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Investigational New Drugs

Elena Elez, Carlos Gomez-Roca, Arturo Soto Matos-Pita, Guillem Argiles, Thibaud Valentin, Cinthya Coronado, Jorge Iglesias, Teresa Macarulla, Sarah Betrian, Salvador Fudio, Katrin Zaragoza, Josep Tabernero, Jean-Pierre Delord
Background Plocabulin (PM060184) is a novel marine-derived microtubule inhibitor that acts as an antitumor agent. This first-in-human study evaluated dose-limiting toxicities (DLT) to define the maximum tolerated dose (MTD) and phase II recommended dose (RD) of plocabulin given as a 10-min infusion on Day (D) 1, D8 and D15 every four weeks. Patients and methods Forty-four patients with advanced solid tumors received plocabulin following an accelerated titration design. Results Plocabulin was escalated from 1...
November 9, 2018: Investigational New Drugs
Kei Saito, Hiroyuki Isayama, Yousuke Nakai, Naminatsu Takahara, Kazunaga Ishigaki, Tsuyoshi Takeda, Ryunosuke Hakuta, Tomotaka Saito, Rie Uchino, Takahiro Kishikawa, Tsuyoshi Hamada, Suguru Mizuno, Takashi Sasaki, Hirofumi Kogure, Saburo Matsubara, Natsuyo Yamamoto, Hideaki Ijichi, Keisuke Tateishi, Minoru Tada, Kazuhiko Koike
Purpose Our previous phase I trial suggested feasibility of addition of leucovorin (LV) to S-1 and gemcitabine therapy in advanced pancreatic cancer. The aim of this phase II trial was to assess the efficacy and toxicity of gemcitabine, S-1 and LV (GSL) combination therapy for advanced pancreatic cancer. Methods Chemotherapy-naïve patients with histologically or cytologically proven advanced pancreatic cancer were enrolled. Gemcitabine was administered at a dose of 1000 mg/m2 by 30 min infusion on days 1, S-1 40 mg/m2 orally twice daily and LV 25 mg orally twice daily on days 1 to 7 every 2 weeks...
November 9, 2018: Investigational New Drugs
Pedro C Barata, Matthew Cooney, Prateek Mendiratta, Ruby Gupta, Robert Dreicer, Jorge A Garcia
Background Mammalian target of rapamycin (mTOR) pathway and angiogenesis through vascular endothelial growth factor (VEGF) have been shown to play important roles in prostate cancer progression. Preclinical data in prostate cancer has suggested the potential additive effect dual inhibition of VEGF and mTOR pathways. In this phase I/II trial we assessed the safety and efficacy of bevacizumab in combination with temsirolimus for the treatment of men with metastatic castration-resistant prostate cancer (mCRPC)...
November 7, 2018: Investigational New Drugs
Xiaofei Zhou, Sandeepraj Pusalkar, Swapan K Chowdhury, Shawn Searle, Yuexian Li, Claudio Dansky Ullmann, Karthik Venkatakrishnan
Aims This two-part, phase I study evaluated the mass balance, excretion, pharmacokinetics and safety of the investigational aurora A kinase inhibitor, alisertib, in three patients with advanced malignancies. Methods Part A; patients received a single 35-mg dose of [14 C]-alisertib oral solution (~80 μCi total radioactivity [TRA]). Serial blood, urine, and fecal samples were collected up to 336 h post-dose for alisertib mass balance and pharmacokinetics in plasma and urine by liquid chromatography-tandem mass spectrometry, and mass balance/recovery of [14 C]-radioactivity in urine and feces by liquid scintillation counting...
November 6, 2018: Investigational New Drugs
Melissa A Reimers, Maryann M Shango, Stephanie Daignault-Newton, Rachel Dedinsky, Danielle Karsies, Shawna Kraft, Liam Riddle, Jeremy A Felton, Bo Wen, Christina Gersch, James M Rae, Bruce G Redman, Ajjai S Alva
Background Pazopanib is approved for metastatic renal cell carcinoma (RCC). We assessed the safety and efficacy of pazopanib with a low fat meal (LFM): <400 cal and < 20% fat or 10 g per meal. Methods A single arm study of pazopanib with a LFM in 16 adult patients with metastatic RCC with a clear cell component, RECIST 1.1 measurable disease, ECOG PS ≤ 2, and ≤ 3 prior therapies. Pazopanib at 400 mg daily given with LFM for 12 weeks. Incremental dose increases up to 800 mg, or irreversible decreases to 200 mg, allowed every 2 weeks...
November 5, 2018: Investigational New Drugs
Fen Wang, Julian Molina, Daniel Satele, Jun Yin, Vun-Sin Lim, Alex A Adjei
Introduction Vatalanib is an oral receptor tyrosine kinase inhibitor that blocks all known VEGF, PDGF, and c-Kit receptors. This phase I study evaluated the safety, tolerability, and biologic activity of the combination of vatalanib with pemetrexed disodium in patients with advanced solid tumors. Methods Patients were administered escalating twice daily doses of vatalanib in combination with pemetrexed disodium in 21-day cycles. A dose expansion cohort was enrolled to further define the maximum tolerated dose (MTD) and further evaluate efficacy...
October 31, 2018: Investigational New Drugs
Eriko Yokoi, Seiji Mabuchi, Kotaro Shimura, Naoko Komura, Katsumi Kozasa, Hiromasa Kuroda, Ryoko Takahashi, Tomoyuki Sasano, Mahiru Kawano, Yuri Matsumoto, Michiko Kodama, Kae Hashimoto, Kenjiro Sawada, Tadashi Kimura
Objective The objective of this study was to evaluate the antitumor effects of lurbinectedin on cervical cancer with a special focus on its effects on cancer stem cells (CSCs). Methods Using two cervical cell lines (ME180 and CaSki cells), the antitumor effects of lurbinectedin were assessed in vitro using the MTS assay and colony formation assay. The growth inhibitory effects of paclitaxel and cisplatin were also evaluated as controls. By employing ALDH1 activity as a marker of CSCs, the antitumor effects of lurbinectedin on cervical CSCs and non-CSCs were individually evaluated...
October 30, 2018: Investigational New Drugs
Huijun Zhao, Juan Ma, Ting Lei, Wanru Ma, Man Zhang
Expression of CD155 differs between tumor and normal tissues, and high expression of this molecule can promote tumor metastasis. Here, we investigate whether CD155 can serve as a target for T cell-mediated immunotherapy of human prostate cancer. We first demonstrate that prostate cancer cells, including PC-3, PC-3 M, and LNCAP cells, express CD155 at high levels. Next, the specific cytotoxic activity of activated T cells (ATCs) armed with a novel anti-CD3 × anti-CD155 bispecific antibody (CD155Bi-Ab) against tumor cells was evaluated by flow cytometry, lactate dehydrogenase assay (LDH), and ELISA...
October 29, 2018: Investigational New Drugs
Y Cai, Fei Wang, Q Liu, Z Li, D Li, Z Sun
Currently, immune checkpoint inhibitors have been shown to extend the survival of many cancer patients. However, few studies have focused on immune checkpoint inhibition for the treatment of patients with oral squamous cell carcinoma (OSCC). Here, by screening at an early stage, we obtained a strain of anti-PD-1 monoclonal antibody (mAb) that targets programmed cell death-1 (PD-1) does not contain the CH1 and CL fragment. In this study, the role of our novel mAb was tested in the treatment of OSCC in vitro and in vivo...
October 27, 2018: Investigational New Drugs
Paul Berveiller, Olivier Mir, Séverine A Degrelle, Vassilis Tsatsaris, Lise Selleret, Jean Guibourdenche, Danièle Evain-Brion, Thierry Fournier, Sophie Gil
Introduction The use of paclitaxel in pregnant cancer patients is feasible in terms of fetal safety, but little is known about the effects of paclitaxel on the placenta. Using three experimental models, we aimed to assess the effects of paclitaxel on the expression of placental drug transporters. Methods In the in vitro model (human primary trophoblast culture), trophoblasts were isolated from normal term placentas and subsequently exposed to paclitaxel. The transcriptional regulation of 84 genes encoding for drug transporters, and the protein expression of ABCB1/P-gp and ABCG2/BCRP were assessed...
October 26, 2018: Investigational New Drugs
Wei Wang, Hua-Fu Zhao, Teng-Fei Yao, Hao Gong
Osteosarcoma (OS) is the most common primary aggressive and malignant bone tumor. Newly diagnostic OS patients benefit from the standard therapy including surgical resection plus radiotherapy and neoadjuvant chemotherapy (MAP chemotherapy: high-dose methotrexate, doxorubicin and cisplatin). However, tumor recurrence and metastasis give rise to a sharp decline of the 5-year overall survival rate in OS patients. Little improvement has been made for decades, urging the development of more effective therapeutic approaches...
October 24, 2018: Investigational New Drugs
Giandomenico Roviello, Roberto Petrioli, Alberto Bonetta, Raffaele Conca, Maria Grazia Rodriquenz, Michele Aieta
The aim of this retrospective study is to evaluate the activity and safety of a steroidal switch from prednisone to dexamethasone in patients with advanced, heavily pre-treated, castration-resistant prostate cancer (CRPC) who progressed on abiraterone acetate. Treatment consisted of oral daily abiraterone plus dexamethasone (0.5 mg once daily) administered until disease progression or unacceptable toxicity. Thirty-six patients were evaluated: all men underwent a prior treatment with enzalutamide. A PSA decrease ≥50% was observed in 11% of patients; median progression-free survival was 10...
October 22, 2018: Investigational New Drugs
Nan Liu, Zhe Jin, Jing Zhang, Jianjun Jin
Two novel series of 1,2,3-triazole-phenothiazine hybrids and dithiocarbamate-phenothiazine hybrids were designed and synthesized by molecular hybridization strategy. Their antiproliferative activity against three gastric cancer cell lines (MKN28, MGC-803 and MKN45) were evaluated. Among them, hybrid 13h displayed the most potent inhibitory activity against gastric cancer MGC-803 cells with an IC50 value of 1.2 μM. Hybrid 13h could inhibit migration by regulating the expression level of N-cadherin, E-cadherin, Vimentin, and actived-MMP2...
October 22, 2018: Investigational New Drugs
Laura W Goff, Nilofer S Azad, Stacey Stein, Jennifer G Whisenant, Tatsuki Koyama, Ulka Vaishampayan, Howard Hochster, Roisin Connolly, Amy Weise, Patricia M LoRusso, Safia N Salaria, Wael El-Rifai, Jordan D Berlin
The authors would like to note that the investigator affiliations have been corrected to reflect the actual affiliations of each author. The authors would also like to note an amendment to the first name of the second author. Nilo Azad was changed to reflect the full name of the author, which is Nilofer S. Azad as shown above. The original article has been corrected.
October 18, 2018: Investigational New Drugs
Peng-Jin Mei, Jin Bai, Fa-An Miao, Zhong-Lin Li, Chen Chen, Jun-Nian Zheng, Yue-Chao Fan
Recently, XRCC1 polymorphisms were reported to be associated with glioma in Chinese population. However, only a few studies reported on the XRCC1 expression, and cancer progression. In this study, we investigated whether XRCC1 plays a role in glioma pathogenesis. Using the tissue microarray technology, we found that XRCC1 expression is significantly decreased in glioma compared with tumor adjacent normal brain tissue (P < 0.01, χ2 test) and reduced XRCC1 staining was associated with WHO stages (P < 0...
October 17, 2018: Investigational New Drugs
Inhwan Hwang, Jihoon Kang, Hei Nga Natalie Ip, Jae Ho Jeong, Kyu-Pyo Kim, Heung-Moon Chang, Changhoon Yoo, Baek-Yeol Ryoo
Background Nab-paclitaxel plus gemcitabine (AG) is standard first-line chemotherapy for patients with metastatic pancreatic cancer (mPC). However, prognostic factors for patients with mPC treated with AG, are largely unknown. We retrospectively identified prognostic factors, including inflammation-based prognostic scores, in patients with mPC, and recurrent pancreatic cancer treated with AG as first-line treatment. Method A total of 203 patients with histologically-confirmed recurrent or metastatic pancreatic cancer who were treated with first-line AG in Asan Medical Center, Seoul, Korea, between February 2016 and December 2016 were included in this analysis...
October 16, 2018: Investigational New Drugs
Naminatsu Takahara, Yousuke Nakai, Hiroyuki Isayama, Takashi Sasaki, Kei Saito, Hiroki Oyama, Sachiko Kanai, Tatsunori Suzuki, Tatsuya Sato, Ryunosuke Hakuta, Kazunaga Ishigaki, Tsuyoshi Takeda, Tomotaka Saito, Suguru Mizuno, Hirofumi Kogure, Minoru Tada, Kazuhiko Koike
Purpose The survival benefit of first-line chemotherapy (CT1) for biliary tract cancer (BTC) is now established but the role of second-line chemotherapy (CT2) has not been fully elucidated yet. Methods Consecutive advanced BTC patients receiving CT1 between 2000 and 2016 were retrospectively studied. We investigated the safety and efficacy of CT2, prognostic factors for residual survival after CT1, and explored subgroups who would benefit from CT2. Results Among 294 patients receiving CT1 for advanced BTC, CT2 was given in 139 patients (47%)...
October 15, 2018: Investigational New Drugs
J R Goffin, G Nicholas, M Mates, D Tu, E Chen, S A Laurie, R Juergens, A Robinson, G Goss, M Reaume, S Sun, K Christink, C Maize, S MacFarlan, X Sun, H Ritter, L Seymour, P A Bradbury
Introduction Selumetinib (AZD6244, ARRY-142886) is a potent inhibitor of MEK1/2, thereby inhibiting phosphorylation of ERK2. We investigated the toxicity and the recommended phase II dose of the combination of selumetinib with two platinum based first line chemotherapy combinations in non-small cell lung cancer. Methods This was a phase I trial of escalating doses of selumetinib with carboplatin (AUC 6), paclitaxel (200 mg/m2 ) (cohort 1) or pemetrexed (500 mg/m2 ) and cisplatin (75 mg/m2 ) (cohort 2) in patients with chemotherapy naïve, advanced or metastatic NSCLC...
October 13, 2018: Investigational New Drugs
Audrey E Kam, Gopichand Pendurti, Umang H Shah, Mohammad H Ghalib, Imran Chaudhary, Jennifer Chuy, Lakshmi Rajdev, Andreas Kaubisch, Santiago Aparo, Ioannis Mantzaris, Sanjay Goel
Background Patients with metastatic colorectal cancer (mCRC) who progress on standard therapies may be eligible for phase I trials. To better delineate the risk-benefit ratio, we assessed toxicities, clinical outcomes and prognostic factors. Methods Records of mCRC patients on phase I trials at our institution over 18 years were reviewed. Univariable (UVA) and multivariable analyses (MVA) were undertaken and a prognostic model developed. Results There were 187 enrollments on 37 phase I trials. Median age was: 59 (29-83) years and number of prior therapies: 3 (0-8)...
October 12, 2018: Investigational New Drugs
Clinton Yam, Rashmi K Murthy, Gaiane M Rauch, James L Murray, Ronald S Walters, Vicente Valero, Abenaa M Brewster, Robert C Bast, Daniel J Booser, Sharon H Giordano, Francisco J Esteva, Wei Yang, Gabriel N Hortobagyi, Stacy L Moulder, Banu Arun
Background Imatinib mesylate is a potent inhibitor of the Abl, KIT and platelet derived growth factor (PDGF) receptor tyrosine kinases. Preclinical data suggest that combining imatinib mesylate with anti-estrogen therapy may be synergistic in hormone receptor-positive breast cancer. We report results of the first phase II trial evaluating the efficacy of the novel combination of imatinib mesylate and letrozole in the treatment of postmenopausal women with metastatic breast cancer. Patients and Methods 45 postmenopausal women with hormone receptor-positive metastatic breast cancer whose tumors demonstrated c-kit and/or PDGFR-β positivity were treated with imatinib mesylate 400 mg PO twice daily and letrozole 2...
October 11, 2018: Investigational New Drugs
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