bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I study of vandetinib in combination with gemcitabine and oxaliplatin in advanced solid malignancies.
Authors: Wang Peng , Owonikoko Taofeek Kunle , Lin Yan , Stoller Ronald G. , Petro Daniel P. , Park Deric M. , Ramanathan Ramesh K. , Chu Edward , Beumer Jan Hendrik , Appleman Leonard Joseph 
Published: March 2020

3037 Background: Vandentinib (VAN) is a tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptor-2 (VEGFR-2) and 3 (VEGFR-3) as well as epidermal growth factor receptor (EGFR) and RET (‘rearranged during transfection’). Combinations of VEGFR kinase inhibitors and cytotoxic agents have been studied with interest, but have been associated with increased toxicity. This phase I trial evaluated the safety, tolerability and maximum tolerated dose of VAN in combination with gemcitabine (GEM) and oxaliplatin (OX). Methods: Subjects with advanced solid malignancy, ≤ 2 prior regimens with adequate hematologic, hepatic and renal function were eligible. GEM and OX were administered intravenously at 1000 mg/m2 and 85 mg/m2 respectively every 14 days. VAN was administered orally at two dose levels: level 1 (200 mg) and level 2 (300 mg) once daily continuously. After a maximum of 6 cycles of GEMOX, non-progressing patients were allowed to continue VAN until progression or intolerance. A dose level was determined to be tolerable if <2 DLTs out of 6 evaluable subjects were observed. Response was assessed by restaging scan after every 2 cycles. Results: A total of 20 subjects were enrolled in the study; 15 male, 5 female. Median age 62 years (47-68). Nine subjects were enrolled on dose level 1 and 11 subjects on dose level 2. One subject in dose level 1 experienced a deep venous thrombosis in cycle 1 deemed a DLT. Thrombocytopenia (worst-grade 3) as well as diarrhea and rash (worst-grade 2) were observed in several patients, without dose-limiting toxicity in cycle 1. Reversible posterior leukoencephalopathy was observed in 1 subject following abrupt self-discontinuation of an antihypertensive mediation. The recommended phase 2 dose was established as GEM (1000mg/m2) OX (85mg/m2) and VAN (300mg). One subject with refractory small cell lung cancer had a confirmed partial response, and 10 subjects (pancreas-7, bladder-2 and biliary-1) achieved stable disease ≥12 weeks. Conclusions: VAN in combination with GEM/OX was well tolerated at full doses of each of the 3 agents. Preliminary anti-tumor activity seen in refractory solid tumors supports further evaluation of this regimen.
First-in-human phase I study of a selective VEGFR/FGFR dual inhibitor sulfatinib in patients with advanced solid tumors.
Authors: Xu Jian-Ming , Wang Yan , Shen Lin , Gong Jifang , Huang Cheng , Ye Chen Yang , Yang Li , Sai Yang , MU Hua 
Published: March 2020

3040 Background: Sulfatinib is a highly selective oral small molecule tyrosine dual inhibitor of vascular endothelial growth factor receptors (VEGFR) and fibroblast growth factor receptors (FGFR). It demonstrated potent in vivo inhibitory effects on a variety of human tumor xenografts. Methods: This phase I dose-escalation study were to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics (PK) profile, and preliminary antitumor activity, and to assess potential pharmacodynamics (PD) markers of sulfantinib when given orally in continuous cycles of 28 days, until disease progression or unacceptable toxicity. Results: Forty one patients (pts) have been enrolled and treated with doses of 50-300mg once or twice daily. Pts had a median age of 50 (36-70) yrs, with 63% male and 93% gastrointestinal tumors. Common adverse events (AEs) included fatigue, hypertension, vomiting, nausea, diarrhea, electrolyte disorder and elevated AST/ALT, mostly grade (G) 1/2. Three DLTs including a G3 coagulation disorders, upper gastrointestinal bleeding and impaired liver function were observed in the 50 and 265mg qd and 150mg bid cohorts, respectively. MTD has not been reached and the dose escalation is ongoing. Among 28 evaluable pts, 10 (36%) had stable disease (SD) for 8 weeks or longer, including liver and neuroendocrine cancer, GIST and solid-pseudopapillary tumor of pancreas. A patient with GIST had SD of 9 months at 265mg qd. There was a significant decrease in soluble VEGFR2 level and increase in FGF23 level after 4-week treatment comparing to the baseline at 265 mg or higher daily doses, indicating inhibition of both VEGFR2 and FGFR. PK analyses showed that sulfatinib was rapidly absorbed with Tmax 1.3~2.8h and half-life of 15.3~19.1h. Both Cmax and AUC displayed dose-proportional increases and no obvious accumulation occurred at day 28. Conclusions: Sulfatinib was well tolerated at doses up to 300 mg per day and demonstrated preliminary anti-tumor activity, especially in liver cancer and GIST. PD marker analysis indicates dual inhibition of VEGFR and FGFR. PK data suggests good dose proportionality in exposure without marked drug accumulation.
Phase Ib study of CNTO 888 (anti-CCL 2) in combination with chemotherapies for treatment of patients with solid tumors.
Authors: Calles Antonio , Brana Irene , LoRusso Patricia , Yee Lorrin , Puchalski Thomas , Seetharam Shobha , Balvers Melan , De Boer Carla , Elsayed Yusri A. , Calvo Emiliano , Tabernero Josep 
Published: March 2020

3059 Background: CC-chemokine ligand 2 (CCL2) is expressed in various malignancies, implicated in angiogenesis, proliferation and metastasis. CNTO888 is a hIgG1κ mAb with selective high CCL2 binding affinity and showed preclinical antitumor activity. Methods: Primary objectives were safety and a recommended dose of CNTO 888 in combination with chemotherapy: Arm 1 - 15 mg/kg CNTO 888 + docetaxel 75 mg/m2 Q3W; Arm 2 - 15 mg/kg CNTO 888 + gemcitabine 1000 mg/m2 on D1 and 8 Q3W; Arm 3 - 15 mg/kg CNTO 888 + paclitaxel 175 mg/m2 and carboplatin AUC6 Q3W; Arm 4 - 10 mg/kg CNTO 888 Q2W + pegylated doxorubicin 50 mg/m2 Q4W. Two (Arms 1, 2, 3) or 4 (Arm 4) prior chemotherapies for advanced disease were allowed. Pharmacokinetic (PK) profile of CNTO 888 and chemotherapies, free and total CCL2, CTC/CEC count, and uNTX were evaluated. Adverse events (AE) and dose limiting toxicities (DLT) were evaluated after 6 subjects completed 1 cycle. Results: 53 subjects (22F/31M) were treated: Arm 1 n=15, Arm 2 n=12, Arm 3 n=12, Arm 4 n=14. Two DLTs occurred: a grade 4 febrile neutropenia (Arm 1) and a grade 3 neutropenia (Arm 2). All 4 combinations were found to be safe and tolerable and continued enrolment to a minimum of 12 subjects evaluable for safety and PK. Best overall response were partial response (PR) (1) and stable disease (18; 2 ≥ 4 months). One subject with pancreatic adenocarcinoma achieved PR, allowing for surgical resection. Most frequently reported (≥ 20%) related serious AEs are: Arm 1: Neutropenia, Stomatitis, Fatigue, Febrile neutropenia, Alopecia. Arm 2: Anemia. Arm 3: Thrombocytopenia, Alopecia, Neutropenia, Asthenia, Fatigue, Anemia, Arthralgia, Nausea, Vomiting. Arm 4: Stomatitis, Rash, Fatigue, Nausea, Anemia, Neutropenia. CNTO 888 did not affect the chemotherapy PK profile; similarly, chemotherapy did not affect the CNTO 888 PK profile. No subjects (n=38) tested positive for antibodies to CNTO 888. Free CCL2 declined 2 hrs post treatment and returned to baseline levels by 48 hrs and continued to increase with further administrations in all treatment arms. There were no consistent changes with other biomarkers. Conclusions: CNTO 888 in combination with standard chemotherapy was well tolerated but few objective responses were seen.
Open-label extension study of the RNAi therapeutic ALN-VSP02 in cancer patients responding to therapy.
Authors: Alsina Maria , Tabernero Josep , Shapiro Geoffrey , Burris Howard , Infante Jeffrey R. , Weiss Glen J. , Cervantes-Ruiperez Andres , Gounder Mrinal M. , Paz-Ares Luis , Falzone Rick , Hill Jamie , Cehelsky Jeffrey , Vaishnaw Akshay , Gollob Jared , LoRusso Patricia 
Published: March 2020

3062 Background: ALN-VSP02 is an RNA interference (RNAi) therapeutic comprised of lipid nanoparticle-formulated small interfering RNAs targeting vascular endothelial growth factor (VEGF)-A and kinesin spindle protein (KSP). In a phase 1 trial, ALN-VSP02 administered as an iv infusion q2 wks was well-tolerated and showed evidence of anti-VEGF pharmacology and antitumor activity. Methods: Patients treated on the phase I trial with stable disease (SD) or better after 4 months (8 doses) were eligible to continue on an extension study until disease progression. Main objectives included continued evaluation of safety/tolerability and assessment of disease response. Results: Seven of 37 patients (18.9%) evaluable for response went onto the extension study, including 1 of 7 (14.2%) at 0.4 mg/kg, 2 of 5 (40%) at 0.7 mg/kg, and 4 of 11 (36.3%) at 1.0 mg/kg. All had progressed after one or more prior therapies. Tumor types included head and neck squamous cell carcinoma, angiosarcoma, endometrial cancer, renal cell carcinoma (RCC, N=2), and pancreatic neuroendocrine tumor (PNET, N=2). At the time of enrollment, 6 had SD and one (endometrial cancer with multiple liver metastases) had an unconfirmed partial response (PR). The average length of time on treatment (including phase I and extension studies) was 9.5 months (range 5-19). As of January 2012, 3 patients remain on study, including the endometrial cancer patient with an ongoing PR who has had >80% tumor regression after 19 months of treatment at 0.7 mg/kg and two patients with RCC and PNET with continued SD after nearly 1 year of treatment at 1.0 mg/kg. The other patients with RCC and PNET at 1.0 mg/kg with SD came off after 8.5 and 5.5 months, respectively, for adverse events that included fatigue or elevated alkaline phosphatase. A decrease in spleen volume, likely an on-target effect and not associated with any adverse events, occurred to a greater degree on the extension study than on the phase I trial and was most pronounced in patients receiving ≥ 12 doses. Conclusions: ALN-VSP02 has preliminary activity against endometrial cancer, RCC and PNET and a favorable safety profile that permits chronic dosing. Phase II trials are warranted in these and other VEGF-overexpressing tumors.
ME-143, a novel inhibitor of tumor-specific NADH oxidase (tNOX): Results from a first-in-human phase I study.
Authors: Kurkjian Carla , Pant Shubham , Burris Howard A. , Bendell Johanna C. , Jones Suzanne Fields , Moore Kathleen N. , Moreno Ofir , Mass Robert D. , Infante Jeffrey R. 
Published: March 2020

3067 Background: ME-143, a second generation isoflavone-derived compound, specifically binds tNOX, shifting the ceramide-S1P equilibrium and resulting in prompt apoptosis via pleotrophic caspase activation. A first generation compound, phenoxodiol (PXD), showed promising phase II activity with cisplatin in ovarian cancer. ME-143 is broadly active against human cancers in both in vitro and in vivo models, with IC50’s 1-2 logs lower than PXD. Toxicology studies up to 140mg/kg (human dose equivalent ~23mg/kg) showed no STD level. The only significant findings were dose dependent hypospermia and testicular atrophy in rats. We report clinical and PK results from the first-in-human phase I study. Methods: A 3+3 dose escalation design was used with 4 dose cohorts: 2.5, 5, 10, and 20mg/kg IV over 30 minutes weekly times 3, followed by a 1 week break, and then continuous weekly dosing in patients with advanced solid tumors. Dense PK sampling was performed at 0, 5, 10, 20, 30, 60, 90, 120, 180, 240, 300, 360 minutes, and 24 hours post-infusion day 1 and 15 of the first treatment cycle. Results: To date, 9 patients have been enrolled, 3 in each of the first 3 cohorts. Median time on treatment is 56 days (range 6 to 62). Five patients have discontinued protocol therapy, all due to PD. No DLT’s have been observed. Related AE’s include grade 1: myalgia (1), anorexia (1), fatigue (2), headache (1), diarrhea (1), vomiting (1) and grade 2: fatigue (1). Preliminary PK analyses in the first 2 cohorts is shown in table below. Conclusions: ME-143 appears to be well tolerated when administered IV. Preliminary PK data suggest that drug levels achieve target concentration extrapolated from pre-clinical studies (AUC0-t ~10mg*hr/mL) and exceed levels obtained with IV PXD in the phase II study (AUC0-t ~2mg*hr/mL) . Updated clinical data from all planned dose cohorts, including the final pharmacokinetic analysis and planned phase II dose, will be presented. [Table: see text]
CD30 expression in nonlymphomatous malignancies.
Authors: Sharman Jeff Porter , Goldschmidt Jerome H. , Burke John M. , Hellerstedt Beth A. , McIntyre Kristi , Yasenchak Christopher A. , Boyd Thomas E. , Ruxer Robert L. , Patel-Donnelly Dipti , Braiteh Fadi S. , Forero-Torres Andres , Savin Michael A. , Albertson Tina Marie ,   McKesson Specialty Health/US Oncology Research
Published: March 2020

3069 Background: CD30 is commonly expressed in Hodgkin lymphoma (HL), anaplastic large cell lymphoma (ALCL), and testicular embryonal carcinoma. Expression of CD30 in other solid tumors and non-lymphomatous malignancies has been reported but not investigated systematically. CD30 is the target of brentuximab vedotin (Adcetris), an antibody drug conjugate (ADC) that is approved for the treatment of patients with relapsed HL and systemic ALCL after failure of other therapies. A study was initiated to determine the incidence of CD30 expression in non-lymphomatous malignancies and to identify patients who may be candidates for treatment with brentuximab vedotin. Methods: Patients with non-lymphomatous malignancies were eligible for screening if they were relapsed or refractory to previous therapy or had no effective treatment options available. Archived tissue from solid tumors was tested for CD30 expression by immunohistochemistry (IHC); fresh bone marrow or blood samples from multiple myeloma or leukemia patients were tested by flow cytometry. Patients were considered CD30 positive and eligible for a companion treatment protocol with brentuximab vedotin if ≥10% of malignant cells stained positive by IHC or ≥20% by flow cytometry. Results: At this interim analysis, a total of 875 patients have been tested for CD30 expression: 95% had solid tumors, 3% had leukemia, and 2% had multiple myeloma. Twenty-two patients (2.5%) were CD30 positive, including 7 of 94 patients with ovarian cancer (7%), 5 of 20 with melanoma (25%), 2 of 5 with mesothelioma (40%), 1 of 4 with skin squamous cell carcinoma (25%), 2 of 41 with triple negative breast cancer (5%), 1 of 37 with pancreatic cancer (3%), 1 of 26 with small cell lung cancer (4%), and 1 of 3 with anal cancer (33%), and thyroid carcinoma (33%). One patient was identified with CD30-positive mast cell leukemia. In positive patients, the percent of CD30-positive malignant cells varied between 10 and 80%. Conclusions: CD30 expression was observed in multiple types of non-lymphomatous malignancies, thereby identifying additional populations who may be candidates for treatment with a CD30-targeted ADC, such as brentuximab vedotin. A companion clinical trial with brentuximab vedotin is currently ongoing.
Targeted therapies for the treatment of non-small cell lung cancer: Bull’s eye or missed target?
Authors: Malik Shakun M. , Johnson John R , Bijwaard Karen , Becker Robert , Keegan Patricia , Pazdur Richard 
Published: March 2020

3074 Background: Targeted drugs approved for advanced non-small cell lung cancer (NSCLC) include bevacizumab [(monoclonal antibody directed against vascular endothelial growth factor-A (VEGF-A)], erlotinib [(an epidermal growth factor receptor kinase (EGFR) inhibitor)] and crizotinib [(an anaplastic lymphoma kinase (ALK) inhibitor)]. The development programs for erlotinib and bevacizumab did not prospectively employ in vitro diagnostic tests to select patients (pts). Post-hoc exploratory analyses for bevacizumab based on VEGF-A levels have not identified subgroups with differential treatment effects: however for erlotinib, pts with activating EGFR mutations had greater improvement in overall response rates (ORR) and progression-free survival. Crizotinib is the first targeted therapy for NSCLC in which pts were selected using an analytically validated investigational test for ALK translocations. Crizotinib received accelerated approval on August 26, 2011 for the treatment of pts with locally advanced or metastatic ALK-positive NSCLC as detected by an FDA-approved test (Vysis ALK Break Apart FISH Probe Kit) that was approved by FDA on the same day. Methods: NDA file for crizotinib was examined. Results: Two single arm trials assessing efficacy of crizotinib monotherapy in ALK positive pts showed ORR of 61% and 50%. At FDA’s request, a cohort of 23 pts that tested negative for the ALK translocation evaluated showed ORR of 26%. Two additional pts had a single assessment and, if confirmed, the response rate would be 37% in this “marker negative” subgroup. Further exploration of this subgroup is a postmarketing commitment. Conclusions: Evaluation of target status (positive or negative) in all pts provides optimal information to guide clinical practice. As observed with crizotinib, responses may be observed in the “marker negative” subgroup. This unexpected finding may reflect the drug’s activity via alternate pathways, selection of a suboptimal biomarker for assessing ALK activation, or selection of a suboptimal cut-point for positive/negative. Accurate diagnostic tests will facilitate drug development with possible greater observed treatment effect and potentially smaller clinical trials.
Phase I and pharmacokinetic study of farletuzumab in solid tumors.
Authors: Sasaki Yasutsuna , Miwa Keisuke , Yamashita Keishi , Fujiwara Keiichi , Katsumata Noriyuki , Fujiwara Yasuhiro , Namiki Masayuki , Koyanagi Nozomu 
Published: March 2020

3084 Background: Farletuzumab (F) is a humanized monoclonal antibody against folate receptor α (FRA). Expression of FRA is reported to be 90% and 40% in ovarian cancer (OC) and gastric cancer (GC), respectively. The purpose of the study is to assess tolerability, pharmacokinetic profile and preliminary antitumor effect in solid tumors. Methods: Patients with OC or FRA expressing solid tumor who are resistant to standard treatments are eligible in the study. After pharmacokinetic (PK) run-in, F was administered by IV injection repeating every week until disease progression. PK profile was analyzed on day1 to day 10 in PK run-in and on day 22 to 29 in cycle 1. Dose limiting toxicities (DLTs) were defined as G4 hematological and G3/4 non-hematological toxicities by NCI-CTCAE. Dose escalation was planed in 4 cohorts (50, 100, 200 and 400mg/m2). Results: Sixteen patients (14 OC and 2GC) received F infusion. Neither DLTs nor G3/4 toxicities were reported in all cohorts. As adverse events, G1/2 infusion reaction (44%), headache (44%), cytokine release syndrome (38%), nausea (31%) and appetite loss (31%) were observed and medically managed. AUC and Cmax.were increased dose-dependently and linear PK profiles were identified with median clearance between 6.02 and 10.54 mL/hr/m2 in each cohort. No tumor shrinkage was recorded, but long-term disease stabilization for 22+ mos. and 10+ mos. were observed in one patient with clear cell OC (100mg/m2) and one patient with GC (400 mg/m2), respectively. No cumulative toxicities were observed in these 2 patients. Conclusions: The toxicities of F in Japanese patients were manageable with similar PK profile as compared with the US population (Konner et al. Clin Cancer Res 2010: 16; 5288-95). Long term disease stabilization is observed in subpopulation of clear cell OC and GC.
Phase I study of sirolimus plus gemcitabine in patients with advanced solid tumors: A Spanish Group for Research on Sarcomas (GEIS) study.
Authors: Martin Liberal Juan , Gil Marta , Jimenez Laura , Ochoa de Olza Maria , Munoz Carmen , Gonzalo Nuria , Rigo Raul , Colom Helena , Sainz Jaspeado Miguel , M. Tirado Oscar , Garcia del Muro Xavier 
Published: March 2020

3096 Background: In preclinical studies, combination of sirolimus with gemcitabine enhances apoptosis in vitro and increases anti-tumor efficacy in vivo. Methods: Patients with advanced solid tumors, age 18-70 years, no prior mTOR inhibitor or gemcitabine, ECOG PS 0-1, and adequate hematological, renal and hepatic function, were enrolled in this phase I study to assess safety, tolerability, pharmacokinetics (PK), and to identify the dose limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended dose (RD) of the combination of sirolimus and gemcitabine. A 3+3 dose escalation design with cohorts of 3-6 patients was used. Sirolimus was given po continuously. Gemcitabine was given iv 10mg/m2/minute on days 1 and 8 every 3 weeks. Dose levels 1, 2 and 3 corresponded to sirolimus 2, 2 and 5mg/24h plus gemcitabine 800, 1000 and 1000mg/m2 respectively. After observing DLTs at higher dose level and poorer mTOR signaling inhibition at lower doses, a new cohort of sirolimus 5mg/24h plus gemcitabine 800 mg/m2 was added. Skin biopsies pre and post treatment were performed to assess the inhibition of mTOR pathway. Results: 19 patients were enrolled: median age 51 years (36-70); gender 12M, 7F. Median number of cycles was 4. Patients were treated at 4 dose levels, the MTD was reached at level 3 and the RD was: sirolimus 5mg/24h and gemcitabine 800mg/m2. 3 DLTs were observed, 1 at dose level 2 and 2 at dose level 3: transaminitis grade 3, thrombocytopenia grade 3 and thrombocytopenia grade 4. Other toxicities grade 1-2 included anemia, neutropenia, asthenia, mucositis and high cholesterol levels. 2 patients achieved partial response (1 uterine cervix cancer and 1 colon cancer). Immunohistochemistry of pS6 in skin biopsies showed significative inhibition of mTOR pathway at RD. PK parameters estimated were in agreement with those previously reported in the literature. No influence of sirolimus administration on gemcitabine clearance was found. Conclusions: Combination of sirolimus and gemcitabine is feasible and safe, allowing administration of active doses of both agents and achieving mTOR signaling inhibition. A phase II study to assess the activity of this combination in sarcomas is ongoing.