bluuebunny/crossref_metadata_2025 huggingface dataset:
Rational molecularly targeted combinations: A parallel-arm phase I trial of the humanized anti-IGF-1R antibody dalotuzumab (D) in combination with the allosteric AKT inhibitor MK-2206 or the gamma secretase inhibitor MK-0752, in patients with advanced solid tumors.
Authors: Brana Irene , Gray Jhanelle Elaine , Haluska Paul , Berger Raanan , Golan Talia , Jones Mary Elizabeth , Gunchenko Alexandra , Cheng Jonathan D. , Siu Lillian L.
Published: March 2020

3027

Background: Two rational strategies to interrogate the IGF-1R pathway were investigated in this parallel-arm phase I trial: 1) vertical inhibition with D and MK-2206 to potentiate PI3K pathway targeting, 2) horizontal crosstalk inhibition with D and MK-0752 to exert effects against cellular proliferation, angiogenesis and stem cell propagation. Methods: Patients (pts) with advanced solid tumors and no prior exposure to agents of the same targets were eligible. Dose escalation was based on a modified toxicity probability interval method (Ji et al, 2010). Arm A is comprised of fixed D dose of 10 mg/m2 IV weekly plus MK-2206 at escalating doses of 90-200 mg PO weekly. Arm B is comprised of fixed MK-0752 dose of 1800 mg PO weekly plus D at escalating doses of 7.5-10 mg/m2 IV weekly. Each cycle = 4 weeks in both arms. Primary objectives were to determine DLT and RP2D of these combinations. Results: 30 patients were enrolled in the dose escalation phase (18 in Arm A and 12 in Arm B) with: median age = 56 (range 36-74); M:F = 13:17; ECOG 0:1 = 12:18; primary diagnosis = colorectal (CRC) (9), NSCLC (3), others (17); prior metastatic regimens = 3 (range 1-4). In Arm A, 1/6 DLT was observed with MK-2206 at 135 mg (G3 serum sickness-like reaction); 2/3 DLTs with MK-2206 at 200 mg (G4 leukopenia/neutropenia; G3 rash). No other G4 or worse adverse events (AEs) were observed. RP2D of Arm A = D 10mg/m2 IV weekly and MK-2206 150 mg PO weekly. Other common AEs in Arm A included: fatigue, rash and nausea. In Arm B, 2/6 DLTs were observed with D at 10 mg/m2 (G3 rash; G3 nausea/vomiting). RP2D of Arm B = D 10mg/m2 IV weekly and MK-0752 at 1800 mg PO weekly based on Ji et al. Other common AEs in Arm B included: anorexia, nausea and fatigue. No PR was observed and SD > 4 months occurred in 4 pts (all in Arm A). PK analyses are ongoing. Conclusions: Targeted combinations of D with MK-2206 or with MK-0752 were both tolerable. Expansion cohorts based on biomarker selection are underway, specifically ovarian cancer with high IGF1 expression/low RAS score for Arm A; and KRAS wild-type CRC with high IGF1/low IGF2 expression for Arm B.
Response of nonenhancing regions in glioblastoma to VEGF-signaling inhibitor cediranib correlates with tumor infiltration.
Authors: Fakhro Summer A , Jennings Dominique , Pinho Marco C , Lin Nancy U. , Sorensen A. Gregory , Batchelor Tracy , Gerstner Elizabeth Robins
Published: March 2020

3036

Background: Antiangiogenic therapy has limited direct antitumor effect in glioblastoma (GBM). Mainly its benefits may derive from anti-permeability and anti edema effects. In GBMs treated with cediranib we found that regions on MRI that are suggestive of being vasogenic edema, according to Diffusion Tensor Imaging (DTI) data, experience a greater decrease in volume than non-enhancing regions suggestive of being tumor infiltrated. Methods: Thirty-four newly diagnosed GBM patients were scanned on 3Tesla Siemens at two pre-therapy time points (2 days apart). Patients were treated with cediranib, standard radiation and temozolomide. Due to technical difficulties, 4 patients were left out of the analysis. Diffusion images were acquired with TR=7500ms, TE=84ms and b-values 0 and 700s/mm2 in 42 directions. A board certified radiologist determined the extent of abnormality on FLAIR and T1-weighted post contrast images. Non-enhancing regions (NER) were determined by subtracting the T1 enhancing area and any necrosis from the FLAIR abnormality. Volume of NERs was observed at baseline and day 47 of treatment. Mean Apparent Diffusion Coefficient (ADC) and mean Fractional Anisotropy (FA) of the NER were used to represent extent of tumor burden. Tumor Infiltration Index (TII), a measure based on comparing DTI metrics in metastatic tumors to GBM, was also derived. Twelve patients with metastatic cancer to the brain who underwent the same imaging and analysis pretreatment were used. High FA and low ADC and TII represent areas with more tumor burden. Results: There was a significant correlation between mean FA in the NERs at baseline and the percent volume reduction of the NER at day 47 (rho=0.45, p<0.02). Similarly, ADC and TII were correlated with percent volume reduction in the NER. Conclusions: DTI metrics have been used in GBMs to measure tumor infiltration. We found volume reduction of NERs to be inversely correlated to tumor burden. Thus, glioma patients with greater vasogenic edema may benefit from a different treatment paradigm than patients with lower vasogenic edema. [Table: see text]
Phase I dose-escalation study of AZD7762 alone and in combination with gemcitabine in Japanese patients with advanced solid tumors.
Authors: Seto Takashi , Esaki Taito , Hirai Fumihiko , Arita Shuji , Nosaki Kaname , Makiyama Akitaka , Kometani Takuro , Fujimoto Chinatsu , Hamatake Motoharu , Takeoka Hiroaki , Agbo Felix , Shi Xiaojin
Published: March 2020

3045

Background: AZD7762, a potent Chk1/Chk2 inhibitor, has been shown to enhance the antitumor activity of gemcitabine in xenograft models (Zabludoff SD et al. Mol Cancer Ther 2008;7:2955–66). Methods: This open-label dose-escalation study evaluated the safety, pharmacokinetics (PK), and preliminary efficacy (RECIST) of AZD7762 alone and in combination with gemcitabine in Japanese patients (pts) with advanced solid tumors (NCT00937664). Pts received AZD7762 iv alone on days 1 and 8 of a 14-day cycle (Cycle 0), followed by AZD7762 plus gemcitabine 1000 mg/m2 on days 1 and 8 of 21-day cycles, in sequential ascending AZD7762 dose cohorts. Results: 20 pts (mean age 60 years) received AZD7762 at doses of 6 (n=3), 9 (3), 21 (6), and 30 mg (8). The most common primary tumor site was lung (n=14). All pts had received ≥1 prior chemotherapy and 18 had metastatic disease. Dose-limiting toxicities (DLTs) occurred in two of six evaluable pts (both 30 mg cohort): one, grade 3 (CTCAE, v3.0) elevated troponin T (Cycle 0; AZD7762 monotherapy); one, neutropenia, thrombocytopenia, and elevated AST and ALT (Cycle 1; combination therapy). Thus, the 30 mg dose was regarded as non-tolerable. DLTs resolved following treatment discontinuation. The most frequently reported adverse events (AEs) in Cycle 0 (AZD7762 monotherapy) were bradycardia (50%), hypertension (25%) and fatigue (15%). Overall, the most common AEs were bradycardia (55%), neutropenia (45%), and hypertension, fatigue, and rash (30% each). AEs grade ≥3 were reported in 11 pts, the most common being neutropenia (45%) and leukopenia (25%). No pt died due to an AE. AZD7762 exposure (Cmax, AUC) increased in an approximately linear manner. Gemcitabine did not appear to affect AZD7762 PK. Arithmetic mean t½ and geometric mean CL of AZD7762 across the dose groups were 16.1–19.4 h and 22.0–32.7 L/h, respectively during the monotherapy cycle, and 15.6–18.3 h and 21.1–24.4 L/h, respectively in combination with gemcitabine. There were no objective responses; five pts (all lung cancer) had stable disease. Conclusions: The maximum tolerated dose of AZD7762 in combinationwith gemcitabine 1000 mg/m2 was determined as 21 mg in Japanese pts.
A phase I trial of the histone deacetylase inhibitor panobinostat (LBH589) and epirubicin in patients with solid tumor malignancies.
Authors: Moore Amy Patricia , Truong Thach-Giao , Thurn Kenneth Ted , Thomas Scott , Ryan Charles J. , Jahan Thierry Marie , DuBois Steven G. , Chan John K. , Rugo Hope S. , Collisson Eric Andrew , Raha Paromita , Chen Stephanie , Reinert Anne , Daud Adil , Munster Pamela N.
Published: March 2020

3058

Background: Preclinical and clinical data suggest pre-exposure of cancer cells to a histone deacetylase inhibitor (HDACi) potentiates topoisomerase inhibitors. HDACi-induced histone acetylation and chromatin modulation facilitates DNA access and target recruitment for topo II inhibitors. In vitro data further suggest effective inhibition of HDAC2 is necessary for enhanced epirubicin-induced apoptosis. Methods: This phase I trial explores the safety, tolerability, and maximum tolerated dose (MTD) of escalating doses of panobinostat given orally on days 1, 3, and 5 followed by epirubicin administered intravenously at 75 mg/m2 on day 5 in 21-day cycles. Histone acetylation and HDAC2 expression are evaluated in pre- and post-treatment peripheral blood mononuclear cells (PBMCs) in all patients and in tumor cells of 16 patients treated at the MTD. Results: 36 patients have enrolled [10M/26F, median age 47 years (22-80)] in 5 panobinostat cohorts: 20, 30, 40, 50, 60 mg. Tumor types include melanoma (n=6), breast (n=6), sarcoma (n=16), ovarian (n=2), lung (n=2), and one each of neuroblastoma, pancreatic, testicular, and colon cancer. Prior to enrollment, patients received a median of 3 (0-8) prior chemotherapy regimens and 40% had anthracyclines. Dose-limiting toxicities (DLTs) included 1/3 grade 3 fatigue and 1/3 grade 4 thrombocytopenia at 60 mg of panobinostat, 1/6 patient experienced grade 3 atrial fibrillation at 50 mg, defining 50 mg panobinostat as the MTD. Non-dose–limiting grade 3/4 hematological toxicities include neutropenia (n=19, 53%), febrile neutropenia (n=6, 17%), thrombocytopenia (n=6, 17%), and anemia (n=4, 11%). Of 34 evaluable patients, 5 had partial responses and 14 had stable disease in anthracycline-refractory sarcomas (4) and Her2neu positive breast cancer (2), and small cell lung cancer. Correlative studies demonstrate increased H4 acetylation in PBMCs on day 3 and 5 suggesting sufficient histone deacetylase inhibition. Conclusions: Sequence-specific combination of panobinostat and epirubicin shows early activity without potentiating epirubicin toxicity. Dose expansion in anthracycline-pretreated sarcoma patients is ongoing.
Evaluation of toxicities of target therapy phase I and II trials on glioblastoma multiforme patients treated by curative radiotherapy: A meta-analysis.
Authors: Santos Marcos Antonio , Lefeuvre Delphine , Le Teuff Gwenael , Bouda Damien , Bourgier Céline , Domont Julien , Dhermain Frederic , Soria Jean-Charles , Deutsch Eric , Pignon Jean-Pierre
Published: March 2020

3063

Background: An important limitation of the combination of target therapies (TT) to radiation (RT) is its potentially high level of toxicity. The objective of this study was to describe and quantify the drug related acute adverse events presented by patients taking part in phase I and/or phase II trials on TT combined to curative RT for the treatment of glioblastoma multiforme (GBM). Methods: A meta-analysis of summary data including all phase I, I/II and II trials published between 2000 and 2011 on newly diagnosed GBM patients treated by TT with RT was performed. Pooled incidence rates (IR) of all and specific toxicities were estimated using a generalized linear mixed model with fixed and random study effects. The pooled median of progression-free (PFS) and overall survivals (OS) were also considered. These results were compared to those obtained by patients receiving standard treatment (ST). Results: Twenty-one trials (8 phases I, 3 phases I/II and 10 phases II), testing 9 different drugs, have been selected, including 915 patients. The median follow-up varied from 1.4 to 34.0 months. The estimated pooled IR of all toxicities was 68.6 [53.5-88.0] per 1000 person-months of follow-up, compared to 20.7 [17.6-24.1] on ST (p<0.001). The pooled IRs of thrombocytopenia, neutropenia or leucopenia, fatigue, gastrointestinal events and treatment-related deaths are 11.2 [7.5-16.9], 9.0 [6.1-13.4], 6.4 [4.1-10.0], 5.5 [2.9-10.2] and 3.2 [1.6-6.4], compared to 4.1 [2.8-5.8], 4.9 [3.5-6.6], 4.6 [3.2-6.4], 0.8 [0.3-1.6] and 0.1 [0.0-0.6], respectively, on ST. Median survival times are 7.7 [6.1-9.8] and 13.8 months [11.9-16.1] on TT studies, and 6.9 [5.8-8.2] and 14.6 [13.2-16.8], on ST, for PFS and OS, respectively, without statistically significant difference (p=0.39 and 0.55). The heterogeneity among specific toxicities and survival endpoints may be partially explained by the study design and/or the intake or not of temozolomide. Conclusions: The use of TT combined to RT represented a significative increase in severe adverse events in patients with GBM compared to ST, whereas no significant difference was observed in survival endpoints. Grants from French Cancer League.
Microarray genomic expression (MAGE)-based therapy for heavily pretreated patients with metastatic solid tumors.
Authors: Rebollo Joseba , Gonzalez Manuel Sureda , Fernandez-Morejon Francisco Jose , Bretcha Pere , Rey Severino , Gonzalez Ramon , Farre Jose , Brugarolas A.
Published: March 2020

3064

Background: Oligonucleotide-MAGE assay to identify tumor targets and potential active drugs based on molecular profiling in chemotherapy resistant/refractory (R/R) patients with metastatic solid tumors. A potential clinical benefit has been observed by Von Hoff et al (JCO 2010;20:4877-83). Methods: Patients (pts) with R/R metastatic solid tumors were included in the study. Pathology confirmed fresh-frozen biopsies were obtained and molecular profiling oligonucleotide-MAGE (Agilent Whole Human Genome 4x44K) results, confirmed whenever possible by IHC, were used to identify potential therapy targets. Results were discussed and offered to pts and the response evaluated using RECIST criteria. OS and PFS were measured from the beginning of therapy. All pts signed informed consent. Results: From August 2010 we performed 70 procedures in 69 pts. No complications derived from the biopsy were observed. Thirty pts did not follow therapeutic recommendations and 9 pts are too early to evaluate. Thirty procedures from 29 pts are clinically evaluable. Ten pts were male and 19 female, with a median (M) age of 57 years (range 41-70). Seven pts had breast cancer, 5 NSCLC, 5 pancreas, 4 CRC, 2 ovary and one each of gastric, parotid gland, biliary tree, head and neck, esophagus and gallbladder cancers, respectively. The M previous treatments were 3 (range 1 to >6). Oligonucleotide-MAGE assay confirmed resistance in 82% of drugs previously used. A M of 3 conventional (range 0-5) and 2 experimental (range 0-4) potentially active drugs were identified. Partial response was observed in 7 (26.9%), stable disease >2 months in 12 (46.1%) and progression in 7 (26.9%) pts. Four pts were not evaluable. MPFS was 4 months (95%CI: 1.815-6.185), MOS was 6 months (95%CI: 3.4-8.6) and 1-year projected OS was 21%. Conclusions: We confirmed that it is possible to identify new potentially active drugs in heavily pretreated solid tumor pts with oligonucleotide-MAGE assay. Therapy based on these drugs showed to be active in one fourth of treated pts. These assays might be also integrated in early tumor stages to aid in the selection of chemotherapy drugs, and for this reason deserve further studies. Updated results will be presented.
OM-RCA-01, an FGFR1 specific humanized antibody for the treatment of renal cell carcinoma (RCC).
Authors: Tsimafeyeu Ilya , Zaveleva Elina , Low Walter
Published: March 2020

3070

Background: Fibroblast growth factor (FGF) receptor 1 (FGFR1) is a potential therapeutic target for the treatment of metastatic RCC. We investigated the preclinical activity of OM-RCA-01, a novel therapeutic humanized anti-FGFR1 antibody with high affinity (Kd of 1.59 nM), in RCC. Methods: To assess the effect of anti-FGFR1 antibody on FGF-mediated signaling, the human renal carcinoma Caki-1 FGFR1-expressing cells were dosed with OM-RCA-01 at 100, 10, and 1 mcg/ml. Control wells were left untreated. Three hours after dosing, bFGF was added at a concentration of 50 ng/ml. Additional control wells were treated with OM-RCA-01 without FGF-stimulation. Cell growth inhibition was determined using Promega’s Cell Titer-Glo assay. CR female NCr nu/nu mice were set up with 1 mm3 Caki-1 tumor fragments sc in flank. Tumor sizes were measured in a blind fashion twice a week with a vernier caliper. Mice with established tumors were randomly divided into vehicle, non-specific IgG or OM-RCA-01 groups per 10 animals in group. Endpoint was significant differences in tumor growth delay. Results: In vitro study showed that bFGF increased proliferation of the human FGFR1-expressing renal carcinoma cells (p=0.011). OM-RCA-01 antibody significantly inhibits FGF-triggered cell proliferation in comparison with control. In vivo, the tumors in untreated mice or mice treated with non-specific IgG continued their aggressive growth to reach the size of 2000 cm3, at which point the mice were killed. In contrast, treatment with OM-RCA-01 not only significant arrested further growth of the tumors (p=0.006) but also demonstrated differences in tumor volume compared with vehicle already on Day 13. A similar anti-tumor activity of OM-RCA-01 was observed when the antibody was given in low (1 mg/kg) or high (10 mg/kg) doses (p=0.917). Administration of 10 mg/kg antibody for up to 35 days resulted in minimal body weight loss and no observations of gross toxicity were made. Conclusions: Targeting FGFR1 blocks FGF/FGFR1 pathway in RCC. Monoclonal antibody OM-RCA-01 has significant early anti-tumor efficacy in Caki-1 xenograft model. Isolated blocking of FGFR1 by low-dose antibody could be safe and effective.
Clinical significance of PRL-3 genomic amplification/expression profiles and preclinical study of PRL-3 inhibitor in human gastrointestinal cancers.
Authors: Yamashita Keishi , Watanabe Masahiko
Published: March 2020

3071

Background: PRL (phosphatase of regenerating liver) is a tyrosine phosphatase that dephosphorylates molecules involved in cancer invasion and metastasis and subsequently activates either PI3 kinase or Src pathway. PRL-3 was initially identified as a gene that is amplified in metastasis of colorectal cancer. We are thinking much of clinical potential of PRL-3 inhibitor as a molecular targeted therapy in GI cancer. Methods: Immunohistochemistry and genomic status were assessed for PRL-3 in esophageal squamous cell carcinoma (ESCC)(n=88), gastric adenocarcinoma (n=173), and colorectal adenocarcinoma (n=107).RNA interference was used to determine its specific functional roles in GI cancers. Preclinical study using PRL-3 inhibitors (1-4-bromo-2-benzylidene rhodanine) was performed in 4 ESCC and 4 gastric cancer cell lines that were intensely expressed for PRL-3, or TE5 which showed basal level expression. Results: (1) PRL-3 expression is associated with lymph node metastasis in primary ESCC (p=0.0012), gastric adenocarcinoma (p<0.0001), and colorectal carcinoma (p<0.0001). In the primary tumors with lymph node metastasis, its expression was recognized in 96, 80, 86%, respectively. (2) If restricted to patients with PRL-3 expression, genomic amplification was found exclusively in stage IV ESCC (30%), and stage III/IV gastric cancer (40%). In colorectal cancer, PRL-3 genomic amplification is found in 35% of stage III/IV, but only in 10% of stage II (p=0.002). (3) PRL-3 RNA interference robustly suppressed metastatic cancer phenotypes. (4) PRL-3 inhibitor suppressed phenotypes as well in a dose dependent manner (0, 1, 10, and 50 mM). Interestingly, 10 mM of the inhibitor could not suppress muscle cell (C2C12) that endogenously express PRL-3, but 50 mM suppressed it. Conclusions: PRL-3 inhibitor has a great clinical potential to suppress tumors with metastatic ability, that was represented by lymph node metastasis or recurrent disease of GI cancers.
Effect of MDV3100, a novel androgen receptor signaling inhibitor, on cell proliferation and tumor size in an apocrine breast cancer xenograft model.
Authors: Bernales Sebastián , Guerrero Javier , Gómez Francisco , Alfaro Iván E. , Protter Andrew A
Published: March 2020

3072

Background: MDV3100, a new androgen receptor (AR) signaling inhibitor, has demonstrated therapeutic effects in men with post-docetaxel prostate cancer (AFFIRM). AR is also expressed in the majority of breast cancers. Molecular profiling of estrogen receptor negative (ER-) breast cancer classifies this disease into basal and molecular apocrine subtypes. Apocrine breast cancer represents ~50% of ER- tumors and is characterized by a steroid response gene signature that includes AR expression. Here we report the effects of MDV3100 on the growth of the ER-/AR+ breast cancer cell line MDA-MB-453 in tissue culture and in an in vivo xenograft mouse model. Methods: MDA-MB-453 cells were maintained in 5% complete or 5% charcoal-stripped serum supplemented with dihydrotestosterone (CSS-DHT). The DHT induced nuclear translocation of AR was determined by subcellular fractionation followed by western blot. AR target gene expression was measured by qPCR. To generate a mouse xenograft model, 5-6 wk old female NOD-SCID-IL2Rgc–/– mice were injected ortotopically with 6x106 MDA-MB-453 cells into the fourth inguinal gland and were administered exogenous DHT (12.5 mg in a 60 day release pellet) or control pellets. When tumor size reached 100 mm3, mice were treated with 10 mg/kg/day MDV3100 or vehicle (0.5% methocel solution) by oral gavage for 33 days. Results: Viability of MDA-MB-453 cells treated with 10 uM MDV3100 was reduced by 10% after 3 days and 27% after 6 days. Treatment with 25 uM MDV3100 reduced cell viability by 27% after 3 days and 36% after 6 days. Similar results were obtained when cells maintained in CSS-DHT were treated with MDV3100. Treatment with MDV3100 blocked DHT-induced nuclear translocation and concordantly reduced the expression of AR-targets fatty acid synthase, prolactin receptor, and gross cystic disease protein-15. In the xenograft model, MDV3100 inhibited tumor growth by 78% as compared to tumors treated with vehicle. Conclusions: MDV3100 reduced cell proliferation in apocrine cell lines. MDV3100 also suppressed exogenous DHT-induced growth of ER-/AR+ tumors in vivo. These results support the evaluation of MDV3100 as a treatment for apocrine tumors.
Translational assessment of the efficacy of CPI-613 against pancreatic cancer in animal models versus patients with stage IV disease.
Authors: Retter Avi S.
Published: March 2020

3075

Background: CPI-613 is a novel agent that selectively targets the altered mitochondrial enzymes of tumor cells, causing apoptosis, necrosis, and autophagia. Results assessing clinical efficacy of CPI-613 translated from animal tumor xenograft models to patients with stage IV pancreatic cancer are presented. Methods: Efficacy of CPI-613 was tested in mice with pancreatic tumor xenografts generated by inoculation of BxPC-3 human pancreatic tumor cells. The safety and efficacy of CPI-613 (70-320 mg/m2), when used in combination with gemcitabine (1,000 mg/m2), was assessed in patients with stage IV pancreatic cancer. Results: In the animal pancreatic tumor xenograft model (n=10/grp), CPI-613 (25 mg/kg, IV, 1x weekly for 4 weeks) suppressed tumor growth by ~100%, when compared to vehicle. The positive control, gemcitabine (50 mg/kg, IV, 1x weekly for 4 weeks), suppressed tumor growth by only ~50%. Median overall survival in tumor-bearing mice treated with CPI-613 was ~240 days, which was significantly longer than those with gemcitabine or vehicle treatments (~65 and ~50 days, respectively). In 6 humans with stage IV pancreatic cancer (Table), the CPI-613+gemcitabine combination was well-tolerated. In those without prior chemotherapy before participating in the clinical trial (first three patients in the table), the CPI-613+gemcitabine combination prolonged survival that correlated with the dose of CPI-613. Conclusions: CPI-613 exhibits efficacy against pancreatic cancer in animal models, which is translational to patients with stage IV disease. [Table: see text]
A phase I study of R04929097, an oral gamma secretase inhibitor, in combination with gemcitabine in patients with advanced solid tumors (PHL-078/CTEP 8575).
Authors: Richter Sue , McWhirter Elaine , Chen Eric Xueyu , Tran Ben , Hotte Sebastien J. , Stathis Anastasios , Hirte Hal W. , Razak Albiruni R.A. , Laughlin Anne , Wang Lisa , Battista Kristina , Stayner Lee-Anne , Ivy S. Percy , Moore Malcolm J. , Oza Amit M. , Siu Lillian L. , Bedard Philippe
Published: March 2020

3082

Background: RO4929097 (RO) is an oral inhibitor of γ-secretase that disrupts Notch signaling. Gemcitabine (GEM) is active against many solid tumors with a favorable toxicity profile suited to combination. The primary objective of this trial is to establish the recommended phase II dose (RP2D) of RO in combination with GEM; secondary objectives include the evaluation of safety, tolerability, pharmacokinetics (PK), biomarkers of Notch signaling and preliminary anti-tumor activity. Methods: Patients (pts) with advanced solid tumors were enrolled in escalating RO dose levels (DL) as follows: DL1 20mg, DL2 30mg; DL3 45mg and DL4 90mg using a 3+3 design. Treatment with RO was administered once daily on days (d) 1-3, 8-10, 15-17, 22-24 and GEM 1000mg/m2 on d1, 8, and 15 in 28d cycles (c). Dose limiting toxicities (DLTs) during c1 were defined as CTCAE v4 grade (g) 3 non-hematological or g4 hematological toxicities, failure to start c2 within <14 days, or failure to receive ≥75% doses of RO or d8 GEM in c1. Serial plasma samples for RO PK were collected on d1 and 10. Results: As of January 2012, 15 pts (median age 55) have been treated. DLTs were: DL1 0/3, DL2 1/7 (g3 ALT), DL3 0/3, DL4 2/2 (g3 AST/ALT and failure to receive ³75% doses); all were reversible. One death (perforated viscus) related to disease progression was observed. Most common g1/2 toxicities were nausea (9), vomiting (6), fatigue (5), hypophosphatemia (5), transaminitis (3) hypomagnasemia (2) and maculopapular rash (2). G3 hypophosphatemia (1) was observed beyond C1. RO PKs demonstrated comparable exposures at 30mg and 45mg (Table). Best response (RECIST 1.1) was stable disease > 4 months in 3 pts (pancreas, tracheal, breast CA). Conclusions: RO and GEM can be safely combined. RO levels achieved exceeded the AUC0-24 for efficacy in preclinical models using daily dosing. The maximum tolerated dose was exceeded at 90mg RO. Dose expansion at 45mg RO is ongoing to confirm the RP2D. [Table: see text]
Associating retinal drug exposure and retention with the ocular toxicity profiles of Hsp90 inhibitors.
Authors: Zhou Dan , Teofilovici Florentina , Liu Yuan , Ye Josephine , Ying Weiwen , Shin Ogawa Luisa , Inoue Takayo , Lee William , Adjiri-Awere Alfred , Kolodzieyski Lev , Tatsuta Noriaki , Wada Yumiko , Sonderfan Andrew J
Published: March 2020

3086

Background: In clinical trials certain Hsp90 inhibitors, including AUY922, SNX-5422, and 17-DMAG have caused visual symptoms suggesting retinal dysfunction; others, including ganetespib and 17-AAG, have not. Previous animal toxicology experiments have suggested that retinal changes may be linked to photoreceptor degeneration or cell death. Here histopathologic changes and/or exposure profiles of Hsp90 inhibitors with or without clinical reports of ocular toxicity were evaluated to understand the observed differences in toxicity profile between agents in this class. Methods: We reviewed visual symptoms among subjects administered ganetespib, a potent Hsp90 inhibitor currently in phase II trials; evaluated retinal morphology in rats and cyno monkeys given ganetespib; and compared TUNEL-positive photoreceptors and drug exposure profiles in the retina of rats treated with AUY922, 17-DMAG, and 17-AAG. Studies of ganetespib’s retinal pharmacokinetics and photoreceptor toxicity in rats are ongoing. Results: AUY922 and 17-DMAG induce visual disorders in the clinic. Both drugs induced marked photoreceptor cell death (increased TUNEL-positive cells) in rats with a high retina/plasma (R/P) exposure ratio, and a slow elimination rate (at 6 h post-dose, over 54% of AUY922 present at 30 min remained in the retina). In contrast, and consistent with an absence of clinical visual changes, 17-AAG at the maximum tolerated dose did not elicit photoreceptor injury. Further, retinal elimination was rapid (at 6 h post-dose, 94% of 17-AAG had been eliminated from the retina, resulting in a low R/P ratio). Ganetespib given by 1‑hour IV infusion on days 1 and 15 of four 21-day cycles did not cause histopathological changes in the retina of rats or cynos. This finding is consistent with very low rate (~3%) of drug-related visual symptoms observed among over 300 subjects to date that received ganetespib in the clinic. Conclusions: Unlike AUY922 and 17-DMAG, ganetespib is not associated with ocular toxicity in humans, primates, or rodents. The findings suggest that Hsp90 inhibitors may elicit visual disorders when associated with high retina/plasma exposure ratio and lower retinal elimination rate.
Endoxifen for breast cancer: Multiple-dose, dose-escalation study characterizing pharmacokinetics and safety in metastatic breast cancer patients.
Authors: Ahmad Ateeq , Sheikh S. , Nagarkar R. , Singh J. K. , Krishnan S. , Shrivastav S. , Shetty P. , Kale P. , Rane R. C. , Ahmad I.
Published: March 2020

3089^

Background: Endoxifen is an active metabolite of tamoxifen, a drug used in the treatment of breast cancer. To be clinically effective, tamoxifen must be converted to endoxifen by CYP2D6. Direct administration of endoxifen would not be subject to pharmacogenetic variations or drug-drug interactions. Our preclinical studies (Breast Cancer Treat 122, 579-584, 2010) have validated the concept of using endoxifen for the treatment of breast cancer. In human (Clin. Pharmacol. Ther. 88, 814-817, 2010), the single oral doses tested up to 4 mg of endoxifen were safe, well tolerated and bioavailable. Methods: A multiple-dose escalating study was conducted in 3 cohorts and each cohort had 6 patients (18 metastatic breast cancer patients). Endoxifen at 3 dose levels (2, 4, or 8 mg) was given once daily for 28 days. Routine laboratory tests, vital signs and electrocardiograms were measured throughout the study. Blood samples for PK analysis were collected after 28 days post dose. Endoxifen in plasma samples was determined using LC-MS/MS. Results: Endoxifen was found to be safe up to 8.0 mg. At steady state, it displays dose-proportional PK with respect to Cmax and AUC ( see Table below). Conclusions: Multiple daily endoxifen doses of 4.0-8.0 mg resulted in endoxifen exposures that would be sufficient for effective therapy. The favorable safety and multiple-dose PK profile of endoxifen warrants further evaluation of safety and efficacy of endoxifen in breast cancer patients. [Table: see text]
Therapy of human solid tumor xenografts with CD74-targeted milatuzumab-SN-38 immunoconjugates.
Authors: Goldenberg David M. , Cardillo Thomas M. , Sharkey Robert M. , Gold David V. , Govindan Serengulam V.
Published: March 2020

3091

Background: CD74 is commonly considered to be an antigen present in hematopoietic cancers, but it is also expressed in a number of solid tumors. The humanized anti-CD74 antibody, milatuzumab (hLL1), was previously shown to have exquisite internalization properties, making it an attractive carrier for drug delivery. In this study, we evaluated hLL1 conjugates of a potent topo I inhibitor, SN-38, for treating solid tumors. Methods: Two hLL1-SN-38 conjugates, possessing either a pH-sensitive linker (‘CL2A’ form) or a cathepsin-B-cleavable linker ("CL2E" form), were examined. In vitro analyses were carried out in the A-375 human melanoma cell line, and therapy experiments were performed in female athymic nude mice bearing established s.c. A-375 or s.c. human pancreatic adenocarcinoma (Capan-1) xenografts using specified doses (i.p.) at a twice weekly × 4 wks schedule; animals were sacrificed when tumor volumes (TVs) reached 1 cm3. Results: Both A-375 and Capan-1 cell lines tested positive for CD74 expression by IHC. In vitro, both SN-38 derivatives liberated free drug at the same rate when exposed to cathepsin-B at pH 5, while serum stabilities for CL2A and CL2E forms of the conjugates were ~ 1 d and >10 d, respectively. In the A-375 melanoma cell line, IC50 for the hLL1-SN-38 conjugates of CL2A and CL2E forms were 5 nM and 34 nM, respectively. In the aggressive A-375 s.c. model of melanoma, in nude mice (n =8; TV: 0.23 ± 0.06 cm3) treated with 12.5 mg/kg protein dose (total 1.7 mg/kg SN-38 eq.) of specific or non-specific SN-38 conjugates of CL2A and CL2E forms, only hLL1-CL2A-SN-38 conjugate was efficacious (Log-rank: P<0.009 vs. all controls), with a median survival time of 28 d vs. 10.5 d for untreated. Likewise, in mice bearing Capan-1 xenografts (n = 8-10; TV=0.27 ± 0.05 cm3), two low doses of hLL1-CL2A-SN-38 (12.5 or 5 mg/kg) significantly improved survival in comparison to saline control mice (p<0.035), whereas the CL2E form and a non-specific control demonstrated no efficacy. Conclusions: These results indicate the therapeutic potential of hLL1-CL2A-SN-38 conjugate and the importance of linker chemistry, and encourage additional testing in other CD74-positive solid cancers.
A phase Ib proof-of-concept study of LBH589 (LBH) and everolimus (EVE) in advanced solid tumors enriched for Epstein-Barr virus (EBV)-related cancers.
Authors: Tan Daniel Shao-Weng , Ng Quan Sing , Chong Dawn Qingqing , Lee Guek Eng , Tan Thuan Tong , Chau Noan Minh , Ang Mei-Kim , Zhong Liz , Chowbay Balram , Connolly John , Tan Eng-Huat , Lim Wan-Teck
Published: March 2020

3098

Background: Histone deacetylase and mTOR inhibition circumvent critical EBV-oncogenic pathways with preclinical studies demonstrating lytic induction in EBV infected cells, as well as immunomodulatory and antiangiogenic effects. Methods: Patients (Pt) with advanced solid tumors enriched for EBV–related cancers were enrolled to determine safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics and preliminary antitumor activity. LBH was instituted 7-days prior to combination treatment. NPC pt received antiviral prophylaxis of either acyclovir (Ac) or valaciclovir (Vc). Serum EBV DNA levels (EBNA-1) were measured weekly and plasma cytokines profiled using a 31-plex Luminex panel. Results: 15 pt have been treated (M:F 13:2, median age 50, R: 38-63) 10 NPC, 5 non-NPC (colon, RCC, breast, gastric, sarcoma) at 3 dose levels – LBH (3x/wk)-EVE (daily):10-2.5, 10-5, 15-5. Two dose limiting toxicities of G4 (grade) thrombocytopenia were observed at LBH15-RAD5. Significant adverse events (AE) (G≥3) were dysphagia (1) and thrombocytopenia (3). Common AEs (G1/2) included fatigue (80%), anorexia (60%), mucositis (53%), xerostomia (26%), dysphagia (26%). Two minor responses were seen (1 NPC, 1 breast) and 2 pt (1 NPC, 1 RCC) had prolonged stable disease (>16 weeks). Modulation of EBV DNA titres was seen only in NPC pt, with median fold-change from baseline of 10.9 (0.05-174). Pt on Ac prophylaxis (n=5) had significant increases in DNA titres (9-174 fold), while those on Vc (n=4) were less pronounced (0.05-11 fold, p<0.03), with one pt (with minor response) having persistent decline in EBV titres. In a limited pt subset (n=9, 30 timepoints), plasma cytokine profiles were consistent with a T-cell response, specifically, elevated levels of FLT3L, IFN-gamma, IL-13 and IL-17. PK and PBMC target modulation studies are being analysed. Conclusions: LBH-EVE results in induction of EBV DNA titres with an associated host T cell response. MTD is LBH10-EVE5 in Asian pt, majority of whom had NPC. A pre-planned expansion cohort that incorporates multi-parametric functional imaging exploring two schedules of LBH in combination with EVE5 is ongoing.
A phase I study of selumetinib (AZD6244/ARRY-142866) in combination with cetuximab (cet) in refractory solid tumors and KRAS mutant colorectal cancer (CRC).
Authors: Deming Dustin A. , Schelman William R. , Lubner Sam Joseph , Mulkerin Daniel , LoConte Noelle K. , Fioravanti Suzanne , Greten Tim , Eickhoff Jens C. , Kolesar Jill , Compton Kathryn , Doyle Laurence A , Wilding George , Duffy Austin G. , Liu Glenn
Published: March 2020

3103

Background: KRAS mutations have been recognized as clinically important predictors of resistance to EGFR-directed therapies in CRC. Oncogenic activation of the RAS/RAF/MEK/ERK signaling cascade mediates proliferation independent of growth factor receptor signaling. We hypothesized that targeting MEK with selumetinib could overcome resistance to cet in KRAS mutant CRC. A phase I study (NCT01287130) was undertaken to determine the tolerability, and pharmacokinetic profiles of the combination of selumetinib and cet, with an expanded cohort in KRAS mutant CRC at the MTD dose to evaluate preliminary anti-tumor activity. Methods: In the dose escalation portion, patients (pts) with advanced solid tumors received fixed dose cet with escalating doses of selumetinib in cohorts of 3-6 pts. In the expansion cohort, 14 pts with KRAS mutant CRC were enrolled at the MTD level. Results: 15 pts (9 M, 6 F), average age of 60 (41-73) years were treated at 3 dose levels in the dose escalation cohort and 14 pts were treated in the expansion cohort. Pts had the following tumor types: CRC 73%, NSCLC 13%, and H&N 13%, and had received a median of 4 (1-8) prior lines of therapy. 33% (only CRC) had prior EGFR-directed therapies. ECOG PS 0 (40%), 1 (53%), 2 (7%). 13 of 15 pts were evaluable for tolerability and response. One DLT for grade 4 hypomagnesemia occurred, and no other grade 4 toxicities were seen. Grade 3 (20%) toxicities included; rash, hyponatremia, and headache. The most common cycle 1 grade 1 and 2 adverse events included acneiform rash (100%), fatigue (54%), nausea/vomiting, (54%), diarrhea (54%), dry skin (46%), fever (23%), and hypomagnesemia (15%). Most pts (60%) required no dose modifications. The MTD was established at selumetinib 75 mg PO BID and cet 250 mg/m2 weekly following a 400 mg/m2load. Best response included 2 PR in pts with CRC and SD in 4 pts (1 SCC of the tonsil, 1 NSCLC, and 2 CRC). Conclusions: The combination of selumetinib and cet is well tolerated, and preliminary anti-tumor activity was observed in multiple pts. Results of the KRAS mutant CRC expansion cohort will be presented.
Validation of a genomic classifier (ColoPrint) for predicting outcome in the T3-MSS subgroup of stage II colon cancer patients.
Authors: Salazar Ramon , Tabernero Josep , Moreno Victor , Nitsche Ulrich , Bachleitner-Hofmann Thomas , Lanza Giovanni , Stork Lisette , Roepman Paul , Simon Iris , Rosenberg Robert
Published: March 2020

3510

Background: Adjuvant therapy for stage II patients is recommended for patients with high risk features, especially with T4 tumors. Adjuvant therapy is not indicated for patients with MSI-H status who are considered of being at low risk of disease relapse. However, this leaves the majority of patients with an undetermined risk. ColoPrint is an 18-gene expression classifier that identifies early-stage colon cancer patients at higher risk of disease relapse. Methods: ColoPrint was developed using whole genome expression data and was validated in public datasets (n=322) and independent patient cohorts from 5 European hospitals. Tissue specimen, clinical parameters, MSI-status and follow-up data (median follow-up 70 months) for patients were available and the ColoPrint index was determined using validated diagnostic arrays. Uni-and multivariate analysis was performed on the pooled stage II patient set (n=320) and the subset of patients who were T3/ MSS (n=227). Results: In the analysis of all stage II patients, ColoPrint classified two-third of stage II patients as being at lower risk. The 3-year Relapse-Free-Survial (RFS) RFS was 91% for Low Risk and 74% for patients at higher risk with a HR of 2.9 (p=0.001). Clinicopathological parameters from the ASCO recommendations (T4, perforation, <12 LN assessed, and/ or high grade) or NCCN guidelines (ASCO factors plus angio-lymphatic invasion) did not predict a differential outcome for high risk patients (p< 0.20). In the subgroup of patients with T3 and MSS phenotype, ColoPrint classified 61% of patients at lower risk with a 3-year RFS of 91% (86-96%) and 39% of patients at higher risk with a 3-year RFS of 73% (63-83%) (p=0.002). No clinical parameter was significantly prognostic in this subgroup. Conclusions: ColoPrint combined with established clinicopathological factors and MSI, significantly improves prognostic accuracy, thereby facilitating the identification of patients at higher risk who might be considered for additional treatment.
Identification and validation of gene expression subtypes in a large set of colorectal cancer samples.
Authors: Budinska Eva , Popovici Vlad Calin , Sikora Katarzyna Otylia , Lapique Nicolas , Tejpar Sabine , Hodgson John Graeme , Weinrich Scott , Roth Arnaud , Bosman Fred , Delorenzi Mauro
Published: March 2020

3511

Background: From a clinical perspective colorectal cancer (CRC) is a heterogeneous disease whose biological background is insufficiently understood. In order to adapt targeted treatment to biologically different categories of CRC patients, in depth understanding of the molecular mechanisms involved in CRC heterogeneity is urgently needed. Methods: Consensus cluster analysis of 1113 stage II-III CRC gene expression profiles from PETACC3 and 4 public datasets defined a set of subtypes which were confirmed in an independent set of 720 samples. The similarity between tumors was based on a set of 54 meta-genes. This approach improves the robustness to measurement noise and gives equal chances to each biological process to be accounted for in the subtype definition. We tested the association of the subtypes with clinical variables, molecular markers and patient survival. Results: We identified and validated 5 major subtypes A-E, with different levels of expression in 6 main molecular processes: epithelial-mesenchymal transition (EMT), immune response, colon crypt differentiation, proliferation, Wnt signaling and chromosome 20q. Significant differences in survival and an enrichment for markers such as MSI, BRAF mutation, site or p53 status were found between the subtypes. In addition, the new subtype classification uncovered heterogeneity within groups defined by these commonly used markers. Survival analysis showed significant prognostic value for meta-genes connected to EMT, proliferation and differentiation. Identical data processing and clustering applied to the validation set on the same meta-genes resulted in subtypes with almost identical expression patterns. Conclusions: We identified and validated robust molecular subtypes in the largest set of stage II-III CRC samples as a combination of multiple molecular processes, that complement current disease stratification based on clinico-pathological variables and molecular markers. The biological relevance of these subtypes was reflected in significant differences in survival. These insights open new perspectives for improving prognostic models and rationalize the prediction of tumor-specific drug sensitivity.
The prognostic importance of miRNA-21 in stage II colon cancer: A population-based study.
Authors: Kjaer-Frifeldt Sanne , Hansen Torben , Nielsen Boye Schnack , Joergensen Stine , Lindebjerg Jan , Sorensen Flemming Brandt , Christensen Rene dePont , Jakobsen Anders Kristian Moeller
Published: March 2020

3513

Background: Adjuvant chemotherapy for stage II colon cancer patients is still controversial and the debate on which patients should be considered as high risk patients is still ongoing. The decision is based on clinical and pathological markers of risk, which are inadequately informative in most of the patients, and better methods are highly needed. The aim of the present study was to investigate the possible prognostic importance of miRNA-21, quantified by in situ hybridization (ISH), in a unique, large population-based cohort of patients treated for stage II colon cancer patients. Methods: The study included all patients diagnosed with stage II colon cancer in Denmark in the year 2003 (711 patients), representing a full population of five million people. Patients receiving adjuvant chemotherapy were excluded (N=15). One paraffin-embedded tissue block was obtained from each patient. A 6μm-thick section was processed for formazan-based chromogenic miR-21 ISH analysis and counter stained with nuclear red. The blue miR-21 ISH signal was assessed by image analysis to obtain two quantitative expression estimates: the total blue area (TB) and the ratio of TB with the nuclear density (TBR). Results: The miRNA-21 signal was predominantly observed in fibroblast-like cells located in the stromal compartment of the tumors. Patients expressing high levels of miRNA-21 (high mean TBR) had significantly inferior cancer specific survival (CSS): HR = 1.26 (95% CI; 1.15-1.60), p <0.001. In the COX regression analysis (including; gender, T-category, malignancy grade, localization, tumor perforation, tumor fixation, number of lymph nodes and MSI status), mean TBR was found to be an independent predictive marker of poor CSS, HR = 1.41 (95%CI; 1.19-1.67, p< 0.001). The same applied to TB. Conclusions: The present study shows that increasing miRNA-21 expression level is significantly correlated to decreasing CSS. Analyses of miRNA-21 should be considered as a potential adjunct in the selection of high risk stage II patients.
MicroRNA signature to predict sensitivity to anti-EGFR monoclonal antibodies in metastatic colorectal cancer (mCRC).
Authors: Cappuzzo Federico , Sacconi Andrea , Landi Lorenza , Biagioni Francesca , Ludovini Vienna , Fontanini Gabriella , Sensi Elisa , Lupi Cristiana , Salvini Jessica , Blandino Giovanni , Crinò Lucio
Published: March 2020

3521

Background: MicroRNAs (MiRNAs) are post-transcriptional regulators that bind to complementary sequences on target messenger RNA transcripts, usually resulting in gene silencing. Microarray technology is a powerful high-throughput tool capable of monitoring the expression of thousands of small noncoding RNAs at once. In the present study we aimed to investigate whether MiRNA signature was predictive for sensitivity to anti-EGFR monoclonal antibodies in mCRC. Methods: A total of 183 mCRC from two independent cohorts (cohort 1: 74 cases; validation cohort: 109 cases) treated with cetuximab/panitumumab either alone (n=19) or in combination with chemotherapy (n=164) were included onto the study. MiRNA arrays were analysed using Agilent’s miRNA platform. Results: MiRNA array analyses identified the cluster miR-99a/Let7c/miR-125b located on 21p11.1 as associated with different outcome to anti-EGFR therapies. In the first cohort, individuals with high signature (n=25, 33.8%) had a significantly longer progression free survival (PFS, 6.1 versus 2.3 months, p=0.01, HR=0.42) and overall survival (OS, 29.8 versus 7.0 months, p=0.04, HR=0.39) than patients with low signature (n=25, 33.8%). Similar results were observed in the validation cohort. Patients with high signature (n=60, 32.8%) had a significantly longer PFS and longer OS than individuals with low signature (PFS 8.2 versus 4.2 months, p=0.04, HR=0.52; OS 12.8 versus 6.8 months, p=0.09, HR=0.65). To further assess the potential confounding effect of KRAS and BRAF mutations, we analyzed the outcome of patients with high and low signature in the 75 cases with KRAS or BRAF mutation and in 90 cases KRAS and BRAF wild-type. In the wild-type population, high signature patients (n=29, 32.2%) had a significantly longer PFS (8.8 versus 4 months, p=0.002, HR:0.46) and longer OS (17.7 versus 10 months, p=0.015, HR=0.62) than low signature individuals, with no difference in the KRAS or BRAF mutated patients. Conclusions: MiR-99a/Let7c/miR-125b signature is useful for improving selection of KRAS/BRAF wild-type mCRC patients candidate for anti-EGFR strategies.