bluuebunny/crossref_metadata_2025 huggingface dataset:
High affinity Fc receptor binding and potent induction of antibody-dependent cellular cytotoxicity (ADCC) in vitro by anti-epidermal growth factor receptor antibody cetuximab
Authors: Kang X. , Patel D. , Ng S. , Melchior M. , Ludwig D. , Hicklin J D.
Published: March 2020

3041

Background: Cetuximab is an IgG1 monoclonal antibody specific for human epidermal growth factor receptor (EGFR). Cetuximab acts as a functional antagonist by blocking ligand (EGF and TGFa) binding to EGFR and, therefore, inhibits EGFR activation and downstream signaling in tumor cells. Methods: In the present study, we analyzed the binding activity of cetuximab to human Fc receptors and tested whether cetuximab can elicit antibody-dependent cellular cytotoxicity (ADCC) in vitro using tumor cell lines expressing various levels of EGFR. Results: Cetuximab bound to human FcRI and FcRIII with high affinity (EC50 of 0.13 nM and 6 nM, respectively), whereas an aglycosylated form of cetuximab or an IgG2 antibody to EGFR (panitumumab) did not bind to FcRI and FcRIII. A panel of head and neck, colon, and breast tumor cell lines were tested for cetuximab-mediated ADCC using human peripheral blood mononuclear cells (PBMC) from normal donors as effector cells. We found that cetuximab-induced ADCC to these tumor cell lines ranging from 20–90% specific killing. Interestingly, the extent of ADCC induced by cetuximab correlated with the level of EGFR expression on cell surface. The aglycosylated form of cetuximab or panitumumab, did not elicit ADCC of EGFR expressing tumor cells, even though cetuximab and panitumumab bind to EGFR with similar affinity (Kd=87 pM and 83 pM, respectively). To identify the immune cell population responsible for ADCC, NK cells were isolated from PBMC and tested in an ADCC assay. Purified NK cells elicited high levels of specific killing of cetuximab bound tumor cells, suggesting that NK cells are one of effector cell populations in human PBMCs responsible for the observed ADCC activity. Conclusions: Thus, cetuximab can effectively link effector cells to EGFR expressing tumor cells and mediate potent ADCC against EGFR-expressing human tumors.

[Table: see text]
Anti-tumor activity of recombinant human Interleukin-21 (rIL-21): Preliminary data from a phase 2a study in patients with stage IV malignant melanoma (MM) without prior treatment
Authors: Davis I. D. , Brady B. , Millward M. , Skrumsager B. K. , Mouritzen U. , Kristjansen P. E. , McArthur G.
Published: March 2020

3055

Background: rIL-21 is a pleiotropic class I cytokine that activates CD8+ T cells and NK cells. The safety and pharmacologic profile of rIL-21 was characterized in two phase 1 dose escalation studies including patients with MM, performed in Australia and the US, respectively. Two dosing schedules were tested: “5+9” (5 days of dosing followed by 9 days of rest) and “3/wk” (dosing 3 times per week for 6 weeks). The maximum tolerated dose (MTD) was determined to be 30 μg/kg for both dosing regimens and two complete remissions (at the 30 μg/kg dose level) were observed in the MM patients. A phase 2a study was initiated to estimate the preliminary efficacy of rIL-21 in patients with advanced MM. Methods: The phase 2a study design is an open-label, two-stage trial. Primary objective: antitumor efficacy as determined by response rate. Secondary objectives: safety, effects on blood biomarkers, and measurement of anti-rIL-21 antibodies. Eligible patients had unresectable MM with measurable disease, no prior systemic therapy (adjuvant interferon was permitted), adequate major organ function, good performance status, no brain metastases, and no evidence of significant autoimmune disease. rIL-21 was administered by i.v. bolus injection using the “5+9” regimen for 6 weeks (= three cycles) at 30 μg/kg dose level. Results: At the time of writing (January 2007), all 14 patients have entered the first stage of the phase 2a study and currently seven patients are evaluable for response after completion of 3 treatment cycles (6 weeks). One patient had a complete remission, five patients had stable disease, and one patient had progressive disease. So far, six patients have gone on to receive further treatment with rIL-21. Similar to the phase 1 experience, treatment with rIL-21demonstrated an acceptable safety profile. Updated interim study results, including response data, will be presented. Conclusions: rIL-21 administered at 30 μg/kg/day using the “5+9” regimen is well tolerated by patients with MM. Preliminary evidence of clinical response has been observed and the second stage of the two-stage phase 2a study has opened for accrual.

[Table: see text]
A phase I, first in man study of weekly IMC-A12, a fully human insulin like growth factor-I receptor IgG1 monoclonal antibody, in patients with advanced solid tumors
Authors: Higano C. S. , Yu E. Y. , Whiting S. H. , Gordon M. S. , LoRusso P. , Fox F. , Katz T. L. , Roecker J. M. , Schwartz J. D.
Published: March 2020

3505

Background: IMC-A12 is a fully human IgG1 monoclonal antibody directed against the human insulin like growth factor-I receptor. The safety and maximum tolerated dose (MTD) of IMC-A12 are being evaluated in an on-going a phase I trial. Methods: Patients (pts) with ECOG PS = 2 and advanced refractory solid tumors receive IMC-A12 weekly for 4 infusions per cycle until progression. After cycle one only, there is a two week observation period. Six cohorts of IMC-A12 are planned at 3, 6, 10, 15, 21, 27mg/kg. Sampling for PK and human anti-human antibodies directed against IMC-A12 occurs before and after the first and fourth doses of each cycle. Results: Fifteen pts have been treated, 7 at 3 mg/g, 4 at 6 mg/kg, 3 at 10 mg/kg and 1 at 15 mg/kg. Data is available for the first 11 pts: 7 male, 4 female, median age 56 years (range: 45–70). Treatment related toxicities for the first 11 pts include: grade 1 pruritis, rash, discolored feces; grade 2 anemia, psoriasis, hyperglycemia, infusion-related reaction; grade 3 hyperglycemia. Four of 11 pts have stable disease: 2 at the 3 mg/kg dose remain stable for >9 months (1 male breast cancer,1 hepatocellular cancer) and 2 at the 6 mg/kg dose (1 bladder, 1 endometrial) were stable after cycle 1. One pt with prostate cancer had >25% decline in PSA and stable radiographic disease at time of study discontinuation (week 5) for DLT. Non-compartmental PK analysis reveals a mean t1/2 of 148 and 209 hrs, mean Cmax of 333 and 415 ug/mL, and mean AUC0-Inf of 51317 and 80727 hr*ug/mL at the 3 and 6 mg/kg dose levels, respectively. Target trough levels have been achieved. Conclusions: Weekly administration of IMC-A12 appears to be well tolerated and the MTD has not been reached. The PK profile is consistent with that of other Mab’s. There is early evidence of clinical activity and correlative IGF biomarker data will be available. IMC-A12 will be further evaluated in prostate, breast, and other cancers.

No significant financial relationships to disclose.
A phase I, pharmacokinetic and pharmacodynamic study of sorafenib (S), a multi-targeted kinase inhibitor in combination with temsirolimus (T), an mTOR inhibitor in patients with advanced solid malignancies
Authors: Patnaik A. , Ricart A. , Cooper J. , Papadopoulos K. , Beeram M. , Mita C. , Mita M. M. , Hufnagel D. , Izbicka E. , Tolcher A. W.
Published: March 2020

3512

Background: The combination of S and T is hypothesized to maximize pathway inhibition by concurrently targeting parallel signaling mechanisms and will abrogate potential resistance mechanisms directed towards the MAPK pathway through increased signaling via the survival pathway involving PI3K/Akt. Methods: Eligible patients (pts) were treated with escalating continuous oral doses of S (200 and 400 mg BID) and weekly T IV (15 mg, 25 mg). S began on day 8 of course 1 to permit PK evaluations of T. PD studies in PBMCs were performed serially in pts. Results: To date, 24 evaluable pts have received 85 courses [median 3;range1–12] in the following S/T dose cohorts; cohort 1: 200 mg/15 mg (n=6), cohort 2: 400 mg/15 mg (n=11), cohort 3: 400 mg/25 mg (n=6), and cohort 4: 200 mg/25 mg (n=1). Patients demographics were males/female 11/13, median age 54.5 [range 27–71] and PS of 0/1/2 : n=9/13/2. Dose limiting toxicities (DLT) were grade 3 typhlitis in 1/6 pts in cohort 1, and mucositis in 1/6 pts in cohort 2. Expansion of cohort 2 to 11 patients resulted in 4 additional DLTs (hand foot syndrome (HFS) x 2 pts, thrombycytopenia/rash x 1 pt, creatinine elevation x 1 pt). 3 of 6 pts in cohort 3 experienced DLT (HFS x 2 pts, thrombocytopenia x 1 pt). PK analyses show no evidence of S effect on T kinetics while Css,min values of S are consistent with those reported in single-agent studies (S 200mg BID median Css,min 4.42 μg/mL [SD 3.05], S 400 mg BID median Css,min 5.11 μg/mL [SD 4.35]). Apparent downregulation of 4E-BP1 and activated forms of p70S6 kinase and ERK was observed in some patients following treatment. Partial responses have occurred in NHL (1 pt) and papillary thyroid cancer (1 pt) and prolonged SD (> 12 mo) has been observed in RCC (1 pt). Conclusions: The combination of S and T demonstrate significant mucocutaneous toxicity at full doses of S, however preliminary PK analyses show no evidence of drug-drug interactions. Characterization of an intermediate dose of S 200 mg BID/T 25 mg IV is ongoing.

[Table: see text]
The effects of paclitaxel (PTX) and 2-methoxyestradiol (2-ME2) on tumor oxygenation and HIF-1α in breast cancer
Authors: Blackwell K. L. , Chi J. , Sidor C. , Burke P. , LaVallee T. , Shaw H. S. , Liotcheva V. , Sims D. , Hobbs L. , Arnott J. , Dewhirst M. W.
Published: March 2020

3517

Background: Radiation activates HIF-1a via a free radical mediated mechanism associated with reoxygenation. This response could be inhibited, resulting in reduced tumor vascularity and proliferation. Preclinical breast cancer models and a Phase Ib clinical trial (CT) were employed to look at the effects of chemo with or without an oral HIF-1a inhibitor, 2-ME2 (EntreMed) on tumor oxygenation and HIF-1a. Methods: Preclinical models of chemo effects on HIF-1a/oxygenation used 4T1 tumors and either doxorubicin (DOX) or cyclophosphamide (CTX). In addition, MDA-MB-231 tumors were treated with 2-ME2 (5days), and HIF-1a/MVD was assessed. In the CT, up to 15 pts with metastatic breast cancer, and biopsiable (>2 cm) non-bone sites were eligible. Tx was: D 1: PTX, 90 mg/m2; D 8: PTX, 90 mg/m2 with 2-ME2 (cohorts of 1,000/1,250/1,500 mg, qid). PTX was given 3 out of 4 wks. Bxs were done at enrollment, D8 (post-PTX), and D22 (post-PTX/2-ME2). Tumors were examined for changes in HIF-1a and CA9 levels, MVD, and genomic signatures of hypoxia. Plasma was obtained for osteoponin, PAI-1, and VEGF. Results: DOX and CTX both led to increases in HIF-1a, oxygenation, vascularity, and proliferation 4–10 days post treatment in the 4T1 model, while 2-ME2 reduced HIF-1a and MVD post treatment (5 d) in the MDA-MB-231 model. The CT opened in 6–2006, 9 pts have consented and 8 pts have undergone sequential biopsies and accrual continues. No DLT have been seen. Biopsy sites include chest wall, liver, and LN. Sufficient tissue/RNA/plasma has been obtained and the planned analyses will be presented. Conclusions: HIF-1a and tumor oxygenation appear to be modulated as a response to chemotherapy. The combination of PTX and 2-ME2 is clinically active, well-tolerated, and could serve as one of the first approaches to target HIF-1a in order to optimize therapy. Supported by Komen Grant BCTR0504044.

[Table: see text]
Inhibition of poly (ADP-ribose) polymerase (PARP) by ABT-888 in patients with advanced malignancies: Results of a phase 0 trial
Authors: Kummar S. , Kinders R. , Gutierrez M. , Rubinstein L. , Parchment R. E. , Phillips L. R. , Low J. , Murgo A. J. , Tomaszewski J. E. , Doroshow J. H.
Published: March 2020

3518

Background: Inhibition of PARP activity sensitizes tumor cells to the effects of DNA damaging agents. We conducted a phase 0 pharmacokinetic (PK) and pharmacodynamic (PD) study of ABT-888, an oral inhibitor of PARP. Methods: The objectives were to determine a dose range at which ABT-888 inhibits PARP in tumor tissue and in peripheral blood mononuclear cells (PBMC); and the PK of ABT-888. Patients with advanced solid tumors refractory to at least one line of therapy were eligible; patients with CLL or follicular lymphomas were also eligible if standard therapy was not currently indicated. A single oral dose of ABT-888 was administered per patient, dose escalations were planned in cohorts of 3 patients each (10 mg, 25 mg, 50 mg, 100 mg, and 150 mg). PBMC and tumor sampling were performed before and after drug administration for real time PK and PD analyses. All patients underwent PBMC sampling; tumor biopsies were planned once significant inhibition of PARP activity in PBMCs was seen in 1 of 3 patients in a cohort or plasma Cmax of 210 nM was achieved in at least 1 patient. Tumor biopsies were performed at baseline in the week prior to drug administration and then 3–6 hours post drug administration. Significant inhibition of PARP activity was defined as at least 0.69 reduction on the log scale, which also satisfied statistical significance. Results: A total of 6 patients have been studied so far, 3 each for the 10 mg and 25 mg cohorts. No treatment related adverse events have been observed. Target Cmax was exceeded in the first cohort, all patients in the next cohort underwent tumor biopsies in addition to PBMC sampling. A trend towards inhibition of PARP activity in PBMCs was observed in the first cohort. Significant inhibition of PAR levels was observed in tumor biopsies from all 3 patients in the second cohort (92%, 99%, 100% reductions respectively, as compared to baseline). Greater than 85% reduction of PAR levels was observed in PBMCs from 2 of the 3 patients in the second cohort (one patient was not evaluable). Conclusions: ABT-888 is orally bioavailable and inhibits PARP activity in PBMCs and tumor cells. Target assay feasibility was established in human samples. Funded in part by NCI Contract N01-CO-12400

No significant financial relationships to disclose.
Combination of 5-azacytidine (5-AZA) and valproic acid (VPA) in advanced solid cancers: A phase I study
Authors: Soriano A. O. , Braiteh F. , Garcia-Manero G. , Camacho L. H. , Hong D. , Moulder S. , Ng C. , Kurzrock R.
Published: March 2020

3547

Background: 5-AZA is a DNA hypomethylating agent. VPA is a histone deacetylase inhibitor (HDACI). The combination of hypomethylating agents and HDACI has synergistic anticancer activity in vitro and in vivo. Based on this, we conducted a phase I study of the combination of 5-AZA and VPA in patients with advanced solid cancers. Methods: 5-AZA was administered SQ daily for 10 days. VPA was given orally daily titrated to 75–100 mcg/ml. Cycles were 28 days long. 5-AZA was started at 20 mg/m2 and escalated using an adaptive algorithm based on toxicity in the prior cohort. Each cohort included 6 patients (pts). Global DNA methylation was estimated with the LINE pyrosequencing assay in peripheral blood mononuclear cells on days 1 and 10 of each cycle. Histone H3 and H4 acetylation was assessed with western blots. Results: Forty seven patients were evaluable. Median age was 60 years (15–77). 5- AZA dose levels included 20, 25, 37.5, 47, 59, 75 and 94 mg/m2. One DLT occurred at 37.5 (Neutropenic fever (NF)). At 75 mg/m2, 1 grade 3 NF and at 94 mg/m2, 3 DLTs (2 NF and 1 thrombocytopenia) were observed. The MTD was 75 mg/m2 SQ daily for 10 days. Other toxicities included drowsiness (N=6), tremor (N=6), hypomagnesemia (N=1), anemia (N=2) and vomiting (N=1). Stable disease (SD) was observed in 16 pts (34%). One pt with rapidly progressive renal cell carcinoma had SD for 6 months (mos). Two pts with leiomyosarcoma of the uterus had SD for 8 and 6 mos. One pt with melanoma and two pts with uveal melanoma had SD for 4 mos. One pt with sinus adenoid cystic carcinoma and 1 with thymic carcinoma had SD for 4 mos. SD was also observed in pts with colon (N=3), sarcoma (N=2), papillary thyroid (N=2) and breast cancer (N=1). Global DNA hypomethylation was demonstrated in all of the doses of 5- AZA. Median LINE methylation pretreatment was 65% (59–70%), it declined to 61% (53–63%) by day 10 (p=0.001) and returned to baseline by day 0 of the next cycle. Histone acetylation was observed in 53% of the pts. Conclusions: The combination of 5-AZA and VPA in patients with advanced solid tumors is safe. The MTD of 5-AZA in combination with VPA was 75 mg/m2 SQ daily for 10 days. DLTs were neutropenic fever and thrombocytopenia. Clinical benefit (SD) was observed in 16 pts (34%). Transient global hypomethylation and histone acetylation were demonstrated.

No significant financial relationships to disclose.
A phase I study of BMS-582664 (brivanib alaninate), an oral dual inhibitor of VEGFR and FGFR tyrosine kinases, in patients (pts) with advanced/metastatic solid tumors: Safety, pharmacokinetic (PK), and pharmacodynamic (PD) findings
Authors: Jonker D. J. , Rosen L. S. , Sawyer M. , Wilding G. , Noberasco C. , Jayson G. , Rustin G. , McArthur G. , Velasquez L. , Galbraith S.
Published: March 2020

3559

Background: Brivanib is an oral prodrug of BMS-540215, a dual tyrosine kinase inhibitor of VEGFR and FGFR signaling. Part A of this study defined an MTD of 800 mg qd (Abstract # 3051, ASCO 2006). Part B investigated expanded doses / schedules for safety, PK and PD. Methods: In Part B, sequential cohorts were treated with 320 mg qd, 800 mg 5 days on/2 off (800I), 800 mg qd (800C), or 400 mg bid. Available data are reported for pts treated at these doses in Part A + B. PK samples were obtained Days 1, 8 and 26. Tumor DCE- MRI parameters, transfer constant (Ktrans), area under the concentration-time curve - first 60 s post contrast injection (AUC60) were measured baseline X 2, Days 2, 8 and 26. Reproducibility was assessed by within pt %CV (wCV). Exposure-response analysis was performed using logistic regression. Serum ELISAs for soluble VEGFR2 and Collagen IV were measured at baseline, Days 8 and 26. Results: Fourteen, 9 and 18 pts were treated at 320, 800I and 800C, respectively. G3/4 AEs at 320, 800I, and 800C respectively were fatigue (21%, 0%, 22%), ↑ transaminase (8%, 11%, 17%), diarrhea (0%, 11%, 11%), hypertension (0%, 0%, 11%), platelets (8%, 0%, 11%). 800C had the greatest change in Ktrans, AUC60 and serum markers at Day 8 and 26 ( Table ). 800I had some recovery Day 2 to Day 8 and a smaller change at Day 26 than 800C. wCV for Ktrans and AUC60 was 26% and 22% respectively. The probability of DCE-MRI change increased with exposure (AUCtau) to BMS-540215. Conclusions: Brivanib has dose-proportional PK and a tolerable safety profile = 800C. PD changes were greatest at 800C. Some recovery in DCE-MRI effect after 2 day dosing break suggests continuous dosing is preferable for biological activity.

[Table: see text]

No significant financial relationships to disclose.
Comparison of 1- and 2-dimensional measurements with volumetric measurements for evaluation of change in tumor size
Authors: Hwang Y. , Ashton E. , Storgard C. , Wong S. , Malseed E. , Hill J. , Goyal L. , Evelhoch J.
Published: March 2020

3563

Background: Change in tumor size is commonly used as a surrogate endpoint for clinical outcome. Measurement of tumor volume, the gold standard for determining tumor size, is not clinically practical. The 2 most commonly used measurements of tumor size ie, longest diameter in axial plane (LD, used in RECIST) and cross product (CP) of LD and the longest perpendicular dimension in axial plane (used in WHO), are surrogates for tumor volume and assume simple tumor geometry. Since most tumors grow and regress irregularly, we determined which of these measurements most accurately reflects change in tumor volume by comparing change in tumor volume calculated using LD or CP with change in measured tumor volume. Methods: Computed tomography (CT) scans of the chest, abdomen, and pelvis were acquired at baseline and 8-week intervals during treatment in 22 patients (pts) enrolled in 2 first-in-human (FIH) clinical trials. CT scans were analyzed by a central reader to obtain LD, CP, and tumor volume. LD (assuming spherical tumor geometry) or CP (assuming spherical or elliptical tumor geometry) was used to calculate volume. The mean bias (μ: mean difference between measured and calculated percent change in tumor volume from baseline [%ΔVol]) and limits of agreement (μ ± 2s [s = standard deviation of difference]) from Bland-Altman analyses (used for assessing agreement between 2 measurement methods) were used for comparisons between measured and calculated %ΔVol. A nested effects model (tumor lesions considered as nested within pts) was used to test significance of differences between measured and calculated %ΔVol. Results: Bland-Altman analyses showed that μ ± 2s was -5% ± 70% for LD, 5% ± 38% for CP (spherical), and 7% ± 33% for CP (elliptical). Nested analyses indicated consistent results with an observed significant difference (p-value = 0.02) between measured and calculated %ΔVol using LD and non-significant differences (p-values = 0.28 and 0.05) using CP (assuming elliptical and spherical geometry respectively). Conclusions: In this diverse FIH population, 2-dimensional tumor measurements (using CP) are better than 1-dimensional tumor measurements (using LD) in representing changes in tumor volume and should decrease noise in the measurement of treatment response.

No significant financial relationships to disclose.
An open label safety and efficacy phase 2a study of the N-cadherin (N-cad) antagonist ADH-1 in subjects with N-cadherin expressing solid tumors
Authors: Chu Q. S. , Knox J. , Batist G. , Venner P. , Chi K. N. , Woods L. , Burris H. A. , Malik R. K. , Peters W. P. , Jonker D. J.
Published: March 2020

3567

Background: Malignant transformation and invasive capacity is highly correlated with N-cad, a cell adhesion molecule expressed on tumor cells and vascular endothelium. ADH-1, a cyclic pentapeptide (CHAVC), is a functional inhibitor of N-cad, and produces apoptosis and tumor vascular disruption in preclinical models. We report results from a Phase 2a study of intravenous (IV) ADH-1 (q 3 W, modified to qW) in subjects with N-cad+ solid tumors. Methods: Subjects with the following N-cad+ refractory tumors with measurable disease were eligible: renal cell (RCC); hepatocellular (HCC); adrenocortical (ACC); gastroesophageal (GE); NSCLC; HNSCC; and breast (HSNCC and breast subjects were only eligible for q3W schedule). ADH-1 was administered at 500 mg/m2 q 3 W, or 600 mg/m2 in the qW schedule. Intra-subject dose escalation was permitted at cycle 3 to 600 mg/m2 (900 mg/m2 with the qW schedule) in the absence of significant toxicity, tumor response or progression. Results: Tumor samples from 159 subjects were tested for N-cad, and 90 were N-cad+ (N-cad+/number tested: GE 13/48, HCC 29/35; NSCLC 16/33; RCC 27/28; ACC 3/8; HNSCC 2/6; Breast 0/1). Forty subjects, 10 on the q3W and 30 on the qW schedule (19 HCC; 7 RCC; 6 NSCLC; 6 GE; 1 ACC; 1 HNSCC) received 121 cycles of ADH-1. The drug was well tolerated, with commonly reported adverse events being Grade 1 or 2 in severity. One subject with HCC had pre-existing renal insufficiency, developed Grade 2 nausea and vomiting 11 days after the 3rd cycle of ADH-1 administered q 3W, leading to non-oliguric renal failure. Following an initial period of recovery, she developed sepsis and died; these events were considered to not be related to study drug. A second subject with HCC developed a hemiparesis due to a Grade 3 intracranial hemorrhage from a previously unknown metastatic brain lesion, 5 days after the 1st dose of ADH-1. There were no complete or partial responses; 32 subjects had SD for =2 cycles, 8 had SD for =4 cycles (4 HCC, ACC, GE, RCC, HNSCC), 6 had SD for =6 cycles (3 HCC, GE, RCC, HNSCC). The longest duration on study was 12 cycles (RCC). Conclusions: ADH-1 was well tolerated and prolonged SD was noted in several subjects.

No significant financial relationships to disclose.
Phase I clinical trial of MLN8054, a selective inhibitor of Aurora A kinase
Authors: Jones S. F. , Cohen R. B. , Dees E. C. , Lee Y. , Papas J. A. , Cooper M. R. , Galvin K. M. , Burris H. A.
Published: March 2020

3577

Background: MLN8054 is a small molecule inhibitor of Aurora A kinase, with > 150-fold greater potency against this enzyme than the structurally related but functionally distinct Aurora B kinase. Because of its structural similarity to benzodiazepines, MLN8054 binds to the gamma-aminobutryic acid alpha 1 benzodiazepine (GABAA a1 BZD) receptor and in preclinical studies caused benzodiazepine-like CNS effects. Methods: MLN8054 was given as capsule by mouth for 7 consecutive days, repeated every 21 days. Cohorts of 3- 6 patients (pts) were enrolled to successively increasing doses until dose-limiting toxicity was seen in = 2 pts at a given dose level. Serial blood samples were collected to estimate PK; skin biopsies were obtained before and 6 hours after the first dose to assess inhibition of Aurora A kinase in basal epithelial cells. Results: 22 pts were enrolled to evaluate single daily doses of 5, 10, 20, 30 and 40 mg/day. MLN8054 was in general rapidly absorbed, displayed dose-proportionate exposure, and had a mean elimination half-life of 35 hours. The ratio of peak to trough plasma concentrations was approximately 5. Reversible grade 2 somnolence was first seen in 3 patients treated at 20 mg/day, and 2/4 patients treated at 40 mg/day experienced reversible grade 3 somnolence. In order to reduce the sedative effects of MLN8054, 16 additional pts were enrolled to doses of 25, 35, 45 and 55 mg/day given as divided doses on a QID schedule. Two of 4 pts treated at the 55 mg/day dose experienced reversible grade 3 somnolence, establishing 45 mg/day as the maximum tolerated total daily dose on a QID schedule. No myelosuppression or mucosal toxicity was seen at any dose with either schedule. Immunohistochemical analysis of skin biopsies from pts treated with once daily dosing did not demonstrate accumulation of cells in mitosis. Three pts with metastatic colorectal cancer treated with single daily doses of MLN8054 received = 8 cycles of treatment. Conclusions: The study is now escalating divided daily dosing of MLN8054 with the co-administration of methylphenidate. Post-treatment skin biopsies are now obtained on Day 7. Duration of treatment will be extended to 14 days, since steady-state concentrations of MLN8054 require 5–7 days of dosing, and because the effects of Aurora A kinase inhibition are duration-dependent.

No significant financial relationships to disclose.
A pharmacogenetic study of docetaxel and thalidomide in patients with androgen-independent prostate cancer (AIPC) using targeted human DMET genotyping platform
Authors: Deeken J. F. , Cormier T. , Price D. K. , Steinberg S. , Tran K. , Liewehr D. J. , Ockers S. B. , Hardenbol P. , Dahut W. , Miao X. , Figg W. D.
Published: March 2020

3580

Background: Pharmacogenetic research holds the promise of individualizing cancer therapy by reducing inter-individual variability in drug response, thus enhancing efficacy and reducing toxicity. Past research has been limited due to the lack of a robust genotyping platform that can screen for single nucleotide polymorphisms (SNPs) in the dozens of genes known to be involved in drug disposition. We pilot tested the new Affymetrix Targeted Human Drug Metabolizing Enzymes and Transporter (DMET) 1.0 panel in an exploratory study of docetaxel and thalidomide. The DMET 1.0 panel tests for 1,229 genetic variations in 169 drug disposition genes, including 49 CYP450 genes, 73 non-CYP genes, and 47 transporters. Methods: DNA samples from 47 patients with AIPC enrolled in a randomized phase II trial using docetaxel and thalidomide vs. docetaxel alone were genotyped using the DMET 1.0 panel. Patients’ response was determined using RECIST criteria. Toxicities were graded using the NCI-CTC, and patients were identified if they experienced grade 3 or 4 toxicity. Given the distinct side effect profiles of these two drugs, specific toxicities were assigned as being due to either docetaxel or thalidomide. An association between the SNP parameters and clinical response or toxicity was tested using Mehta’s modification to Fisher’s exact test. Reported results were limited to those where p<0.01. Results: Six SNPs in three genes were associated with response to therapy: PPAR-delta (p=0.0011), SULT1C2 (p=0.0083), and CHST3 (4 SNPs, p=0.0001 to 0.0034). For toxicities associated with docetaxel, five SNPs in three genes were identified: UGT1A1 (2 SNPs, p=0.0009 to 0.0094), UGT1A9 (2 SNPs, p=0.0016 to 0.0096), and CYP2A7 (p=0.0027). SNPs in CYP2B6 (p=0.0033), ABCC1 (p=0.0036), and ABCC6 (p=0.0075) were associated with toxicities from thalidomide. Conclusion: We identified nine genes in which SNPs were potentially significantly associated with clinical response and toxicity to treatment. These results highlight the important role that non-CYP450 and phase II drug metabolizing enzymes may play in the efficacy and disposition of docetaxel and thalidomide. Confirmatory studies are warranted.

No significant financial relationships to disclose.
A phase I study of intravenous tetra-O-methyl nordihydroguaiaretic acid in patients with refractory malignancy
Authors: Goel S. , Burris H. , Mendelson D. , Gollamudi R. , Stern J. , Frazer N. , Jones S. , Gordon M. , Mani S.
Published: March 2020

3584

Background: Tetra-o-methyl nordihydroguaiaretic acid (terameprocol-also EM-1421 or M4N) is a semi-synthetic derivative of a naturally occurring plant lignan. Terameprocol blocks cell cycle progression by inhibiting expression of the Sp1-dependent cdk1 gene and promotes apoptosis by inhibiting survivin. Methods: A dose escalation, open-label study enrolled patients (pt) with malignancies refractory to surgery, radiation therapy, and/or chemotherapy. Terameprocol was administered daily by intravenous infusion for 5 days (d) every 28 d over 30 minutes, with dose escalation (100, 200, 375, 750, 1,500, 2,200, and 3,300 mg) in cohorts of 3–6 pt. Tumor measurement (CT and PET scans) was performed at baseline and every 2 to 4 cycles. Pt at the 2,200mg and 3,300mg doses had circulating tumor cells (CTC) measured prior to dosing. Pharmacokinetics (PK) was evaluated for the first 2 cycles. Results: Twenty nine pt (17 male), median age 61 years, with gynecological (21%), lung (17%), colorectal (17%), or other cancer (45%) were enrolled. All pt were evaluable for toxicity and 21 pt for efficacy. At the highest dose (3,300 mg/d), dose limiting toxicity (DLT) of metabolic acidosis/respiratory failure considered drug related was observed in 1 of 3 pt, and no additional pt was enrolled at this dose. The next lower dose cohort (2,200 mg/d) was expanded (11 pt) and no DLT has been observed. Best response by RECIST criteria included a partial response in 1 pt and stable disease in 6 pt. Three pt discontinued for reason other than progression, and 11 had progressive disease. Pharmacokinetics demonstrated dose linearity. The volume of distribution was 300–1,000 liters, and the half-life ∼ 20–30 hours. No obvious trend was seen in CTCs. Across all doses, 108 adverse events, with 10 severe events, were observed. Conclusions: Terameprocol is well tolerated up to a dose of 2,200 mg and warrants further evaluation. Expansion continues at this dose level. There is clinical benefit in this refractory population that warrants further investigation.

No significant financial relationships to disclose.
Pharmacodynamic properties of the anti-IGF-IR monoclonal antibody CP-751,871 in cancer patients
Authors: Pollak M. N. , Lacy M. Q. , Lipton A. , Demers L. , Leitzel K. , de Bono J. S. , Yin D. , Roberts L. , Sharma A. , Gualberto A.
Published: March 2020

3587

Background: The Insulin like Growth Factor I receptor (IGF-IR), a tyrosine kinase, is widely expressed in human tissues. IGF- IR and its ligands (IGF-I and IGF-II) are expressed by many human cancers (e.g., breast, prostate, colorectal and non-small cell lung). Binding of the ligands to the IGF-IR activates key cellular signaling pathways important for stimulating cellular proliferation and inhibiting apoptosis. IGF- I and IGF-II are present in the circulation, but also locally expressed in neoplastic tissue. Bioavailability of these ligands is regulated by a family of IGF binding proteins (IGFBPs1–6). CP-751,871, a fully human monoclonal antibody, is a highly specific and potent inhibitor of IGF-IR activation. In vitro experiments show that binding of CP 751,871 to IGF-IR induces receptor internalization and degradation. This antibody has been shown to have antineoplastic activity using both in vivo and in vitro pre-clinical models. Methods: Blood samples were collected for characterization of the pharmacokinetic and pharmacodynamic properties of CP-751,871 in phase 1 trials of this agent given to cancer patients either alone or in combination with chemotherapy. The endpoints assessed included among others: CP-751,871 plasma concentrations, total and free IGF-I, IGFBP-3, soluble IGF-IR and IGF-IR expression on granulocytes and tumor cells. Results: CP 751,871 exposure increased with dose over the 800-fold dose range investigated. Pharmacokinetic profiles were consistent with target-mediated disposition. A dose-dependent downregulation of soluble IGF-IR serum concentration and IGF-IR expression was observed, with sustained inhibition for the entire dosing period (3–4 week cycles) observed at doses ≥ 1.5 mg/kg. As predicted for an agent that interferes with IGF-I action, IGF-I and IGFBP-3 serum levels were up-regulated in a similar dose-dependent manner. Conclusions: The pharmacodynamic endpoints of clinical trials provide evidence that CP-751,871 targets IGF-IR in granulocytes, tumor cells and tissues involved in regulation of the growth hormone -IGF-I axis. These data provide proof of principle for the use of CP-751,871 as a first-in-class therapeutic approach to inhibit the IGF-IR pathway in cancer patients.

No significant financial relationships to disclose.
Phase I dose escalation pharmacokinetic study of erlotinib after failure of prior chemotherapy in patients with advanced NSCLC who continue to smoke
Authors: Hughes A. N. , O’Brien M. , Dunlop D. , Petty W. , Rankin E. , Chick J. , Conlan M. , Woll P. , Nicolson M. , Price A.
Published: March 2020

3597

Background: The survival benefit associated with erlotinib is greater in never smokers than in current smokers. Former/never smokers experience a higher incidence of toxicity (e.g., rash) than current smokers, potentially due to greater erlotinib exposure. A higher dose of erlotinib, if feasible, may improve outcome in current smokers. Methods: A 2-part study was initiated to investigate the feasibility of escalating erlotinib to define the MTD in smokers and evaluate pharmacokinetics in patients (pts) dosed at this MTD versus 150 mg/d. Part I: sequential cohorts of advanced NSCLC pts currently smoking =10 cigarettes/d for = 1yr, ECOG PS 0–1, adequate organ function, and no prior EGFR inhibitor, received escalating doses of erlotinib for 14 days until DLT was seen in 2/6 pts. Part II: Upon identification of the MTD, pts were randomized between MTD and 150 mg/d erlotinib and PK assessed at D14. Pts could receive erlotinib beyond D14 until PD or toxicity. Results: Twenty-two pts were enrolled in Part I at 4 dose levels (#pts (MTD-evaluable pts)/dose level in mg/d): 3(3)/200, 6(3)/250, 8(6)/300 and 5(5)/350). Median/range age was 61 yrs (45–69) with 13 males and 9 females. Histology was Adenocarcinoma (9/22), Squamous (6/22) and other (7/22). Fourteen pts had prior RT and all had prior CT (median/range # prior regimens 1 (1–2)). Median/range # cigarettes smoked and duration of smoking was 18/d (10–40) and 42 yrs (10–54), respectively. DLT was observed in 1/6 MTD- evaluable pts at 300 mg/d (G3 rash) and 2/5 pts at 350 mg/d (G3 acneiform dermatitis and G3 fatigue/decreased ECOG PS). Otherwise treatment was well tolerated with common G1/2 toxicities limited to skin toxicity (59%), diarrhea (55%), and nausea, vomiting and metabolic or eye disorders (each 14%). Conclusions: The MTD of erlotinib in NSCLC pts who continue to smoke was 300 mg/d. Part II continues to compare the steady state PK of erlotinib at 300 versus 150 mg/d. The potential benefits of a higher dose of erlotinib in current smokers may warrant further evaluation.

No significant financial relationships to disclose.
First-in-human study of the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of PF-00299804, a small molecule irreversible panHER inhibitor in patients with advanced cancer
Authors: Schellens J. H. , Britten C. D. , Camidge D. R. , Boss D. , Wong S. , Diab S. , Guo F. , Maguire R. P. , Letrent S. P. , Eckhardt S. G.
Published: March 2020

3599

Background: There are scientific rationale for inhibitors which provide combined and irreversible blockade of HER family members. PF-00299804 is an orally available, potent, irreversible small molecule inhibitor of the HER tyrosine kinases. Methods: The safety, tolerability, PK, PD, and efficacy of PF-00299804 administered orally once daily in 3-week cycles were assessed in patients with advanced solid tumors using an accelerated dose-escalation design. Safety assessments included adverse event (AE), laboratory, ECG, and LVEF assessments. PK parameters were determined after a single lead-in dose and on Day 14 by non-compartmental techniques. PD measures included assessment of HER-related signaling pathways via IHC analyses of serial skin and, in some patients, tumor biopsies. Serial 18F-FDG- PET/CT has been performed on a subset of patients with scans being classified according to modified EORTC criteria by a central reader. Results: 32 pts have been treated across 8 sequential dose levels ranging from 0.5 to 60 mg. The most common AEs were diarrhea, fatigue, nausea, and rash. 3/6 patients at 60 mg experienced a DLT [hand-foot syndrome (1), dehydration related to diarrhea(1), mucositis(1)]. Cmax and AUC of PF-00299804 increased with dose in an approximately proportional manner. Accumulation ranged from 3.3 to 6.8, suggesting a terminal t1/2>24 h. At the 30 mg dose level, mean Day 14 drug concentration was above the predicted efficacious concentration for tumor growth inhibition based on A431 xenograft model. Of 7 sets of PET data evaluated thus far, partial responses (PR) have been observed in 2 patients. A PR as assessed using RECIST criteria has been reported in 1 of 2 patients with advanced refractory NSCLC treated to date. Conclusions: Daily administration of PF-00299804 across many dose levels appears safe and tolerable. Diarrhea, fatigue, nausea, and rash are the most frequent AEs. Evaluation of 45 mg/d as the potential MTD is ongoing. Systemic exposures at doses = 30 mg exceed the threshold for efficacy as predicted from preclinical studies. Clinical and biological activity of PF-00299804 was observed including a PR in 1 of 2 patients with advanced refractory NSCLC.

No significant financial relationships to disclose.
Quality of life in patients with advanced colorectal cancer treated with cetuximab: Results of the NCIC CTG and AGITG CO.17 trial
Authors: Au H. , Karapetis C. , Jonker D. , O’Callaghan C. , Kennecke H. , Shapiro J. , Tu D. , Wierzbicki R. , Zalcberg J. , Moore M.
Published: March 2020

4002

Background: Cetuximab prolongs survival in pretreated advanced colorectal cancer (CRC) patients (pts). For these pts, the effect of palliative treatment on quality of life (QOL) is also an important outcome. Methods: CO.17 was a randomized controlled trial (n=572) of cetuximab combined with best supportive care (BSC) vs BSC alone in pts with pretreated epidermal growth factor receptor-positive advanced CRC. Primary endpoint was survival. QOL was a secondary endpoint using the EORTC QLQ-C30 at baseline, 4, 8, 16, and 24 weeks (wks). Primary endpoint for QOL compared physical function (PF) and global health status (Global) mean changes from baseline to 8 and 16 wks using Wilcoxon test. Negative change scores denote worsening QOL. The proportion of pts in either arm with at least a 10 unit deterioration at 8 and 16 wks from baseline was compared using Fischer’s exact test. Kaplan-Meier estimates and logrank tests on median time to definitive QOL deterioration, defined as at least a 10 unit deterioration in PF or Global, were evaluated. Exploratory analyses of all other scale and symptom change scores at 8 and 16 wks were also performed. Results: Compliance rates for QOL questionnaires was high at baseline, 94% each arm, but did drop off over time: 73% vs 60% at week 8 and 60% vs 39% at week 16 for cetuximab vs BSC, respectively. PF change scores at 8 wks were -3.9 for cetuximab vs -8.6 for BSC (p=.046); at 16 wks -5.9 vs -12.5 (p=.027). Global change scores were -0.5 vs -7.1 (p=.008) and -3.6 vs -15.2 (p=.008) at 8 and 16 wks respectively. The proportion of pts with deteriorating PF was 25% for cetuximab vs 35% for BSC at 8 wks (p=.051) and 30 vs 43% at 16 wks (p=.069). Deteriorating Global was seen in 23 vs 38% at 8 wks (p=.004) and 31 vs 49% at 16 wks (p=.0011). Time to PF deterioration was 5.4 months [95% CI 3.8–5.7] for cetuximab vs 3.7 months [2.0–3.9] for BSC (p=.022). Time to Global deterioration was 5.4 [3.9–5.7] vs 3.7 months [2.1–3.9] (p=.062). Exploratory analyses of all other scale and symptom change scores at 8 and 16 wks showed all differences of p<.05 also favored cetuximab. Conclusions: Cetuximab provides palliation in pretreated pts with advanced CRC, delaying deterioration in QOL as well as improving survival.

[Table: see text]
A pooled safety and efficacy analysis examining the effect of performance status (PS) on outcomes in nine first-line treatment (rx) trials (cts) of 6,286 patients (pts) with metastatic colorectal cancer (MCRC)
Authors: Goldberg R. M. , Köhne C. H. , Seymour M. T. , de Gramont A. , Porschen R. , Saltz L. , Rougier P. , Tournigand C. , Grothey A. , Sargent D. J.
Published: March 2020

4011

Background: While pt PS is a known prognostic factor in MCRC, most phase III CTs enroll < 10% PS2 pts. This pooled analysis compares safety and efficacy in PS 0–1 versus (v) PS 2 MCRC pts on first-line CTs testing both single agents and combination rx. Methods: This retrospective analysis included 6,286 MCRC pts (509 PS 2) from 9 CTs (control arms: 5 5FU/LV, 2 FOLFOX, 1 FUFOX, 1IFL). Five CTs specifically compared mono to combination rx (3,814 pts; 335 PS 2). The primary endpoint was progression-free survival (PFS). Other endpoints included grade 3+ adverse events, 60-day all cause mortality, overall survival (OS), and response rate (RR). Efficacy endpoints were explored in both the full set of 9 CTs & the subset of 5 CTs that compared mono to combination rx. Results: Severe (grade 3+) nausea (7.0% v 13.0%; P < .0001), vomiting (6.4% v 10.5%; P = .0002), and stomatitis (2.0% v 4.2%; P = .0332) were significantly higher in PS 2 pts. PS 2 was not associated with incidence of severe diarrhea or neutropenia. 60-day all cause mortality was significantly higher in PS 2 pts (2.8% v 12.0% in PS 0–1 v PS 2 respectively, P <.0001). PS 2 was a prognostic factor for PFS (HR=1.52, P < .0001, median 7.6 v 4.9 months (mos) in PS 0–1 v 2), OS (HR=2.18, P < .0001, median 17.3 v 8.5 mos in PS 0–1 v 2), & RR (OR=0.60, P < .0001, 43.5% v 32.0% in PS 0–1 v 2). The relative benefit of experimental (exp) v control rx did not differ in PS 0–1 v PS 2 pts for RR, PFS, or OS (see table ). This was true both when assessing all 9 CTs and the subset of 5 mono v combination rx CTs. Conclusions: In CTs, pts with PS 2 derive similar advantages with regard to efficacy from superior Rx as do pts with PS 0–1, but with higher risk of some gastrointestinal toxicities. Twelve percent of PS 2 pts die within 60 days of rx start. Median OS is < 9 months. While current Rx does provide benefit, new approaches are required to approach 1 year median survival for PS 2 pts.

[Table: see text]

No significant financial relationships to disclose.
Meeting the 12 lymph nodes (LN) benchmark in colorectal cancer surgery: A comparison of NCCN and SEER data
Authors: Rajput A. , Skibber J. , Engstrom P. , Weiser M. , Wilson J. , Shibata S. , Romanus D. , terVeer A. , Earle C. , Schrag D.
Published: March 2020

4015

Background: The American College of Pathology has suggested that 12 or more LN be examined from colorectal cancer surgical specimen. Both ASCO and NCCN have considered adopting the 12 LN threshold as a quality metric. The purpose of this study was to determine whether the 12 LN benchmark is achieved at NCCN specialty centers. Methods: Patients with newly diagnosed stage I-III colon or rectal cancer, who had primary surgery at NCCN centers in 2005–6 were selected (n=345). Similarly, data from 14,019 stage I-III colorectal patients diagnosed in 2002 in a SEER region were obtained to determine the extent to which this goal was met in a population-based sample. Patient characteristics of age, gender, location, stage and number of positive nodes were compared for NCCN and SEER data in regards to number of nodes evaluated. Univariate logistic regression models were developed to identify factors associated with the 12 LN target at the NCCN. Factors evaluated were number of positive nodes, age, gender, comorbidity score, ECOG performance status, insurance, location, stage, surgery technique, and NCCN center. Results: As detailed in the Table , 89% of the 2005–6 NCCN sample and 45% of the SEER sample had at least 12 LN evaluated. For patients treated at NCCN centers, stage I compared to stage III (OR=0.20; 95% CI=0.08 to 0.48, p<0.0001) and rectal cancer (OR=0.44; 95% CI=0.22 to 0.88, p=0.02) were each less likely to achieve the 12 LN target. Conclusions: For patients operated on at NCCN centers, at least 12 LN are almost always removed and examined as part of an oncologic resection. In population based samples, this target is achieved in less than half of cases. With longer follow-up we will be able to link this potential quality metric directly to outcomes and thereby better inform whether increasing the number of nodes evaluated is an important priority for cancer control. Table 1 . Characteristics of CRC patients who did and did not have 12 or more LN evaluated at primary resection.

[Table: see text]

No significant financial relationships to disclose.