challenges of these complex, innovative clinical trial designs and highlighting challenges from each perspective can we begin to address these challenges. The 2018 AAADV Workshop convened a panel of experts from relevant disciplines to highlight the challenges that are created by master protocols, and, where appropriate, offer strategies to address these challenges.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3544DOI Listing
April 2019

Correction to: Phase I study combining the aurora kinase a inhibitor alisertib with mFOLFOX in gastrointestinal cancer.

Invest New Drugs 2018 12;36(6):1158

Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Vanderbilt University, 2220 Pierce Avenue, PRB 777, Nashville, TN, 37232, USA.

The authors would like to note that the investigator affiliations have been corrected to reflect the actual affiliations of each author. The authors would also like to note an amendment to the first name of the second author. Nilo Azad was changed to reflect the full name of the author, which is Nilofer S. Azad as shown above. The original article has been corrected.
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http://dx.doi.org/10.1007/s10637-018-0679-5DOI Listing
December 2018

Dose escalation results from a first-in-human, phase 1 study of glucocorticoid-induced TNF receptor-related protein agonist AMG 228 in patients with advanced solid tumors.

J Immunother Cancer 2018 09 25;6(1):93. Epub 2018 Sep 25.

Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium.

Background: This open-label, first-in-human, phase 1 study evaluated the safety, pharmacokinetics, pharmacodynamics, and maximum tolerated dose (MTD) of AMG 228, an agonistic human IgG1 monoclonal antibody targeting glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR), in patients with refractory advanced solid tumors.

Methods: AMG 228 was administered intravenously every 3 weeks (Q3W). Dose escalation was in two stages: single-patient cohorts (3, 9, 30, and 90 mg), followed by "rolling six" design (n = 2-6; 180, 360, 600, 900, and 1200 mg). Primary endpoints included incidence of dose-limiting toxicities (DLTs), AEs, and pharmacokinetics. Additional endpoints were objective response and pharmacodynamic response.

Results: Thirty patients received AMG 228, which was well tolerated up to the maximum planned dose (1200 mg). No DLTs occurred; the MTD was not reached. The most common treatment-related AEs were fatigue (13%), infusion-related reaction (7%), pyrexia (7%), decreased appetite (7%), and hypophosphatemia (7%). Two patients had binding anti-AMG 228 antibodies (one at baseline); no neutralizing antibodies were detected. AMG 228 exhibited target-mediated drug disposition, and serum exposure was approximately dose proportional at 180-1200 mg and greater than dose proportional at 3-1200 mg. Doses > 360 mg Q3W achieved serum trough coverage for 95% in vitro GITR occupancy. Despite GITR coverage in peripheral blood and tumor biopsies, there was no evidence of T-cell activation or anti-tumor activity.

Conclusions: In patients with advanced solid tumors, AMG 228 Q3W was tolerable up to the highest tested dose (1200 mg), exhibited favorable pharmacokinetics, and provided target coverage indicating a pharmacokinetic profile appropriate for longer intervals. However, there was no evidence of T-cell activation or anti-tumor activity with AMG 228 monotherapy.

Trial Registration: ClinicalTrials.gov, NCT02437916 .
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http://dx.doi.org/10.1186/s40425-018-0407-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156919PMC
September 2018

Phase I study combining the aurora kinase a inhibitor alisertib with mFOLFOX in gastrointestinal cancer.

Invest New Drugs 2019 04 6;37(2):315-322. Epub 2018 Sep 6.

Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Vanderbilt University, 2220 Pierce Avenue, PRB 777, Nashville, TN, 37232, USA.

Overexpression and cellular mis-localization of aurora kinase A (AURKA) in gastrointestinal cancers results in chromosomal instability, activation of multiple oncogenic pathways, and inhibition of pro-apoptotic signaling. Inhibition of AURKA causes mitotic delays, severe chromosome congression, and activation of p53/p73 leading to cell death. Our preclinical data showed cooperative activity with the AURKA inhibitor alisertib and platinum agents in cell lines and xenografts, and suggested an optimal treatment window. Therefore, this study was designed to determine the maximum-tolerated dose (MTD) of alisertib in combination with modified FOLFOX (mFOLFOX), as this is a standard platinum-based therapy for gastrointestinal cancers. Standard 3 + 3 dose escalation was used, where the starting dose of alisertib was 10 mg twice daily (Days 1-3), with leucovorin (400 mg/m) and oxaliplatin (85 mg/m) on Day 2 followed by continuous 46-h 5-FU (2400 mg/m) infusion on Days 2-4 in 14-day cycles. Fourteen patients with advanced gastrointestinal cancers were enrolled and two doses explored; two patients were not evaluable for dose-limiting toxicity (DLT) and replaced. Two patients experienced DLTs at 20 mg of alisertib (Grade 3 fatigue (n = 2); Grade 3 nausea, vomiting, dehydration with hospitalization (n = 1)). MTD was 10 mg alisertib with 85 mg/m oxaliplatin and 2400 mg/m 5-FU. Most frequent toxicities were nausea (57%), diarrhea, fatigue, neuropathy, and vomiting (43%), and anorexia and anemia (36%); most were Grade 1-2. One patient with colorectal cancer had a partial response of 12 evaluable patients, and four patients had stable disease. Alisertib in combination with mFOLFOX did not demonstrate unexpected side effects, but the regimen was only tolerable at the lowest dose investigated.
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http://dx.doi.org/10.1007/s10637-018-0663-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6401337PMC
April 2019

First-in-human study of the anti-HB-EGF antibody U3-1565 in subjects with advanced solid tumors.

Invest New Drugs 2019 02 28;37(1):147-158. Epub 2018 Jul 28.

Daiichi Sankyo Inc., 211 Mt Airy Rd, Basking Ridge, NJ, 07290, USA.

U3-1565 is a monoclonal antibody directed against heparin-binding epidermal growth factor-like growth factor (HB-EGF), which mediates angiogenesis via induction of vascular endothelial growth factor (VEGF-A). This first-in-human study characterized the safety, tolerability, efficacy, pharmacokinetics, and pharmacodynamics of U3-1565 in subjects with advanced solid tumors. In Part 1 (dose escalation following a modified 3 + 3 design), Cohorts 1-4, U3-1565 was administered at 2, 8, 16, and 24 mg/kg every 3 weeks for Cycle 1 and every 2 weeks thereafter. In Part 1, Cohort 5, and in Part 2 (dose expansion), U3-1565 was administered at 24 mg/kg every week. Thirty-six subjects were enrolled and treated (15 in Part 1; 21 in Part 2). No subject experienced dose limiting toxicity and maximum tolerated dose was not reached. All drug-related events were Grade 1 or 2 in severity, with fatigue and rash predominating. Following treatment with U3-1565, 1 subject with metastatic colorectal cancer experienced partial response and 6 subjects achieved stable disease. Four subjects completed the study main phase (first 12 cycles) and entered the extension phase. Of the 6/36 subjects with high (> 1500 pg/ml) baseline VEGF-A levels, all showed a decrease in VEGF-A (median - 60% [-22% to -97%]). Of the remaining subjects, only 19/30 showed a decrease (median - 18% [-2% to -82%]). Subjects with high VEGF-A baseline levels remained on treatment longer (3/6 entered study extension phase versus 1/30), and were more likely to show disease control (3/6 versus 4/30). In conclusion, U3-1565 demonstrates both proof of mechanism and clinical activity across different tumor types.
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http://dx.doi.org/10.1007/s10637-018-0646-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886232PMC
February 2019

Network Rewiring in Cancer: Applications to Melanoma Cell Lines and the Cancer Genome Atlas Patients.

Front Genet 2018 10;9:228. Epub 2018 Jul 10.

J. Craig Venter Institute, La Jolla, CA, United States.

Genes do not work in isolation, but rather as part of networks that have many feedback and redundancy mechanisms. Studying the properties of genetic networks and how individual genes contribute to overall network functions can provide insight into genetically-mediated disease processes. Most analytical techniques assume a network topology based on normal state networks. However, gene perturbations often lead to the rewiring of relevant networks and impact relationships among other genes. We apply a suite of analysis methodologies to assess the degree of transcriptional network rewiring observed in different sets of melanoma cell lines using whole genome gene expression microarray profiles. We assess evidence for network rewiring in melanoma patient tumor samples using RNA-sequence data available from The Cancer Genome Atlas. We make a distinction between "unsupervised" and "supervised" network-based methods and contrast their use in identifying consistent differences in networks between subsets of cell lines and tumor samples. We find that different genes play more central roles within subsets of genes within a broader network and hence are likely to be better drug targets in a disease state. Ultimately, we argue that our results have important implications for understanding the molecular pathology of melanoma as well as the choice of treatments to combat that pathology.
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http://dx.doi.org/10.3389/fgene.2018.00228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6048451PMC
July 2018

Phase 0 Trial of AZD1775 in First-Recurrence Glioblastoma Patients.

Clin Cancer Res 2018 08 24;24(16):3820-3828. Epub 2018 May 24.

Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut.

AZD1775 is a first-in-class Wee1 inhibitor with dual function as a DNA damage sensitizer and cytotoxic agent. A phase I study of AZD1775 for solid tumors suggested activity against brain tumors, but a preclinical study indicated minimal blood-brain barrier penetration in mice. To resolve this controversy, we examined the pharmacokinetics and pharmacodynamics of AZD1775 in patients with first-recurrence, glioblastoma. Twenty adult patients received a single dose of AZD1775 prior to tumor resection and enrolled in either a dose-escalation arm or a time-escalation arm. Sparse pharmacokinetic blood samples were collected, and contrast-enhancing tumor samples were collected intraoperatively. AZD1775 total and unbound concentrations were determined by a validated LC/MS-MS method. Population pharmacokinetic analysis was performed to characterize AZD1775 plasma pharmacokinetic profiles. Pharmacodynamic endpoints were compared to matched archival tissue. The AZD1775 plasma concentration-time profile following a single oral dose in patients with glioblastoma was well-described by a one-compartment model. Glomerular filtration rate was identified as a significant covariate on AZD1775 apparent clearance. AZD1775 showed good brain tumor penetration, with a median unbound tumor-to-plasma concentration ratio of 3.2, and achieved potential pharmacologically active tumor concentrations. Wee1 pathway suppression was inferred by abrogation of G arrest, intensified double-strand DNA breakage, and programmed cell death. No drug-related adverse events were associated with this study. In contrast to recent preclinical data, our phase 0 study of AZD 1775 in recurrent glioblastoma indicates good human brain tumor penetration, provides the first evidence of clinical biological activity in human glioblastoma, and confirms the utility of phase 0 trials as part of an accelerated paradigm for drug development in patients with glioma. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-3348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6865048PMC
August 2018

Phase I Study of CC-486 Alone and in Combination with Carboplatin or nab-Paclitaxel in Patients with Relapsed or Refractory Solid Tumors.

Clin Cancer Res 2018 09 15;24(17):4072-4080. Epub 2018 May 15.

Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee.

This large two-part, three-arm phase I study examined the safety and tolerability of CC-486 (an oral formulation of azacitidine, a hypomethylating agent) alone or in combination with the cytotoxic agents, carboplatin or nab-paclitaxel, in patients with advanced unresectable solid tumors. Part 1 ( = 57) was a dose escalation of CC-486 alone (arm C) or with carboplatin (arm A) or nab-paclitaxel (arm B). The primary endpoint was safety, MTD, and recommended part 2 dose (RP2D) of CC-486. In part 2 ( = 112), the primary endpoint was the safety and tolerability of CC-486 administered at the RP2D for each treatment arm, in tumor-specific expansion cohorts. Secondary endpoints included pharmacokinetics, pharmacodynamics, and antitumor activity of CC-486. At pharmacologically active doses CC-486 in combination with carboplatin or nab-paclitaxel had a tolerable safety profile and no drug-drug interactions. The CC-486 RP2D was determined as 300 mg (every day, days 1-14/21) in combination with carboplatin (arm A) or as monotherapy (arm C); and 200 mg in the same dosing regimen in combination with nab-paclitaxel (arm B). Albeit limited by the small sample size, CC-486 monotherapy resulted in partial responses (three/eight) and stable disease (four/eight) in patients with nasopharyngeal cancer. Three of the stable disease responses lasted more than 150 days. CC-486 is well tolerated alone or in combination with carboplatin or nab-paclitaxel. Exploratory analyses suggest clinical activity of CC-486 monotherapy in nasopharyngeal cancer and provided the basis for an ongoing phase II clinical trial (ClinicalTrials.gov identifier: NCT02269943). .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-3716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853187PMC
September 2018

Evaluation of pre-analytical factors affecting plasma DNA analysis.

Sci Rep 2018 05 9;8(1):7375. Epub 2018 May 9.

Center for Noninvasive Diagnostics, Translational Genomics Research Institute, Phoenix, AZ, USA.

Pre-analytical factors can significantly affect circulating cell-free DNA (cfDNA) analysis. However, there are few robust methods to rapidly assess sample quality and the impact of pre-analytical processing. To address this gap and to evaluate effects of DNA extraction methods and blood collection tubes on cfDNA yield and fragment size, we developed a multiplexed droplet digital PCR (ddPCR) assay with 5 short and 4 long amplicons targeting single copy genomic loci. Using this assay, we compared 7 cfDNA extraction kits and found cfDNA yield and fragment size vary significantly. We also compared 3 blood collection protocols using plasma samples from 23 healthy volunteers (EDTA tubes processed within 1 hour and Cell-free DNA Blood Collection Tubes processed within 24 and 72 hours) and found no significant differences in cfDNA yield, fragment size and background noise between these protocols. In 219 clinical samples, cfDNA fragments were shorter in plasma samples processed immediately after venipuncture compared to archived samples, suggesting contribution of background DNA by lysed peripheral blood cells. In summary, we have described a multiplexed ddPCR assay to assess quality of cfDNA samples prior to downstream molecular analyses and we have evaluated potential sources of pre-analytical variation in cfDNA studies.
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http://dx.doi.org/10.1038/s41598-018-25810-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5943304PMC
May 2018

Nonlinear mixed effects dose response modeling in high throughput drug screens: application to melanoma cell line analysis.

Oncotarget 2018 Jan 15;9(4):5044-5057. Epub 2017 Dec 15.

J. Craig Venter Institute, La Jolla, CA, USA.

Cancer cell lines are often used in high throughput drug screens (HTS) to explore the relationship between cell line characteristics and responsiveness to different therapies. Many current analysis methods infer relationships by focusing on one aspect of cell line drug-specific dose-response curves (DRCs), the concentration causing 50% inhibition of a phenotypic endpoint (IC). Such methods may overlook DRC features and do not simultaneously leverage information about drug response patterns across cell lines, potentially increasing false positive and negative rates in drug response associations. We consider the application of two methods, each rooted in nonlinear mixed effects (NLME) models, that test the relationship relationships between estimated cell line DRCs and factors that might mitigate response. Both methods leverage estimation and testing techniques that consider the simultaneous analysis of different cell lines to draw inferences about any one cell line. One of the methods is designed to provide an omnibus test of the differences between cell line DRCs that is not focused on any one aspect of the DRC (such as the IC value). We simulated different settings and compared the different methods on the simulated data. We also compared the proposed methods against traditional IC-based methods using 40 melanoma cell lines whose transcriptomes, proteomes, and, importantly, BRAF and related mutation profiles were available. Ultimately, we find that the NLME-based methods are more robust, powerful and, for the omnibus test, more flexible, than traditional methods. Their application to the melanoma cell lines reveals insights into factors that may be clinically useful.
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http://dx.doi.org/10.18632/oncotarget.23495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5797032PMC
January 2018

Trastuzumab emtansine: determining its role in management of HER2+ breast cancer.

Future Oncol 2018 Mar 7;14(7):589-602. Epub 2017 Dec 7.

Yale Cancer Center, PO Box 208028, New Haven, CT 06510, USA.

Trastuzumab emtansine is an antibody-drug conjugate comprised of the anti-HER2 monoclonal antibody trastuzumab linked to DM1 (emtansine), a potent cytotoxic maytansinoid derivative, by a stable linker. This structure results in improved tumor-directed cytotoxicity in HER2+ breast cancer with reduced systemic toxicities, particularly the cardiac toxicities associated with single agent trastuzumab. Phase III trials have demonstrated improved progression-free and overall survival in heavily pretreated patients with advanced HER2+ breast cancer, with an acceptable toxicity profile. However, its role in first-line treatment is less clear. Ongoing studies continue to evaluate its role in neoadjuvant and adjuvant management of HER2+ breast cancer.
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http://dx.doi.org/10.2217/fon-2017-0477DOI Listing
March 2018

Precision Medicine: Progress, Pitfalls, and Promises.

Mol Cancer Ther 2017 12;16(12):2641-2644

The University of Texas MD Anderson Cancer Center, Houston, Texas.

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http://dx.doi.org/10.1158/1535-7163.MCT-17-0904DOI Listing
December 2017

Twenty-First Century Precision Medicine in Oncology: Genomic Profiling in Patients With Cancer.

Mayo Clin Proc 2017 10;92(10):1583-1591

Yale Cancer Center, Yale School of Medicine, New Haven, CT.

The advent of next-generation sequencing has accelerated the implementation of genomic profiling in the care and management of patients with cancer. Initial efforts have focused on target identification in patients with advanced cancer. Prognostication, resistance detection, disease monitoring, and early detection efforts are also underway. This review highlights some of the challenges in this evolving space. This includes choosing between gene-panel and comprehensive approaches, DNA and transcriptome data integration, reduction of false-positive variants, addressing tumor heterogeneity, establishment of workflows to address unsolicited findings, and data sharing and privacy concerns.
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http://dx.doi.org/10.1016/j.mayocp.2017.08.002DOI Listing
October 2017

Trastuzumab emtansine versus treatment of physician's choice in patients with previously treated HER2-positive metastatic breast cancer (TH3RESA): final overall survival results from a randomised open-label phase 3 trial.

Lancet Oncol 2017 06 16;18(6):743-754. Epub 2017 May 16.

University Hospitals Leuven, Leuven, Belgium.

Background: In the randomised, parallel assignment, open-label, phase 3 TH3RESA study, progression-free survival was significantly longer with trastuzumab emtansine versus treatment of physician's choice in previously treated patients with HER2-positive advanced breast cancer. We report results from the final overall survival analysis of the TH3RESA trial.

Methods: Eligible patients for the TH3RESA trial were men and women (aged ≥18 years) with centrally confirmed HER2-positive advanced breast cancer previously treated with both trastuzumab and lapatinib (advanced setting) and a taxane (any setting) and with progression on two or more HER2-directed regimens in the advanced setting. Patients had to have an Eastern Cooperative Oncology Group performance status of 0-2, left ventricular ejection fraction of at least 50%, and adequate organ function. Patients were randomly assigned (2:1) by an interactive voice and web response system with permuted block randomisation in blocks of six to receive trastuzumab emtansine (3·6 mg/kg intravenously every 21 days) or treatment of physician's choice administered per local practice. Randomisation was stratified by world region, number of previous regimens for advanced breast cancer, and presence of visceral disease. On Sept 12, 2012, the study protocol was amended to allow patients with disease progression to crossover from treatment of physician's choice to trastuzumab emtansine. The coprimary endpoints for TH3RESA were investigator-assessed progression-free survival and overall survival in the intention-to-treat population. We report results from a preplanned second interim analysis of overall survival, which was planned for when approximately 67% (n=330) of 492 expected deaths had occurred. This study is registered with ClinicalTrials.gov, number NCT01419197.

Findings: Between Sept 14, 2011, and Nov 19, 2012, 602 patients were enrolled from 146 centres in 22 countries and randomly assigned to trastuzumab emtansine (n=404) or treatment of physician's choice (n=198). At data cutoff (Feb 13, 2015), 93 (47%) of 198 patients in the physician's choice group had crossed over to trastuzumab emtansine. Overall survival was significantly longer with trastuzumab emtansine versus treatment of physician's choice (median 22·7 months [95% CI 19·4-27·5] vs 15·8 months [13·5-18·7]; hazard ratio 0·68 [95% CI 0·54-0·85]; p=0·0007). As the stopping boundary for overall survival was crossed, this overall survival analysis serves as the final and confirmatory analysis of overall survival and the study was terminated according to the protocol. The incidence of grade 3 or worse adverse events was 161 (40%) of 403 patients in the trastuzumab emtansine group and 87 (47%) of 184 patients in the treatment of physician's choice group. Of the most common grade 3 or worse adverse events (affecting ≥2% of patients in either group), those with a 3% or greater difference in incidence between groups that were more frequent with treatment of physician's choice than with trastuzumab emtansine were diarrhoea (three [1%] of 403 patients in the trastuzumab emtansine group vs eight [4%] of 184 patients in the treatment of physician's choice group), neutropenia (ten [3%] vs 29 [16%]), and febrile neutropenia (one [<1%] vs seven [4%]); whereas those that were more frequent with trastuzumab emtansine were thrombocytopenia (24 [6%] of 403 patients vs five [3%] of 184 patients) and haemorrhage of any type (17 [4%] of 403 vs one [<1%] of 184). Serious adverse events were reported in 102 (25%) of 403 patients in the trastuzumab emtansine group and 41 (22%) of 184 in the physician's choice group. Deaths from adverse events were reported in three patients (2%) in the physician's choice group (of which one was judged to be treatment related) and nine (2%) in the trastuzumab emtansine group (of which three were judged to be treatment related).

Interpretation: In patients who had progressed on two or more HER2-directed regimens, trastuzumab emtansine treatment resulted in a significant improvement in overall survival versus treatment of physician's choice. These data further solidify the role of trastuzumab emtansine in the management of patients with previously treated HER2-positive advanced breast cancer, and validate HER2 as a therapeutic target even after multiple lines of previous therapy.

Funding: F Hoffman-La Roche/Genentech.
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http://dx.doi.org/10.1016/S1470-2045(17)30313-3DOI Listing
June 2017

A First-in-Human, Phase I, Dose-Escalation Study of TAK-117, a Selective PI3Kα Isoform Inhibitor, in Patients with Advanced Solid Malignancies.

Clin Cancer Res 2017 Sep 10;23(17):5015-5023. Epub 2017 May 10.

Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain.

To evaluate the safety, MTD, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of TAK-117 (MLN1117/INK1117), an investigational PI3Kα-selective inhibitor, in patients with advanced solid tumors. Seventy-one patients received oral TAK-117 once daily [100-300 mg ( = 24)] or 3 days per week [Monday-Wednesday-Friday (MWF), 200-1,200 mg ( = 27); Monday-Tuesday-Wednesday (MTuW), 200-900 mg ( = 20)], in 21-day cycles. Dose escalation proceeded via a 3 + 3 design. TAK-117 once-daily dosing was associated with dose-limiting grade ≥3 alanine/aspartate aminotransferase (ALT/AST) elevations, resulting in a narrow range of tolerable doses (100-150 mg once daily). With MWF/MTuW dosing, no dose-limiting ALT/AST elevations occurred until the MTD of 900 mg; total weekly dose was 2.6-fold that of 150 mg once daily. Drug-related grade ≥3 adverse events occurred in 25%/22%/35% (including hyperglycemia in 0%/7%/15%) of once-daily/MWF/MTuW patients. TAK-117 (100-1,200 mg) exhibited moderately fast oral absorption, a generally dose proportional increase in exposure, and plasma half-life of approximately 11 hours. Total weekly exposures with 900 mg MWF/MTuW dosing were approximately 4 times greater than with 150 mg once daily. Skin pS6 expression was suppressed at ≥200 mg. There were 3/1/0 partial responses (once daily/MWF/MTuW) and 5/7/5 patients had stable disease lasting ≥3 months (all mutated). Intermittent dosing of TAK-117 had an acceptable safety profile and enabled higher doses and total weekly exposures versus once-daily dosing. Although the potential for TAK-117 as single-agent therapy appears limited, further evaluation in combination approaches for advanced solid tumors is warranted. .
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http://dx.doi.org/10.1158/1078-0432.CCR-16-2888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858996PMC
September 2017

A phase I dose-escalation study of Selumetinib in combination with Erlotinib or Temsirolimus in patients with advanced solid tumors.

Invest New Drugs 2017 10 19;35(5):576-588. Epub 2017 Apr 19.

Yale Cancer Center, 55 Park Street, Ste First Floor, New Haven, CT, 06519, USA.

Background Combinations of molecularly targeted agents may provide optimal anti-tumor activity and improve clinical outcomes for patients with advanced cancers. Selumetinib (AZD6244, ARRY-142886) is an oral, potent and highly selective, allosteric inhibitor of MEK1/2, a component of the RAS/RAF/MEK/ERK pathway which is constitutively activated in many cancers. We investigated the safety, tolerability, and pharmacokinetics (PK) of selumetinib in combination with molecularly targeted drugs erlotinib or temsirolimus in patients with advanced solid tumors. Methods Two-part study: dose escalation, to determine the maximum tolerated dose (MTD) of selumetinib in combination with erlotinib 100 mg once daily (QD) or temsirolimus 25 mg once weekly, followed by dose expansion at the respective combination MTDs to further investigate safety and anti-tumor effects. Results 48 patients received selumetinib plus erlotinib and 32 patients received selumetinib plus temsirolimus. The MTD with erlotinib 100 mg QD was selumetinib 100 mg QD, with diarrhea being dose limiting. The most common all grade adverse events (AEs): diarrhea, rash, nausea, and fatigue. Four (8.3%) patients had ≥12 weeks stable disease. The MTD with temsirolimus 25 mg once weekly was selumetinib 50 mg twice daily (BID), with mucositis and neutropenia being dose limiting. The most commonly reported AEs: nausea, fatigue, diarrhea, and mucositis. Ten (31.3%) patients had ≥12 weeks stable disease. The combination PK profiles were comparable to previously observed monotherapy profiles. Conclusions MTDs were established for selumetinib in combination with erlotinib or temsirolimus. Overlapping toxicities prevented the escalation of selumetinib to its recommended phase II monotherapy dose of 75 mg BID.

Trial Registration: ClinicalTrials.gov NCT00600496; registered 8 July 2009.
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http://dx.doi.org/10.1007/s10637-017-0459-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5613062PMC
October 2017

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

Invest New Drugs 2018 02 17;36(1):36-44. Epub 2017 Apr 17.

Yale University, New Haven, CT, USA.

Background Voxtalisib, a PI3K/mTOR inhibitor, has shown antitumor activity in capsule formulation in patients with solid tumors. This Phase I study assessed safety and pharmacokinetics of voxtalisib administered as immediate-release tablets in patients with solid tumors (NCT01596270). Methods A "3 + 3" dose escalation design was used. Adverse events (AEs), pharmacokinetics (PK), food effect and tumor response were evaluated. Results Thirty-two patients received voxtalisib doses ranging from 50 mg to 70 mg once daily (QD) and 17 patients received voxtalisib doses ranging from 30 mg to 50 mg twice daily (BID), for two 28-day cycles. Dose-limiting toxicities (DLTs) were Grade 3 fatigue (two patients at 70 mg QD, one patient at 40 mg BID) and Grade 3 rash (two patients at 50 mg BID). The maximum tolerated dose (MTD) was 60 mg for QD and 40 mg for BID regimens. Common treatment-emergent AEs were diarrhea (41%), nausea (37%) and fatigue (33%). Voxtalisib appeared to follow linear PK, with a general increase in plasma exposure with dose and no significant accumulation. Administration with food caused a slight decrease in exposure; however, given the high variability observed in the exposure parameters, this should be interpreted with caution. Best response was stable disease in 29% and 50% of patients (QD and BID regimens, respectively). Conclusions The safety profile of voxtalisib tablets at the MTD in patients with solid tumors was consistent with that observed with voxtalisib capsules. Given the limited activity observed across multiple clinical trials, no further trials of voxtalisib are planned.
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http://dx.doi.org/10.1007/s10637-017-0467-7DOI Listing
February 2018

A phase 2 study of vorinostat in locally advanced, recurrent, or metastatic adenoid cystic carcinoma.

Oncotarget 2017 May;8(20):32918-32929

Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.

Purpose: Vorinostat is a histone deacetylase inhibitor (HDACi). Based on a confirmed partial response (PR) in an adenoid cystic carcinoma (ACC) patient treated with vorinostat in a prior phase 1 trial, we initiated this phase 2 trial.

Methods: Vorinostat was administered orally 400 mg daily, 28 day cycles. The primary objective was to evaluate response rate (RR). Exploratory studies included whole exome sequencing (WES) of selected patients.

Results: Thirty patients were enrolled. Median age of patients was 53 years (range 21-73). Median number of cycles was 5 (range 1-66). Lymphopenia (n = 5), hypertension (n = 3), oral pain (n = 2), thromboembolic events (n = 2) and fatigue (n = 2) were the only grade 3 adverse events (AEs) that occurred in more than 1 patient. Eleven patients were dose reduced secondary to drug-related AEs. Two patients had a partial response (PR), with response durations of 53 and 7.2 months. One patient had a minor response with a decrease in ascites (for 19 cycles). Stable disease was the best response in 27 patients. Targeted and WES of 8 patients in this trial identified mutations in chromatin remodeling genes highlighting the role of the epigenome in ACC.

Conclusion: Vorinostat demonstrated efficacy in patients with ACC supporting the inclusion of HDACi in future studies to treat ACC.
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http://dx.doi.org/10.18632/oncotarget.16464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5464838PMC
May 2017

Cu-MM-302 Positron Emission Tomography Quantifies Variability of Enhanced Permeability and Retention of Nanoparticles in Relation to Treatment Response in Patients with Metastatic Breast Cancer.

Clin Cancer Res 2017 Aug 15;23(15):4190-4202. Epub 2017 Mar 15.

Merrimack Pharmaceuticals, Inc, Cambridge, Massachusetts.

Therapeutic nanoparticles are designed to deliver their drug payloads through enhanced permeability and retention (EPR) in solid tumors. The extent of EPR and its variability in human tumors is highly debated and has been proposed as an explanation for variable responses to therapeutic nanoparticles in clinical studies. We assessed the EPR effect in patients using a Cu-labeled nanoparticle, Cu-MM-302 (Cu-labeled HER2-targeted PEGylated liposomal doxorubicin), and imaging by PET/CT. Nineteen patients with HER2-positive metastatic breast cancer underwent 2 to 3 PET/CT scans postadministration of Cu-MM-302 as part of a clinical trial of MM-302 plus trastuzumab with and without cyclophosphamide (NCT01304797). Significant background uptake of Cu-MM-302 was observed in liver and spleen. Tumor accumulation of Cu-MM-302 at 24 to 48 hours varied 35-fold (0.52-18.5 %ID/kg), including deposition in bone and brain lesions, and was independent of systemic plasma exposure. Computational analysis quantified rates of deposition and washout, indicating peak liposome deposition at 24 to 48 hours. Patients were classified on the basis of Cu-MM-302 lesion deposition using a cut-off point that is comparable with a response threshold in preclinical studies. In a retrospective exploratory analysis of patient outcomes relating to drug levels in tumor lesions, high Cu-MM-302 deposition was associated with more favorable treatment outcomes (HR = 0.42). These findings provide important evidence and quantification of the EPR effect in human metastatic tumors and support imaging nanoparticle deposition in tumors as a potential means to identify patients well suited for treatment with therapeutic nanoparticles. .
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http://dx.doi.org/10.1158/1078-0432.CCR-16-3193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790129PMC
August 2017