bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I safety and tolerability of once daily oral afatinib (A) in combination with gemcitabine (G) in patients with advanced solid tumors.
Authors: Zanetta Sylvie , Bennouna Jaafar , Isambert Nicolas , De-Montserrat Helene , Squiban Patrick J. , Delord Jean-Pierre 
Published: March 2020

e13009 Background: A is an orally bioavailable, irreversible, ErbB Family Blocker. This open label, Phase I, dose escalation trial investigated the safety, tolerability and pharmacokinetics of A in two parallel dose cohort expansion parts, in combination with either G (Part A) or docetaxel (Part B) in patients with relapsed or refractory solid tumors. Preliminary results from Part A are presented here. Methods: Eligible patients (confirmed diagnosis of advanced solid tumors, ECOG PS 0–1) received once-daily, oral dosing of A in combination with G, given intravenously at Day 1 and at Day 8 of every 3 week cycle. Dosing of A started on Day 2 of Cycle 1. The primary objective was to establish the maximum tolerated dose (MTD) based on the occurrence of dose limiting toxicities (DLTs) observed in Cycle 1. Dose escalation was performed with cohorts of 3–6 patients using a 3+3 design. Initial starting dose level was A 30 mg/day and G 1000mg /m², escalating up to A 50 mg/day and G 1250 mg/m², until the MTD was reached, and followed by a PK expansion cohort of 12 patients at the MTD level. Incidence and severity of AEs were recorded. Results: To date, 19 patients have been treated on study with the following baseline characteristics: mean age (53.7 years), women (63.2%) and number of prior chemotherapies (≤2: 26%, >2: 74%). Twelve patients received 2–4 cycles of treatment and five patients received 4 or more cycles. AEs observed in most patients were diarrhea (89.5%) and rash (63.2%). In Cycle 1, DLTs were experienced by one patient out of six receiving A 30 mg and G 1250 mg/m². MTD was exceeded at a dose level of at least A 40 mg/day and G 1250 mg/m². An intermediate dose level of A 40 mg/day and G 1000 mg/m² is currently under evaluation. Conclusions: In patients with relapsed or refractory advanced solid tumors, the combination of A with G is well tolerated, with manageable AEs. Dose finding is ongoing and MTD, safety profile and preliminary evidence of activity are anticipated to be reported at time of presentation.
Personalizing cancer treatment of combined targeting of PI3K/AKT and MAPK pathways in advanced cancer patients harboring simultaneous oncogenic alterations in both signaling pathways.
Authors: Shimizu Toshio , Tolcher Anthony W. , Papadopoulos Kyriakos P. , Beeram Muralidhar , Rasco Drew Warren , Smith Lon S. , Drengler Ronald L. , Gunn Shelly , Smetzer Leslie , Mays Theresa A. , Kaiser Brianne , Wick Michael Jude , Patnaik Amita 
Published: March 2020

e13025 Background: Frequent coactivation of both PI3K/AKT and MAPK pathways has been seen in a number of different tumor types. Preclinical studies also provide a clear rationale for the co-inhibition of these, "semi-parallel" pathways. Methods: We reviewed the records of 1,672 consecutive advanced cancer patients (pts) in our Phase I Clinical Trials Program and investigated the clinical impact of simultaneous blockade of both PI3K/AKT and MAPK pathways in patients with oncogenic alterations in both signaling pathways from 317 pts who received PI3K pathway inhibitor and/or MAPK pathway inhibitor. Results: 163 of 317 pts (51.4%) were tested for comprehensive tumor genomic analysis using DNA array-based CGH/PCR-based DNA sequencing. PI3K pathway genetic alterations (PIK3CA mutation, n=3; PTEN deletion, n=18; AKT amplification, n=10) were detected in 29 of the 163 (17.8%) pts. RAS/RAF pathway genetic alterations (KRAS mutation, n=33; HRAS mutation, n=4; BRAF mutation, n=6) were detected in 43 of the 163 (26.4%) pts. Simultaneous oncogenic alterations in both PI3K/AKT and MAPK pathways were detected in 12 pts (colorectal cancer, n=7; pancreatic cancer, n=2; melanoma, n=2; non-seminomatous germ cell tumor, n=1). Six of 8 (75%) pts treated with personalized treatment based on dual pathways inhibition had tumor regression with prolonged duration of time to treatment failure compared to that of pts treated with single pathway inhibition. A pt with pancreatic cancer harboring simultaneous KRAS mutation and AKT2 amplification treated with combination MEK1/2 inhibitor and AKT inhibitor showed central cavitations of numerous lung metastatic lesions along with a decrease in CA19-9, which may reflect treatment effect. Conclusions: These data could serve as a platform for therapeutic decision making. The strategy of targeting parallel pathways may be especially important in pts with coexisting PI3K/AKT and MAPK pathway genetic alterations. The data also suggest the need to further investigate the role of molecular profiling and matching pts with targeted drugs for personalized treatment.
CGTG-102 (Ad5/3-D24-GMCSF), a novel oncolytic adenovirus, in patients with refractory solid tumors: Experience from an advanced therapy access program.
Authors: Von Euler Mikael , Kanerva Anna , Nokisalmi Petri , Koski Anniina , Diaconu Iulia , Cerullo Vincenzo , Joensuu Timo K. , Oksanen Minna , Pesonen Sari , Kangasniemi Lotta , Ranki Tuuli , Heiskanen Raita , Hemminki Akseli 
Published: March 2020

e13035 Background: Following preclinical testing CGTG-102, a 5/3 chimeric oncolytic adenovirus armed with human GMCSF, has been used to treat 115 refractory cancer patients. Methods: Eligibility criteria included refractory advanced solid tumors, no major organ deficiencies and written informed consent. Patients were treated with either a single treatment or serial treatments with one or more viruses. Intra tumoral administration was performed under ultrasound guidance. The initial dose, 8 x 1010 Viral Particles (VP), was based on published safety results and preclinical testing and escalated in later patients. A routinely tolerated dose of 3 x 1011 VP was deemed optimal and is the target dose for clinical development. To reduce regulatory T-cells, low-dose cyclophosphamide 50 mg/day was given. Adverse Reactions (AR) were scored according to CTCAE 3.0. Imaging was done by CT before and ~2 months after treatment. Response was scored according to RECIST 1.1, including injected and non-injected lesions. Decrease not fulfilling PR was scored as minor response (MR). Results: The most common ARs were pain (82%), fever (81%), fatigue (79%), nausea (54%) and hemoglobin decrease (48%). Pain is mostly tumor pain or pain in the injected tumor, which may be causally related to the MOA of the therapy. Most ARs were G1 or G2; 6 were G4: 2 Hb decrease, 2 pulmonary embolism and single reports of thrombocytopenia and pericardial effusion, most probably due to the underlying disease.Imaging was performed when clinically useful. 65/115 are evaluable by imaging: 3% PR, 11% MR, 40% SD and 46% PD. Best results were obtained in Breast Cancer, Melanoma, Soft Tissue Sarcoma, Mesothelioma and Ovarian Cancer. Median survival in this heavily pre-treated refractory population is 164d, 95% CI 122d – 206d. Mean survival is 281d reflecting that approx. 30% survive more than 300d and 15% up to 600d. A wide range of samples are being analyzed to further characterize the viral and immunological aspects of the therapy. Conclusions: CGTG-102 is a novel oncolytic adenovirus with good safety profile and encouraging signs of efficacy. Formal clinical studies are underway in several tumor types in both US and EU.
Phase I clinical trial of multi-antigen peptide vaccines therapy using cancer-testis antigens for patients with advanced or recurrent breast cancer.
Authors: Fujita Tomoyuki , Yoshida Atsushi , Nishimura Hajime , Koshikawa Kayoko , Nagura Naoya , Yoshida Koji , Miyoshi Yasuo , Yamauchi Hideko , Nakamura Seigo , Nakamura Yusuke , Fujimori Minoru 
Published: March 2020

e13037 Background: Cancer-testis (CT) antigens are proteins that are normally expressed only in the human germline, but are also present in a significant subset of malignant tumors. The practical importance of these proteins is that, due to their restricted expression pattern, they are frequently recognized by the immune system of cancer patients. Moreover, this antigenicity has raised the possibility of their use as vaccines to stimulate immune responses in order to combat tumor growth. As a result, many aspects of CT antigens have been examined in studies performed worldwide. Here we report the results of a phase I clinical trial combining five kinds of CT peptide (CDCA1,URLC10,KIF20A,DEPDC1,MPHOSPH1) vaccination. Methods: The subjects of the trial were HLA-A24-positive patients with metastatic and advanced breast cancer. The mixture of peptides was subcutaneously injected weekly with dose-escalation (doses of 0.5, 1, and 2 mg of each peptide/body, three patients/cohort). Safety, efficacy and immunological parameters were assessed. Results: No adverse events were observed in any patients. Of the 9 patients who completed at least one cycle of the treatment, 4 (44%) developed immunological reactions at the injection site. Specific cytotoxic T lymphocytes (CTLs) reacting to any peptide were induced in 7 (78%) of the 9 patients. Of the 7 patients who completed at least two cycles of the treatment, tumor regression compatible with stable disease (SD) was noted in 4 patients. The remaining patients had progressive disease (PD). The vaccine therapy was tolerable and safe at all doses. Conclusions: Combination therapy with CT antigens has therapeutic potential for patients with breast cancer. Peptide-specific CTLs against peptides in the vaccine were induced at a high rate, even in heavily pretreated patients. From an immunological perspective, the optimal dose for further clinical trials is ≥1 mg/body.
Role of chronic macrophage activation in patients with primary breast cancer.
Authors: Thein Mya Sanda , Jain Alka , Ingaramo Maria Clara , Kohli Antia , Fedarko Neal 
Published: March 2020

e13042 Background: Breast cancer progression has been associated with altered immune function and macrophage activation. Neopterin (Neo), a GTP metabolite, is secreted by interferon-γ activated macrophages. Chitotriosidase (ChT), a member of the glycosyl hydrolase family, is secreted by chronically activated macrophages. Osteopontin (OPN), a phosphorylated glycoprotein, produced by tumor and immune cells, is a modulator of macrophage activity and infiltration. OPN and neopterin have been studied separately as markers of solid malignancy including breast cancer. Methods: The purpose of our study was to test for correlations between breast cancer presence and stage with macrophage produced markers of acute (Neo), and chronic (ChT) macrophage activation as well as tumor/immune cell produced marker of macrophage infiltration (OPN). The study included 66 patients with primary breast cancer (Group I: 14 with metastatic disease) and 111 participants in a control group (Group II). Serum levels of OPN and Neo were measured by ELISA, while ChT levels in serum were measured by enzyme activity assays. Comparisons between groups were analyzed by Mann Whitney U test. Results: ChT and OPN levels were significantly higher in Group I compared to Group II (Table I). ChT was elevated at early stage disease while OPN increased with more advanced disease. Although Neo was not increased in patients with breast cancer, a subgroup analysis within group I demonstrated that it was higher in patients with metastatic disease (6.8 vs 9.3 p <0.01). Conclusions: High levels of ChT in breast cancer patients may indicate that chronic macrophage activation plays a significant role in early breast cancer progression. OPN and Neo, elevated in late stage and metastatic disease, respectively may be useful biomarkers of tumor aggressiveness and/or metastatic progression. Further studies should be done to validate these biomarkers and understand the role of acute and chronic macrophage activation in cancer progression. [Table: see text]
Open label phase I/II study of Wilms' tumor gene 1 (WT1) mRNA-transfected autologous dendritic cell vaccination in patients with solid tumors.
Authors: Willemen Yannick , Huizing Manon Thirza , Smits Evelien , Anguille Sébastien , Nijs Griet , Stein Barbara , Van Tendeloo Viggo , Peeters Marc , Berneman Zwi N. 
Published: March 2020

e13051 Background: Active specific immunotherapy, aimed at stimulating tumor-specific immunity, is widely under investigation to determine its place in cancer treatment. Methods: We are conducting an open label phase I/II clinical trial to evaluate the feasibility, toxicity and immunogenicity of intradermal vaccination with keyhole limpet hemocyanin (KLH)-exposed WT1 mRNA-transfected autologous monocyte-derived dendritic cells (DC). Recruitment has finished, but vaccination and follow-up continue. Vaccination consists of biweekly intradermal injection of 10 million DC in the medial region of the arm close to the axilla. Clinical evaluation with PET, CAT or MRI is done before start of the vaccination and repeated every 8 weeks. After 4 vaccinations patients undergo a delayed-type hypersensitivity (DTH) skin test to evaluate immunological responses. Results: 18 patients (8 breast cancer and 3 astrocytoma patients, 1 melanoma, 1 mesothelioma, 1 ovarian, 1 colon, 1 esophageal, 1 renal cell and 1 peritoneal cancer patient) were included in this trial from May, 2010 until January, 2012 to whom we administered a total of 175 vaccines. The median number of vaccines produced per patient was 15 (range 5-34). Median follow-up from start of the vaccination is 26 weeks (range 2-83). All evaluable patients exhibited local symptoms such as itching and/or redness at the sites of injection after the second vaccination and onward (n=17) and displayed positive DTH skin reactions (induration ≥2 mm) to the vaccine and its components (n=15). Systemic side effects were limited to 2 patients who each experienced a single episode of flu-like symptoms within 24 hours after vaccination. Thus far, 3 patients died of disease progression, while 7 others had progressive disease and 6 had stable disease at the most recent evaluation compared to before vaccination according to RECIST 1.1. Of the latter group 4 patients received another form of therapy at some point during vaccination. Conclusions: Based on these results our WT1 mRNA-transfected DC vaccination appears to be feasible and safe for patients with solid tumors. Furthermore, our vaccine is capable of inducing immune responses in these patients.
Tailored endpoints: A proposal for design of future clinical trials in metastatic breast cancer (MBC).
Authors: Fontanella Caterina , Bonotto Marta , Driol Pamela , Valent Francesca , Gerratana Lorenzo , Russo Stefania , Andreetta Claudia , Minisini Alessandro , Mansutti Mauro , Sottile Roberta , Fasola Gianpiero , Puglisi Fabio 
Published: March 2020

e13058 Background: Widespread access to active agents against MBC has produced significant improvements in survival, even though few phase III trials are powered to detect overall survival (OS) effects. However, regulatory agencies hold OS as gold standard for approval of new drugs. OS can be portioned into the sum of progression-free survival (PFS) and survival post-progression (SPP). Recent data suggest that OS is a reasonable primary endpoint only when median SPP is short. On the other hand, patients enrolled in first-line trials could have a long life-expectancy. Aim of this study was to evaluate PFS, OS and SPP in a consecutive series of patients with MBC in order to obtain information as a basis for design of future clinical trials. Methods: Four hundred patients with MBC diagnosed from January 2004 to February 2011 at University Hospital of Udine, Italy, were included in the study. We examined the role of potential of disease and patients’ characteristics in influencing the different measures of outcome. Results: Median OS was 33.71 months (mo), in line with the best literature. Median PFS at first-line (PFS1) was 9.33 mo, with linear decrease at second (5.06), third (3.58), and fourth (3.19) line, respectively. Median SPP after first-line (SPP1) was 18.69 mo. Interestingly, differences in outcome were noticed according to immunophenotype. The best prognosis was observed in luminal A disease (OS= 46.72 mo, PFS1= 15.61 mo, SPP1= 25.43 mo). In luminal B disease, median OS was 27.66 mo, PFS1 8.94 mo, and SPP1 13.21 mo, respectively. In patients with HER2-positive disease, mainly treated with anti-HER2 therapy, outcome approached that of luminal A disease (OS= 41.10 mo, PFS= 9.89 mo, SPP1 18.69 mo). Patients with triple negative disease (TNBC) experienced the worst prognosis (OS= 8.54 mo, PFS1= 4.04 mo, SPP1= 2.83 mo). Conclusions: The study demonstrated different results in the measures of outcome according to the line of treatment and specific disease characteristics. As a consequence, endpoints of clinical trials should be tailored taking into consideration prognostic/predictive factors as well as the line of treatment.
Phase Ib study of TSPP (thymidilate synthase poly-epitope peptide) vaccine in combination with GOLFIG chemoimmuno-burst in advanced colon cancer patients: Results from the TSPP/VAC-1/c trial.
Authors: Correale Pierpaolo , Pastina Pierpaolo , Botta Cirino , Rossetti Maria Grazia , Apollinari Serena , Bestoso Elena , Fioravanti Antonella , Guidelli Giacomo , Chellini Federico , Mantovani Giovanni , Gori Savellini Gianni , Carbone Salvatore Francesco , Ricci Veronica , Basile Assunta , Pagliuchi Marco , Tagliaferri Pierosandro , Pirtoli Luigi , Cusi Maria Grazia 
Published: March 2020

e13098 Background: TSPP is a poly-epitope peptide anticancer vaccine able to generate a thymidylate syntase (TS) specific T cell response with antitumor activity in preclinical models, expecially when used in sequential combination with 5-FU. TS is in fact involved in DNA replication and is the major pharmacological target of fluoropyrimidines whose activity leads in turn to TS upregulation. On these basis we designed a phase Ib trial where we investigated the safety and the immunobiological activity of TSPP + GOLFIG (Gemcitabine + FOLFOX-4 + GM-CSF + IL-2) regimen. Methods: TSPP/VAC-1 (Eudract 2009-016897-33) is a monocentric dose finding Phase Ib trial. 12 pretreated metastatic colon cancer patients were enrolled between April and November 2011. All of them received biochemotherapy according to the GOLFIG regimen biweekly and TSPP (on day 7) diluted in motanide ISA720 (1:1) at the dosage of 100 (3 patients), 200 (3 patients) and 300 ug (6 patients). Results: No life-threatening adverse events were observed. Grade 3 leucopenia (2 cases), thrombocitopenia (3 cases), anemia (3 cases), nausea/vomiting (2 cases), and dyarrhea (4 cases) along with 3 cases of oxaliplatin reaction were recorded. Fever and flu-like symptoms were common along cytokine administration. An IFN-gamma ELISPOT assay recorded an increase in TS specific CTL precursors in 3/6 evaluable patients; it was also observed an increase in lymphocytes, eosinophils, terminal effector memory and central memory T cells and in both c-ANCA and p-ANCA (P= 0.02) in the peripheral blood and a significant reduction in inflammatory markers (LDH, CRP and ESR). Quality of life analysis revealed a general improvement in patients’health state along the treatment. 1 partial response, 6 disease stabilizations and 2 progessions of disease were recorded. TSPP Maximal Tolerated Dose was not reached, while the Optimal Biological Dose was identified at 300 ug. Conclusions: Our results suggest that the GOLFIG + TSPP vaccine combination is safe and immunologically active and deserves to be evaluated in a further phase II trial.
Interesting possibilities to improve the safety of ipilimumab.
Authors: Bakacs Tibor , Moss Ralph W , Mehrishi Jitendra , Szabo Miklos 
Published: March 2020

e13102 Background: The problem of the ipilimumab therapy is that a common molecular target (CTLA-4 receptor) is expressed on the targeted and non-targeted T cells, respectively. We suggest that the frequency of immune-related adverse events can be reduced by treating conditions in which the number of the targeted cells is larger than the non-targeted ones and/or by improving the accuracy of the targeting. Methods: The first approach was tested in a phase I clinical trial in patients with relapsed malignancy following allogeneic hematopoietic stem cell transplantation. An ipilimumab blockade was used against CTLA-4 positive allogeneic T cells (responding patients had greater than 80% donor T-cell chimerism). The graft-versus-malignancy (GVM) effects were augmented without a significant impact on graft-versus-host disease (GVHD). A feasible approach could also be pretargeting that has been worked out for radioimmunodetection and radioimmunotherapy. To this end we suggest a testable thought experiment for the treatment of chronic lymphocytic leukemia (CLL). First a streptavidin (StAv) modified anti-CD19 mAb is administered, which is followed by the subsequent delivery of biotin labeled anti-CTLA-4 mAb. The latter endows T cells with the ability to travel to tumor sites without prematurely succumbing to apoptosis, while streptavidin’s ultra-high affinity for biotin (10-15M) ensures a tight bond to the biotin labeled anti-CTLA-4. Results: Using the law of mass action we calculated that above 1 mg/L ipilimumab concentration (i.e. about 5 mg/patient ~70kg) more than 80% of anti-CD19-StAv sensitized B cells will have been bound to anti-CTLA-4-biotin sensitized T cells. Conclusions: This way, the forces of the immune system liberated by the anti-CTLA-4 antibody blockade could be focused with laser sharp accuracy on CLL cells without collateral damage to normal host cells. One should note that 0.3 mg/kg ipilimumab alone already caused mild autoimmunity.
Autologous heterotopic transplant of peripheral blood associated to chemotherapy as immunotherapy of solid tumors.
Authors: Lasalvia-Prisco Eduardo M. , Goldschmidt Pablo , Galmarini Felipe , Vazquez Jesus , Lasalvia-Galante Eduardo E. , Golomar Wilson , Cucchi Silvia 
Published: March 2020

e13105 Background: Successive developed configurations of Autologous Heterotopic Transplant of Peripheral Blood (AHTOPB) were reported lately. In advanced stages of different primary tumors, AHTOPB has improved the antitumoral effect of chemotherapy (CH). A cohort of patients (pts) was selected from these trials to explore the biological response modifications (angiogenesis, immunity) associated to such antitumoral effect. Methods: From 6 reported 2-arm trials (CH and AHTOPB+CH treated), 60 pts were selected, 5 from each arm and trial. Trials referred to Breast, NSC Lung, prostate, ovary, pancreas, colon. Inclusion criteria: histology confirmed, M1 stage, unresectable, measurable according Response Evaluation Criteria in Solid Tumors (RECIST), PS 0-2 according Eastern Cooperative Oncology Group (ECOG), not previous CH, organic functions preserved. Exclusion criteria: brain M1, treated comorbility, additional antitumor treatment. AHTOPB procedure as it was described: 1) Cyclophosphamide low dose, 2) Immunization site conditioning with activated autologous blood, 3) Immunization with tumor antigens released to the blood inside heat shock proteins. CH: standard first line recommended for each tumor. Assessments. In venous blood sample pre/post treatment: T-Regulatory cells (T-Reg); Activated Dendritic cells (aDC); Lymphocyte Proliferative Index AHTOPB challenged (LPI); Angiostatin (AT); Interleukine-2 (IL2); Interleukine-12 (IL12); Gamma Interferon (G-If). In sentinel lymph-node of immunization site post AHTOPB treatment: T-Reg and aDC. In clinical follow up: 30-day Tumor Growth (TG) according RECIST; Disease control rate (DCR), Overall Survival (OS), Toxicities (Tx) according NCI (≥3). Measurements were expressed as % of pretreatment mean value in same primary tumor; % of 2 treatments were statistically compared using two tailed Student T-test. Results: Arm AHTOPB+CH, comparable to arm CH, evidenced significant decrease T-Reg, VEGF, TG, and increase aDC, LPI, AT, IL2, IL12, G-If, DCR. No significant different toxicity. Conclusions: In cancer pts, ATHOPB+CH elicits the conditioning to produce biological responses compatible with antitumor immunotherapy.