bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I clinical trial of a genetically modified and oncolytic vaccinia virus GL-ONC1 with green fluorescent protein imaging (NCT009794131).
Authors: Khan Khurum Hayat , Young Anna-Mary , Mateo Joaquin , Tunariu Nina , Yap Timothy Anthony , Tan David Shao Peng , Mansfield David , Wong Mabel , Riisnaes Ruth , Harrington Kevin J. , De Bono Johann Sebastian
Published: March 2020

3062

Background: GL-ONC is a genetically engineered virus attenuated by insertion of the ruc-gfp (Renilla luciferase and Aequorea green fluorescent protein fusion gene), beta-galactosidase (lacZ) and beta-glucuronidase (gusA) reporter genes into the FL14.5L, J2R (thymidine kinase) and A56R (hemagglutinin) loci, respectively. A phase I trial of intravenous (i.v) GL-ONC1 was pursued to evaluate safety, tolerability, tumour delivery, neutralising antibody development and antitumor activity. Methods: GL-ONC1 was administered at escalating doses (1x105, 1x106, 1x107, 1x108, 1x109, 3x109 plaque forming units (pfu) on day 1; 1.667x107 and 1.667x108, 1.667x109pfu on days 1-3) utilizing a 28-day cycle and a 3+3 dose escalation design. Paired biopsies before treatment and on day 8 for pharmacodynamic and viral delivery evaluation were obtained. Green flourescent protein (GFP) imaging was performed on skin rash and mucosal tumour lesions at baseline and after each cycle. Results: To date, 33 patients (pts) across 8 cohorts have been treated with 1 dose limiting toxicty reported of grade 3 transaminitis after a single infusion at 1x109pfu. Other reported adverse events (n) included pyrexia (26), musculoskeletal pain (10), fatigue (8), nausea and vomiting (4). 2 pts had transient transaminitis; both had liver metastases, which may have contributed to this. 2 pts developed minimally symptomatic poxvirus skin pustules, which appeared green by GFP and were positive to viral plaque assay (VPA). Overall, stable disease (SD) by RECIST was seen at >24 weeks (n=6) and 8-12 weeks (n=5). 2 out of 4 pts in cohort 8 (one with cholangiocarcinoma and another with non-small cell lung caner) achieved SD for median 5.5 months, with a drop in tumour markers at the time of infusions. Conclusions: GL-ONC1 is well tolerated; more frequent delivery of the virus (2 weekly, at the same dose) is planned in an attempt to increase agent exposure. Clinical trial information: NCT009794131.
Immunotherapy with CpG-ODN in neoplastic meningitis: A phase I trial.
Authors: Ursu Renata , Taillibert Sophie , Psimaras Dimitri , Banissi Claire , Bailon Olivier , Le Rhun Emilie , Guillamo Jean Sebastien , Marantidou Athina , Hoang-Xuan Khê , Belin Catherine , Carpentier Antoine F
Published: March 2020

3065^

Background: TLR9 agonists, such as phosphorothioate oligodeoxynucleotides containing CpG motifs (CpG-ODNs), are immunostimulating agents with antitumor effects in animal models. Neoplastic meningitis is a devastating disease, with no efficient therapeutic available. A phase I trial was conducted in patients with neoplastic meningitis to define the safety profile of subcutaneous injections, combined or not with intra-CSF administration of a CpG ODN. Methods: The diagnostic of neoplastic meningitis was based on a positive CSF cytology or on the association of clinical symptoms with meningeal enhancement on MRI. Cohorts of 3-6 patients were treated for 5 weeks with escalating doses of CpG-28 (level 1 and 2: 0.1and 0.3 mg/kg/week subcutaneously (sc); level 3 to 6: 0.3mg/kg sc associated with 3/7/12/18 mg intrathecally every other week). Concomittant treaments with radiotherapy or chemotherapy were allowed. The primary endpoint was tolerance. Secondary endpoints were time until neurological progression and survival. Results: Twenty-nine (29) patients were included. Primary cancer was malignant glioma (n=15), lung carcinoma (n=7), breast cancer (n=3), melanoma or melanocytoma (n=2), ependymoma (n=1), and colorectal cancer (n=1). At diagnosis median age was 56 years and median KPS was 70%. The treatment was well tolerated. Adverse effects possibly or probably related to the studied drug consisted in grade 2 lymphopenia, anemia and neutropenia (n=19), local erythema at injection sites (n=14), fever (n=10) and seizure (n=11). Two serious adverse events were considered as possibly or probably related to the protocol: one local infection and one intra-cerebral haemorrhage. Interestingly, median survival was higher in patients (n=8) who were concomitantly treated with bevacizumab a time of protocol (19 weeks vs 15 weeks, p=0.11). Conclusions: CpG-28 was well tolerated at doses up to 0.3mg/kg subcutaneously and 18 mg intrathecally. Main side effects were limited to local erythema, lymphopenia and fever. Combination with bevacizumab warrants further clinical investigations. Clinical trial information: P060301.
AFM11, a CD19/CD3 bispecific tandab, to facilitate T-cell-mediated killing of CD19+ cells.
Authors: Zhukovsky Eugene , Reusch Uwe , Burkhardt Carmen , Knackmuss Stefan , Fucek Ivica , Eser Markus , McAleese Fionnuala , Ellwanger Kristina , Little Melvyn
Published: March 2020

3068

Background: CD19, due to broader expression on B cell subtypes, is an attractive alternative to CD20 as a target for treatment of B cell malignancies. T cells are potent tumor-killing effectors that cannot be recruited by full length antibodies, however TandAb technology harnesses their cytotoxic nature for oncology indications. The CD3 RECRUIT TandAb AFM11 enables T cells to potently and specifically kill CD19+ tumors and possesses advantageous PK properties enabling intravenous dosing. Methods: We constructed AFM11, a human bispecific tetravalent antibody with two binding sites for both CD3 and CD19. In vitro efficacy and safety were evaluated on CD19+ cell lines and primary tumors. In vivo efficacy was evaluated in a murine NOD/scid xenograft model reconstituted with human PBMC. Results: In vitro assays demonstrate higher potency and efficacy of target cell lysis by AFM11 relative to a bispecific tandem scFv. CD8+ T cells dominate early cytotoxicity (4 hrs) while after 24 hrs both CD4+ and CD8+ T cells equally contribute to tumor lysis with EC50 of 0.5 – 5 pM; cytotoxicity is independent of cell CD19 density. AFM11 exhibits similar cytotoxicity at Effector:Target ratios from 5:1 to 1:5 and facilitates T cell serial killing of its targets. AFM11 activates T cells only in the presence of CD19+ cells. In PBMC cultures AFM11 induces CD69 and CD25 expression, T cell proliferation, and production of IFN-γ, TNF-α, IL-2, IL-6, and IL-10. Depletion of CD19+ cells from PBMC abrogates these effects, and indicates strict CD19+ target-dependent T cell activation. Thus, AFM11 should not elicit the devastating cytokine release observed when full length antibodies bind CD3. Cell lysis by AFM11 is restricted to CD19+ targets asCD19- bystanders are not lysed in co-culture assays. Up to one week co-incubation with AFM11 does not inhibit T cell cytotoxicity and thus it does not induce anergy. In vivo AFM11 exhibits a dose-dependent growth inhibition of Raji tumors; a single dose of AFM11 exhibits similar efficacy as 5 daily injections. Conclusions: AFM11 is a highly efficacious novel drug candidate for the treatment of CD19+ malignancies with an advantageous safety profile and anticipated dosing regimen.
The effect of copper nanoparticles on the progression of tumor in vivo.
Authors: Kachesova Polina Sergeevna , Goroshinskaya Irina Aleksandrovna , Borodulin Vladimir Borisovich
Published: March 2020

3084

Background: The study of the anticancer activity of copper nanoparticles (CuNP) measuring 70-75 nm in rats transplantable tumors. Methods: Experiments were carried out on white outbreed male rats with transplanted sarcoma 45 (9.10-dimethyl-1.2-benzanthracene-induced fusiform cell fibrosarcoma, S-45) and Pliss’s lymphosarcoma (Pliss). 0.5 ml of tumor tissue suspension (1x106 cells) in saline was inoculated subcutaneously in rat dorsal region for induction of sarcoma 45 or Pliss's lymphosarcoma. 7-8 days after tumors transplantation the animals were divided into three groups. Group 1: control (rats received 0.3 ml of saline only). Group 2: CuNP in 0.9% w/v of NaCl were injected intratumorally (1.25 mg/kg bodyweight). Group 3: The same amount of CuNP was injected intraperitonially. Animals received nanoparticles four times a week for one week, then after a week's break, the procedure was repeated. The associated nanoparticles are spherical in shape and have an oxide film on its surface. CuNP effect on tumor growth was determined by the mass (M) and size (V) of tumors. Results: The analysis of the received data showed that administration of CuNP to rats with S-45 caused reduced growth rates or cases with complete regression (8 of 17 cases) in 67.0% of experimental animals independently of injection way (V=0.81±0.3 cm3, M=0.91±0.3 g). The other 33% of rats with S-45 showed tumor growth (V=7.58±1.3 cm3, M=9.2±1.6 g). Overall, for the entire group of animals with S-45, nanoparticles inhibited tumor growth of 45%. In the control group there was an increase of tumor growth (V=9.0±1.8 cm3, M=10.4±2.5 g). CuNP introduction to animals with Pliss caused a delay in tumor growth and partial or complete regression (12 of 28 eight cases) in 40.0-48.0% of the rats in the route of Cu injection (V=1.4±0.8 cm3, M=10.4±2.5g). Observation of the remaining animals revealed tumor growth (V=60.6±5.93 cm3, M=67.13±8.7 g). In the whole group tumor growth inhibition was 50.0%. In the control group we observed increase of tumor growth (V=62.1±5.21 cm3, M=75.9±8.2 g). Conclusions: Thus the study showed that the copper nanoparticles possess antiproliferative activity, can inhibit the growth of transplanted tumors in rats and may be potentially used in anticancer medical therapy.
Preclinical testing using novel CT20p petide-nanoparticle combination in breast cancer.
Authors: Vishnubhotla Priya , Boohaker Rebecca J , Lee Michael W , Nemec Kathleen N , Khaled Amr , Santra Santimukul , Perez G.Micheal , Perez J.Manuel , Khaled Annette R
Published: March 2020

3085

Background: Patients with metastatic breast cancer may be initially responsive to treatment, but a significant number develop refractory disease. There is a critical unmet need to develop effective therapeutic approaches given the unique metabolism of tumor cells. Methods: We examined the cytotoxic properties of a novel peptide, CT20p, derived from the C-terminus of Bax. For delivery to cells, the amphipathic nature of CT20p allowed it to be encapsulated in polymeric nanoparticles (NPs). NPs were made using aliphatic hyperbranched polyester (HBPE) that incorporated surface carboxylic groups and interior hydrophobic cavities for encapsulation of CT20p. To examine the cytotoxic potential and targeting capacity of CT20p-NP-HBPE, we treated MDA-MB-231 and MCF-10A breast cancer cell lines with the combination and measured changes in mitochondrial function, cell metabolism and induction of cell death. The ability of CT20p-NP-HBPE to cause tumor regression was examined by subcutaneously implanting MDA-MB-231 cells in nude mice. Results: Initial results showed that CT20p caused the release of calcein from mitochondrial-like lipid vesicles, without disrupting vesicle integrity, and, when expressed as a fusion protein in cells, localized to mitochondria. While the peptide alone had little effect upon intact cells, when encapsulated and delivered by nanoparticles, CT20p-HBPE-NPs proved an effective killer of breast cancer cells. CT20p-NP-HBPE initiated non-apoptotic cell death within 3 hours of treatment by targeting mitochondria and deregulating cellular metabolism. Nanoparticles alone or nanoparticles encapsulating a control peptide had minimal effects. The cytotoxicity of CT20p-NP-HPBE was most pronounced in breast cancer cells, sparing normal, epithelial cells. In implanted breast tumors, CT20p-NP-HBPE accumulated in tumors within 24 hours and reduced tumor burden by 50-80%. Conclusions: These results reveal the innovative features of CT20p that allow nanoparticle-mediated delivery to tumors and the potential application in combination therapies that target the unique metabolism of cancer cells.
Role of mesenchymal stem cells in delivering Newcastle disease virus to glioma cells and glioma stem cells and enhancing the oncolytic effect of the virus by secreting TRAIL.
Authors: Slavin Shimon , Kazimirsky Gila , Ziv-Av Amotz , Brodie Chaya
Published: March 2020

3100

Background: Newcastle disease virus (NDV), an avian paramyxovirus, is tumor selective and oncolytic by induction of apoptosis. Preclinical and clinical studies in patients with glioblastoma (GBM) using NDV demonstrated occasional clinical benefits with no major side effects. Limitations to the use of NDV as virotherapy of GBM is the inefficient delivery into cancer cells in the brain. Methods: Mesenchymal stromal cells (MSCs) can migrate towards cancer cells. We examined potential delivery of oncolytic effect of NDV (MTH-68/H) against glioma cell lines and glioma stem cells (GSCs) and the ability of MSCs to deliver NDV to glioma cells and GSCs in culture. Results: NDV induced a dose-dependent cell death in the glioma cells U87, A172 and U251 with maximal effects at 10 MOI. In contrast, we found only small level of apoptosis or changes in self-renewal in three GSCs infected with NDV. We found that MSCs derived from bone marrow, adipose tissue and cord were successfully infected by NDV and were able to deliver the virus to co-cultured glioma cells and GSCs. In addition, treatment of glioma cells and GSCs with culture supernatant of infected MSCs increase apoptosis of glioma cells as compared to the effect of direct infection of glioma cells. Moreover, the culture supernatants of the infected MSCs induced cell death in GSCs that were resistant to the oncolytic effect of NDV, suggesting that factor(s) secreted by the infected MSCs sensitized the glioma cells and GSCs to the cytotoxic effects of NDV. Using antibody array and ELISA we identified TRAIL as the factor secreted from infected MSCs. Indeed, treatment of infected glioma cells with TRAIL increased the cytotoxic effect of NDV and sensitized GSCs to the oncolytic effects of NDV. Conclusions: MSCs can be employed to deliver NDV to GBM. In addition, MSCs can also sensitize glioma cells and GSCs to oncolysis by NDV. Considering the resistance of GSCs to chemotherapy and radiation therapy, treatment of GBM with MSC-mediated targeted oncolytic NDV may provide a new clinical tool for treatment of GBM and eradication of GSCs.
Do ascorbic acid and viscum album improve PFS in NSCLC?
Authors: Raza Fatima Zehra , Ranjan Smita , Kloecker Goetz H.
Published: March 2020

3102

Background: Intravenous vitamin C achieves 70 times higher plasma concentrations of ascorbate as a similar oral dose. Such pharmacologic concentrations(0.3-20mM) kill cancer cells but not normal cells, through extracellular H2O2 generation. Ascorbate treatment depleted ATP and induced autophagy in prostate cancer cells; gemcitabine with ascorbate resulted in 50% inhibition of growth in pancreatic tumor xenografts in mice models. A phase I/II study for pancreatic cancer patients is underway. Viscum album (mistletoe) is widely used in Europe as complementary therapy. Its cytotoxic and immunomodulatory effects are poorly understood. Additional treatment with subcutaneous mistletoe injections improved quality of life in gastric cancer patients in a study. Methods: We report the case of a 54 year old male smoker with adenocarcinoma of the lung (pT4N2M1a), EGFR/RAS/ALK negative. After 5 cycles of chemotherapy (carboplatin/taxol x 3, then carboplatin/pemetrexed x 2) scans showed continued progression. The patient made an informed decision to stop further chemotherapy and initiated complementary medical means, receiving high dose IV vitamin C (75 g, 2 x week) and subcutaneous mistletoe injections every other day, for the last seven months. Results: Six months into the non-standard therapy, a PET/CT shows a PR by RECIST and decreased FDG activity of the biopsy proven primary and metastatic site. The patient feels well, a year now after being diagnosed with advanced NSCLC. Conclusions: Whether the PR and the surprisingly long PFS is due to IV ascorbic acid and/or mistletoe is unknown. A review of the literature reveals reports of similar astonishing clinical results after treatment with either agent. A registry and biorepository of cases treated with alternative modalities may discover markers and biological mechanisms to explain these surprising reports.
Systematic analysis of potential targets for immunotherapy in acute myeloid leukemia.
Authors: Hourigan Christopher Simon , Goswami Meghali , Alkharouf Nawal , Bhagwat Medha , Sardon Heidi May , Williams Ann L , McCoy J. Phillip , Ito Sawa , Strickland Stephen Anthony , Savani Bipin N. , Fraser James W , Sadrzadeh Hossein , Fathi Amir Tahmasb , Qin Lu , Hess Allan , Smith B Douglas , Karp Judith E. , Barrett A. John
Published: March 2020

3104

Background: The ability to target myeloid malignancies using immunotherapy, without allogeneic transplantation, depends on the capability to target leukemic clones while sparing normal tissues. A variety of putative leukemia associated antigens (LAA) have been identified but an evidence-based list of targets for acute myeloid leukemia (AML) has not yet been established. Methods: De-identified, clinically annotated, samples of peripheral blood and/or bone marrow aspirate from untreated AML patients were collected under IRB-approved protocols from three NCCN cancer centers. Samples were analyzed for commonly observed somatic mutations in ASXL1, DNMT3A, FLT3, IDH1/2, KIT, NPM1, NRAS, RUNX1, TET2, and WT1. Gene expression of 75 consensus LAAs were determined using a custom-designed RT-PCR array. 12 samples underwent extended LAA analysis by flow sorting into “bulk leukemia” and “stem cell enriched” populations. LAA expression was normalized using the geometric mean of three control genes. Results: Samples from 48 AML patients (30 blood, 22 marrow) were suitable for analysis. Average age of patients was 53 (24-86), 50% were female. Cytogenetics were favorable (17%), intermediate (65%) or adverse (19%); 29% presented with a white blood cell count >50,000. Over 10,000 individual data-points were collected. Five distinct patterns of LAA expression were observed in blood from AML patients compared to healthy donors. Conclusions: Understanding the heterogeneity and patterns of AML LAA expression between individuals allows the rational prioritization of potential targets for immunotherapy. Based on our data we predict that targeting any single LAA will likely often be ineffective but that it may be possible to create an inclusive panel of multiple targets with coverage of most AMLs, eliminating the need for individualized personalization of therapy. Such AML antigen signatures may also have utility for minimal residual disease monitoring. [Table: see text]
Bevacizumab continuation versus no continuation after first-line chemo-bevacizumab therapy in patients with metastatic colorectal cancer: A randomized phase III noninferiority trial (SAKK 41/06).
Authors: Koeberle Dieter , Betticher Daniel C. , Von Moos Roger , Dietrich Daniel , Brauchli Peter , Baertschi Daniela , Matter-Walstra Klazien , Winterhalder Ralph C. , Borner Markus M. , Anchisi Sandro , Moosmann Peter , Kollar Attila , Saletti Piercarlo , Roth Arnaud , Frueh Martin , Kueng Marc , Popescu Razvan A. , Schacher Sabina , Hess Viviane , Herrmann Richard
Published: March 2020

3503

Background: Chemotherapy plus bevacizumab is a standard option for first-line treatment in metastatic colorectal cancer patients. We assessed whether no continuation is non-inferior to continuation of bevacizumab after stop of first-line chemotherapy. Methods: In an open-label, phase 3 multicenter study conducted in Switzerland, patients with unresectable metastatic colorectal cancer having non-progressive disease after 4-6 months of standard first-line chemotherapy plus bevacizumab were randomly assigned in a 1:1 ratio to continuing bevacizumab (7.5 mg/kg every 3 weeks) or no treatment. CT scans were done every 6 weeks between randomization and disease progression. The primary endpoint was time to progression (TTP). A non-inferiority limit for hazard ratio (HR) of 0.727 was chosen to detect a difference in TTP of 6 weeks or less, with a one-sided significant level of 10% and a statistical power of 85%. Results: The per-protocol population comprised 262 patients. Median follow-up is 28.6 months (range, 0.6-54.9 months). Median TTP was 17.9 weeks (95% CI 13.3-23.4) for bevacizumab continuation and 12.6 weeks (95% CI 12.0-16.4) for no continuation; HR 0.72 (95% CI 0.56-0.92). Median progression free-survival and overall survival, both measured from start of first-line treatment, was 9.5 months and 24.9 months for bevacizumab continuation and 8.5 months (HR 0.73 (95% CI 0.57 - 0.94)) and 22.8 months (HR 0.87 (95% CI 0.64 – 1.18)) for no continuation. Median time from randomization to second-line treatment was 5.9 months for bevacizumab and 4.8 for no continuation. Grade 3-4 adverse events in the bevacizumab continuation arm were uncommon. Conclusions: Non-inferiority could not be demonstrated. The 95% confidence intervals for the TTP HR indicate superiority of bevacizumab continuation after stop of first-line chemotherapy. The median differences in TTP and in time between randomization and start of second-line treatment were of moderate magnitude being less than 6 weeks. The results of an accompanying cost analysis will be presented at the meeting. Clinical trial information: NCT00544700.
A randomized clinical trial of chemotherapy compared to chemotherapy in combination with cetuximab in k-RAS wild-type patients with operable metastases from colorectal cancer: The new EPOC study.
Authors: Primrose John Neil , Falk Stephen , Finch-Jones Meg , Valle Juan W. , Sherlock David , Hornbuckle Joanne , Gardner-Thorpe James , Smith David , Imber Charles , Hickish Tamas , Davidson Brian , Cunningham David , Poston Graeme John , Maughan Tim , Rees Myrrdyn , Stanton Louise , Little Louisa , Bowers Megan , Wood Wendy , Bridgewater John A.
Published: March 2020

3504

Background: Resection of liver metastases from colorectal cancer with or without neoadjuvant chemotherapy is the standard of care. The EPOC study (Nordlinger et al, Lancet 2008) randomised patients between surgery and surgery with chemotherapy and demonstrated an improvement in 3 year progression free survival (PFS) of 7·3% (from 28·1% to 35·4%). As a rational extension to the EPOC study data, the New EPOC study evaluates the benefit of cetuximab, an EGF receptor antibody, in addition to standard chemotherapy in patients with operable liver metastases. Methods: 272 patients were randomised between February 2007 and November 2012 into the New EPOC study. Eligible patients were required to be k-RAS wild type, have operable liver metastases and to be sufficiently fit for chemotherapy and surgery. Patients with the primary tumour in situ, and those who required short course rectal radiation were eligible. Patients were randomised to receive a fluoropyrimidine and oxaliplatin plus or minus cetuximab for 12 weeks before, then 12 weeks following surgery. Patients who had been treated with adjuvant oxaliplatin could receive irinotecan and 5 – fluorouracil. Results: Following a recommendation from the Independent Data Monitoring Committee on 19/11/2012, the New EPOC study was stopped when the study met a protocol pre-defined futility analysis. With 45.3% (96/212) of the expected events observed, progression free survival was significantly worse in the cetuximab arm (14.8 vs 24.2 months, HR (95%CI) 1.50037 (1.000707 to 2.249517) p< 0.048). The result of a pre-planned analysis excluding the 23 patients treated with irinotecan based chemotherapy was similar (15.2 vs 24.2 months, HR 1.565546 (1.014967-2.414793) P<0.043). Conclusions: Although the data are immature, the accumulation of more events is unlikely to change this result. In patients with resectable liver metastases and K-RAS wt tumours the addition of cetuximab to chemotherapy is not beneficial. Clinical trial information: ISRCTN22944367.
Maintenance therapy with bevacizumab with or without erlotinib in metastatic colorectal cancer (mCRC) according to KRAS: Results of the GERCOR DREAM phase III trial.
Authors: Tournigand Christophe , Chibaudel Benoist , Samson Benoit , Scheithauer Werner , Lledo Gérard , Viret Frederic , André Thierry , Ramée Jean François , Tubiana-Mathieu Nicole , Dauba Jérôme , Dupuis Olivier , Rinaldi Yves , Mabro May , Aucoin Nathalie , Khalil Ahmed , Latreille Jean , Louvet Christophe , Brusquant David , Bonnetain Franck , de Gramont Aimery ,   GERCOR
Published: March 2020

3515

Background: The primary analysis of DREAM demonstrated that a maintenance therapy (MT) with bevacizumab (Bev) + EGFR TKI erlotinib (E) significantly improved progression-free survival (PFS) after a 1st-line Bev-based induction therapy (IT) in patients (pts) with unresectable mCRC. Methods: Pts were randomized to MT after an IT with FOLFOX-bev or XELOX-bev or FOLFIRI-bev between Bev alone (Bev 7.5 mg/kg q3w; arm A) or Bev+E (Bev 7.5 mg/kg q3w, E 150 mg/d ; arm B) until PD or unacceptable toxicity. Primary endpoint was PFS on MT. Secondary endpoints included PFS from inclusion, overall survival (OS) and safety. The impact of KRAS tumor status on treatment efficacy was evaluated in an exploratory analysis. Results: 700 pts were registered and 452 pts were randomized (228 in arm A, 224 in arm B). KRAS status was available for 413/452 (91%) pts. The median duration of MT was 3.6 m. Results for MT are presented below (Table). In the registered population, median OS was 24.9m (22.5 – 27.3). Conclusions: Maintenance treatment with bev + erlotinib increases PFS over maintenance with bev alone in pts with mCRC but does not prolong OS. Further follow-up will determine the impact of 2nd or 3rd line anti-EGFR Mabs in this study. Contrasting with anti-EGFR Mabs, KRAS tumor status is not mandatory to select pts with mCRC for treatment with erlotinib. Clinical trial information: NCT00265824. [Table: see text]
Tumor-related and treatment-related colostomy-free survival (CFS) following chemoradiation (CRT) using mitomycin (MMC) or cisplatin (CisP), with or without maintenance 5FU/CisP chemotherapy (CT) in squamous cell carcinoma of the anus (SCCA): Results of ACT II.
Authors: Glynne-Jones Robert , Kadalayil Latha , Meadows Helen , Cunningham David , Samuel Leslie M. , Geh Ian , Lowdell Charles , James Roger David , Beare Sandy , Begum Rubina , Ledermann Jonathan A. , Sebag-Montefiore David ,   on behalf of the ACT II Study Group
Published: March 2020

3532

Background: Concurrent CRT is standard treatment for patients (pts) with SCCA. We explore tumor- and treatment-related CFS in a phase III trial (ACT II), which mandated standardised radiation fields and a uniform dose (50.4Gy in 28 daily fractions of 1.8Gy). Methods: The ACT II trial (940 pts) compared both CisP (n=468) versus MMC (n=472) combined with 5-FU/CRT, and 2 cycles of maintenance CT (Maint, n=448) versus none (No-maint, n=446). We investigated the association between CFS and baseline factors (age, sex, T stage, size of tumour, nodal status) and treatment using Cox regression. CFS events included baseline colostomies not reversed at first follow up after treatment and post-treatment colostomies. Results: Median follow-up (all pts) was 5.1 years. Median age: 58 years; tumour site – canal (84%), margin (14%); stage T1-T2 (52%), T3-T4 (46%); N+ (32%), N0 (62%). Of 884 evaluable patients only 20/118 (17%) baseline colostomies were reversed within 8 months, and 37 later. 112 pts had a post-treatment colostomy due to persistent disease (98) or morbidity (14). The 5-year CFS rates by stage were 86% T1, 77% T2, 57% T3 and 47% T4; 72% N0, 60% N+; by treatment arm 68% MMC/Maint, 70% CisP/Maint, 68% MMC/No-maint and 65% CisP/No-maint respectively. The 5-year CFS rates were 72% and 60% for N0 and N+ respectively. The most significant predictors of colostomy in multivariable Cox regression analyses were T stage, sex and baseline haemoglobin (p<0.001 for all). Men were more at risk than women (adjusted HR 1.64; 95% CI: 1.26, 2.14). Age, site of primary or treatment did not impact on CFS. Although significant in univariate analysis, nodal status did not influence CFS when adjusted for other baseline factors. Conclusions: In the largest trial in anal cancer, neither the type of CRT (5FU/CisP vs. 5FU/MMC) nor maintenance chemotherapy improved CFS. 34% (61/177) of all colostomies were baseline fashioned prior to treatment and never reversed after all treatments. The major predictive factors for CFS were T stage, sex and haemoglobin levels. Clinical trial information: NCT00025090.
Cetuximab and chemotherapy in the treatment of patients with initially “nonresectable” colorectal (CRC) liver metastases: Long-term follow-up of the CELIM trial.
Authors: Folprecht Gunnar , Gruenberger Thomas , Bechstein Wolf , Raab Hans-Rudolf , Weitz Juergen , Lordick Florian , Hartmann Joerg Thomas , Lang Hauke , Trarbach Tanja , Stoehlmacher-Williams Jan , Liersch Torsten , Ockert Detlev , Jaeger Dirk , Steger Ulrich , Suedhoff Thomas , Kohne Claus-Henning
Published: March 2020

3538

Background: CRC liver metastases can be resected after downsizing with intensive chemotherapy schedules, with a strong correlation between the response and resection rates. Cetuximab plus chemotherapy has been shown to increase the rates of tumor response and resection of liver metastases. (Van Cutsem et al, JCO 2011). Methods: Patients (pts) with technically non-resectable and/or with > 4 liver metastases were randomized to treatment with FOLFOX/cetuximab (arm A) or FOLFIRI/cetuximab (arm B) and evaluated regarding resectability every 2 months. Resection was offered to all patients who became resectable during the study. K-ras and b-raf status were retrospectively evaluated. Data on tumor response and resection were reported earlier (Folprecht et al, Lancet Oncol 2010). Overall and progression free survival were analyzed in December 2012. Results: Between Dec 2004 and March 2008, 56 pts were randomized to arm A, 55 to arm B. For the current analysis, 109 pts were evaluable for overall survival (OS), and 106 patients for PFS. The median OS was 35.7 [95% CI: 27.2-44.2] months (arm A: 35.8 [28.1-43.6], arm B: 29.0 [16.0-41.9], HR 1.03 [0.66-1.61], p=0.9). The median PFS was 10.8 [9.3-12.2] months (Arm A: 11.2 [7.2-15.3], Arm B: 10.5 [8.9-12.2], HR 1.18 [0.79-1.74], p=0.4). Patients with R0 resection had a better OS (median: 53.9 [35.9-71.9] mo) than patients without R0 resection (27.3 [21.1-33.4] mo, p=0.002) and a better PFS (median 15.4 [11.4-19.5] and 8.9 [6.7-11.1] mo in R0 resected and not R0 resected pts, p<0.001). The 5 year survival in R0 resected patients is 46.2% [29.5-62.9%]. Conclusions: This study confirmed a favourable long term survival of patients with initially “nonresectable” CRC liver metastases treated in a multidisciplinary approach of neoadjuvant chemotherapy with cetuximab and subsequent metastasectomy in pts who became resectable. Clinical trial information: NCT00153998. [Table: see text]
A phase II study of combination epigenetic therapy in metastatic colorectal cancer (mCRC): A phase II consortium (P2C)/Stand Up 2 Cancer (SU2C) study.
Authors: Azad Nilofer Saba , El-Khoueiry Anthony B. , Mahoney Michelle R. , Adkins Douglas , Flynn Patrick J. , Bahary Nathan , Kim George P. , Pitot Henry Clement , Erlichman Charles , Donehower Ross C. , Herman James Gordon , Baylin Stephen , Ahuja Nita ,   P2C
Published: March 2020

3539

Background: Therapy with decitabine and entinostat (ENT: HDAC inhibitor) shows synergistic effect in re-expression of tumor-suppressor genes and growth inhibition in CRC cell lines and in vivo studies. Methods: We conducted a phase II, multi-institutional study of SQ 5-azacitidine (AZA) and oral ENT in mCRC pts. A 28 day cycle included: AZA at 40 mg/m2 d1-5 and 8-10 with ENT 7 mg d3 and 10. Initial eligibility criteria included: ECOG PS 0-1, good end organ function, and biopsiable disease for cohort A (CoA). An interim analysis indicated that toxicity which crossed pre-specified safety boundary was secondary to disease. A 2nd cohort B (CoB) with eligibility restrictions: <2 prior regimens in KRAS-mutated CRC pts, <3 prior regimens if KRAS wild-type, and liver disease limited to <30% of volume was accrued. Serial tumor biopsies and research blood were collected to assess for methylation/expression changes in circulating tumor DNA and biopsies, respectively. The primary endpoint was response as measured by RECIST criteria using a 2-stage Simon design. Results: 47 pts were initially enrolled (24 CoA, 23 CoB). Pts received a median of 2 cycles on both cohorts (1-16 CoA, 2-6 CoB). Pts had a median of 4 prior therapies for CoA (range 2-9) and 3 for CoB (range 2-6). Gr 4 AEs attributable to treatment for CoA included hyperglycemia (1) and hypokalemia (1); other common Gr 3 AEs included anemia (3), decreased lymphocytes (7), fatigue (3), and nausea (3). CoB pts experienced grade 3 chest pain (1), neutropenia (2), leucopenia (2), urinary tract obstruction (1), and hypophosphatemia (1). No responses have been observed. Results of translational objectives will be presented at the meeting. Conclusions: SQ AZA and ENT therapy does not have clinical activity as defined by confirmed response in aCRC. Follow-up for survival, response to subsequent therapy, and correlative analysis are ongoing. Supported in part by N01-CM-2011-00099. Clinical trial information: NCT01105377. [Table: see text]
Use of RAS pathway activation or KRAS mutation status to predict cetuximab response in CRC patient-derived xenografts.
Authors: Li Henry , Chen Dawei , Guo Sheng , Cai Jie , Chen Yiyou , Wery Jean-Pierre
Published: March 2020

3544

Background: Cetuximab was approved for treating EGFR-expressing metastatic colorectal carcinoma (mCRC) without patient stratification. Subsequent retrospective clinical studies resulted in an exclusion criterion for patients with KRAS mutations at codons 12 and 13. However, only a fraction of patients with wtKRAS benefit from the treatment. Recent analyses indicated that patients with KRAS mutation at codon 13 can also benefit. We set out to investigate whether KRAS mutations, or any other factors, are good biomarkers for CRC-cetuximab therapy patient stratification. Methods: We have established patient derived xenografts (PDX) from treatment-naive Asian CRC patients to discover biomarker predictive of cetuximab response. We conducted a clinical trial style study (“patient avatar trial”) of cetuximab using a randomly selected cohort of 26 EGFR+ PDXs. The antitumor activities were analyzed against KRAS mutation status and a published expression-signature. Results: We identified 12/26 (~46%) as cetuximab responders and 14/26 non-responders (defined by 50% tumor growth inhibition threshold). All 14 non-responders are mutated for one or more of KRAS, BRAF (V600E), EGFR, AKT and PIK3CA oncogenes. In contrast, 5/11 responders analyzed are wild-type for all these genes. Importantly, 5/11 responders have activating KRAS mutations at codons 12/13, contradictory to the currently practiced clinical exclusion criteria, but consistent with more recent clinical findings. Most interestingly, the observed cetuximab activity in this cohort of 26 PDXs has a surprisingly strong correlation to a published RAS pathway score. Conclusions: Our results indicated strong predictive power of cetuximab-CRC-PDX trial and RAS signature, and warrant prospective clinical studies for further confirmation.
Stereotactic body radiotherapy response and local control rates for hepatic oligometastases.
Authors: Goodman Ben , Johnson Cynthia S , Gebregziabher Netsanet , Maluccio Mary A. , Helft Paul R. , Chiorean E. Gabriela , Cardenes Higinia Rosa
Published: March 2020

3546

Background: Stereotactic body radiation therapy (SBRT) is a non-invasive, effective technique in the treatment of hepatic oligometastases from solid tumors. We present response and local control rates from our single institution experience. Methods: We treated 79 metastatic liver lesions from 64 different patients using stereotactic body radiation therapy. One colorectal cancer patient was treated three times and four patients were treated twice. Among the 79 metastatic liver lesions treated, 85% had prior chemotherapy. The primary cancer site included: Colorectal 66%, Non-colorectal GI 14%, Breast 6%, Ovarian 5%, NSCLC 3%, and other 6%. The mean GTV size was 37.3 (cc). The mean GTV diameter was 3.1 (cm). The median total dose was 54 (Gy) with the minimum and maximum total dose being 30 and 60 (Gy). Results: The overall local control rate was 94.2%, with estimates at 12, 24, 36, and 48 months being 96.1%, 87.9%, 87.9% and 87.9% following SBRT treatment. When comparing colorectal cancer patients vs all other primary cancer sites, the one year local control rate was 93.4% and 100%. The two and three year local control rates for colorectal cancer vs other primary cancer sites were 84.9% vs 90.9%. Best response was examined as a 4 level response (CR,PR,SD,PD) per the RECIST criteria. Overall, 67% of patients had a response, and less than 3% of patients had progression with SBRT treatment. For colorectal cancer patients, 79% had a response to treatment. Only 21% of colorectal cancer patients did not respond, however, the majority of these patients still had stable disease following treatment. Non-colorectal primary site cancers had a response in 50% of the lesions following SBRT treatment. The remaining 50% of non-colorectal primary cancers were stable following SBRT treatment and none progressed. The median dose for CR, PR, or SD was 54 Gy. The median dose for patients with progressive disease was less than 50 Gy. The observed CTC toxicities were limited with mostly grade 1-2 toxicity and only two grade 4 and one grade 5 toxicity. Conclusions: Stereotactic body radiation therapy is an effective treatment option for patients with hepatic oligometastases with a limited toxicity profile.
Analysis of overall survival and safety during the course of the phase III VELOUR trial comparing FOLFIRI and ziv-aflibercept or placebo in mCRC patients who progressed on prior oxaliplatin treatment.
Authors: Ruff Paul , Lakomy Radek , Prausová Jana , Van Hazel Guy A. , Moiseyenko Vladimir , McKendrick Joseph , Boelle Emmanuelle , Castan Remi , Macarulla Teresa , Van Cutsem Eric
Published: March 2020

3574

Background: VELOUR, a large, international, randomized, placebo (pbo)-controlled study, compared efficacy and safety of FOLFIRI with ziv-aflibercept (known as aflibercept outside the United States) or with pbo in 1,226 metastatic colorectal cancer patients who received prior oxaliplatin treatment. Ziv-aflibercept demonstrated statistically significant, clinically meaningful improvements in median overall survival (OS) (13.5 vs 12.06 mos; hazard ratio [HR]=0.817, P=0.0032), progression-free survival, and response rate. This analysis estimates treatment effect and safety over time course of the study. Methods: HRs by 6-mo time periods were estimated using piecewise Cox proportional hazard model. NCI-CTCAE v3.0 was used to grade adverse event (AE) severity. Results: HR improved over time (Table), consistent with survival curves that continue to separate past the median time point, indicating that the magnitude of ziv-aflibercept treatment effect continues to increase over time. Incidence of grade 3 AEs (45.1% vs 62.0%) was higher in the ziv-aflibercept/FOLFIRI arm; incidences of grade 4 AEs were 17.4% (pbo) vs 21.4% (ziv-aflibercept). More common AEs only occurred in a small proportion of ziv-aflibercept/FOLFIRI cycles (eg, grade ≥3 hypertension and diarrhea occurred in 3.6% and 2.8% of cycles, respectively). The majority of grade 3/4 AEs occurred in early treatment (first 3-4 cycles). Most patients experienced only a single episode of grade ≥3 AEs with ziv-aflibercept/FOLFIRI. Importantly, AEs in VELOUR did not impact patients’ ability to receive chemotherapy. Conclusions: Treatment with ziv-aflibercept/FOLFIRI showed continuous, consistent improvement in OS over time. While combined grade 3/4 AEs were higher with ziv-aflibercept, AEs occurred early in treatment in a small proportion of total cycles; the majority were single-episode in nature. Clinical trial information: NCT00561470. [Table: see text]
Detection of the BRAFV600E protein in human colon carcinomas by a mutation-specific antibody.
Authors: Smyrk Thomas C. , Tougeron David , Thibodeau Stephen N. , Singh Shalini , Muranyi Andrea , Shanmugam Kandavel , Grogan Thomas M. , Alberts Steven R. , Shi Qian , Sinicrope Frank A. ,   North Central Cancer Treatment Group
Published: March 2020

3576

Background: BRAF encodes a serine-threonine kinase that is a downstream effector of activated RAS. A point mutation (V600E) in BRAF occurs in a subset of colorectal cancers (CRCs) and is associated with adverse outcome and may predict non response to anti-EGFR antibodies. Detection of a BRAFV600E mutation in a CRC with microsatellite instability indicates a sporadic origin and excludes Lynch Syndrome. While BRAFV600E mutation status is determined using a DNA-based assay, antibodies against the BRAFV600E protein have recently been developed. We examined mutant BRAFV600E protein expression and its concordance with mutation status. Methods: Primary stage III colon carcinomas (50 BRAFV600E mutation carriers and 25 wild-type cases) were studied from a completed phase III adjuvant trial comparing FOLFOX +/- cetuximab (NCCTG N0147). In archival resection specimens, immunohistochemistry (IHC) was performed using a pan-BRAF antibody and a V600E mutation-specific antibody raised against an immunogenic synthetic peptide derived from the internal region of the BRAFV600E protein. BRAFV600E mutations in codon 15 were analyzed in extracted DNA using a multiplex, allele specific PCR–based assay. BRAF staining was scored independently by two pathologists blinded to mutation status. Results: In primary colon carcinomas stained with a pan-BRAF antibody, diffuse cytoplasmic staining for BRAF proteins was detected in 74 of 75 carcinomas with one case deemed non-evaluable. Using the mutation-specific BRAFV600E antibody, diffuse cytoplasmic staining was detected in 49 of 74 tumors without appreciable heterogeneity of expression. Among these 49 tumors expressing mutant BRAFV600E proteins, all (100%) were found to carry a BRAFV600E mutation according to a DNA-based assay. In contrast, absent BRAFV600E staining was observed in all 25 tumors that were found to have wild-type copies of BRAFV600E detected using a PCR-based assay. Conclusions: For the detection of mutant BRAFV600E, complete concordance was found between IHC and a DNA-based method in colon carcinomas. This finding supports the use of IHC as a simplified strategy to screen CRCs for mutant BRAFV600E proteins in routine clinical practice to inform clinical decision-making.
Phase II study of dacarbazine for metastatic colorectal cancer: Final results with MGMT analysis.
Authors: Amatu Alessio , Sartore Bianchi Andrea , Moutinho Catia , Bencardino Katia , Bonazzina Erica , Pietrogiovanna Lisa , Venturini Filippo , Gambaro Alessandra , Marrapese Giovanna , Belotti Alessandro , Esteller Manel , Siena Salvatore
Published: March 2020

3581

Background: O6-methylguanine-DNA-methyltransferase (MGMT) is a DNA repair protein removing mutagenic and cytotoxic adducts from O6-guanine in DNA. Approximately 40% of colorectal cancers (CRCs) display MGMT deficiency due to promoter hypermethylation leading to silencing of the gene. Alkylating agents, such as dacarbazine, exert their antitumor activity by DNA methylation at the O6–guanine site, inducing base pair mismatch, therefore activity of dacarbazine could be enhanced in CRCs lacking MGMT. We conducted a phase II study with dacarbazine in CRCs who had failed standard therapies (oxaliplatin, irinotecan, fluoropyrimidines, and cetuximab or panitumumab if KRAS wild type). Methods: All patients had tumor tissue assessed for MGMT as promoter hypermethylation in double-blind for treatment outcome. Patients received dacarbazine 250 mg/m2 i.v. qd for 4 consecutive days q21 until PD or intolerable toxicity. We employed a Simon two-stage design to determinate if the ORR would be ≥ 10%. Secondary endpoints included association of response, PFS and disease control rate with MGMT status. Results: Sixty-eight patients were enrolled from May 2011 to March 2012. Patients received a median of 3 cycles of dacarbazine [range 1-12]. Grade 3-4 toxicities included: fatigue (41%), nausea/vomiting (29%), constipation (25%), platelet count decrease (19%), anemia (18%). Overall, 2 patients (3%) achieved partial response (PR) and 8 patients (12%) had stable disease (SD). Disease control rate (PR+SD) was significantly associated with MGMT promoter hypermethylation in the corresponding tumors. Conclusions: Objective clinical responses to dacarbazine in metastatic CRC patients are confined to those tumors harbouring epigenetic inactivation of the DNA repair enzyme MGMT. Clinical trial information: 2011-002080-21.
Impact of nodal metastasis on survival of stage IV colon cancer: Analysis of National Cancer Data Base (NCDB).
Authors: Shaik Mohammed , Korant Alpesh K. , Saha Supriya Kumar , Johnston Gregory , Dhar Vikrom K. , Abadeer Benjamin , Wiese David , Arora Madan L. , Stewart Andrew , Saha Sukamal
Published: March 2020

3582

Background: Nodal metastasis (mets) is an important prognostic factor in the staging of colon cancer (CCa). However, the significance of nodal mets in stage IV CCa remains undetermined. Therefore, we investigated the impact of nodal mets on 5 year overall survival (5-yr OS) in stage IV CCa. Methods: Patients (pts) from the NCDB who had been diagnosed with histologically confirmed Stage IVCCa from 1998-2010 were divided into two groups: with(+ve) or without(-ve) nodal mets and the 5 yr OS was compared using the Kaplan Meier Curves. Multivariate analysis was performed using CoxProportional regression model. An adjusted hazard ratio(aHR) was calculated for pts with nodal mets compared to those without nodal mets after adjusting for age, grade and tumor size. Results: 70,387 pts from the NCDB with stage IV CCa were included in our analysis. Of these, 12,363(17.5%) had no nodal mets (TN0M1), 23,052(32.7%) had 1-3 nodal mets (TN1M1), and 34,972 (49.69%) had 4 or more nodal mets (TN2M1) involved at the time of diagnosis (Table 1a).The overall nodal positivity was 82.4%. The 5-yrOS of all stage IV pts was 10.7% (Table 1b); 5 yr OS for node -ve pts was 18.4% versus 9.2% for node +ve pts (p<0.0001)(Table1b). The 5 yr OS of N1 and N2 was 12% and 7.2%, respectively. The aHR of pts with nodal mets versus without nodal mets was 1.8 (95% CI of 1.7-1.9), after adjusting other prognostic covariates. Conclusions: Stage IV CCa with nodal mets is associated with an increased risk of death compared to node-negative disease. The number of positive lymph nodes at the time of diagnosis is also an important risk factor. [Table: see text]