bluuebunny/crossref_metadata_2025 huggingface dataset:
Suppression of HOX A cluster genes inhibits proliferation and induces cell death in human mixed-lineage leukemias
Authors: Faber J. , Krivtsov A. , Stubbs M. , Wright R. , van den Heuvel-Eibrink M. , Kung A. , Zwaan C. , Armstrong S.
Published: March 2020

14020

Background: Leukemias harboring translocations of the mixed lineage leukemia locus (MLL) are generally associated with poor clinical prognosis. Using gene expression profiling we and others have previously shown that Homeobox (HOX) A cluster genes are highly expressed in leukemias with MLL rearrangements. Methods: Here we studied the role of aberrant HOXA9 expression in human MLL- rearranged and non-rearranged leukemias utilizing an shRNA mediated knockdown approach. Results: Three different shRNA constructs targeting human HOXA9 were synthesized and stably introduced into t(9;11) MOLM14 cells utilizing a lentiviral vector system. 75–80% HOXA9 RNA knockdown was confirmed by quantitative PCR and Western Blot analysis. In a panel of 17 AML/ALL cell lines (7 MLL rearranged, 10 non rearranged), HOXA9 directed shRNA inhibited cell proliferation starting as early as 48h after transduction, and induced apoptosis beginning at 72h. Interestingly, impaired cell proliferation and induction of apoptosis was significantly higher in the MLL rearranged cell lines (mean viability: 51.88%) than in the non-rearranged cells (mean viability: 90.98%; p=0.007) and also significantly correlated with the baseline HOXA9 mRNA expression before knockdown (R= 0.8, p=0.00017). We then further analyzed the effect of HOXA9 knockdown in MLL rearranged and non-rearranged primary human AML cells. Similar to our findings in cell lines, a marked induction of cell death was observed, which was significantly higher in leukemias with an MLL translocation (p=0.005) and also significantly correlated with the baseline HOXA9 mRNA expression (R= 0.8, p=0.001). Next, the in vivo effect of HOXA9 knockdown was assessed by transplanting luciferase-expressing SEMK2 (t4;11) cells into SCID-beige mice followed by in vivo bioluminescent imaging. Leukemia burden was significantly reduced in HOXA9 shRNA treated mice (n=10) with a peak difference at day 15 (p=0.000059) shortly before mice of the control group (n=10) succumbed from overt leukemia. At this point all mice of the HOXA9 shRNA treated group were still healthy with no signs of leukemia. Conclusions: Taken together our data implicates that depletion of HOXA9 might be a novel approach for targeted therapy in human MLL rearranged leukemias.

No significant financial relationships to disclose.
Comparison of enzastaurin pharmacokinetics and safety in the once daily (QD) and twice daily (BID) dose regimens: A phase I study
Authors: Hanauske A. , Musib L. , Weigang-Köhler K. , Yilmaz E. , Graefe T. , Kuenen B. , Thornton D. , Lahn M. , Darstein C. , Giaccone G.
Published: March 2020

14021

Background: Enzastaurin, an oral serine/threonine kinase inhibitor, suppresses signaling through PKCβ and the PI3K/AKT pathway to induce tumor cell apoptosis, reduce proliferation, and suppress tumor-induced angiogenesis. Objectives of this phase 1b study included the comparison of safety and PK data for enzastaurin and its active metabolites in the QD (once daily) and BID (twice daily) regimens. Methods: Patients (pts) with advanced or metastatic cancer were enrolled. In cycle 1, pts received 500 mg enzastaurin QD from days 1–15 and 250 mg BID from days 16–30. In subsequent 21-day cycles, 500 mg/m2 pemetrexed was administered as a 10-minute intravenous infusion on day 1, with 250 mg enzastaurin BID. Folic acid and vitamin B12 supplementation was given to pts prior to and during pemetrexed administration. For comparison of enzastaurin QD versus BID, PK sampling was performed on days 15 and 29 of cycle 1. Results: Interim data for cycle 1 are presented for 26 patients who received 1 dose of enzastaurin. Twenty patients (9 F, 17 M; median age 60 years [range: 43–80]; ECOG =2) completed cycle 1. Hematological toxicities (grade [Gr] =3) were reported on a total of 9 pts. Lymphopenia occurred in 8 pts in BID regimen (1 Gr 3) and 2 pts in QD. Leukopenia (n=1), neutropenia (n=1), hypokalemia (n=1) and SGPT increase (n=1) were reported only in BID regimen. Chromaturia (n=15) was observed in both regimens. Hypoalbuminemia (n=2) and fatigue (n=2) were equally common in both regimens. Pharmacokinetic data for the two regimens is shown in the table . Exposures increased by approximately 50% and 40% for enzastaurin and total analyte (enzastaurin + metabolites), respectively. Conclusions: In comparison to QD dosing, enzastaurin exposures are increased modestly after BID dosing. This increase in exposure did not cause any clinically significant worsening of toxicities in most patients.

[Table: see text]

[Table: see text]
Poly-adeninosinediphosphate-ribose polymerase inhibitors as sensitizers for therapeutic treatments in human tumor and blood mononuclear cells
Authors: Ji J. , Redon C. , Pommier Y. , Kinders R. , Parchment R. , Hollingshead M. , Yang S. , Murgo A. , Tomaszewski J. , Doroshow J.
Published: March 2020

14024

Background: Poly(ADP-ribose) (PAR) polymerase-1 (PARP-1) is a molecular sensor of DNA breaks that facilitates DNA repair and controls genomic stability. Treatment with single doses of ABT-888, a novel potent PARP-1 inhibitor, reduced PAR levels in peripheral blood mononuclear cells (PBMCs) and tumor biopsies in an on-going Phase-0 trial at the NIH Clinical Center. As a corollary to this study, we investigated whether ABT-888 can act as a sensitizer for radiation therapy and chemotherapy in human cancer cell culture, xenograft tumors and PBMCs to support future combination clinical trials. Methods: Inhibition of PARP-1 by ABT-888 was determined by a quantitative PAR chemiluminescence immunoassay validated for the Phase 0 trial. Since gamma-H2AX (?-H2AX) is a marker of DNA damage, we also developed and validated ?H2AX assays to monitor the effects of PARP-1 inhibition during treatment with Topo I inhibitors and radiation. Human monocytic leukemia (THP-1) and breast carcinoma (MCF-7) cell lines were treated with Topo I inhibitors including indenoisoquinoline, camptothecin and topotecan or irradiated with 0.5 to 10 Gy in the presence of ABT 888. We further evaluated these effects in human blood ex vivo to confirm the observations made in cell culture. Results: We found that ABT-888 inhibited PAR, but did not significantly increase DNA damage. Combination of ABT-888 with a Topo I inhibitor produced over 275% increase of DNA damage in THP-1 leukemia cells compared to indenoisoquinoline alone. ?H2AX foci per cell were 9.5 ± 0.8 in MCF-7 treated with 0.5 Gy/50 nM ABT-888 in comparison to 4.0 ± 0.6 with radiation alone. When whole blood was treated in the presence of ABT-888, camptothecin- induced DNA damage in PBMCs was also increased 2–3 fold, with maximum ?H2AX expression at 2 hours post treatment. Conclusions: We conclude that ABT-888 is a highly potent PARP-1 inhibitor that can enhance the DNA damaging effects of chemotherapy and radiation therapy of human cancer. Funded by NCI Contract N01-CO-12400.

No significant financial relationships to disclose.
A phase I trial of AVN944 in patients with advanced hematologic malignancies
Authors: Klisovic R. B. , Tricot G. , Coutre S. , Kovacsovics T. , Giles F. , Genna T. , Bol D. K. , Strovel J. W. , Hamilton J. M. , Mitchell B.
Published: March 2020

14026

Background: AVN-944 is an inhibitor of inosine monophosphate dehydrogenase (IMPDH), an enzyme that catalyzes the rate- limiting step in guanine nucleotide synthesis, and induces apoptosis in malignant hematopoietic cell lines in vitro. Methods: This phase I study employed open-label dose escalations in patients (pts) with relapsed, refractory hematologic cancers with safety, pharmacokinetic (PK), pharmacodynamic, & efficacy endpoints. Between 12/05 and 1/07 a total of 70 cycles of AVN944 at 25 (7pts), 50 (6pts), 75 (7pts), 100 (7pts) or 125 mg (3pts) b.i.d. orally X 21d every 28d were administered to 30 pts with AML (12), ALL (2), CLL (3), and multiple myeloma (13). Peripheral blood mononuclear cell (PBMC) or leukemic blast samples were obtained from all pts pre and post-receiving AVN944 to determine effects on GTP pools, IMPDH activity, and to correlate these changes to response in a 32-gene set that relates directly to cellular pathways dependent upon guanine nucleotide biosynthesis. Results: Pharmacokinetics were dose proportional with mean Tmax=1 hour, T1/2=1.5 hours, Cmax=2800 ng/ml and AUC=7228 hr.ng/ml at the 100 mg b.i.d. dose. Toxicities were generally mild-moderate and/or not attributed to AVN944. Twelve serious adverse events (SAEs) occurred in 8 pts; 7 of 8 had AML. No SAEs was attributed to AVN944. DLT was not seen. No protocol defined responses were seen. Twelve of 24 assessable pts had stable disease of 2 to 10 months duration. Changes in the gene expression set correlated with disease stability. Conclusions: AVN944 is well tolerated with oral b.i.d. dosing. Stabilization of disease was observed in half of the pts. Gene expression correlated with stable versus progressive disease.

[Table: see text]
A single agent, phase I pharmacodynamic study of nimotuzumab (TheraCIM-h-R3) in patients with advanced refractory solid tumors
Authors: Brade A. M. , Magalhaes J. , Siu L. , Oza A. , Lovell S. , de Borja M. , Pond G. , Sherman I. , Hedley D. , Chen E.
Published: March 2020

14030

Background: Nimotuzumab (N) is a humanized mAb against the EGFR extracellular ligand binding domain. Although well tolerated when combined with radiotherapy in previous studies and lacking usual toxicities of EGFR-targeting agents, the pharmacodynamics (PD) of N has not been elucidated. This phase I study was designed to evaluate the safety, tolerability and PD of N. Methods: Eligibility criteria included advanced solid tumors refractory to standard therapy and ECOG PS = 0 - 2. IV N was administered weekly x 6 and then every other week (6 weeks = 1 treatment cycle). Tumor, skin and liver biopsies obtained pre- and 2 and 7 weeks post-treatment were evaluated using computer-based, whole mount assessment of immunohistochemical staining. Results: Accrual was completed 21/09/06, 17 patients (11m/6f, median age 63, 13 colorectal cancer, ECOG 0:1:2 = 6:10:1, prior therapy 1:2:3+ = 2:6:9) were registered and 16 patients were treated on 4 dose levels (100, 200, 400 and 800 mg) for a total of 43 treatment cycles (1 patient deemed ineligible after registration did not receive study therapy). Treatment was well tolerated. One dose-limiting toxicity was observed (dose level 1 - grade 3 fatigue possibly attributable to N) . Skin toxicity was mild (Gr 1/2 in 7/1 patients). Confirmed stable disease was seen in 6 patients, a confirmed partial response in 1 patient with prolonged progression-free status observed in 3 patients for 5.8, 14.1 and 18.7 months (the latter two remain on study). Baseline and week 2 biopsies of tumor/skin/liver were evaluable in 12/13/7 pts. Week 7 tumor/skin/liver biopsies in initially responding or stable patients were evaluable in 6/8/6 pts. Post treatment (week 2), EGFR staining decreased in 8/12 matched tumor [mean ratio (post/pre): 0.79 range: (0.37, 1.91)], 8/13 skin [0.96 (0.40, 1.31)] and 5/7 liver [0.88 (0.62, 1.17)] biopsies. No significant relationship was detected between pre/post-treatment EGFR expression with either response or toxicity. Evaluation of downstream targets of EGFR (in tumor, skin and liver) is ongoing and will be presented. Conclusions: Overall nimotuzumab was well tolerated and exhibits mild skin toxicity. Prolonged progression free-survival was observed in 3/16 of these heavily pre-treated patients.

No significant financial relationships to disclose.
Statistical considerations for a phase 0 trial
Authors: Rubinstein L. V. , Steinberg S. M. , Kummar S. , Low J. , Parchment R. , Kinders R. , Gutierrez M. , Murgo A. J. , Doroshow J. H. , Tomaszewski J.
Published: March 2020

14038

Background: Phase ‘0’ clinical trials are small first in man studies to determine a dose or dose range which results in a desired biologic effect. Novel statistical designs are needed due to the limited number of patients and the complexities of analyzing primary pharmacodynamic endpoints. Methods: In general, the effect of the agent will be evaluated, based on a biologic endpoint(s), at two levels, the individual participant level (for a given dose amount), and the agent dose amount level (across individual participants). At the participant level, the effect is preferably defined as a dichotomous outcome. The statistical criteria should be such that the threshold is not surpassed with more than .10 probability, for a given participant, at a given dose amount, for the null hypothesis case of no true biologic effect. At the dose amount level, the effect rate is defined as the probability that a randomly chosen participant will satisfy the participant level threshold. The statistical criteria for declaring an observed effect rate to be significant should be such that the over-all probability of declaring the agent effective (summed across all dose amounts) should not exceed .10 for the null hypothesis case of no true biologic effect. A target effect rate, measured across participants, should be given, and the power to detect it, for a given dose amount, should be estimated. Ideally, there will be multiple pre-agent administration endpoint measurements, per participant, to define variability. Examples: 1. If 10 participants are accrued to a single dose amount, an observed effect rate for that dose amount could be defined to be significant if at least 2 of the 10 participants satisfy the participant threshold, yielding 85–90% power to detect a 35% effect rate. 2. If 5 participants are accrued to each of 2 dose amounts, an observed effect rate for a particular dose amount could be defined to be significant if at least 2 of the 5 participants satisfy the participant threshold, yielding approximately 90% power to detect a 60% effect rate. 3. If 3 participants are accrued to each of 4 dose amounts, an observed effect rate for a particular dose amount could be defined to be significant if at least 2 of the 3 participants satisfy the participant threshold, yielding approximately 90% power to detect an 80% effect rate.

No significant financial relationships to disclose.
EPC2407, a new beta-tubulin vascular disrupting agent with potent apoptosis and cell growth inhibition
Authors: Anthony S. P. , Von Hoff D. , Whisnant J. K. , Tseng B. Y.
Published: March 2020

14043

Background: Compounds which bind to colchicine-like sites of microtubules have contributed greatly to the armamentarium of cancer therapies. But new modes of administration of taxanes and potent new vascular disruption agent molecules such as combretastatin continue to challenge drug development for ways to improve the therapeutic index in this important class. EPC2407 is a novel 4-aryl chromene of nM anti-tumor potency; it is crossing the translational bridge based on an array of preclinical anti-tumor pharmacology and supported by multiple toxicology trials which included drug exposure data. Methods: Vascular disrupting agents demand careful preclinical workup. What we have done is summarized in the table below. This data is from cellular metabolic, cell proliferation, vascular endothelial, in vivo tumor, and animal toxicokinetic and safety studies. Results: Please see table below of the preclinical experiments. Conclusions: A Phase I clinical trial has been designed and initiated to replicate the safety margin shown by the analysis of preclinical drug exposure data. The critical safety issue for human dosing was the dose exposure which might produce the well known ECG abnormality of delayed repolarization or prolonged QTc. A dose related QTc effect was demonstrated in cynomolgus monkeys after a 2 min infusion which achieved acute plasma exposures higher than 3836 nM. These effects were dose related and persisted only through 4 short half-lives of the parent compound. Initial human analysis fails to show any prolongation of the QTc. [JW1] [JW1]THE END HERE, all else was draft.

[Table: see text]

No significant financial relationships to disclose.
Combination of fulvestrant and lapatinib in non-HER2-overexpressing and adriamycin-resistant breast cancer cell lines
Authors: Emde A. M. , Maslak K. , Liu H. , Reles A. E. , Possinger K. , Eucker J.
Published: March 2020

14050

Background: We evaluated whether combination of lapatinib, a dual tyrosine kinase inhibitor against EGFR and HER2, and fulvestrant, a full estrogen receptor antagonist, is superior in EGFR and HER2 overexpressing and non-overexpressing breast cancer cell lines regarding cell growth inhibition and effects on the protein expression level on special proteins such as PDK1 and ERK1/2. Methods: MTT assay and western blot analysis were performed in the different breast cancer cell lines BT474, T47D, MCF-7 and Adriamycin resistant MCF7 cells. Incubation time was 72h. Concentration of both agents in western blot: 1x10exp-7M, in MTT assay 10exp-11M to 10exp-5M. Results: MTT assay showed a significant stronger proliferation inhibition by lapatinib and fulvestrant in BT474 cells and non- overexpressing T47D cells at a concentration of 10E-7M compared to single agent treatment. By western blot analysis, we found a synergistic downregulation of PDK1 in the combination treatment both in BT474 and AR MCF7 cells, whereas not in T47D cells. In MCF7 cells a downregulation of p-PDK1 was observed after treatment with fulvestrant alone as well as lapatinib plus fulvestrant. Regarding ERK1/2, a synergistic downregulation could be observed in AR MCF7 cells. A downregulation of a p-ERK was detected in MCF-7 cells after treatment with lapatinib, fulvestrant or both. Conclusion: A synergistic action of lapatinib and fulvestrant was observed in all 4 cell lines despite their different receptor status regarding EGFR, HER2 and ER alpha. Shadeo et al. (2005) showed different copy number profiles in these breast cancer cell lines regarding the examined pathways. We could show by western blot analysis that the combination treatment had inhibitory effect on these cell lines according to their individual up-regulated pathways. Altogether, this suggests that the combination is a promising treatment not only in EGFR and HER2 over-expressing breast cancer and that treatment effect is also dependent on up-regulated pathways more likely than receptor status.

No significant financial relationships to disclose.
A randomized phase 2 trial of combretatstatin A4 phosphate (CA4P) in combination with paclitaxel and carboplatin to evaluate safety and efficacy in subjects with advanced imageable malignancies
Authors: Akerley W. L. , Schabel M. , Morrell G. , Horvath E. , Yu M. , Johnsson B. , Arbogast K.
Published: March 2020

14060

Background: CA4P is the lead compound in a class of agents termed Vascular Disrupting Agents. Phase I studies of CA4P demonstrated toxicities that do not overlap those of chemotherapy. In vitro studies show synergistic cytotoxicity for CA4P and chemotherapy. This study was designed to assess safety, toxicity and tumor perfusion of CA4P at 2 doses when combined with paclitaxel and carboplatin at fixed doses. Methods: A one stage, randomized trial for subjects with imageable tumors by DCE-MRI for perfusion. Subjects received either 45 or 63 mg/m2 CA4P IV on Days 1, 8, and 15, then 200 mg/m2 paclitaxel and AUC 6 carboplatin on Day 2 of each 21 day cycle. After completion of 6 cycles, subjects could continue with CA4P alone. DCE-MRI was measured prior and 24 hours after the first dose of CA4P. Results: 13 subjects were accrued from 3/05–11/05. 78 cycles were administered and 1 subject continues active therapy on cycle 19. The median number of cycles administered was 6. Both 45 and 63 CA4P with paclitaxel/carboplatin were well tolerated. The most frequent adverse events are listed in Table 1 . Grade 3–4 AEs were similar between the two dose groups. Table 1 : Most Frequent AEs by CA4P Dose DCE-MRI data showed a mean reduction in blood flow for both dose groups (46% vs. 19% respectively) confirming CA4P’s tumor vascular disrupting capabilities. Tumor responses were observed and were similar between both dose groups. Best overall response through cycle 6 was 3 PR, and 6 SD. Two subjects with thyroid cancer were randomized to the low dose group and completed cycle 6. The 1st had SD and progressed after cycle 6. The 2nd achieved PR and progressed after 8 cycles. These subjects also had the greatest reduction in tumor blood flow. Ktrans was reduced by 73 and 79% 24 hours post CA4P. Conclusion: These doses of CA4P in combination with paclitaxel and carboplatin were well tolerated, demonstrated anti-tumor activity and reduction of tumor blood flow.

[Table: see text]

No significant financial relationships to disclose.
A phase I study of NGR-TNF, a novel vascular targeting agent, in patients with refractory solid tumors (EORTC 16041)
Authors: Heerschap A. , Fiedler W. , Marreaud S. , van Laarhoven H. , Govaerts A. , Peters M. , Toma S. , Bordignon C. , Punt K. , Van Herpen C.
Published: March 2020

14074

Background: NGR-TNF is a novel agent exploiting a tumour homing peptide (cNGRCG) that selectively targets CD13 that is expressed on the neovasculature of solid tumors. Preclinical data show that its antitumour activity is achieved by a change of vascular permeability (at low doses) and damage of tumour-associated blood vessels (at high doses). This phase I study is being conducted to assess its safety, PK, PD, MTD, and optimal biological dose in patients (pts) with advanced solid tumours. Methods: NGR-TNF was administered once every 3 weeks by a 20 min IV infusion to cohorts of 3–6 pts. The starting dose was 0.2 μg/m2. Dose escalation was performed with a doubling of the dose until grade 2 toxicity was observed; thereafter a modified Fibonacci schedule was used. PK and PD analysis in blood was performed during the first 4 cycles. DCE-MRI was performed in cycle 1 at baseline and 2 hours after start of the infusion to document modification of the tumour vascularity. Anti-tumour activity was assessed by CT scan every 2 cycles. Results: 45 pts were treated and 133 cycles of treatment completed up to now. 12 DLs have been visited (0.2 to 14.36 μg/m2). One DLT (bronchospasm G 3) was observed at DL4 (1.3 μg/m2) and the DL was extended to 7 pts. As no other DLT was observed, dose escalation was continued. Since then no additional pt experienced dose-limiting toxicity. As 3/18 first pts experienced chills G 2 during injection time, the study was amended and infusion time increased to 1 hour. Since then 1/14 next pts had G 2 chills. Overall most frequently related adverse events reported in the first 34 pts: chills 76%, fever 44%, nausea 20%, constipation 12%, diarrhea 9%, anorexia and hypotension 6%. PK/PD analysis for the plasma levels of TNF-RI and TNF-RII showed a better profile for the 60 min compared with the 20 min infusion. At DL = 1.3 μg/m2 most pts showed a decrease in kep and the number of pixels with a low fraction of kep and Ktrans significantly increased (p<0.05), as seen with other anti- vascular agents. Stable disease was observed in 39% of pts, with a median duration of 11 wks (range 5–36). No responses were observed. Conclusions: NGR-hTNF is well tolerated and some biological activity was observed by DCE-MRI. Study enrollment is ongoing.

[Table: see text]
First-in-human phase I trial of a cyclodextrin-containing polymer-camptothecin nanoparticle in patients with solid tumors
Authors: Yen Y. , Synold T. , Schluep T. , Hwang J. , Oliver J. , Davis M. E.
Published: March 2020

14078

Background: IT-101 is a de novo designed experimental therapeutic comprised of linear, cyclodextrin(CD)-containing polymer conjugates of camptothecin(CPT) that assemble into ca. 40 nm diameter nanoparticles via polymer-polymer interactions that involve inclusion complex formation between the CPT and the CD. Particle size, near neutral surface charge and CPT release rate were specifically designed into IT-101. Published pre-clinical animal studies show extended circulation times (t1/2 of ca. 20 h in rodents), tumor accumulation, slow release of the CPT and anti-tumor efficacy that directly correlate to the properties of the nanoparticle. Release of CPT can disassemble the nanoparticle into individual polymer chains that have size ca. 10 nm that are capable of renal clearance (t1/2 of several minutes in rodents). Methods: Patients with relapsed or refractory cancer were evaluated every two cycles of therapy (90 minute IV infusions of IT- 101 in D5W on days 1, 8 and 15 of a 28 day cycle). Three dose levels of 6, 12 and 18 mg CPT eq./m2 have been tested. Results: At the time of this interim analysis, eight patients have been enrolled and five evaluated. In general, IT-101 is well tolerated and pancytopenia is the DLT. The expected MTD is 12 mg/ m2.Three out of five patients demonstrated stable disease on CT scan evaluation. One pancreatic cancer patient remains stable for 6 months. PK data are available from the first 5 patients. Total and free CPT display biphasic elimination from plasma with mean terminal elimination half lives of 38±3.7 and 61±43 hours, respectively. The mean Vd and CLsys of total CPT are 6.1±1.4 L and 0.1±0.03 L/h and are unrelated to dose over the range tested, with a mean total-to-free AUC ratio of 10.7±3.7. Conclusions: These first in human PK data for IT-101 confirm that 40 nm particles with near neutral surface charge provide favorable PK properties. The stable disease rate, although not yet conclusive, is consistent with promising efficacy. The preliminary results of this phase I study warrant continued enrollment that is ongoing.

No significant financial relationships to disclose.
Oblimersen can be administered by subcutaneous (SC) and brief intravenous (IV) infusion: Clinical pharmacokinetics and pharmacodynamics (PK/PD) in patients with advanced cancer
Authors: Lin C. , Papadopoulos K. , Patnaik A. , Sankhala K. , Takimoto C. H. , Rodon J. , Julian T. , Brown B. D. , Tolcher A. W.
Published: March 2020

14083

Background: Oblimersen (OBL) is a phosphorothioate oligodeoxynucleotide that decreases Bcl-2 protein levels. OBL has been administered by continuous intravenous infusion (CIVI) in most clinical studies. However, recent preclinical data suggest that equivalent or superior antitumor efficacy can be achieved with intermittent administration. We conducted a dose-ranging PK/PD study of OBL given by bolus SC injection and brief IV infusion to evaluate the feasibility of intermittent dosing. Methods: In this within-subject dose-escalation study, OBL was administered subcutaneously (SC) at doses of 75, 150 and 225 mg. In part II of the study, OBL was administered by 2-hr IV infusion beginning at 150 mg on day 1, by single-dose SC injection on day 8, and 2-hr IV daily x 5 consecutive days. Pharmacokinetics were assessed by non-compartmental analysis. Pharmacodynamic measurements of Bcl-2 levels in peripheral blood mononuclear (PBM) cells were made using Western blot analysis. Results: OBL absorption after SC administration was rapid with a Tmax of ∼2 hours. Mean Cmax values were 0.76, 1.70 and 3.10 μg/ml for the 75, 150 and 225 mg SC doses, respectively. Mean AUC0- inf values were 7.78, 15.36 and 25.57 hr*μg/mL. Plots of dose-normalized Cmax and AUC vs. dose showed slopes close to zero, indicating approximate dose proportionality. AUC0–24 exposure with the 225 mg SC dose was similar to previously established 24-hr steady-state AUCs after 3 mg/kg CIVI. SC injection was associated with an inflammatory erythematous grade 1 rash at the injection site that resolved within 7 days. The 150 mg 2-hr IV infusion x 1 or daily x 5 has been well-tolerated. Conclusions: OBL exposure from a single SC injection is similar to a 24-hr 3 mg/kg CIVI, and the 2-hr IV infusion is currently being evaluated. Both schedules appear to be well- tolerated, may reduce requirements for CIVI, and could be incorporated into intermittent dosing regimens.

No significant financial relationships to disclose.
Phase I study of CYT997, a novel cytotoxic and vascular disrupting agent, given as a 24-hour intravenous infusion to patients with advanced solid tumours
Authors: Lickliter J. , Smith G. , Burge M. , Coulthard A. , Wyld D. , Wilks A. , Vasey P.
Published: March 2020

14115

Background: CYT997 is a novel tubulin-binding small molecule which inhibits microtubule assembly and also demonstrates potent vascular-disrupting activity in preclinical tumour models. Methods: CYT997 was administered by continuous infusion over 24 hours every 3 weeks to patients with advanced cancer. Dose escalation proceeded by a standard phase I design (3 patients per dose level) for the first 18 patients; subsequently, an accelerated titration design (1 patient per dose level) was utilized. Intrapatient dose escalation was permitted. Pharmacokinetic (PK) analyses were performed in the first cycle. Tumour response was determined every second cycle using RECIST criteria. Pharmacodynamic effects on the tumour vasculature were assessed with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Results: 22 patients (M/F: 11/11; median age 57.5, range 28–75) were enrolled with tumour types including melanoma (4), renal cell (4), colorectal (2), non-small cell lung (2) and adenoid cystic (2) carcinomas, mesothelioma (2) and others (6). A total of 66 cycles of CYT997 were administered (median 2/patient, range 1–6) over 10 dose levels (7, 14, 23, 35, 49, 65, 86, 114, 152 and 202 mg/m2). No dose-limiting toxicity was observed. Because of grade-2 injection site reactions in 2 patients (one each at dose levels 3 and 4), all subsequent patients received CYT997 via a central venous access device. Other toxicities included grade-2 renal toxicity at dose- level 8 in one patient with abnormal baseline renal function and grade-1 QTc prolongation in one patient at dose-level 10. No myelosuppression, gastrointestinal toxicity or clinically-significant cardiac toxicity were observed. PK data revealed dose-related increases in Cmax and AUC values. Six patients had stable disease after 4 cycles of CYT997. Conclusions: CYT997 was well tolerated at the doses studied and accrual to the 269 mg/m2 dose level will now proceed.

No significant financial relationships to disclose.
A phase 1 study of the selective cyclin dependent kinase inhibitor P276–00 in patients with advanced refractory neoplasms
Authors: Hirte H. W. , Raghunadharao D. , Baetz T. , Hotte S. , Rajappa S. , Iacobucci A. , Sharma S. , Parikh H. , Kulkarni S. , Patil S. , Gaston S.
Published: March 2020

14117

Background: In human cancers, genetic and epigenetic events result in over-expression of cyclins or absence or diminished levels of Cdk inhibitors, providing tumor cells with selective growth advantage. This has prompted the development of pharmacological Cdk inhibitors that could potentially produce anti-tumor effect. P276–00 is a selective Cdk4-D1 and Cdk1-B inhibitor. This study was designed to determine the maximum tolerated dose (MTD), toxicity profile, pharmacokinetics, and antitumour activity of P276–00 given intravenously to patients with advanced refractory solid tumours. Methods: P276–00 was administered in escalating doses to cohorts of eligible patients (pts), starting with a dose of 9 mg/m2 as a 30 minute iv infusion day 1 to 5, and day 8 to 12, q 3 weekly. To date 22 pts have been entered on the study (cohort 1 - 4 pts at 9 mg/m2, cohort 2 - 4 pts at 12.6 mg/m2, cohort 3 - 6 pts at 17.6 mg/m2, cohort 4 - 8 pts at 24.6 mg/m2) with PS 0–2, and mean age of 56 years. Pharmacokinetic profiles were obtained on cycle 1 days 1 and 5. Skin biopsies were obtained immediately prior to starting study treatment and on day 21 of cycle 2 and will be analyzed for Ki67, cleaved caspase 3, phospho-Rb, cyclin D1 and cdk4, and microarray. Results: To date dose limiting toxicity has occurred in one pt. Grade 3 fatigue occurred in 1 pt at 17.6 mg/m2. The most common drug-related adverse events, which were all grade 1 or 2, were fatigue, nausea, hypotension, sweating, and dry mouth. No Grade 3 biochemical toxicities have been reported so far. There have been no responses noted to date. 4 pts have stable disease after 2 cycles. Pharmacokinetic results: The Cmax, t1/2, and AUC0–8 on day 1 were as follows: 9 mg/m2- 315 ng/mL, 6.6 hr, 883 ng.h/mL; 12.6 mg/m2- 402 ng/mL, 5.5 hr, 848 ng.h/mL; 17.6 mg/m2- 589 ng/mL, 5.3 hr, 1289 ng.h/mL; 24.6 mg/m2- 621 ng/mL, 5.6 hr, 1286 ng.h/mL. Conclusions: P276–00 is well tolerated, but grade 3 fatigue has been noted in 1 pt at 17.6 mg/m2 dose level. We have observed confirmed stable disease in one patient. PK results indicate that at 9 mg/m2,12.6 mg/m2, 17.6 mg/m2 and 24.6 mg/m2 we are able to cross the cdk4 enzyme IC50 approximately 10, 13, 19 and 20 times and cross the anti-proliferative IC50 1.1, 1.4, 2.1 and 2.2 times respectively. Accrual continues at the 34.4 mg/m2 dose level.

No significant financial relationships to disclose.
Reversible tumor metastases growth acceleration following bevacizumab interruption and surgical resection of metastases
Authors: Boisserie T. , Cacheux W. , Vignaux O. , Dousset B. , Soubrane O. , Chaussade S. , Goldwasser F.
Published: March 2020

14119

Background: The addition of bevacizumab (BV), an anti-VEGF monoclonal antibody with antiangiogenic activity, to cytotoxic chemotherapy (CH) improves survival in metastatic colorectal cancer patients (pts). Reversal of VEGF inhibition is associated with rapid vascular regrowth in tumors in vivo (M.R. Mancuso et al, J Clin Invest; 116(10): 2610–2621, 2006). In the clinical setting, the consequences of BV interruption are poorly documented, especially in interactions with the surgical resection of liver metastases. Methods: We describe the kinetics of tumor growth prior to, during, and after interruption of BV and under BV reintroduction, in consecutive colorectal cancer pts experiencing objective response under CH+BV, followed by surgical resection of metastases. We measured either clinically, of using CT-scan, the diameter of target lesions according to RECIST criteria, and the doubling time. Results: 7 pts (3 F, 4M), with median age of 54 years (41–70), were treated with 5-FU based CH (+oxaliplatin: 5; + irinotecan: 1 pt) and BV for metastatic colo- (6 pts) rectal (1 pt) cancer received a median number of 6 (4–18) cycles. Median time between BV interruption and surgery: 8 weeks (3–12). Under BV, all pts experienced objective response, with a median tumor reduction of 13%/month (extr: 6–15%). After BV interruption, under CH alone, 2/7 pts experienced disease progression, with a tumor growth of the residual disease of +7% and +200%/month, respectively. In pts who underwent surgery, during the off therapy period, tumor growth occurred in all 7 pts with a kinetics of +17 to +400%/month. Tumor growth doubling time after BV interruption ranged between 2 and 5 weeks. Reintroduction of BV re-induced a tumor response in 5/7 pts with a median time to response of 8 weeks (6–12) and a reduction of 10%/month. Conclusions: We show reproducible evidence of tumor growth acceleration following BV interruption. Surgery might transiently modify the balance between angiogenic and anti-angiogenic factors. We suggest to reduce the duration of BV interruption and to restart BV as soon as possible after surgery. These observations justify a large prospective analysis of the variations of tumor growth in this setting.

No significant financial relationships to disclose.
Silibinin’s effect on total EGFR, Erb-b2, and Erb-b3 expression in human colon cancer
Authors: Hogan F. , Krishnegowda N. K. , Kahlenberg M. S.
Published: March 2020

14124

Purpose: Flavonoid, silibinin, has been shown to have strong chemotherapeutic activity in prostate, breast, bladder, skin, ovarian, and colon cancer. It has no documented LD50 and has been proven safe in multiple animal models and human trials. Cell cycle arrest and inhibition of protein levels of various cyclins are commonly reported in silibinin’s mechanism of action. We investigated silibinin’s activity on upstream cell-signaling targets, EGFR, Erb-b2, Erb-b3, Akt, Erk1/2, and mTOR, using three human colon cancer cells lines: Fet, Geo, HCT 116. Methods: The MTT cell-viability assay and FACS analysis were performed after silibinin treatment to substantiate its effect on proliferation and cell-cycle. Western blots for EGFR, Erb-b2, Erb-b3, Erk1/2, Akt, and mTOR were completed and quantified with densitometry. Standardization of protein loading was confirmed with cytoskeletal and house-keeping proteins, B-actin and GAPDH. Means were contrasted using analysis of variance with Dunnet’s correction for multiple testing. All statistical testing was two-sided with a significance level of 5%. Results: The MTT assay revealed a dose-dependent inhibitory effect. Treatment of FET and GEO at 75 micrograms/ml resulted in 50% inhibition of cell-viability (IC-50) at 72 hrs. An IC50 dose of 40 ug/ml was established for HCT116. FACS analysis demonstrated statistically significant cell-cycle arrest in all cell lines. G2-M phase arrests in Fet and Geo cell lines (p<0.001) and a G1 arrest in HCT116 (p=0.005) were noted. Western blots showed decreased protein level expressions of total and phospho-EGFR, Erb-b2, Erb-b3, Akt, Erk1/2, and mTOR. Conclusions: Inhibition of protein expression levels of the Erb-b family of receptor tyrosine kinases plays a role in the mechanism of silibinin’s action. Strong inhibition of protein levels of total EGFR, Erb-b2, and Erb-b3 was noted as well as downstream decreases in total Erk1/2, Akt, and mTOR. Given silibinin’s inhibition of cancer proliferation and its safety profile, it is a promising compound requiring further mechanistic study, and applications in cancer therapy should be pursued given its effects on the Erb-b class of receptor tyrosine kinases and intermediary proteins, Erk1/2, Akt, and mTOR.

No significant financial relationships to disclose.
Anti-lactadherin antibodies in anti-angiogenic cancer therapy of breast cancer stem cells
Authors: Epenetos A. A. , Bower G. , Deonarain M. , Bonney L.
Published: March 2020

14138

Background: Angiolix (Hu-Mc3) is a humanized monoclonal antibody that recognizes a migrating adhesion molecule called Lactadherin. This novel antibody has a high affinity for its antigen and recognizes an epitope on Lactadherin which interacts with the the ’RGD’- motif found on integrin receptors on newly formed endothelial cells. Lactadherin binding leads to signalling via a VEGF-independent integrin receptor signalling cascade leading to vascular endothelial cell profileration. Lactadherin binding may also increase the potency of VEGF-VEGF receptor signalling. Methods: We studied the expression of Lactadherin on breast cancer cell lines, the biodistribution of Angiolix in human breast cancer xeografts and its ability to inhibit tumor growth in vivo. Results: Our data show that tumor cells express lactadherin in vivo and that Angiolix could achieve more than 75% growth inhibition of human breast cancer growing as xenografts . Conclusions: In view of the recent finding that cancer stem cells can over-express the pro-angiogenic VEGF and make a major contribution to tumor vasculature proliferation leads to the possibility that Angiolix may be able to act to specifically target breast cancer stem cell and cause tumor regression by blocking the growth of tumor vasculature by its ability to neutralise Lactadherin-integrin receptor binding.

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Can antisense oligonucleotides targeted K-ras gene downregulate the expression of MMP-2 and MMP-9 in orthotopically implanted pancreatic cancer in Syrian golden hamsters
Authors: Morioka C. Y. , Costa F. P. , Saito S. , Lima E. M. , Watanabe A. , Huang C. C.
Published: March 2020

14147

Background: Matrix metalloproteinases (MMP), especially MMP-2 and MMP-9, are thought to play major roles in pancreatic cancer growth and metastasis.Ras activates a multitude of downstream activities with roles in cellular processing, including invasion and metastasis.Therefore, antisense oligonucleotides (ASO) targeting K-ras gene may be a therapeutic approach. Aim: To elucidate the effectiveness of this gene therapy in growth, invasiveness,and expression of MMPs,in hamster experimental pancreatic cancer model. Materials and Methods: HaP-T1,a cell line derived from BHP-induced pancreatic cancer was used.Transfection with ASO were performed.MTT and MTT agarose assays were performed.MMP-2 and MMP-9 production by HaP-T1 was determined by gelatin zymography.For in vivo experiments,subcutaneously resected tumors were implanted orthotopically in Syrian golden hamsters,which were divided in 3 groups:Positive control (PC),Sense treated hamsters (STH), and Antisense treated hamsters (ATH).Follow up was done.Animals of each group were sacrificed at Days 10,17,24,31,and 38,to study local response and metastatic sites.Survival time was studied. Specimens were studied histopathologically.Orthotopic pancreatic tumor MMP production was measured by gelatin zymography. Results: ASO inhibited the tumoral growth.They downregulated active forms of MMP-2 and MMP-9 in a dose dependent manner in vitro.PC,STH,and ATH survived in average 72.7, 74,3, and 82,7 days,respectively.Spontaneous lymph node metastases were found from 31 days in ATH group,while PC and STH groups showed metastases and direct invasion to adjacent organs from 17 days.After death,metastatic sites were similar in the 3 groups.ASO downregulated the activation of MMP-9, more than MMP-2 in vivo. Conclusions: ASO targeted K-ras gene suppressed tumor growth in vitro and in vivo.ASO also downregulated the activation of MMP-2 and MMP-9 in vitro.However, it downregulated more MMP-9 than MMP-2 in vivo.Nevertheless, it can be a good choice in management of pancreatic cancer because MMP play an important role in the process of metastasis.

No significant financial relationships to disclose.
Single institutional experience with rituximab in the treatment of B cell lymphoproliferative malignancies and autoimmune disorders
Authors: Jajeh A. , Catchatourian R. , Samuel J. , Hussein L. , Yim B. , Jacob-Sharma J. , Menini P.
Published: March 2020

14150

Background: This is a retrospective analysis of usage of rituximab( Rituxan) a monoclonal antibodies against CD20 expressing B lymphocytes.The duration of period studied is from December first,2004 to July first,2006.This involved one single institution, John Stroger hospital of Cook County,chicago. Methods: A total of two hundred and thirty 230 treatment courses recorded.This involved a total of 208 patients.Some patients treated with more than one course in combination with different chemotheraputic agents. Results: . A total of 208 patients received Rituxan. Median number of doses is 8 (range 1–18). This include 92 patients with Diffuse large B-cell NHL, six patients with Burkitt’s lymphoma, thirty six patients with low grade NHL, three patients with mantle cell lymphoma, three patients with orbital lymphoma, three patient with AIDS related NHL, twenty seven patients with chronic lymphocytic leukemia CLL, ten patients with MALT/Gastric lymphoma, ten patients with ITP and 7 patient with warm autoimmune hemolysis, 7 patients given Rituxan as part of Rheumatoid Arthritis treatment. The complete response rate CR, near CR, partial response improved with adding Rituxan to 85% in Diffuse large grade Bcell lymphoma, one third high IPI score. Only 15% were refractory or relapsed after response. In low grade Bcell NHL 1/3 of patients received multiple prior treatments and the response rate were improved and disease progression was delayed. Most patients are of younger mean age 55 range (19–80).One third of patients recieved maintenace rituxan .Transfusion reaction occurred in less than 10%, severe leucopenia 3%, GI perforation in one patient, focal leukoencephalopathy PML in one with CNS involvement, tumor lysis syndrome occured in three patients, severe mucocutaneous reaction occured in one patient.One patient with RA and warm immune hemolysis died with sever pancytopenia after two months from recieving four doses. . Conclusions: This is a single institution experience where 60 percents are african american. This also show that Rituxan usage has became a standard therapy in Bcell lymphoproliferative malignancies.The improvement in response rate and progression free survival match other published phase III multicentered studies.

No significant financial relationships to disclose.
Feasibility of combining humanized anti-epidermal growth factor receptor monoclonal antibody h-R3 (nimotuzumab) with chemotherapy-A study of toxicity profile and tolerance
Authors: Pendharkar D. , Gupta S. , Pal M. K. , Hakim S. , Rashid T.
Published: March 2020

14151

Background. Anti-EGFR antibodies have been approved in combination with radiotherapy for the treatment of head and neck squamous cell carcinoma(SCCHN) and being tried in glioblastoma multiforme(GBM). The overall toxicity profile is tolerable. There is no data available on Humanized Anti EGFR antibody in combination with chemotherapeutic agents. Nimotuzumab, the humanized MAb derived from ior EGFR/R3, is a genetically engineered IgG1, with high affinity and specificity to EGFR. This study was undertaken to record the immediate and early toxicity of combining Nimotuzumab with various chemotherapeutic agents. Methods. Patients with SCCHN and GBM, scheduled to receive chemotherapy alone were additionally given 400mg of Nimotuzumab, every three weeks. Two patients with GBM received weekly Nimotuzumab 200 mg along with radiation and chemotherapy. Overall 19 events have been analyzed. The chemoschedules used in combination with Nimotuzumab included-Docetaxel, Carboplatin and Capecitabine in patients with SCCHN and Temozolamide/ Procarbazine in GBM. Antibody infusion was always preceded by antihistaminics and dexamethasone. Results.The combination of Nimotuzumab with chemotherapy was well tolerated. There were no acute infusion related events. No febrile, allergic or anaphylactic episodes were seen. Cutaneous rash classical of other EGFR blockers was not recorded. Two episodes of grade 3 diarrhea, and four events of asthenia were seen. Dryness of the mouth was a complaint in SCCHN patients. None of the patients showed neurological or cardiovascular adverse events. Hematological and biochemical derangements were not observed. Conclusion. Nimotuzumab can safely be combined with various chemotherapeutic agents .There is no unacceptable toxicity associated with combination of chemotherapy and humanized anti-EGFR monoclonal antibody. New schedules combining Nimotuzumab and chemotherapy can be safely explored.

No significant financial relationships to disclose.