bluuebunny/crossref_metadata_2025 huggingface dataset:
An exploratory study to investigate the immunomodulatory activity of BMS-936558 in patients with metastatic clear-cell renal cell carcinoma.
Authors: Drake Charles G. , Fishman Mayer N. , Curti Brendan D. , Kim Jenny J. , Stadler Walter Michael , McNeel Douglas G. , Choueiri Toni K. , Redman Bruce , Hudes Gary R. , Jure-Kunkel Maria , McDonald Dan , Gupta Ashok Kumar , Pathak Ashutosh Kumar , Wigginton Jon , Sznol Mario
Published: March 2020

TPS2613

Background: With the enhanced understanding of the immune response to a tumor, new immunotherapeutic agents may expand treatment options for metastatic renal cell carcinoma (mRCC). The programmed death-1 (PD-1) receptor is upregulated by activated lymphocytes, and upon binding to its ligands, inhibits lymphocyte function. In a phase 1 study of the anti-PD-1 monoclonal antibody BMS-936558, encouraging antitumor activity has been observed in patients with previously treated mRCC. Responses occurred in extensive mRCC and were durable in many patients. Here we describe an exploratory study to investigate the immune-regulatory activity of various doses of BMS-936558 in patients with metastatic clear-cell RCC. Methods: Eighty patients with metastatic clear-cell RCC will be enrolled in this open-label, parallel group, randomized study. Patients who have received prior treatment with ≥3 therapies, including ≥1 anti-angiogenic therapy, will be enrolled in Arms 1-3 (~20 patients per arm); 20 treatment-naïve patients will be enrolled in Arm 4. BMS-936558 will be administered every 3 weeks until disease progression or unacceptable toxicity at 0.3 mg/kg (Arm 1), 2 mg/kg (Arm 2), and 10 mg/kg (Arms 3 and 4). Patients in the 0.3-mg/kg group may escalate to 2 mg/kg if not responding. Tumor assessments will occur every 6 weeks for the first 12 months then every 12 weeks for the remainder of the study. The primary objective is to evaluate the effects of BMS-936558 on the frequency of circulating immune cell subsets, levels of soluble factors associated with immune responses, and tumor infiltrating lymphocyte populations (based on pre-treatment and week 5 paired biopsies). Secondary objectives are to assess the safety, tolerability, antitumor activity, and immunogenicity of BMS-936558. Exploratory objectives include the association of clinical activity and safety with selected biomarkers in peripheral blood and tumor microenvironment and the characterization of the pharmacokinetics of BMS-936558. As of February 1, 2012, 30 patients were enrolled.
A phase I study of BMS-936558 in combination with gemcitabine/cisplatin, pemetrexed/cisplatin, or carboplatin/paclitaxel in patients with treatment-naive, stage IIIB/IV non-small-cell lung cancer.
Authors: Gettinger Scott N. , Rizvi Naiyer A. , Shepherd Frances A. , Chow Laura Q. , Laurie Scott Andrew , Spigel David R. , Sbar Eric , Shen Yun , Brahmer Julie R.
Published: March 2020

TPS2615

Background: Lung cancer is the leading cause of cancer-related mortality worldwide and non-small-cell lung cancer (NSCLC) accounts for ~85% of all cases. Platinum-based chemotherapy alone or in combination with bevacizumab is considered first-line standard of care for advanced NSCLC. Despite such therapy, most patients (pts) will experience disease progression within 6 months and die from their disease within 1 year. Programmed death-1 (PD-1) is a coinhibitory receptor that negatively regulates T-cell activation; PD-1 expression by tumor infiltrating lymphocytes is associated with poor prognosis in NSCLC. BMS-936558 is a fully human anti-PD-1 monoclonal antibody that blocks ligand interaction with PD-L1 and PD-L2. In a phase 1 trial, BMS-936558 had antitumor activity at doses of 1-10 mg/kg in pts with advanced tumors, and impressive tumor responses in heavily pre-treated pts with NSCLC. Here we describe a phase 1 study planned to evaluate the safety and tolerability of BMS-936558 in combination with 3 standard, platinum-based doublet chemotherapy regimens in pts with NSCLC. Methods: Treatment-naïve pts with stage IIIB/IV NSCLC will be enrolled. Treatment arms will include: A) gemcitabine 1250 mg/M2 on day 1 (D1) and day 8 (D8)/cisplatin 75 mg/M2 D1/BMS-936558 D1; B) pemetrexed 500 mg/M2 D1/cisplatin 75 mg/M2 D1/BMS-936558 D1; and C) carboplatin AUC 6 D1/paclitaxel 200 mg/M2 D1/BMS-936558 D1. The starting dose of BMS-936558 will be 10 mg/kg for each treatment arm. A decision to de-escalate to a lower dose (2 or 0.3 mg/kg) will be guided by the number of dose-limiting toxicities reported per treatment arm. Chemotherapy will be given for 4 cycles (1 cycle = 3 weeks). BMS-936558 will be administered every 3 weeks until disease progression, intolerable toxicity, or withdrawal of consent. The primary objectives are to assess safety and tolerability by measuring the frequency of adverse events (AEs), serious AEs, and laboratory abnormalities; secondary objectives are to determine the overall response rate and disease control rates based on RECIST 1.1. As of February 1, 2012, 2 patients were enrolled.
Safety, pharmacokinetics, and antitumor activity of MEDI-573, an investigational monoclonal antibody that targets IGF-I and IGF-II, in adult patients with advanced solid tumors.
Authors: Haluska Paul , Menefee Michael E. , Plimack Elizabeth R. , Rosenberg Jonathan E. , Northfelt Donald W. , LaVallee Theresa , Huang Wenmei , Yu Xiang-Qing , Viner Jaye , LoRusso Patricia
Published: March 2020

TPS2618

Background: MEDI-573 is an investigational dual-targeting human antibody that neutralizes IGF-I/-II ligands and inhibits IGF‑1R and insulin receptor-A (IR-A) signaling pathways. By sparing IR-B and its hybrid receptors, MEDI-573 may achieve antitumor activity without perturbing glucose homeostasis. Objectives of this phase 1 dose-escalation and expansion study are to evaluate safety and determine the maximum tolerated dose (MTD), optimal biologically effective dose, pharmacokinetics, pharmacodynamics, and immunogenicity of MEDI-573 in adult patients with solid tumors. Methods: Patients with advanced solid tumors, Karnofsky status ≥60, and adequate organ function were treated with escalating doses of MEDI-573 IV once weekly (0.5 to 15 mg/kg) or every 3 weeks (30 or 45 mg/kg q3w) using a 3+3 design. Three patients per dose level were evaluated for safety. A biomarker-rich dose-expansion arm tested weekly 5 or 15 mg/kg MEDI‑573 in patients with advanced bladder cancer. Results: Preliminary data are presented for 43 patients (25 M, 18 F), median age 64 years. No dose-limiting toxicities or serious toxicity patterns occurred at any dose level. Drug-related adverse events occurring in ≥10% of patients were fatigue (28%), decreased appetite (23%), nausea (16%), diarrhea (14%), and anemia (12%); the majority were ≤ grade 2. Perturbations in insulin and growth hormone were not observed. Clinically significant changes in serum glucose were rare. The MTD was not reached after completely enrolling patients through the highest dose, 45 mg/kg IV q3w. Serum exposure of MEDI-573 increased with increasing dose. Full suppression of IGF‑I/-II was achieved with weekly and q3w dosing. No neutralizing antibodies against MEDI‑573 were detected. Of 43 patients, 8 (19%) had stable disease ≥12 weeks. The longest exposure was 21 months in a patient with well-differentiated liposarcoma. Conclusions: MEDI-573 demonstrated an acceptable safety profile at all doses tested. No dose-limiting toxicity or serious toxicities, including those related to glucose homeostasis, were detected. These preliminary results support further clinical development.
A phase I clinical trial of autologous, anti-CD19 gene targeted T cells for adults with B cell acute lymphoblastic leukemia (B-ALL).
Authors: Davila Marco L. , Riviere Isabelle , Wang Xiuyan , Bartido Shirley , Stefanski Jolanta , Taylor Clare , Olszewska Malgorzata , Borquez-Ojeda Oriana , Qu Jinrong , Wasielewska Teresa , Frattini Mark G. , Sadelain Michel , Brentjens Renier J.
Published: March 2020

TPS2619

Background: Complete remission (CR) rates for B-ALL in adults is high (>80%), but overall survival remains low (approximately 30%). Patients with relapsed disease have a very poor prognosis with a median survival measured in months. Therefore, there is a dire need for novel therapies for adults with relapsed or minimal residual B-ALL. To this end we have developed a novel T cell therapy for B cell malignancies using patient derived T cells genetically modified to express the 19-28z chimeric antigen receptor (CAR), an artificial T cell receptor specific to the CD19 antigen expressed on most B cell tumors. Human T cells retrovirally modified to express the 19-28z CAR successfully targets and eradicates B cell tumors in vitro and systemic human B cell cancers in mice. We have recently published the results of our initial Phase I clinical trial experience (Brentjens, Rivière et al., Blood 2011) utilizing this technology in adults with chronic lymphocytic leukemia. These results suggest clinical activity and demonstrate a persistence of 19-28z+ T cells that is inversely associated with tumor burden. These studies suggest that 19-28z+ T cells may be particularly effective in relapsed B-ALL because these tumors retain a degree of chemotherapy sensitivity, which will allow the infusion of T cells after salvage chemotherapy when patients have low tumor burdens. To our knowledge, this is the first clinical trial using autologous CD19 targeted T cells in adults with B-ALL. Methods: We are enrolling patients to a Phase I T cell dose escalation trial (NCT01044069). Adults with CD19+ B-ALL classified as a CR, relapsed, or refractory are eligible for enrollment. After patients are enrolled they are leukapheresed to obtain peripheral blood T cells, which are then retrovirally transduced to express the 19-28z CAR and expanded in our GMP gene transfer facility. Enrolled patients with relapsed or refractory B-ALL undergo a cycle of re-induction chemotherapy and conditioning cyclophosphamide followed by infusion of autologous 19-28z+ T cells. To date, 11 patients have been enrolled and 2 patients have been infused with 19-28z+ T cells.
Design of a phase I clinical trial with PNT2258, a novel DNA interference oligonucleotide (DNAi), in patients with advanced solid tumors.
Authors: Rasco Drew Warren , Tolcher Anthony W. , Patnaik Amita , Papadopoulos Kyriakos P. , Amaya Alex , Gaylor Shari , Moore Timothy David , Forgey Robert , Goodwin Neal , Bisgaier Charles L. , Rodrigueza Wendi V.
Published: March 2020

TPS3110

Background: With the knowledge that Bcl-2 facilitates drug resistance and cell survival, a DNA interference (DNAi) strategy was applied to silence Bcl-2 in cancer cells and promote apoptosis. DNAi differs from cytoplasmic mRNA targeting (antisense, RNAi, and miRNA targets) as it targets genomic DNA, blocking transcription. PNT100, a first in class DNAi, is a novel single-stranded 24-base unmodified DNA designed to bind to an upstream region of the Bcl-2 promoter. The drug product (PNT2258) is PNT100 encapsulated in a specialized pH tunable liposome and is being assessed for safety and tolerability in a phase I trial. PNT2258 avoids the toxicities associated with modified oligonucleotides and double-stranded RNAs; since the liposome formulation is anionic and contains no surface spacers, vehicle toxicities are minimal. Xenograft experiments demonstrated marked single agent activity in a diffuse large cell lymphoma, and therapy potentiation when combined with either rituximab in Daudi-Burkitt’s Lymphoma or docetaxel in A375 melanoma. Methods: An open-label, single-arm, first-in-man phase I dose-escalation study of PNT2258 in patients with advanced solid tumors was designed to evaluate safety, tolerability, dose-limiting toxicities, pharmacokinetics, and pharmacodynamics of PNT2258 to recommend a dose for phase II studies. In this phase I study, pharmacodynamic effects of PNT2258 will be evaluated through analyses of soluble serum and plasma markers and peripheral blood mononuclear cells. Patients will receive PNT2258 as an intravenous infusion over 2 hours once daily for 5 consecutive days (days 1-5) of each 21-day treatment cycle (3 weeks). The starting dose of 1 mg/m2 with PNT2258 administered to one patient per cohort and dose-escalation will proceed by dose-doubling in each successive cohort until a dose level of 64 mg/m2 is attained, provided no dose-limiting toxicities are observed in cycle 1. Thereafter, dose escalations shall proceed at 33% increments of the previous cohort dose-level to 85, 113, and 150 mg/m2 with expansions of up to six patients per cohort as needed. The ten planned dose cohorts have been completed with all patients enrolled.
A phase I and pharmacologic study of MM-111, a bispecific HER2/HER3 antibody fusion protein, in combination with multiple treatment regimens in patients with advanced HER2-positive solid tumors.
Authors: Richards Donald A. , Braiteh Fadi S. , Anthony Stephen Patrick , Edenfield Jeff , Hellerstedt Beth A. , Raju Robert N. , Conkling Paul , Smith David A. , Becerra Carlos , Cohn Allen Lee , Denlinger Crystal Shereen , Garbo Lawrence E. , Wu Hillary H. , Garcia Agustin , McDonagh Charlotte , Frye Sasha , Agresta Samuel V. , Moyo Victor M.
Published: March 2020

TPS3111

Background: The HER2/HER3 oncogenic heterodimer is a potent HER receptor pairing with respect to strength of interaction, receptor tyrosine phosphorylation, and downstream signaling through mitogen activated protein kinase and phosphoinositide-3 kinase pathways. MM-111 is a novel bispecific antibody fusion protein that inhibits ligand activated HER3 signaling through abrogation of ligand binding specifically in HER2 overexpressing tumors. In preclinical models of HER2+ solid tumors, MM-111 inhibits ligand-induced HER3 phosphorylation, cell cycle progression, and tumor growth. HER2 is a well-established target of anticancer agents such as trastuzumab and lapatinib, specifically in breast and gastric tumors. Preclinical data demonstrate that MM-111 potentiates the antitumor activity of both trastuzumab and lapatinib and this phase I study seeks to determine if MM-111 can be safely used in combination with various standard of care HER2 targeting regimens, namely; (1) trastuzumab, cisplatin and, capecitabine, (2) trastuzumab and lapatinib, and (3) trastuzumab and paclitaxel. Methods: This is a multi-arm phase I, open label, multicenter, dose-escalation study of MM-111 in an add-on design that evaluates the safety, pharmacokinetics (PK), and anti-tumor activity of MM-111 in combination. Each arm is designed to run as a separate phase I study to address safety and tolerability of each combination. For eligibility, patients are required to have documented advanced HER2-positive cancer, with adequate bone marrow, hepato-renal and cardiac function. The dose escalation for each arm utilizes a standard “3 + 3” design with MM-111 dosed initially at a moderate dose of 10 mg/kg and escalated up to 20 mg/kg to identify a phase II dose in combination with each regimen. Once the maximum tolerated dose or phase II dose is identified, expansion cohorts will accrue to further evaluate these combinations. The flexibility of the design allows additional combinations arms to be added. Key exploratory analyses will include an evaluation of safety, PK, and efficacy as evidenced by best overall response and duration of response.
Phase lb combination trial of a MEK inhibitor, pimasertib (MSC1936369B), and a PI3K/mTOR inhibitor, SAR245409, in patients with locally advanced or metastatic solid tumors.
Authors: Infante Jeffrey R. , Gandhi Leena , Shapiro Geoffrey , Burris Howard A. , Bendell Johanna C. , Baselga José , Hsu Karl , Faivre Théa , Asatiani Ekatherine , Heist Rebecca Suk
Published: March 2020

TPS3118

Background: The PI3K/mTOR and MAPK signaling pathways are frequently aberrantly activated in tumors and interact to promote growth and resistance to treatment. Simultaneous inhibition of both pathways may enhance antitumor activity. This trial investigates the combination of pimasertib, a highly selective MEK1/2 inhibitor, and SAR245409, a dual PI3K/mTOR inhibitor (ClinicalTrials.gov NCT01390818). Maximum tolerated dose (MTD) when administered once daily (qd) as a single agent to solid tumor patients (pts) is 90 mg for both compounds. Methods: Pts with advanced solid tumors characterized by frequent alterations of the MAPK or PI3K/mTOR pathways (pancreatic, thyroid, colorectal, non-small cell lung, endometrial, renal, breast, ovarian and melanoma) and/or with identified alterations in genes activating these pathways, adequate performance status and organ function, and no retinal disease are eligible for entry. The primary objective of the trial is to determine the MTD of the combination therapy. Secondary objectives include: safety, pharmacokinetics (PK), pharmacodynamics (PD), biomarker identification and antitumor efficacy (response rate via RECIST v1.1). Both compounds are dosed together qd continuously in 21 day cycles. The study uses a classical 3 + 3 design, with modified Fibonacci (decreasing increments) dose escalation based on occurrence of dose-limiting toxicities (DLTs). In parallel with dose escalation, more pts may be enrolled in already tested lower dose level (DL) cohorts to further evaluate PK, PD, safety and antitumor activity. After MTD confirmation, additional pts may be enrolled in up to 4 disease-specific cohorts based on scientific rationale, and observed preclinical and clinical activity signals. As of January 25th 2012, 20 pts have been treated. No DLTs have been reported.
The GAIN-C study (BP25438): Randomized phase II trial of RG7160 (GA201) plus FOLFIRI, compared to cetuximab plus FOLFIRI or FOLFIRI alone in second-line KRAS wild type (WT) or mutant metastatic colorectal cancer (mCRC).
Authors: Cervantes-Ruiperez Andres , Markman Ben , Siena Salvatore , Pericay Carles , Aprile Giuseppe , Bridgewater John A. , Cubillo Antonio , Waterston Ashita Marie , Garcia-Carbonero Rocio , Kozloff Mark , McKendrick Joseph James , Samuel Leslie M. , Perez-Fidalgo Jose Alejandro , Strickland Andrew H. , Bencardino Katia , Moya Irene , Lutrino Stefania Eufemia , Mancao Christoph , Manenti Luigi , Tabernero Josep
Published: March 2020

TPS3637

Background: GA201 is a novel, dual-acting, humanized, glycoengineered IgG1 anti-EGFR monoclonal antibody, with enhanced antibody-dependent cellular cytotoxicity (ADCC) activity in combination with signal inhibition. GA201 demonstrates significantly enhanced in vitro/vivo activity compared to cetuximab (cet) both as a single agent and in combination with irinotecan, in both KRAS mutant and BRAF mutant models and promising clinical activity in ph I and neo-adjuvant trials (Paz Ares et al, JCO 2011) including KRAS mutant mCRC. A randomized ph II program was launched: one study in NSCLC and GAIN-C in mCRC (NCT01326000), which is presented here. Methods: Main inclusion criteria are progression on 1L containing oxaliplatin, ECOG 0-1, and adequate hematological and liver function. Main exclusion criteria: prior anti-EGFR treatment. A total of 160 patients in 2L mCRC (stratified for EGFR expression, disease progression before or after 6 months after starting 1L, prior treatment with bevacizumab Y vs N) will be randomized to receive either GA201 (day 1, 8 of cycle 1 then q2W) or cet (qW) + FOLFIRI q2W (KRAS WT) or to receive GA201+ FOLFIRI or FOLFIRI alone (KRAS mutant). Collection of archival tumor plus a mandatory fresh tumor biopsy at baseline were implemented because ph I data showed that EGFR expression is not concordant between the two specimen types and to optimize assessment of potential immune related biomarkers. The fresh tumor biopsy will be centrally analyzed for EGFR (immunohistochemistry) and KRAS status. Primary objective is progression free survival; secondary endpoints are to define objective response rates, the safety profile, pharmacokinetics and pharmacodynamics. A comprehensive biomarker program (blood and tumor), mainly immune-phenotyping, immunohistochemistry in tumor samples (Ventana) and immune functional tests (including adaptive responses) were set up to investigate potential predictive biomarkers and the mode of action of GA201. Study is ongoing worldwide in 9 countries with the safety run-in phase completed in Nov 2011. Recruitment is planned to be completed by end of April 2012.
A pilot trial of a combination of therapeutic vaccines (GI-4000 and GI-6207) as adjunctive therapy with first-line therapy with bevacizumab plus either FOLFOX or FOLFIRI in stage IV patients with newly diagnosed Ras-mutant positive or negative metastatic colorectal cancer.
Authors: Marshall John , Hwang Jimmy J. , Pishvaian Michael J. , He Aiwu Ruth , Weiner Louis M. , Sandene Erin K. , Gulley James L. , Heery Christopher Ryan , Schlom Jeffrey , Speyer Sue , Richman Joni , Ferraro John , Coeshott Claire , Cohn Allen , Apelian David , Rodell Timothy C.
Published: March 2020

TPS3638

Background: A promising approach for the treatment of cancer is the development of vaccines that target specific tumor antigens. In the metastatic CRC patient population, targeted and active immunotherapy may inhibit cancer progression and improve survival. This trial is designed to evaluate the efficacy, immunogenicity, and safety of GI-4000 plus standard therapy in patients with metastatic colorectal cancer. GI-4000 is a proprietary immunotherapy that uses whole, heat-killed recombinant Saccharomyces cerevisiae yeast (called Tarmogens = Targeted Molecular Immunogens). GI-4000 is designed to activate a cellular immune response to target cells with activating ras mutations. Tarmogens have been shown to elicit selective killing of target cells that express a number of cancer antigens, including mutated Ras, by activation of antigenspecific T cell mediated responses. Methods: The study population consists of subjects with metastatic colorectal cancer with an activating mutation in ras. Newly diagnosed subjects receive FOLFOX (or FOLFIRI) + bevacizumab (Bev) + GI- 4000; 3 weekly injections of GI-4000 are followed by 8 cycles of Bev + FOLFOX (or FOLFIRI); day 1 and 2 every 14 days. Doses of GI-4000 are administered on day 8 of each cycle. Upon completion of chemotherapy, GI-4000 continues along with Bev maintenance every 2 weeks for up to 5 years or until subjects experience intolerance, disease recurrence, or death. If Bev is stopped, GI-4000 may continue on the same maintenance schedule alone. Subjects that have already completed standard chemotherapy (FOLFOX or FOLFIRI) may enter the study and receive Bev + GI-4000 every 2 weeks for up to 5 years. Enrollment is ongoing and will continue up to 52 subjects.
A randomized, double-blind, placebo-controlled, multicenter, multinational, phase II trial of L-BLP25 in patients with colorectal carcinoma following R0/R1 hepatic metastasectomy.
Authors: Schimanski Carl Christoph , Moehler Markus Hermann , Lang Hauke , Schoen Michael , Smith-Machnow Victoria , Kanzler Stephan , Hegewisch-Becker Susanna , Doerfel Steffen , Seehofer Daniel , Bechstein Wolf , Heike Michael , Overkamp Friedrich , Kullmann Frank , Voehringer Matthias , Heinemann Volker , von Wichert Goetz , Kasper Stefan , Greil Richard , Samonigg Hellmut , Galle Peter Robert
Published: March 2020

TPS3641^

Background: Approximately 15-20% of patients diagnosed with colorectal cancer (crc) develop metastatic disease. Surgical resection remains the only potentially curative treatment. 5-year survival following R0-resection of liver metastases lies ~28 -39%. Recurrence occurs in ~70% of pts. Adjuvant chemotherapy has not significantly improved clinical outcomes. The primary objective of the LICC trial (L-BLP25 in Colorectal Cancer) is to analyze whether L-BLP25, an active cancer immunotherapy, extends recurrence-free survival (RFS) time over placebo in colorectal cancer pts following R0/R1 resection of hepatic metastases. L-BLP25 targets MUC1 glycoprotein, which is highly expressed in hepatic metastases from crc. In a phase IIB trial, L-BLP25 showed acceptable tolerability and a trend toward longer survival in pts with stage IIIB NSCLC. Methods: This is a multinational, phase II, multicenter, randomized, double-blind, placebo-controlled trial with a sample size of 159 pts from 20 centers in 3 countries. Pts must have stage IV cr adenocarcinoma limited to liver metastases. Following complete resection of the primary tumor and all syn-/metachronous metastases, eligible pts are randomized 2:1 to receive either L-BLP25 or placebo. Those allocated to L-BLP25 receive a single dose of 300 mg/m2 cyclophosphamide (CP) 3 days before first L-BLP25 dose, then primary treatment with sc L-BLP25 930 μg once weekly for 8 weeks, followed by maintenance doses at 6-week (years 1 and 2) and 12-week (year 3) intervals until recurrence. In the control arm, CP is replaced by saline solution and L-BLP25 by placebo. Primary endpoint: RFS time. Secondary endpoints: OS time, safety status, tolerability, RFS/OS in MUC-1 positive cancers. Exploratory immune response analyses are planned. First recruitment was of Q3 2011. To date, 8 of 20 centers are initiated and 4 pts recruited. Completion of recruitment is scheduled for Q3 2013. Primary endpoint will be assessed in Q3 2016: Follow-up will end Q3 2017. No interim analysis is planned. Design and implementation of this vaccination study in colorectal cancer is feasible. No major issues identified during setup of the study.
FOLFIRI plus 5 mg/kg of bevacizumab versus 10 mg/kg as second-line therapy in patients with metastatic colorectal cancer who have failed first-line bevacizumab plus oxaliplatin-based therapy: A randomized phase III study (EAGLE Study).
Authors: Nakamura Masato , Mishima Hideyuki , Iwamoto Shigeyoshi , Takahashi Takao , Tamagawa Hiroshi , Munemoto Yoshinori , Hata Taishi , Denda Tadamichi , Morita Yoshitaka , Inukai Michio , Murata Akihiko , Kunieda Katsuyuki , Nagata Naoki , Kurachi Yoshitaka , Oshiro Takashi , Ina Kenji , Miyamoto Yuji , Shimoyama Tatsu , Oba Koji , Sakamoto Junichi
Published: March 2020

TPS3642

Background: There has been much controversy about continuation of bevacizumab (BV) with a second-line regimen after progression on a BV-containing first-line regimen. Recently, it was announced that a phase III study (AIO 0504 / ML 18147) met its primary endpoint of overall survival. It means BV-based regimen (5 mg/kg) extends survival when continued beyond initial treatment in patients with metastatic colorectal cancer(mCRC). The verified data from a randomized phase III study (E3200) indicates that BV at 10 mg/kg in the second-line setting followed by BV-naive treatment extends survival. The dose of BV 5 mg/kg could be lower than the recommended dose in the second-line CRC treatment. Thus we planned this second line phase III study (EAGLE study) to evaluate the appropriate dose of BV (5 or 10 mg/kg) with FOLFIRI in patients with mCRC who have failed BV plus oxaliplatin-based first line regimen. Methods: EAGLE is a multicenter randomized phase III study of FOLFIRI plus BV 5 mg/kg versus 10 mg/kg in mCRC who have failed BV plus oxaliplatin-based first line regimen (UMIN000002557).The primary endpoint is PFS. The secondary endpoints are the toxicity, response rate, time to treatment failure, OS. Eligible patients were older than 20 years of age, had histologically proved CRC, ECOG performance status 0 or 1, adequate organ function, progression or difficult to continue after BV plus oxaliplatin-based first line regimen, more than four times administration of BV and oxaliplatin in the first-line. Patients were randomized 1:1 to FOLFIRI with BV 5mg/kg or 10 mg/kg.The planned sample size was 370 patients to detect 30% risk reduction (median PFS assumed to be 5.0 months in arm A, 7.0 months in arm B) with 90% power assuming a two-sided significance level of 0.05, an accrual time of 2.5 years and a follow-up time of 1 year. Between September 2009 to January 2012, 387 patients were enrolled at 100 sites in Japan. This phase III study will answer the question of the appropriate dose of BV after progression on a BV-containing first-line regimen.
Dasatinib combined with gemcitabine (Gem) in patients (pts) with locally advanced pancreatic adenocarcinoma (PaCa): Design of CA180-375, a placebo-controlled, randomized, double-blind phase II trial.
Authors: Evans T.R. Jeffry , Van Cutsem Eric , Moore Malcolm J. , Purvis Joseph D. , Strauss Lewis C. , Rock Edwin P. , Lee Jennifer , Lin Chihche , Rosemurgy Alexander , Arena Francis P. , Gara Michelle , Armstrong Elizabeth , O'Dwyer Peter J.
Published: March 2020

TPS4134

Background: Dasatinib, a potent oral BCR-ABL and SRC family kinase (SFK) inhibitor, is approved for first- and second-line therapy of Philadelphia chromosome-positive chronic phase chronic myeloid leukemia (CML) in pts with newly diagnosed CML or CML resistant/intolerant to prior therapy. SRC expression and activity is upregulated in PaCa and correlates with reduced survival in resected high-grade PaCa (Morton, Gastroenterology 2010) and resistance to Gem, a PaCa standard of care (Duxbury, J Am Coll Surg 2004). In preclinical PaCa studies, inhibition of SFKs with dasatinib reduces tumor cell proliferation, migration, and invasion; increases apoptosis; sensitizes cells to Gem; and inhibits development of metastases in vivo either alone or in combination with Gem (Duxbury, Clin Cancer Res 2004; Duxbury, J Am Coll Surg 2004; Nagaraj, Mol Cancer Ther 2010; Morton, op cit). Phase I clinical studies of dasatinib and Gem therapy in PaCa have demonstrated feasibility and suggested efficacy of the combination (Uronis, ASCO 2009, abstract e15506). Methods: This double-blind phase II study tests whether addition of dasatinib to Gem is tolerable and improves efficacy in pts with histologically/cytologically confirmed unresectable locally advanced nonmetastatic PaCa. Eligible pts, aged ≥18 years with Eastern Cooperative Oncology Group performance status ≤1 and adequate organ function, are randomized 1:1 to Gem 1000 mg/m2 IV once weekly (Weeks 1–3 of a 4-week cycle) plus either dasatinib 100 mg once daily or matched placebo. Pts are treated until progression, unacceptable toxicity, withdrawal of consent, or study termination. The primary endpoint is OS, and secondary endpoints are progression-free survival and safety. Exploratory endpoints include freedom from distant metastases, measures of pain and fatigue, overall response rate, and carbohydrate antigen 19-9. Final study analysis will be conducted after 135 deaths; all pts will be followed for survival. To date, 23/200 pts have enrolled; estimated primary completion date is March 2013. ClinicalTrials.gov identifier: NCT01395017.
TOPGEAR: An international randomized phase III trial of preoperative chemoradiotherapy versus preoperative chemotherapy for resectable gastric cancer (AGITG/TROG/EORTC/NCIC CTG).
Authors: Leong Trevor , Smithers Mark , Michael Michael , Gebski Val , Boussioutas Alex , Miller Danielle , Zalcberg John Raymond , Wong Rebecca , Haustermans Karin
Published: March 2020

TPS4141

Background: Optimal management of patients with resectable gastric cancer remains unknown. Since the INT0116 and MAGIC trials, there are 2 standards of care for adjuvant therapy: postoperative chemoradiotherapy (CRT) and perioperative ECF chemotherapy. The important question arising from these studies is whether CRT is superior to chemotherapy alone as adjuvant therapy. This randomized phase II/III trial will compare CRT to chemotherapy alone in the preoperative setting. Methods: Patients with resectable adenocarcinoma of the stomach or gastroesophageal junction will be randomized to receive either preoperative chemotherapy alone (ECFx3 as per MAGIC regimen) or preoperative CRT (ECFx2 followed by 45Gy of radiation with concurrent 5-FU). Following surgery, both groups will receive 3 further cycles of ECF. The trial is being conducted in two Parts; Part I (phase II component) will recruit 120 patients with the aim of demonstrating sufficient efficacy and safety of preoperative CRT, as well as trial feasibility. Part II (phase III component) will recruit a further 632 patients to provide a total of 752. The primary endpoint for Part I is pathological complete response rate, and for Part 2 it is overall survival. The trial includes formal quality of life and biological sub-studies. In addition, the trial incorporates a rigorous quality assurance program that includes real time central review of radiotherapy plans and central review of surgical technique. Current status: This study is an international, intergroup trial led by the Australasian Gastro-Intestinal Trials Group (AGITG), in collaboration with the Trans-Tasman Radiation Oncology Group (TROG), European Organisation for Research and Treatment of Cancer (EORTC) and the NCIC Clinical Trials Group. To date, 36 patients have been recruited from 20 sites in Australia and New Zealand; European and Canadian sites will commence recruitment in 2012.
Design of a phase II randomized, open-label trial of DN24-02, an autologous cellular immunotherapy targeting HER2/neu, in patients with surgically resected urothelial cancer at high risk of recurrence.
Authors: Bajorin Dean F. , Sharma Padmanee , Sims Robert Brownell , Sandler Andrew , Lerner Seth P.
Published: March 2020

TPS4673

Background: Despite surgical resection and the use of (neo)adjuvant chemotherapy, up to 50% of patients with invasive urothelial carcinoma will have disease recurrence and eventually die of metastatic disease. New approaches are needed for these patients. Approximately 50% of patients with high-risk pathologic features have evidence of HER2 expression in the primary tumor or involved lymph nodes. DN24-02 is an autologous cellular immunotherapy targeting HER2, which is based on Dendreon’s Antigen Delivery Cassette technology – the same platform used for sipuleucel-T (an FDA-approved treatment for asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer). Each dose of DN24-02 is manufactured by culture of peripheral blood mononuclear cells obtained by leukapheresis with a recombinant antigen that comprises components of the intra- and extracellular domains of the HER2 antigen linked to GM-CSF. A product similar to DN24-02 has shown evidence of safety and immune response in phase I studies. Objectives: The primary objective is to determine whether DN24-02, given as adjuvant therapy following surgical resection, can prolong survival compared to standard of care (SOC). Secondary objectives are to evaluate disease-free survival, safety, and immune responses to DN24-02. Methods: Eligible patients will have undergone surgical resection of a primary urothelial cancer, with either ≥pT2 or pN+ staging, and HER2 expression ≥1+ by IHC based on pathologic review. Approximately 180 patients will be randomized (1:1) to receive three IV infusions of DN24-02 as adjuvant therapy approximately every 2 weeks, or SOC. Stratification will include 1) neoadjuvant chemotherapy vs surgery alone; and 2) positive (pN+) vs negative lymph node involvement (pN0). Other adjuvant chemotherapy will not be allowed. Patients can be treated per SOC if there is disease recurrence. Patients will be monitored for evidence of recurrence by imaging, and followed for survival. Cellular and serological immune responses will be assessed at baseline and post-DN24-02 therapy.
Neoadjuvant therapy preceding cytoreductive nephrectomy to develop individualized first-line therapy with everolimus for advanced renal cell carcinoma (RCC).
Authors: Sonpavde Guru , Amiel Gilad , Margulis Vitaly , Link Richard E , Lerner Seth P. , Raj Ganesh , Mayer Wesley A , Palapattu Ganesh S. , Lotan Yair , Sagalowsky Arthur I. , Higgins Linda C , Tello Sebrina A , Pavia-Jimenez Andrea , VonMerveldt Dendra , Brugarolas James
Published: March 2020

TPS4678

Background: Everolimus (E), an orally administered mTOR inhibitor, is the conventional agent for progressive disease following vascular endothelial growth factor (VEGF) inhibitors for advanced RCC. Given the excellent tolerability and convenient oral administration, a rationale may be made to develop E as first-line therapy for selected patients. The period between diagnosis and cytoreductive nephrectomy (CN) may be utilized for brief therapy to capture biologic activity in tumor tissue and facilitate individualized systemic therapy. The agent may be resumed following CN and continued until progression. Pharmacodynamic (PD) alterations from baseline to CN tumor tissue may predict progression-free survival (PFS). We hypothesized that the application of this paradigm to E may enable the employment of first-line E in patients predicted to optimally benefit. Methods: This is a 27-patient phase II trial being conducted at the Baylor College of Medicine and University of Texas Southwestern, and 5 patients have been enrolled currently. Patients with ≥3 poor risk factors or those who refuse or are ineligible for VEGF inhibitors and have untreated metastatic RCC are eligible. Adequate hematologic, renal and hepatic function is required. The primary endpoint is PFS and secondary endpoints are response, survival and toxicities. Exploratory endpoints are tumor tissue, peripheral blood mononuclear cell (PBMC) and plasma PD studies and pharmacokinetic (PK) studies, and their association with PFS. PD studies include DNA, mRNA, protein and miRNA studies to evaluate the mTORC1 among other pathways. Patients initially undergo 4 core biopsies of the primary renal mass for fresh frozen tumor. Patients then receive E 10 mg orally once daily for 3-5 weeks. CN is performed within 24-48 hours after the last dose of E. At the time of CN and before separation from the vascular supply, 3 core biopsies are performed. E is resumed 2-4 weeks after CN and continued until progression or intolerable toxicities. Clinical and laboratory assessments are performed every 4-5 weeks, and imaging is performed every 8 weeks. A progressing metastatic site will be biopsied (4 core biopsies).
EVERSUN: A phase II trial of everolimus alternating with sunitinib as first-line therapy for advanced renal cell carcinoma (RCC) (ANZUP trial 0901).
Authors: Davis Ian D. , Gebski Val , Chatfield Mark D. , Grimison Peter S. , Kannourakis George , Boland Amy L , Thompson Jennifer , Stockler Martin R. ,   Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP)
Published: March 2020

TPS4681

Background: Treatment of RCC has improved due to better understanding of its biology. New targeted therapies have improved time to progression and overall survival but the optimal sequencing of agents is unknown. Currently drugs are given sequentially, usually starting with sunitinib and often followed by an mTOR inhibitor or another VEGFR-targeted therapy, but resistance to both drugs eventually occurs probably due to host adaptive responses. We hypothesize that resistance might be delayed by planned alternation of treatments. Methods: EVERSUN is a single-arm, two-stage, multicenter, phase II clinical trial aiming to determine the activity and safety of an alternating regimen of two therapies with different targets (sunitinib and everolimus) in patients with advanced RCC. Key eligibility criteria: RCC with a clear cell component; metastatic or locally advanced disease not suitable for resection; ECOG performance status 0-1; low or intermediate MSKCC prognostic score. The primary endpoint is the status of being alive and progression-free (RECIST 1.1) 6 months after registration. Target accrual of 55 subjects gives 95% power and 95% confidence to distinguish between 6-month progression free survival rates of 64% or lower vs 84% or higher using a Simon 2-stage minimax design. The criteria for further evaluation come from the pivotal trial of single agent sunitinib as first line therapy for RCC, in which the 6-month progression free survival rate was 74%. Trial treatment is administered in 12-week (wk) cycles consisting of 4 wks of sunitinib (50 mg daily) followed by 2 wks rest, followed by 5 wks of everolimus (10 mg daily) followed by 1 wk rest. Disease progression is interpreted as failure of the most recent drug taken. Participants who stop one drug because of toxicity or disease progression, on or before the 6 month assessment, will continue the other drug until subsequent progression or prohibitive toxicity on the second drug. EVERSUN is an ANZUP Cancer Trials Group Ltd. trial coordinated by the NHMRC Clinical Trials Centre. Accrual commenced in September 2010 with 38/55 participants recruited as of the 31-Jan-12 from 17 Australian sites (ACTRN12609000643279).
A phase II biomarker assessment of tivozanib in oncology (BATON) trial in patients (pts) with advanced renal cell carcinoma (RCC).
Authors: Hutson Thomas E. , Rathmell Kimryn , Hudes Gary R. , Kabbinavar Fairooz , Vogelzang Nicholas J. , Knox Jennifer J. , Cowey C. Lance , Cho Daniel C. , Choueiri Toni K.
Published: March 2020

TPS4686

Background: Tivozanib is an oral, potent, and selective tyrosine kinase inhibitor targeting all three vascular endothelial growth factor (VEGF) receptors; it showed efficacy and tolerability in a Phase II trial in pts with advanced RCC (Nosov et al. JCO 2011;29[18S]:4550). Preclinical studies have identified a 42-gene tivozanib resistance signature (Jie et al. EORTC-NCI-AACR 2010; abstract 608) that may be predictive of tivozanib sensitivity. This study (NCT01297244) is designed to evaluate these potential biomarkers for tivozanib activity in pts with advanced RCC. Methods: Pts with advanced RCC (stratified as clear cell or non-clear cell) who underwent nephrectomy and received ≤1 prior systemic treatment (no prior VEGF- or mammalian target of rapamycin–targeted therapy) entered this open-label, single-arm study conducted in the United States and Canada beginning January 2011. Pts receive tivozanib 1.5 mg/d orally (3 weeks on, 1 week off schedule). Primary objectives include correlation of biomarkers in blood (e.g. VEGF, hepatocyte growth factor [HGF]) and tumor tissue (e.g. CD68, hypoxia-induced factor, VEGF, HGF, and gene expression profiles) with clinical activity and/or treatment-related toxicity, and 6-month progression-free survival (PFS) rate. Secondary objectives include overall response rate (ORR), PFS, safety and tolerability, and pharmacokinetics. Contingency table methods will be used for biomarker correlation with ORR, and Cox proportional-hazards regression for correlation with PFS. Sample size (100 pts) is estimated based on clinical considerations and the precision with which 6-month PFS can be estimated. Biomarkers were defined at study outset; the requirement of prior nephrectomy ensured availability of primary tumors as controls for correlative analysis. As of January 2012, the study completed enrollment of 100 pts, demonstrating a large number of pts can be enrolled to a biomarker study with well-defined candidate genes and critical inclusion criteria to facilitate compliance. Tivozanib biomarkers evaluated in this study, along with those evaluated in other solid tumors, may play an important role in optimizing patient selection.
Comparison of two doses of cabazitaxel plus prednisone in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) previously treated with a docetaxel (D)-containing regimen.
Authors: Eisenberger Mario A. , Hardy-Bessard Anne-Claire , Mourey Loic , Mainwaring Paul N. , Ford Daniel , Shapiro Jeremy David , Carles Joan , Ng Siobhan , Gil Thierry , Alekseev Boris , Ivanov Sergey , Facchini Thomas , Legouffe Eric , Apolikhin Oleg , Pandha Hardev S. , Beeker Aart , Karyakin Oleg , Zhang Wendy , Chadjaa Mustapha , De Bono Johann Sebastian
Published: March 2020

TPS4692^

Background: The phase III TROPIC study (NCT00417079) reported a significant improvement in overall survival (OS) for cabazitaxel (Cbz) + prednisone (P;CbzP) (25 mg/m2 IV Q3W/10 mg PO QD) vs mitoxantrone (M) + P (MP) (median OS 15.1 vs 12.7 mos; HR 0.70; P < 0.0001) in pts with mCRPC (also known as hormone-refractory prostate cancer) previously treated with a D-containing regimen. CbzP is approved by the FDA, EMA and other health authorities for the treatment of pts with mCRPC that has progressed after a D-containing regimen. Cbz toxicity is consistent with other taxanes; compared with M, more hematologic toxicities are reported (primarily Grade 3–4 neutropenia). Phase I/II studies identified 20 and 25 mg/m2 as recommended doses; 25 mg/m2 was selected for the phase III TROPIC study. As pooled data show Grade 3–4 neutropenia incidence is lower with Cbz < 25 mg/m2 (61%) vs ≥ 25 mg/m2 (74%), it is of interest to assess if reducing the Cbz approved dose in mCRPC lessens hematologic toxicity and is non-inferior in terms of efficacy. Methods: PROSELICA (NCT01308580) is a randomized, open-label, multinational, phase III study comparing 20 mg/m2 and 25 mg/m2 Cbz for efficacy and tolerability. Pts with a life expectancy > 6 mos, ECOG PS ≤ 2, histologically/cytologically confirmed metastatic prostate adenocarcinoma resistant to hormone therapy and previously treated with a D-containing regimen are eligible. Pts are randomized 1:1 to receive Cbz 20 mg/m² or 25 mg/m² IV Q3W + P 10 mg PO QD, treated until disease progression, unacceptable toxicity or withdrawal of consent (max 10 cycles), and stratified according to ECOG PS, measurable disease (yes/no) and region. The primary endpoint is OS (non-inferiority design). Secondary endpoints include safety, progression-free survival (PCWG2 criteria), PSA and pain progression and response, tumor response in pts with measurable disease and health-related quality of life. Cbz PK and pharmacogenomics will be assessed in pt subgroups. Planned enrollment is 1,200 pts. Study start was in May 2011; as of Jan 2012, 270 pts had been enrolled. The first DMC meeting recommended continuing the study without change.
A randomized, open-label, phase II study of MDV3100 alone or in combination with leuprolide and dutasteride as neoadjuvant therapy to prostatectomy in intermediate and high-risk prostate cancer.
Authors: Montgomery Robert B. , Joshua Anthony , Hannah Alison L. , Peterson Amy C. , Lopez Christian , Gleave Martin Edwin , Taplin Mary-Ellen
Published: March 2020

TPS4695

Background: MDV3100 is a potent androgen receptor (AR) signaling inhibitor (ARSI) that inhibits AR signaling via three mechanisms: inhibition of androgen binding to AR, inhibition of AR nuclear translocation, and inhibition of nuclear AR-DNA binding. In vivo, MDV3100 induces significant prostate cancer apoptosis, an effect not seen with anti-androgens. To date, the use of neoadjuvant androgen deprivation therapy has not led to an improvement in time to PSA progression (Soloway 2002; Aus 2002). While serum androgens may be suppressed using luteinizing hormone-releasing hormone agonists, intratumoral levels of androgens remain, driving continued AR signaling and prostate cancer survival. More effective inhibition of AR signaling may improve local and systemic disease control. Methods: MDV3100-07 will assess the effect of 6 mos of neoadjuvant AR blockade with AR inhibition alone (MDV3100) or in combination with maximal suppression of androgens (MDV3100 +leuprolide [L] + dutasteride [D]). Eligible patients will have treatment-naive localized prostate cancer and be candidates for radical prostatectomy. Patients must have either PSA > 10 ng/mL or Gleason score ≥ 7 (4 + 3) with ≥3 cores containing tumor. Patients with evidence of metastatic/nodal disease are excluded. All patients receive MDV3100 (160 mg/d PO); those randomized to MDV3100+L+D therapy also receive L (22.5mg IM q3m) and D (0.5 mg/day PO). Serum/tumor androgen levels will be serially assessed. Tissue from the diagnostic and prostatectomy specimens will be evaluated for androgen levels, AR signaling profiles, and selected markers of apoptosis and mitotic indices. The primary efficacy endpoint is pathological complete response (pCR) rate at time of radical prostatectomy. For each arm, the percent of patients who achieve a pCR will be compared to the percent pCR in patients treated with neoadjuvant leuprolide, estimated to be 5% in a mixed low-to-intermediate risk population. Target Accrual: 40 pts will be randomized 1:1 to MDV3100 or MDV3100+L+D therapy. Keywords:MDV3100, prostate cancer, androgen receptor, anti-androgen, Phase 2, neoadjuvant.