bluuebunny/crossref_metadata_2025 huggingface dataset:
Changes in shedding of soluble tumor necrosis factor receptors (sR1/R2) and in dynamic MRI as early predictors of outcome with NGR-hTNF.
Authors: Zucali Paolo A. , Simonelli Matteo , De Vincenzo Fabio , Santoro Armando , Lambiase Antonio , Bordignon Claudio
Published: March 2020

e22145

Background: Dose-response curve of NGR-hTNF, a selective antivascular agent, is typically biphasic with activity shown either at low dose (LD) or high dose (HD). Receptor shedding may block drug activity. Vascular effects at LD are characterized by early vessel stabilization and late vessel damage, while at HD by rapid vessel disruption. Methods: 60 pts (median age: 61; M/F: 44/16; PS 0/≥1: 25/35; median prior lines: 3) received in 2 ph I trials NGR-hTNF at LD (0.2-1.6 µg/m2; n=14) or HD (60-325 µg/m2; n=46) every 3 weeks. We tested the impact of early changes (post 1st dose) in baseline-normalized plasma receptor levels (n=60) and in DCE-MRI-assessed Ktrans (n=49) on treatment effect, including disease control (DC, rate of pts progression free at 6 weeks by RECIST criteria) and progression free survival (PFS). Results: Baseline receptor levels were not related to outcome. Post-dosing levels of sR1 (median, 4.6 ng/mL; interquartile range, 2.8-5.7) and sR2 (8.6; 4.5-10.7) increased with dose (p<.0001 for both), with median values of sR1 (0.3) and sR2 (0.5) at LD being significantly lower than those of sR1 (4.9) and sR2 (9.6) at HD (p<.0001 for both). Using as cutoff the 1st quartile, low sR1 levels (≤2.8 ng/mL) correlated with improved DC (OR=4.9; p=0.01) and PFS (HR=0.30; p=.003). In low vs high groups, median DC duration was 7.4 vs 2.9 months and 6-month PFS was 29% vs 0%, respectively. By adjusting for baseline covariates (age, sex, PS and prior lines), low sR1 levels remained independently associated with better DC (p=.02) and PFS (p=.008). Similar effects were noted for sR2. Levels of sR1 (r=-0.35; p=.01) and sR2 (r=-0.27; p=.07) inversely correlated with early fractional decreases in Ktrans, which resulted in median values unchanged after LD (4%; p=.73) and reduced after HD (-32%; p=.009). However, Ktrans significantly declined over time after both LD (-24%; p=.04) and HD (-44%; p=.001). Early changes in Ktrans did not relate with DC as defined by RECIST, but smaller decreases in Ktrans were associated with longer PFS (HR=0.56; p=.04). Conclusions: NGR-hTNF at LD is associated with better outcome than at HD likely due to early effects that involve minimal receptor shedding and vessel stabilization. Clinical trial information: NCT00878111-NCT00914628.
Secreted alkaline phosphatase defined by ms17-57 mab and ectopically expressed on the surface of GI cancer cells as a potential therapeutic target.
Authors: Feng Runhua , Li Ming , Gao Jianpeng , Chen Xuehua , Sun Jianyu , Wang Yuling , Zhang Dongqing , Feng Zhenqing , Liu Binya , Zhu Zhenggang , Lu Mason , Lee Jeffrey Edwin
Published: March 2020

e22169

Background: There remains considerable interest in generating monoclonal antibody (mAb) directed against specific tumor targets for antigen (Ag) discovery, diagnosis and therapy. In this investigation, mAbs were generated against potentially novel Ags on the cancer cell surface using a flow cytometry-high throughput screening (FACS-HTS) strategy. Methods: Mixed live cells from four human gastric cancer (GC) cell lines were used as the immunogen in A/J mice; Sixteen highly positive hybridoma colonies were selected via FACS-HTS using a total of 20,000 colonies in sixty-seven 96-well plates against live cells (mixed human GC cells versus normal human PBMC). The purified ms17-57 and control commercial ALP mAbs were used to confirm the target Ags, which were identified as alkaline phosphatases (ALPs) expressed on the GC cell surface through a combination of western blot, immunoprecipitation and mass spectrometry (MS). Results: MS identified the Ags recognized by ms17-57 to be two variants of a secreted ALP, PALP and IALP (Placental and Intestinal ALP). These proteins belong to a hydrolase enzyme family responsible for removing phosphate groups from many types of molecules (i.e. dephosphorylation). Immunohistochemical staining using ms17-57 demonstrated significantly higher staining of gastrointestinal (GI; gastric and colorectal) cancer tissues than normal (non-cancer) GI control tissues (P<0.01), and confirmed binding of ms17-57 to be restricted to a functional epitope expressed on the cancer cell surface. Proliferation assay using the PALP/IALP-expressing GC cell lines demonstrated that ms17-57 inhibited cell growth by 32±8%. Transwell cell migration assay documented that ms17-57 can inhibit PALP/IALP-expressing GI cancer cell migration. Conclusions: Our findings indicate that PALP and IALP can be ectopically expressed in the extracellular matrix of GI cancers, and that ms17-57 directed against PALP/IALP identified through HTS can inhibit GI cancer cell growth and migration. This investigation provides an example of identification of cancer biomarkers representing promising therapeutic targets using mAb generated through a novel HTS technology.
Relationship of Ki-67 proliferative index and metastatic tumor of breast cancer.
Authors: Kobayashi Kokoro , Ito Yoshinori , Ogiya Akiko , Gomi Naoya , Horii Rie , Takahashi Shunji , Hatake Kiyohiko , Akiyama Futoshi , Iwase Takuji
Published: March 2020

e22190

Background: The metastatic breast tumor tends to be more aggressive with high proliferation, but this has not been proven in clinical sampling of metastatic tumors. Methods: Forty-eight patients who had histological specimens of both primary and metastatic sites of luminal breast cancer (ER and/or PgR positive and HER2 negative) were examined. We classified them as luminal A (LA) with Ki-67 labeling index of less than 14% and as luminal B (LB) with Ki-67 labeling index of more than 14%. We analyzed their overall survival (OS) and progression free survival (PFS) of 1st line treatment of each subtype of primary and metastatic tumors. Results: Subtypes of primary tumors and metastatic tumors were as follows; the primary tumor: LA; 34 patients (70.8%), LB; 14 (29.2%), metastatic tumors: LA; 21 (43.8%), LB; 27 (56.2%). Patients with LA of the primary tumor demonstrated statistically longer OS (LA; 72.5 months, LB 39.6 months, p=0.009). OS depended on the subtype of the primary tumor. In contrast, patients with LB of a metastatic tumor showed a statistically worse PFS (LA; 20.5 months, LB; 11.5 months, p=0.040). PFS of the 1st line treatment for MBC depended on the subtype of the metastatic tumor. Conclusions: The frequency of LB was increased on metastatic tumors and tended to acquire a higher proliferation index. This suggests that characterization of metastatic tumors could be better as an indicator of subsequent treatment for MBC. [Table: see text]
Recombinant growth/differentiation factor-5 enhances cell proliferation and tendogenic differentiation of human periodontal ligament stem cells in vitro.
Authors: Xia Dengsheng , Sumita Yoshinori , Tran Simon
Published: March 2020

e22191

Background: To investigate the function of growth/differentiation factor-5 (GDF-5) on cell proliferation and tendogenic differentiation of human periodontal ligment stem cells (PDLSCs) in vitro. Methods: PDLSCs were obtained from human healthy periodontal ligaments of wisdom teeth. Immunofluorescence cytochemistry was used to detect the characters of mesenchymal stem cells (MSCs) in PDLSCs. Recombinant mouse GDF-5 (rmGDF-5) protein was used to stimulate the PDLSCs. Tetrazolium reduction assay was carried out for cell proliferation. Alkaline phosphatase (ALP) activity was measured by ALP activity assay and ALP staining. Real-time RT-PCR was performed to detect the gene expressions of aggrecan (ACAN), collagen, type III (COL3), scleraxis (SCX), decorin (DCN), tenomodulin (TNMD) and tenascin C (TNC) in PDLSCs after stimulated by rmGDF-5 protein. Results: 5.6% STRO-1 positive cells was detected in primary PDLSCs. The cell proliferation of PDLSCs was enhanced by rmGDF-5 in a dose-dependent manner at 0, 20, 100 and 500 ng/ml of concentration. The special markers of tendogenic differention, ACAN, COL3, SCX and TNMD were up-regulated at mRNA level after rmGDF-5 treatment for 1, 2 or 3 weeks, and the 20 ng/ml was the more effective than 100 ng/ml and 500 ng/ml for rmGDF-5 in PDLSCs. The expressions of TNC and DCN were increased at 4 or 8 hours after 20, 50 and 100 ng/m rmGDF-5 treatment. The ALP activity results showed that ALP activities were decreased paralleled with increased rmGDF-5 concentration. Conclusions: The rmGDF-5 could promote the cell proliferation and tendogenic differentiation of PDLSCs in vitro.
“Druggable” alterations detected by ion torrent in metastasis colorectal cancer patients.
Authors: Fang Weijia , Radovich Milan , Zhou Anwu , Zheng Yulong , Zhao Peng , Huang Wenying , Mao Chenyu , Zheng Yi , Jia Yankai , Zheng Shusen
Published: March 2020

e22192

Background: The frequency and poor prognosis of metastasis colorectal cancer (mCRC) emphasizes the need of better markers for both treatment and prognosis. Here we describe an approach of identifying somatic variants in exonic regions of key cancer genes. Methods: Formalin-fixed paraffin embedded (FFPE) tissues biopsied from mCRC patients were collected. DNA was extracted and sequenced on the Ion Torrrent Personal Genome Machine.For targeted amplification, we used the Ion AmpliSeq Cancer Panel which is designed to detect 739 mutations in 604 loci from 46 oncogenes and tumor suppressor genes with as little as 10ng of input DNA.Sequencing results were then analyzed using the Ampliseq Variant Caller plug-in within Ion Torrent Suite Software. Ingenuity Pathway Software was used to do pathway analysis. Cox regression was tested regarding the potential relationship between the alteration numbers and the clinical factors including response rate, disease free survival and overall survival, etc. Results: Among 10 specimens, we identified 66 genetic alterations in 24 genes after excluding the germline mutations according the dbSNP database. 41% of those alterations were also present in the COSMIC database (Catalogue of Somatic Mutations in Cancer). No clinical factor was found to be significantly associated with the alteration numbers by univariate analysis. Notably, there are 11 genes including the expected APC, BRAF, KRAS, PIK3CA and TP53 that were mutated in at least 2 samples. Pathway analysis identified “Colorectal Cancer Metastasis Signaling” as the top mutated canonical pathway. This analysis further revealed mutated genes in the classic signal pathways of Wnt, PI3K/AKT, and TGF-beta/SMAD as significantly present. Interestingly, 90% of specimens harbored at least one “druggable” alteration (range from 1 ~ 6)that has been linked to a target treatment or is currently being investigated in clinical trials. Those pairs of drug and targeted genes are vemurafenib to BRAF; cetuximab to EGFR; palifermin to FGFR2; pazopanib to FGFR3; AEE 788 to KDR and BEZ235 to PIK3CA. Conclusions: DNA deep sequencing of key cancer related genes enables identification of “druggable” mutations for individual colorectal cancer patients.
In vivo optical pathology of paclitaxel efficacy on the peritoneal metastatic xenografts of gastric cancer using multiphoton microscopy.
Authors: Tanaka Koji , Shimura Tadanobu , Okigami Masato , Toiyama Yuji , Morimoto Yuhki , Kitajima Takahito , Kondo Satoru , Kawamura Mikio , Saigusa Susumu , Okugawa Yoshinaga , Ohi Masaki , Inoue Yasuhiro , Uchida Keiichi , Araki Toshimitsu , Mohri Yasuhiko , Mizoguchi Akira , Kusunoki Masato
Published: March 2020

e22205

Background: Peritoneal metastasis shows an extremely poor prognosis in patients with gastric cancer. Clinically, the tumor response to chemotherapeutics depends on anatomical location of metastasis. Metastatic tumor xenografts have been shown to be more resistant to chemotherapy than subcutaneous non-metastatic tumor xenografts in preclinical murine model. We have reported a method of in vivo optical pathology using multiphoton microscopy (MPM) in colorectal liver metastatic tumor xenograft model. Aim: We established a method of time-series in vivo optical pathology of peritoneal metastatic xenografts of gastric cancer using MPM. Then, we imaged and evaluated paclitaxel efficacy in the tumor microenvironment with regard to both tumor cell itself and intravascular change in tumor vessels. Methods: Red fluorescent protein (RFP) expressing human gastric cancer cell line (NUGC4) was inoculated into the peritoneal cavity of green fluorescent protein (GFP) expressing nude mice. Paclitaxel (10 mg/kg) was administered three times a week for more than three weeks. Intravital MPM was performed before and after paclitaxel treatment for the exteriorized peritoneal metastatic lesion in the same living mouse. Results: Four to six weeks later, RFP-NUGC4 cells formed macroscopic peritoneal metastases. Red-colored cancer cells and green-colored surrounding stroma with tumor vessels were clearly imaged at the cellular level (in vivooptical pathology). Their cross-sectional images were obtained from the tissue surface to the area of depth of 200 μm (z-stacks imaging). After paclitaxel treatment, tumor cell fragmentation, condensation, swelling and intracellular vacuoles were observed. Within the tumor vessels, platelet aggregation and platelet adhesion to endothelial cells were observed. Conclusions: In vivo optical pathology using MPM provides histopathological information about three-dimensional tissue microarchitecture without tissue shrinkage by fixation and tissue destruction by microtome-sectioning. Our method may become a powerful tool to evaluate the tumor response to new chemotherapeutics on ‘metastatic site’ in preclinical tumor xenograft model.
Comparison of chemoradiotherapy (CRT) and chemotherapy (CT) in patients with a locally advanced pancreatic cancer (LAPC) controlled after 4 months of gemcitabine with or without erlotinib: Final results of the international phase III LAP 07 study.
Authors: Hammel Pascal , Huguet Florence , Van Laethem Jean-Luc , Goldstein David , Glimelius Bengt , Artru Pascal , Borbath Ivan , Bouche Olivier , Shannon Jenny , André Thierry , Mineur Laurent , Chibaudel Benoist , Bonnetain Franck , Louvet Christophe
Published: March 2020

LBA4003

The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Monday, June, 3, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.
A phase III randomized trial of chemoimmunotherapy comprising gemcitabine and capecitabine with or without telomerase vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer.
Authors: Middleton Gary William , Valle Juan W. , Wadsley Jonathan , Propper David , Coxon Fareeda Y. , Ross Paul J. , Madhusudan Srinivasan , Roques Tom , Cunningham David , Corrie Philippa , Greenhalf William , Shaw Victoria , Cox Trevor F. , Silcocks Paul , Nanson Gemma , Neoptolemos John P.
Published: March 2020

LBA4004

The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Monday, June, 3, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.
A phase II study of oral ENMD-2076 administered to patients (pts) with advanced soft tissue sarcoma (STS).
Authors: Loong Herbert H. F. , Blackstein Martin E. , Gupta Abha A. , Hogg David , Mackay Helen , Dhani Neesha C. , Oza Amit M. , Moore Malcolm J. , Razak Albiruni R.A.
Published: March 2020

TPS10593

Background: The use of angiogenic and Aurora kinase inhibitors has been shown to abrogate tumour growth in STS. ENMD-2076 is an oral Aurora A and angiogenic kinase inhibitor that has demonstrated single-agent activity in sarcoma cell lines. Prior phase I dose escalation study has determined the maximum tolerated dose of ENMD-2076 to be 160mg/m2, with a recommended starting dose of 275mg/day. In that study, one patient with STS experienced durable stable disease (21 months). Primary Objective: To determine the activity of ENMD-2076 in advanced STS (with ≤1 prior line of therapy) as defined by 6-month progression-free survival rate (PFSR). Secondary Objectives: (i) To determine the safety and tolerability of ENMD-2076, (ii) To determine the objective response rate (ORR) as per RECIST criteria and duration of response, (iii) To perform exploratory analysis of factors associated with survival. Study Design and Methodology: This is a single-center, open-labeled phase II study of ENMD-2076 in advanced STS. Pts are commenced on 275 mg daily dose on a 28 day cycle. Treatment-emergent adverse events will be assessed by the NCI-CTCAE (4.0). Radiographic or clinical tumour measurements will occur every 2 cycles. Sample Size Justification: It is assumed that ENMD-2076 shall be deemed non-efficacious in this population if the true 6- month PFSR probability is <15% (p0), whilst a 6-month PFSR probability >40% will be considered positive for activity. This translates to a minimum of 21 evaluable subjects required in the study, within which ≥6 patients need to have shown lack of progression at 6 months in order for this study to be considered positive. This design has a significance level of 10% and power of 90%. Methods: PFSR at 6-months will be estimated using the Kaplan-Meier method. ORR will be estimated and 2-sided 95% exact binomial confidence interval will be provided. Study Progress: At deadline for abstract submission, 3 patients have been enrolled onto this study. Clinical trial information: NCT01719744.
Phase II study of ruxolitinib in patients with pStat3+ breast cancer.
Authors: Lin Nancy U. , Gelman Rebecca Sue , Brock Jane E. , Bardia Aditya , Mayer Erica L. , Overmoyer Beth , Wang Vivian , Iannone Marie , Krop Ian E. , Polyak Kornelia , Winer Eric P.
Published: March 2020

TPS1134

Background: Multiple lines of evidence implicate the IL-6/JAK2/Stat3 signaling pathway in metastatic progression and therapeutic resistance in breast cancer (Marotta et al, JCI2011; Britschgi et al, Cancer Cell 2012). Ruxolitinib, an oral inhibitor of JAK1 and JAK2, is approved for the treatment of intermediate or high-risk myelofibrosis, but has not been extensively tested in solid tumors. Methods: Pts with triple-negative breast cancer or inflammatory breast cancer of any subtype are eligible for prescreening of archival tumor tissue for pStat3 expression by immunohistochemistry. Pts with high (Cohort A; T-score >5) or low (Cohort B; T-score 3-4) pStat3 expression, measurable disease, adequate organ function, ECOG PS 0-2, and progression through > 1 line of prior therapy may proceed to receive ruxolitinib, 25 mg orally twice daily. Staging studies are performed at baseline (BL) and every 8 weeks (wk). Baseline tumor biopsy is required for pts who have accessible disease, with an optional biopsy at progression. Blood for IL-6, CRP, and circulating tumor cells are collected at BL, Wk 4, and off-treatment. Patient reported outcomes including EORTC QLQ C-30 and the M.D. Anderson Symptom Inventory are collected at BL, Wk 4, Wk 8, and off-treatment. Statistical Considerations: The primary endpoint of this open-label phase 2 trial is objective response by RECIST 1.1. The study is designed to distinguish between a response rate of 5% versus 20% in each cohort, separately. If > 2 responses out of 21 pts are observed in the first stage of Cohort A, a further 20 pts will be entered on that cohort; the agent will be deemed worthy of further study if > 5 of the total 41 pts achieve an objective response (power 0.90, type I error 0.046). Cohort B will open to accrual if Cohort A passes the first stage. If > 2 responses out of 21 pts are observed in the first stage of Cohort B, a further 20 patients will be entered into Cohort B, and the agent will be deemed worthy of further study if > 5 of the total 41 pts achieve an objective response (power 0.90, type I error 0.046). Study Status: A total of 85 patients have consented for prescreening of tumor tissue. As of January 3, 2013, 5 of a planned 41 patients with high pStat3 IHC scores have been treated with ruxolitinib, and accrual is ongoing. Clinical trial information: NCT01562873.
A phase I study of the BCR-ABL tyrosine kinase inhibitor nilotinib and cetuximab in patients with solid tumors that can be treated with cetuximab.
Authors: Smaglo Brandon George , Wang Hongkun , Steadman Kenneth , Murray Joseph , Pishvaian Michael , He Aiwu Ruth , Hwang Jimmy J. , Subramaniam Deepa Suresh , Deeken John F. , Weiner Louis M.
Published: March 2020

TPS2624

Background: Therapeutic blockade of Epidermal Growth Factor Receptor (EGFR) signaling with the monoclonal antibody cetuximab is clinically effective in the treatment of patients with metastatic squamous cell carcinoma of the head and neck or KRAS wildtype colorectal cancer. However, these patients eventually become resistant to this therapy. An exploration of the EGFR signaling network using an EGFR network-focused small interfering RNA library identified potential regulators of resistance to EGFR-targeted therapies. The ABL1 gene was identified as a central node to target in this complex genomic pathway. In a preclinical EGFR-expressing cancer cell line model, targeting c-abl, the gene product of ABL1, using nilotinib was found to be highly synergistic in decreasing cell survival when combined with anti-EGFR targeted therapy. Methods: We have initiated an open-label Phase I study for patients who progressed after standard therapies for metastatic KRAS wildtype colorectal cancer or metastatic head and neck squamous cell carcinoma. Enrolled patients must have adequate performance status and organ function. Treatment consists of cetuximab 400 mg/m2 on day 1, then 250 mg/m2 once weekly, and nilotinib twice daily, starting on day 1, according to a traditional 3+3 dose escalation, from 200mg to 300mg BID. Patients are restaged every 2 cycles (every 8 weeks). The primary endpoint is the maximum tolerated dose (MTD) of nilotinib when used in conjunction with cetuximab. Secondary endpoints are clinical benefit rate (defined as rates of stable disease, partial response, and complete response) and response rate. Additionally, biopsies of metastases obtained prior to and after initiation of therapy will be used to establish primary tumor cell cultures using conditional cellular reprogramming to permit the dynamic study of signaling and drug sensitivity through an evaluation of evidence of a drug effect on EGFR signaling and on Antibody-Dependent Cell-Mediated Cytotoxicity. An additional 10 colorectal cancer patients will be treated as an expansion cohort at the MTD. This expansion cohort data may be used to plan a Phase II trial in the future.
FGFR: Proof-of-concept study of AZD4547 in patients with FGFR1 or FGFR2 amplified tumours.
Authors: Smyth Elizabeth Catherine , Turner Nicholas C. , Popat Sanjay , Morgan Shethah , Owen Kate , Gillbanks Angela , Jain Vikram Kumar , Cunningham David
Published: March 2020

TPS2626

Background: Genetic modifications of the FGFR family of transmembrane tyrosine kinase growth factor receptors are described in a range of cancers. Amplification of FGFR2 is detected in up to 10% of oesophagogastric cancers where it is associated with poor prognosis. FGFR1 amplification has also been demonstrated in 10% of breast cancers, is more common in luminal B ER positive tumors, and is also associated with inferior survival outcomes. Finally, FGFR1 amplification has been described in up to 22% of squamous cell lung cancers. AZD4547 is a potent and selective inhibitor of FGFR-1, 2 and 3 receptor tyrosine kinases. Preclinically, AZD4547 potently inhibits growth in FGFR amplified gastric and lung cancer cell lines and induces dose dependent tumor growth inhibition and regression in FGFR amplified tumour xenograft and patient derived explant models. Methods: This is an open label, phase II non-randomised multi-centre study to assess the efficacy of AZD4547 monotherapy and resulting molecular changes in serial biopsies in pts with previously treated FGFR1 amplified advanced breast cancer, FGFR2 amplified advanced oesophagogastric cancer, or FGFR1 amplified advanced squamous lung cancer. Eligibility include centrally verified FGFR amplified tumour (ratio >2.2), PS=0-2, ability to comply with the collection of tumor biopsies (mandatory at baseline and on days 10-14), calcium and phosphate within normal limits, measurable disease (RECIST 1.1), and no history of significant eye disease. Pts may be prescreened for FGFR amplification on archival tissue while undergoing first line or adjuvant chemotherapy. Sixteen pts will be enrolled per cohort. All pts will receive AZD4547 80mg bd on a two week on, one week off schedule. The primary endpoint is correlation between change in pERK in pretreatment and day 10-14 biopsy and change in tumour diameter on week 8 CT. Secondary endpoints include ORR, DCR and PFS. Multiple exploratory translational endpoints are also planned. The study is currently open at the Royal Marsden Hospital and will open at 15 selected UK cancer centres. This study is sponsored by the Royal Marsden Hospital, funded by AstraZeneca and has been adopted to the UK National Cancer Research Network (NCRN) portfolio. Clinical trial information: 2011-003718-18.
A phase I dose-escalation study evaluating the effects of nivolumab (anti-PD-1; BMS-936558; ONO-4538) in patients (pts) with select relapsed or refractory hematologic malignancies.
Authors: Lesokhin Alexander M. , Gutierrez Martin , Halwani Ahmad Sami , Ansell Stephen Maxted , Armand Philippe , Borrello Ivan , Segota Zdenka E , Cohen Adam D. , Talpaz Moshe , Cattry Deepika , Turner Tracy , Mezes Maria , Hartman Christina , Gupta Ashok Kumar , Kim Su Young , Wigginton Jon M. , Timmerman John
Published: March 2020

TPS3113

Background: Programmed death-1 (PD-1) is an immune checkpoint receptor that inhibits T-cell activation upon interaction with its ligands PD-L1 or PD-L2. Increased PD-L1 expression has been reported with various hematologic malignancies and may prevent the host immune response from exerting an antitumor effect on the malignant cells. Nivolumab, a fully human IgG4 monoclonal PD-1 receptor blocking antibody, has demonstrated antitumor activity in pts with solid tumors including melanoma, renal cell carcinoma, and non-small cell lung carcinoma. We hypothesized that nivolumab could also mediate antitumor activity in pts with hematologic malignancies, a significant area of unmet medical need. We describe a phase I study to evaluate the effects of nivolumab in pts with select hematologic malignancies. Methods: This open-label, two-part study will enroll approximately 100 pts. During dose escalation, successive cohorts of pts with relapsed or refractory hematologic malignancies will be treated using a 6+3 escalation design. Pts will receive 1 or 3 mg/kg nivolumab IV every 2 weeks (wks) (the first dose will be followed by a 3-wk evaluation period), for 2 years, with the potential for an additional year of therapy for pts who progress during the follow-up period. Subsequently, 5 tumor-specific cohorts of 16 pts will be enrolled at the maximum tolerated dose (MTD) for multiple myeloma, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma/primary mediastinal B-cell lymphoma, and chronic myelogenous leukemia. Response will be assessed at wks 4, 8, 16, 24, and every 16 wks thereafter. The primary study objective is to establish dose limiting toxicities, the MTD, and the recommended phase II nivolumab dose. Secondary objectives are to characterize nivolumab pharmacokinetics, immunogenicity, preliminary antitumor activity, and the potential association between PD-L1 expression on tumor cells and clinical efficacy. Exploratory objectives include investigation of the immunoregulatory effects of nivolumab in peripheral blood, bone marrow, and/or tumor. Pts are currently being enrolled at 3 mg/kg. Clinical trial information: NCT01592370.
Biomarker correlation to clinical response in phase I/II trials of the adjuvant breast cancer vaccine neuvax (nelipepimut-S or E75).
Authors: Berry John S. , Trappey Alfred F , Sears Alan K. , Vreeland Timothy J , Clifton Guy T. , Hale Diane F. , Patil Ritesh , Holmes Jarrod P. , Ponniah Sathibalan , Mittendorf Elizabeth Ann , Peoples George Earl , Van Echo David C.
Published: March 2020

TPS3126

Background: We completed phase I/II clinical trials with NeuVax (nelipepimut-S), a HLA-A2/A3-restricted, HER2-derived peptide vaccine. The vaccine was administered in the adjuvant setting to prevent recurrence in breast cancer patients rendered disease-free with standard-of-care therapy. Here, we examine the relationship between in vitro immunologic response (IR) and clinical recurrence (CR) after 5-year follow-up. Methods: The phase I/II trials were performed as dose-escalation/schedule-optimization trials enrolling node positive and high-risk, node-negative patients (pts) with tumors expressing any level of HER2 (IHC 1+,2+,or 3+). HLA-A2/A3+ pts were enrolled in the vaccine group (VG) while HLA-A2/A3- pts were followed prospectively as an untreated control group (CG). The VG was given 4-6 monthly intradermal inoculations of nelipepimut-S+GMCSF (immunoadjuvant) during the primary vaccine series (PVS). In vitro IR was assessed for E75-specific, cytotoxic T lymphocyte clonal expansion by HLA-A2:IgG dimer assay and expressed as mean dimer index (mdi) at baseline, after PVS (R6), and six months after the PVS. HER2 under-expression was defined as an IHC 1/2, and a FISH < 2.2. VG and CG pts were followed for CR over 60 months. P-values were calculated using the Fisher’s exact test. Results: Of the 195 pts enrolled, 8 withdrew, leaving 187 evaluable pts; 108 in the VG and 79 in the CG. R6 dimer assays were available for 86 pts in the VG. The mean R6 dimer in the VG is 0.63 mdi+.08. Of the 30 pts with an R6 dimer above the mean, only one recurred, compared to eight of the 56 below the mean (p=.09). The difference between baseline and maximum mdi was available in 56 HER2 under-expressing VG pts. Of the 26 pts above the mean difference (1.08 mdi +.17), one recurred, compared to six CR in the 30 pts below the mean (p=.06). There were no CR in pts with HER2 under expression with a mean difference ranked in the top third. Conclusions: In prospective, completed phase I/II trials of NeuVax (nelipepimut-S), patients who exhibit robust in vitro IR have lower recurrence rates. This finding suggests that nelipepimut-specific CTL clonal expansion is a valid biomarker for CR in pts treated with NeuVax. Clinical trial information: NCT00841399.
CALM study: A phase II study of intratumoral coxsackievirus A21 in patients with stage IIIc and stage IV malignant melanoma.
Authors: Andtbacka Robert Hans Ingemar , Kaufman Howard , Daniels Gregory A. , Spitler Lynn E. , Lutzky Jose , Hallmeyer Sigrun , Whitman Eric D. , Nemunaitis John J. , Zhou Karl , Karpathy Roberta , Weisberg Jeffrey Ira , Shafren Darren
Published: March 2020

TPS3128

Background: Coxsackievirus A21 (CVA21: CAVATAK) is a naturally occurring "common cold" virus. CVA21 displays potent oncolytic activity against both in vitro cultures of cancer cells and against in vivo xenografts of human cancers in mouse models of melanoma, prostate cancer, breast cancer and multiple myeloma, all which exhibit high surface ICAM-1 expression, which is used for viral entry. In mouse human melanoma xenograft CVA21 challenge models, progeny virus released from infected cells is capable of targeting adjacent cells, entering the systemic circulation, and destroying micro-metastatic foci. In a phase 1 study, two intralesional injections of CVA21 were shown to reduce or stabilize the growth of injected melanoma lesions. Methods: The CALM study investigates the efficacy and safety of intratumoral CVA21 in approximately 63 pts with treated or untreated unresectable Stage IIIC-IVM1c melanoma. Pts are treated with up to 3 x 108 TCID50 intratumorally on study days 1, 3, 5 and 8 and then every three weeks for a further 6 injections. Key eligibility criteria are ≥ 18 yrs old, ECOG 0-1, and at least 1 injectable cutaneous, sc, or nodal tumor >1.0 cm. The primary endpoint is irPFS at 6 months following tx; secondary endpoints include durable response rate and OS. A 2-stage Simon’s minimax design will be employed. Based on data from previous trials and literature, a target overall irPFS at 6 months of 22.5% versus a projected rate of 10% in the target population is selected. With an alpha level of 5% and 80% of power, a total of 54 evaluable patients will be required to test the null hypothesis that the true irPFS rate is <10% versus the alternative hypothesis that the true irPFS rate is at least 22.5%. Thirty-five patients will be treated at Stage I. If 3 or more objective responses (CR or PR) are achieved by modified RECIST 1.1 criteria in the first 35 patients, then the study will complete enrollment. Results: Currently, 21 patients have been enrolled on the study and treated with CVA21 injections. The treatment has been well tolerated. The Stage I interim efficacy endpoint of > 3 objective responses has been achieved, and the second stage of the study is proceeding with a planned enrollment of a total of 63 patients. Clinical trial information: NCT01227551.
A phase III study of the impact of a physical activity program on disease-free survival in patients with high-risk stage II or stage III colon cancer: A randomized controlled trial (NCIC CTG CO.21).
Authors: Booth Christopher M. , Courneya Kerry S. , Vardy Janette L. , Jonker Derek J. , Gill Sharlene , Brundage Michael , van der Ploeg Hidde , Dhillon Haryana M. , O'Brien Patti , Goddard Emma , Pollak Michael N. , Friedenreich Christine , Tu Dongsheng , Wong Rebecca , Meyer Ralph M.
Published: March 2020

TPS3647

Background: Observational data indicate that physical activity (PA) is strongly associated with colon-cancer specific survival. NCIC CTG CO.21 (CHALLENGE) is designed to determine the effects of a structured PA intervention on disease-control outcomes for survivors of high-risk stage II or III colon cancer who have completed adjuvant chemotherapy within the previous 2-6 months. Methods: Phase III randomized controlled trial. Target sample size of 962 patients is powered to detect a Hazard Ratio of 0.75 for disease-free survival (DFS). Trial participants will be stratified by centre, disease stage, body mass index, and performance status, and will be randomly assigned to a structured, individualized PA intervention or to general health education materials. The PA intervention will consist of a behavioural support program and supervised PA sessions delivered over a 3-year period, beginning with regular face-to-face sessions and tapering to less frequent face-to-face or telephone sessions. The goal of the PA program is to increase weekly PA by 10 MET hours/week. The PA program is delivered by physical activity consultants trained in exercise physiology and behavior change. Outcomes: The primary endpoint is DFS. Important secondary endpoints include multiple patient-reported outcomes (including those that address fatigue), objective physical functioning, biologic correlative markers (including assessment of the insulin pathway), and an economic analysis. Current Enrollment: The study is open at 19 centers in Canada and 20 centers in Australia. Accrual as of February 4, 2013 includes 212 registered and 184 randomized patients. Summary: Cancer survivors and cancer care professionals are interested in the potential role of PA to improve multiple disease-related outcomes, but a randomized controlled trial is needed to provide compelling evidence to justify changes in health care policies and practice. Clinical trial information: NCT00819208.
Efficacy and safety of gemcitabine in combination with TH-302 compared with gemcitabine in combination with placebo in previously untreated patients with metastatic or locally advanced unresectable pancreatic adenocarcinoma: The MAESTRO trial.
Authors: Van Cutsem Eric , Fram Robert J. , Schlichting Michael , Ryan David P.
Published: March 2020

TPS4148

Background: Tumors often consist of highly hypoxic subregions that are resistant to chemotherapy and radiotherapy. The investigational hypoxia-targeted drug TH-302 is reduced at its nitroimidazole group, and under hypoxic conditions releases the DNA alkylator bromo-isophosphoramide mustard (Br-IPM). A randomized Phase IIb trial of TH-302 in pts with metastatic or locally advanced unresectable pancreatic adenocarcinoma (PDAC) confirmed a significant PFS improvement (p=0.008) in pts treated with TH-302 at 340 mg/m2+ gemcitabine compared with gemcitabine alone (Borad et al, ESMO 2012). Skin and mucosal toxicities, mainly Grade 1/2, and myelosuppression (thrombocytopenia, neutropenia and anemia) were the most common AEs related to TH-302 and did not lead to increases in treatment discontinuation. Grade 3/4 myelosuppression was more frequent in the TH-302 + gemcitabine arm. AEs leading to treatment discontinuation as well as non-hematological serious AEs were balanced across arms. Methods: This is a Phase III, randomized, double-blind, placebo-controlled trial (NCT01746979) of gemcitabine + TH-302 compared with gemcitabine + placebo in pts with locally advanced unresectable or metastatic PDAC. The study is designed to detect a 25% risk reduction of death with 90% power and two-sided alpha of 5%. A total of 660 pts are planned to be randomized 1:1. Key eligibility criteria include histologically or cytologically confirmed disease, no prior chemotherapy or systemic therapy (except as specified in the protocol), ECOG performance status 0 – 1, and bilirubin ≤ 1.5x upper limit of normal. Randomized pts receive TH-302 + gemcitabine or gemcitabine + placebo in 4-week cycles until progressive disease, intolerable toxicity, or pt withdrawal. The primary objective is to evaluate OS. Secondary objectives include PFS, objective response, and disease control; safety and tolerability; pt-reported QoL and pain; CA 19-9 levels and PK of TH-302; exploratory pharmacogenomic markers and potential predictive biomarkers. Enrollment to the study is ongoing. Clinical trial information: NCT01746979.
Pertuzumab (P) with trastuzumab (T) and chemotherapy (CTX) in patients (pts) with HER2-positive metastatic gastric or gastroesophageal junction (GEJ) cancer: An international phase III study (JACOB).
Authors: Tabernero Josep , Hoff Paulo Marcelo , Shen Lin , Ohtsu Atsushi , Yu Ron , Eng-Wong Jennifer , Kang Yoon-Koo
Published: March 2020

TPS4150

Background: Human epidermal growth factor receptor 2 (HER2) is overexpressed in ~20% of gastric cancers. Specific targeting of HER2 by T in combination with CTX has demonstrated significantly improved overall survival (OS) vs CTX in pts with advanced gastric or GEJ cancer (Bang Lancet 2010). In HER2-positive 1L metastatic breast cancer the combination of T plus docetaxel with a second HER2-targeted antibody, P, demonstrated significant improvement of progression-free survival (PFS) and OS vs placebo+T+docetaxel (Baselga NEJM 2012; Swain SABCS 2012). Based on these positive findings with HER2-targeted therapies in gastric and breast cancer, JACOB, a double-blind, placebo-controlled, randomized Phase III study, is designed to evaluate efficacy and safety of P+T+CTX in pts with HER2-positive 1L metastatic gastric or GEJ cancer. Methods: Pts will be randomized 1:1 to receive P+T+cisplatin+fluoropyrimidine or the same regimen replacing P with placebo, q3w (P: 840 mg; T: 8 mg/kg first dose, then 6 mg/kg; cisplatin: 80 mg/m2; 5-fluorouracil: 800 mg/m2/24 h given continuously for 120 h or capecitabine: 1000 mg/m2 bid for 14 days). P/placebo+T will be given until progressive disease (PD) or unacceptable toxicity. On or before Cycle 6, CTX should only be discontinued for PD or unacceptable toxicity. Continuation of CTX after Cycle 6 is at the discretion of pt and physician. Randomization will be stratified by region (Japan vs North America/Western Europe/Australia vs Asia [excluding Japan] vs South America/Eastern Europe), prior gastrectomy, and HER2-positivity (IHC 3+ vs IHC 2+ and ISH+). Primary endpoint: OS; secondary endpoints include PFS, objective response rate, duration of response, clinical benefit rate, safety, pharmacokinetics of P, and patient-reported outcomes. Tumor and blood samples for biomarker evaluation will be collected. The study is estimated to have 80% power to detect a significant improvement in OS at a two-sided α-level of 5% (HR=0.777), with ~502 deaths required for the primary analysis. Target enrollment is 780 pts from ~200 sites and 35 countries; FPI is planned for April 2013. NCT01774786 Clinical trial information: NCT01774786.
RILOMET-1: An international phase III multicenter, randomized, double-blind, placebo-controlled trial of rilotumumab plus epirubicin, cisplatin, and capecitabine (ECX) as first-line therapy in patients with advanced MET-positive gastric or gastroesophageal junction (G/GEJ) adenocarcinoma.
Authors: Cunningham David , Al-Batran Salah-Eddin , Davidenko Irina , Ilson David H. , Murad André M. , Tebbutt Niall C. , Jiang Yizhou , Loh Elwyn , Dubey Sarita ,   RILOMET-1 investigators
Published: March 2020

TPS4153

Background: Rilotumumab is an investigational, fully human monoclonal antibody to hepatocyte growth factor/scatter factor that inhibits signaling through the MET receptor. In a randomized phase II study in patients with advanced G/GEJ adenocarcinoma, addition of rilotumumab every 3 weeks (Q3W) to ECX showed trends toward improved overall survival (OS) and progression-free survival (PFS) compared with ECX alone. In patients with high tumor MET expression and high rilotumumab exposure, the treatment effect of rilotumumab combined with ECX was significantly enhanced. Methods: In this phase III study, patients (planned N=450) are randomized 1:1 to ECX (intravenous [IV] epirubicin 50 mg/m2 on day 1, IV cisplatin 60 mg/m2 on day 1, and oral capecitabine 625 mg/m2 twice daily on days 1−21) plus double-blind rilotumumab 15 mg/kg or placebo IV Q3W. Randomization is stratified by disease extent (locally advanced vs metastatic) and Eastern Cooperative Oncology Group (ECOG) score (0 vs 1). Key eligibility criteria include previously untreated, pathologically confirmed unresectable locally advanced or metastatic G/GEJ adenocarcinoma; ECOG score 0 or 1; ≥18 years old; MET-positive by centralized immunohistochemistry; HER2-negative; adequate organ function; and ≥6 months since neoadjuvant/adjuvant therapy. The primary endpoint is OS. Key secondary endpoints include PFS, 12-month survival rate, objective response, OS in MET expression tertiles, safety, and pharmacokinetics. An exploratory objective is to assess associations between outcomes and tumor and circulating biomarkers. Enrollment began in November 2012, and the trial continues to accrue. An independent data monitoring committee will conduct planned interim reviews for safety and efficacy. Status: recruiting participants. Sponsored by Amgen Inc. Clinical trial information: NCT01697072.
A randomized controlled trial comparing modified gemcitabine plus oxaliplatin (mGEMOX) to gemcitabine plus cisplatin in the management of unresectable gall bladder cancer.
Authors: Sharma Atul , Chaudhary Surendra Pal , Shukla N. K. , Mohanti B. K. , Deo S. V. S. , Pal Sujoy , Raina Vinod , Thulkar Sanjay , Vishnubhatla Sreenivas , Kumar Rakesh , Iyer V. K.
Published: March 2020

TPS4162

Background: In a recently conducted study we have shown that combination of gemcitabine and oxaliplatin is superior to 5 fluorouracil and leucoverine or best supportive care. (Sharma A, Dwary AD, Mohanti BK,et al. Best supportive care compared with chemotherapy for unresectable gall bladder cancer:A randomized controlled study. J Clin Oncol. 2010; 28: 4581-4586.) In another recent publication from UK, gemcitabine and cisplatin combination was found superior to gemcitabine alone in biliary tract cancers (J W Valle, HS Wasan, DD Palmer, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Eng J Med. 2010;362:1273-1281.).The current study is being planned to see whether the combination of gemcitabine and oxaliplatin is equivalent (equivalence study) to gemcitabine and cisplatin in these patients. Methods: Primary end point of the study is overall survival in subjects receiving mGEMOX or GemCis regimen. Secondary end points are: a) Comparison of progression free survival in 2 groups; b) Response rates in two groups; c) Identification of genes predictive of responses in a subset of patients; d) To evaluate role of PET CT in GBC patients predicting disease activity. Sample size was calculated taking median survival of 9.5 months in our previous study with mGEMOX and 11.7 months with GemCis. For this total of 216 patients are required (108 in each arm); to make for major protocol violation and lost to follow up additional 22 patients in each arm will be enrolled. Thus in total 260 patients (130) in each arm will be recruited. This will have alpha and beta values of 0.05 and 0.20 respectively. So far 103 patients have been enrolled and interim analysis is being planned. Treatment protocol: Cycles will be repeated every 3 weeks. Arm A- mGEMOX. Inj Oxaliplatin 80 mg/m22 hours infusion in Dextrose 5% Day 1 and 8. Inj Gemcitabine 900 mg/m2IV 30 minutes infusion day 1 and 8 maximum of 6 cycles. Arm B- GEMCIS. Inj Cisplatin 25 mg/m2PO Days 1 and 8. Inj Gemcitabine 1000 mg/m2IV 30 minutes infusion day1and 8 maximum of 8 cycles. Clinical trial information: CTRI/2010/091/001406.
Phase III randomized sequential open-label study to evaluate the efficacy and safety of sorafenib followed by pazopanib versus pazopanib followed by sorafenib in the treatment of advanced/metastatic renal cell carcinoma (SWITCH-2 study).
Authors: Gschwend Juergen , Beeker Aart , de Santis Maria , Brehmer Bernhard , Zaiss Matthias R. , Schirrmacher-Memmel Silke , Von Verschuer Ulla , Bos Monique M.E.M. , Pahernik Sascha , Grimm Marc-Oliver , Krause Steffen , Retz Margitta
Published: March 2020

TPS4591

Background: Sorafenib (SO) and pazopanib (PA) are both effective treatments for metastatic RCC (mRCC). For optimal treatment of mRCC patients (pts) it is essential to compare efficacy and safety of different sequential 1st and 2nd line treatments. The primary endpoint of this study is to evaluate if total PFS of SO followed by PA is non-inferior to PA followed by SO. Secondary objectives include time to progression during second-line treatment; time to first-line treatment failure in each arm, and PFS in first- and second-line treatment; overall survival; disease control rate in first- and second-line, safety and tolerability, and health-related quality of life. Also, a comprehensive translational research programme is integrated. Methods: Major inclusion criteria: pts with metastatic/advanced RCC not suitable for cytokines and for whom study medication constitutes first-line therapy; 18-85 years, ECOG PS 0 or 1, MSKCC score low or intermediate; at least one measurable lesion (RECIST 1.1). 544 pts will be randomized to the sequence SO→PA or PA→SO. Treatment under each drug continues until progression or intolerable toxicity. Between 1st and 2ndline therapy will be a treatment-free period of 1-4 wks. SO and PA are given in their registered doses. Pts undergo CT/MRI after every second cycle, i.e. after every 8 wks. The experimental arm will be considered to be non-inferior as long as the lower limit of the HR 95 % confidence interval (one-sided) excludes a median total PFS lower than 13.1 mos (=non inferiority margin). 383 events need to be observed to have 80% power to reject the null hypothesis of inferiority (HR ≥1.225) when the true HR=0.95. Recruitment started in June 2012. Study centers are in Germany, The Netherlands, and Austria. Clinical trial information: NCT01613846.