bluuebunny/crossref_metadata_2025_split huggingface dataset:
Final results of a phase I study of TH-302, a hypoxia-activated cytotoxic prodrug (HAP)
Authors: Bendell J. C. , Weiss G. J. , Infante J. R. , Chiorean E. G. , Borad M. , Tibes R. , Jones S. F. , Langmuir V. K. , Kroll S. , Burris H. A. 
Published: August 2020

2573 Background: TH-302 is a 2-nitroimidazole prodrug of the DNA alkylator, bromo-isophosphoramide mustard (Br-IPM). TH-302 is essentially inactive under normoxia but in severe hypoxia and in the presence of certain reductases, it is reduced and Br-IPM is released. Methods: Eligible patients (pts) had ECOG ≤1, advanced or metastatic solid tumors, evaluable by RECIST, and acceptable hematologic, liver and renal function. A modified accelerated titration design was used. TH-302 was administered intravenously over 30–60 minutes on Day 1, 8 and 15 of a 28-day cycle. CT scans were obtained after every 2 cycles. Detailed pharmacokinetic sampling was performed on Days 1 and 15. The primary objectives of this study were to determine the dose limiting toxicity (DLT) and the maximum tolerated dose (MTD). Results: Twenty-nine pts enrolled at 3 sites at 9 dose levels from 7.5–670 mg/m2. Median age: 64y. 20 male/9 female. ECOG 0/1: 16/13. Primary tumor: prostate (8), colorectal (8), lung (5) other (8). Two of 5 pts at 670 mg/m2 had DLT: Herpes simplex perianal/rectal ulcers and dehydration due to mucositis. Reversible skin and mucosal adverse events (AE) occurred in 12 of 15 (80%) pts at ≥480 mg/m2 including grade 3 events in 3 pts. The most common TH-302-related AEs were nausea, skin lesions, vomiting and fatigue. Hematologic toxicity was mild and limited: two pts with grade 1 and one pt with grade 2 neutropenia and five pts with grade 1 thrombocytopenia. Five pts had grade 3 and one grade 4 lymphopenia. Four pts have enrolled at an intermediate dose of 575 mg/m2 with no DLT so this is likely the MTD and is well above the predicted biologic effective dose of 100 mg/m2. One pt with SCLC treated at 480 mg/m2 and one with melanoma treated at 670 mg/m2 had unconfirmed partial responses; 12 pts had stable disease (6 continuing after 4 or more cycles), 7 had PD, 4 were unevaluable and 4 are too early to assess. Cmax and AUC for TH-302 and Br-IPM increased linearly with no accumulation at Day 15. Conclusions: Weekly TH-302 has remarkably little hematologic toxicity. Skin and mucosal AEs have developed at the higher dose levels. Skin/mucosa are known to have hypoxic regions. TH-302 is the first HAP to demonstrate tumor responses in Phase I. The MTD is likely 575 mg/m2. Studies in combination with chemotherapy are ongoing. [Table: see text]
First-in-human study of a novel nucleoside analogue, CP-4126, in patients with advanced solid tumors
Authors: Nilsson B. , Hendlisz A. , Castella M. , Aamdal S. , Dueland S. , Nyakas M. , Evans J. , Venugopal B. , Rasch W. , Awada A. 
Published: August 2020

2577 Background: CP-4126 (gemcitabine 5'-elaidic acid ester) is a novel nucleoside analogue with proven preclinical antitumor activity. Unlike gemcitabine, the intracellular uptake of CP-4126 is independent of nucleoside transporters. The aims of this study were to determine the safety, toxicity, MTD and the RD of CP-4126, to describe its pharmacokinetic (PK) characteristics, and to assess its preliminary antitumor activity. Methods: Patients (pts) with refractory solid tumors, performance status ECOG < 2, with adequate haematologic, renal and hepatic function were enrolled in this dose escalation study (1–6 pts per dose level (DL)). CP-4126 was administered on days (d) 1, 8 and 15 every 4 week by a 30 min IV infusion. Start dose was 30 mg/m2/d and the dose was increased by 100% until toxicity > CTCAE grade 2 occurred. Standard DLT definitions were used. Activity was assessed at the end of every 2nd cycle (cy). Plasma and urine PK were determined during d1 (24 hrs) of cy1; plasma at all DLs and urine at DL= 1400 mg/m2/d. Results: 39 pts have been included, (m =24; f =15 ), median age 60 (range 19–78), receiving 96 cycles (range 1–9) of treatment, with 1 pt/DL from 30 to 240 mg/m2/d. The first grade 2 AE (neutropenia) was reported at 480 mg/m2/d. Most frequent toxicities include nausea, vomiting, fatigue and anorexia, the majority of mild severity (grade 1–2). 5 DLTs have been reported; 800 mg/m2/d (1 pt - d8 dose delay >2 weeks due to grade 3 thrombocytopenia and anaemia); 1000 mg/m2/d (1 pt died 48 hrs after treatment start due to acute lung damage); 1400 mg/m2/d (1 pt - fatigue grade 3); 2 pts at 1600 mg/m2/d (grade 3 ALT/AST elevation [1 pt]; 1 pt grade 4 neutropenia and grade 3 fatigue). Stabilisation of disease (≥ 3 months) reported in 5 pts (pancreas, colon and ovarian cancer) lasting between 3.5 to 8 months. One ovarian pt had a 28.3% reduction in tumor mass. CP-4126 was detected in plasma up to 24 hrs post-dosing. AUC for dFdC exposure was significantly higher than reported with gemcitabine at comparable dose levels. Urinary excretion of the main metabolite dFdU during the first 24 hrs was approximately 60% of dose. Conclusions: CP-4126 is well tolerated and accrual is ongoing at 1400 mg/m2/d to establish RD for phase II studies. Updated results including plasma and urine PK will be presented. [Table: see text]
Phase I clinical results of an APC-targeted hCGβ vaccine (CDX-1307) with TLR agonists
Authors: Morse M. , Chapman R. , Powderly J. , Keler T. , He L. , Ramakrishna V. , Vitale L. , Clay T. , Green J. , Davis T. 
Published: August 2020

3006 Background: Effective immunization requires efficient antigen delivery to antigen presenting cells (APCs). Antigens attached to the human antibody B11, targeting mannose receptors on APCs, have been shown to be processed and presented efficiently, and generate robust immune responses when combined with toll-like receptor (TLR) agonists. The CDX-1307 vaccine is composed of B11 fused with hCGβ, a tumor antigen correlated with advanced stage of disease and poor prognosis in a number of common epithelial cancers, but reported at variable rates of expression. Methods: Two phase I studies investigate intradermal (id) vs. systemic (iv) administration of CDX-1307. Patients with advanced epithelial cancers known to frequently express hCGβ receive 4 biweekly vaccinations of CDX-1307, alone or in combination with immunostimulants including GM-CSF (GM), the TLR3 agonist Poly-ICLC, and the TLR7/8 agonist resiquimod. Results: Dose-escalation is complete. In the id study, 37 patients received CDX-1307 at doses of 0.3, 1.0, and 2.5 mg, then 2.5 mg + GM, 2.5 mg + GM + Poly-ICLC, and 2.5 mg + GM + resiquimod. 2.5 mg + GM + Poly-ICLC + resiquimod is planned. In the iv study, 24 patients were treated at 1, 3, 10, and 30 mg, as well as 10 mg + GM and 30 mg + GM. 30 mg + GM + Poly-ICLC is enrolling. Treatment-related toxicities were generally mild to moderate with no dose-limiting toxicities, most frequently injection site reactions and fatigue in the id study, and fatigue, myalgia, and flu-like illness in the iv study. Humoral responses to hCGβ were increased in 56% of the analyzed patients receiving adjuvants. Serum hCGβ was frequently elevated at study entry or during treatment (males = 88%, females = 53%, pancreatic = 89%, colorectal = 78%, breast = 47%). hCGβ decreases were seen in some patients with immune responses. To date, a significant mixed response was seen in one patient with pancreatic cancer (id), while stable disease has been seen in 4 patients (2 with breast cancer = 25, 27 weeks and 2 with colorectal cancer = 9+ weeks). Conclusions: CDX-1307 is well tolerated and results in immune responses that are enhanced by immunostimulants. Elevated hCGβ was detected at a higher than expected frequency in these tumors. [Table: see text]
A randomized trial of personalized peptide vaccine (PPV) plus low-dose estramustine (EMP) versus full-dose EMP in patients with hormone-refractory prostate cancer
Authors: Noguchi M. , Uemura H. , Kumon H. , Nasu Y. , Hirao Y. , Matsuoka K. , Kakuma T. , Yamada A. , Itoh K. 
Published: August 2020

3007 Background: Personalized selection of the right peptides for each patient could be a novel peptide-based immunotherapy for boosting anti-cancer immunity in many patients (pts). This randomized study evaluated the anti-tumor effect and safety of PPV plus a low-dose EMP compared with full dose EMP for patients with hormone-refractory prostate cancer (HRPC). Methods: This was a randomized (1:1), open labeled, cross-over study in pts with HRPC. Pts were randomized to arm A; PPV plus low-dose EMP (280 mg/day) or arm B; full dose EMP (560 mg/day) according to age and PSA levels. In arm A, prevaccination plasma were measured for their IgG levels for each of the 14 or 12 candidate peptides which can induce HLA-A2 or A24-restricted CTL activity against cancer cells followed by biweekly subcutaneous administration of the top four peptides (3mg each) showing the strongest IgG responses. Disease progression (PD) was defined as three consecutive and 125% increase from baseline PSA levels at least two weeks apart or objective PD by RECIST criteria. After PD, pts were treated with the opposite regime. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival and toxicity. The planned sample size was 80. Results: A total of 54 pts from 4 institutions were enrolled between June 2006 and December 2008. The accural into arms A and B was 27 and 27 pts, respectively. The main pts characteristics are (arm A/B): median age 71/69 years, EOCG performance status 0/1 96%/4% and 100%/0%, HLA A2/A24/A2A24 40%/32%/28% and 54%/27%/19%, median PSA 27/25 ng/ml, and metastatic HRPC 96%/85%. All pts were evaluable for their response at the time of interim analysis. The personalized peptide vaccination was well tolerated with no major adverse effects. Increased levels of IgG responses to the vaccinated peptides were observed in 20 of 23 (87%) patients tested. The median PFS time was 246 days in the arm A group and 85 days in the arm B, respectively. The PFS time in the arm A was statistically longer than that in the arm B (log-rank test: p = 0.0007, hazard ratio: 0.27, 95%CI: 0.12 to 0.615). Conclusions: PPV plus low-dose EMP was associated with improvement in PSA-based PFS compared to full-dose EMP alone. No significant financial relationships to disclose.
Vaccination of renal cell cancer (RCC) patients with modified vaccinia Ankara (MVA) delivering tumor antigen 5T4 administered alone or with interleukin 2 (IL-2) or interferon-alpha (IFN)
Authors: Amato R. , Hernandez-McClain J. , Harrop R. , Cen P. , Doshi G. 
Published: August 2020

3026 Background: The attenuated vaccinia virus (MVA) has been engineered to deliver the tumor antigen 5T4 (TroVax). More than 90% of RCCs overexpress the 5T4 antigen. A series of clinical trials were conducted to evaluate the effectiveness of MVA 5T4 as a single agent or in combination with either IL-2 or IFN. Methods: Eligibility: Pathologic diagnosis of clear cell or papillary RCC, progressive measurable metastases, any prior therapy, adequate physiological parameters, Karnofsky performance status ≥ 80%, and no active CNS involvement. A regimen of MVA 5T4 alone or in combination with IL-2 or IFN was given. Results: A total of 53 pts received MVA 5T4 alone or in combination with IL-2 or IFN. 13 pts received MVA 5T4 alone, 25 pts received low dose subcutaneous IL-2, and 15 pts received IFN. Clinical responses were assessed by measuring changes in tumor burden via computed tomography or magnetic resonance imaging scan. 5T4-specific cellular and humoral responses were monitored throughout the study. 5T4 was well tolerated with no serious adverse events attributed to vaccination. Of 48 intention-to-treat pts, 43 mounted 5T4-specific antibody responses. 2 pts showed a complete response for > 36 months and 2 other pts had a partial response for > 24 months and 12 months respectively. 20 pts demonstrated disease stabilization for ≥ 3 months. Median progression-free survival and overall survival for all pts was 3.6 months (range 0.8–29.7) and 13.2 months (range 1–38) respectively. A significant relationship was detected between the magnitude of 5T4-specific antibody response and overall survival. Conclusions: 5T4, whether administered alone or in combination, was well tolerated. High frequency of 5T4-specific immune responses and associated enhanced patient survival is encouraging and warrants further investigation. [Table: see text]
Antitumor activity of PSMA ADC after progression on docetaxel in a mouse xenograft model of human prostate cancer
Authors: Ma D. , Zhang H. , Kennedy B. , Parsons T. , Olson W. C. 
Published: August 2020

3030 Background: Currently, there are no approved therapies for castration-resistant metastatic prostate cancer that has progressed following docetaxel therapy. Prostate-specific membrane antigen (PSMA) is an attractive target for antibody-targeted therapy of prostate cancer due to its abundant and restricted expression on the surface of prostate cancer cells. We have developed a novel antibody-drug conjugate (ADC) by linking a fully human PSMA monoclonal antibody to monomethylauristatin E (MMAE), a potent tubulin inhibitor. Here, we describe the use of PSMA ADC in a mouse model to treat xenografted human prostate tumors that have progressed following docetaxel therapy. Methods: Nude mice were implanted subcutaneously with 5 x 106 C4–2 human prostate cancer cells. Animals were first randomized to receive weekly intravenous (IV) doses of either 2 mg/kg docetaxel (n = 50) or vehicle (n = 10). Docetaxel significantly reduced tumor growth (p = 0.025) during the initial phase of the study; however, most of the tumors later progressed. When the tumor volume of an animal in the docetaxel group exceeded 400 mm3, the animal was rerandomized to receive continued docetaxel therapy (n = 18) or weekly IV doses of 6 mg/kg PSMA ADC (n = 18). Treatment effects were assessed by measuring tumor volume and overall survival. When tumor volume was assessed to be ≥2,000 mm3, animals would be sacrificed. Results: At 134 days following tumor implantation, the survival rate was 100% for animals in the PSMA ADC treatment group; 94% of these mice had tumor sizes <100 mm3. In the continued docetaxel treatment group, 14 of 18 animals that were sacrificed when their tumors exceeded 2,000 mm3; the survival rate was 22%. Therefore, PSMA ADC treatment significantly shrank tumors and increased overall survival of animals compared to continued docetaxel treatment (p < 0.0001). Conclusions: PSMA ADC had antitumor activity in mice to xenografted human prostate tumors that had progressed following docetaxel treatment. Treatment with PSMA ADC significantly extended survival in this setting. [Table: see text]
Peritoneal carcinomatosis immunotherapy with the trifunctional anti-EpCAM x anti-CD3 antibody catumaxomab in patients with colon, gastric, or pancreatic cancer: Long-term results after a 2-year follow-up
Authors: Ströhlein M. , Lordick F. , Rüttinger D. , Schemanski O. , Jaeger M. , Lindhofer H. , Hennig M. , Lahr A. , Heiss M. 
Published: August 2020

3033 Background: Peritoneal carcinomatosis (PC) from gastrointestinal (GI) cancer is associated with a poor outcome. The trifunctional antibody catumaxomab may induce remission by redirecting T-lymphocytes and Fcγ-receptor I/III positive accessory cells to tumor cells. The aim of this study was to investigate the treatment of PC with intraperitoneal catumaxomab. Methods: Patients with epithelial cell adhesion molecule (EpCAM)-positive PC from GI cancer were enrolled in a multicenter phase I study and received four sequential intraperitoneal catumaxomab infusions on days 0, 3, 7, and 10 at increasing doses. Results: Twenty-four patients were enrolled. The maximum tolerated dose (MTD) was reached at 10, 20, 50, and 200 μg on days 0, 3, 7, and 10, respectively. The most common drug-related adverse events at the MTD were fever, vomiting, abdominal pain, skin toxicity, and nausea. Eleven of 17 evaluable patients (65%) were progression-free at final examination: one patient had a complete response and three patients had a partial response. EpCAM-positive cells in peritoneal lavage samples decreased in six of 10 evaluable patients. Patient survival was compared in a post hoc matched-pair analysis with PC patients treated with conventional intravenous chemotherapy. Median survival from the time of diagnosis of PC was 502 days in study patients versus 180 days in control patients (log-rank p = .0083). Conclusions: Intraperitoneal treatment with catumaxomab had an acceptable safety profile. Elimination of tumor cells from peritoneal lavage samples, delayed disease progression, and prolonged survival indicate that intraperitoneal catumaxomab is a promising option for the treatment of PC from GI cancer. [Table: see text]
Effect of CD37 small modular immuno-pharmaceutical (SMIP) on direct apoptosis in chronic lymphocytic leukemia cells via transcriptional up-regulation of the BH3 family member BIM
Authors: Byrd J. C. , Lapalombella R. , Ramanunni A. , Andritsos L. A. , Flynn J. M. , Baum P. , Thompson P. , Muthusamy N. 
Published: August 2020

3035 Background: CD37 is a tetraspan transmembrane family protein selectively expressed on normal and transformed B-cells. A novel CD37SMIP was previously demonstrated to mediate superior direct apoptosis and NK-cell mediated killing of chronic lymphocytic leukemia (CLL) and other B-cell malignancies. Methods: Given the superior in vitro apoptosis observed with CD37SMIP treatment and early clinical activity observed in highly refractory CLL patients, we hypothesized that a unique mechanism of cell killing was utilized by CD37SMIP. This was pursued in preclinical studies outlined below. Results: Unlike many other agents utilized to treat CLL, death mediated by CD37SMIP does not depend upon caspase activation. Nonetheless, CD37SMIP treatment of CLL cells promotes time-dependent induction of mitochondrial membrane depolarization, mitochondrial translocation of Bax, and up-regulation of Bim protein. CD37SMIP Bim protein induction occurred concomitantly with an increase in BIM mRNA levels. Electrophoretic mobility shift assay using oligonucleotides of the BIM promoter demonstrated increased protein binding activity in nuclear extracts derived from CD37SMIP treated cells and the physical interaction of FoxO3a transcription factor with the FoxO3a responsive element in the BIM promoter was demonstrated using a “protein pull down” assay and confirmed by chromatin immunoprecipitation assays. Furthermore, CD37SMIP treatment significantly increased BIM promoter regulated luciferase reporter expression in B-CLL cells. Consistent with a primary role of Bim up-regulation in mitochondrial membrane destabilization and apoptosis, transfection of CLL cells with BIM siRNA resulted in inhibition of CD37SMIP-induced mitochondrial membrane depolarization and apoptosis. Conclusions: These studies demonstrate CD37SMIP mediated apoptosis in CLL cells occurs via FoxO3a-dependent transcriptional up-regulation of BIM protein. This distinct mechanism of apoptosis utilized by CD37SMIP contrasts it with other agents used for CLL treatment. Additionally, it provides a mechanism for the promising clinical activity of TRU-016 (humanized CD37SMIP) observed to date in refractory CLL patients. [Table: see text]
Dendritic cell-based vaccination in combination with gemcitabine/S-1 in patients with advanced pancreatic cancer
Authors: Okamoto M. , Yusa S. , Shimamura K. , Ogawa T. , Tomoda T. 
Published: August 2020

3037 Background: Pancreatic cancer has a poor prognosis. Tumor-specific cytotoxic T lymphocytes (CTLs) can be activated in vivo by dendritic cell (DC)-based vaccination. However, clinical responses to the immunotherapy with DC vaccination have only been observed in a minority of patients with solid cancer. Combination with other treatment modalities such as chemotherapy may overcome immunoresistance of cancer cells. It has been shown previously that gemcitabine as well as S-1 sensitises human pancreatic carcinoma cells against CTL-mediated lysis. In the current study, the clinical efficacy of the DC vaccine pulsed with the peptide derived from pancreatic cancer-associated antigen in combination with gemcitabine/S-1 has been evaluated in the patients with advanced, inoperable pancreatic cancer. Methods: Thirteen patients with advanced, inoperable pancreatic cancer refractory to standard treatment were entered the study. DCs that were generated from CD14+ monocytes from leukapheresis by 6-day cultivation with granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin (IL)-4 were matured by OK-432, a streptococcal agent, and were pulsed with the pancreatic cancer-associated antigen. These DCs (1 x 107) were intradermally administered 5 times at 14-day intervals concomitantly combined with gemcitabine and/or S-1. Results: Of the 13 patients, complete response (CR) was observed in 2 (15.4%), partial response (PR) in 7 (54.8%), stable disease (SD) in 2 (15.4%), progressive disease (PD) in 2 (15.4%). Response rate was 69.2%. Survival rate, quality of life, and performance status were markedly increased. Severe side effects of more than grade 3 that were assessed in accordance with NCI-Common Toxicity Criteria v.2.0, were not observed. Conclusions: It was strongly suggested that the DC vaccination pulsed with cancer associated-peptid in combination with gemcitabine and/or S-1 was safety and effective in the patients with the inoperable pancreatic cancer refractory to standard treatment. No significant financial relationships to disclose.
Pharmacodynamic effects of administration of maytansine conjugated anti-CD22 monoclonal antibodies to cynomolgus monkeys
Authors: Fuh F. K. , Fuji R. , Poon K. A. , Manning W. , Berry K. K. , Ramakrishnan V. , Polson A. , Ebens A. , Prabhu S. , Williams M. 
Published: August 2020

3051 Antibody-based B-cell specific therapeutic approaches have revolutionized the treatment of non-Hodgkin's lymphomas (NHL) as well as other hematological malignancies. However, a large variability in clinical response has been observed, and the need to develop effective new treatments remains urgent. A promising approach is the use of antibody-drug conjugates (ADCs), cytotoxic drugs covalently linked to antibodies through specialized chemical linkers for the treatment of NHL. CMC-544, an antibody to a B-cell specific glycoprotein CD22 conjugated to the cytotoxin calicheamicin, has shown clinical activity in patients. In addition, antibodies directed to B-cell targets such as rituximab and epratuzumab are in clinical trials for the treatment of NHL and autoimmune disorders. We have generated10F4v3, an anti-CD22 antibody conjugated to the antimitotic agent maytansine (10F4v3-DM1). DM1 disrupts cellular mitosis through inhibition of tubulin polymerization when internalized into cells. The anti-CD22 DM1 conjugate was shown to have significant potency in preclinical efficacy models of NHL. In order to further characterize this antibody-drug conjugate in preclinical studies, we first evaluated the binding characteristics of the 10F4v3 to peripheral blood B-cells from various geographical sources of cynomolgus monkeys. 10F4v3 bound to peripheral blood B-cells from all cynomolgus monkeys of Indonesian and Mauritian origins, but displayed only limited binding to cynomolgus monkeys of Chinese and Cambodian origins. Therefore, further preclinical evaluation of 10F4v3-DM1 was conducted in Indonesian cynomolgus monkeys to examine the safety, pharmacokinetic, and pharmacodynamic effects in monkeys. B-cells and B-cell subsets were depleted in peripheral blood and lymphoid tissue (spleen, bone marrow) at all doses, with no apparent dose-dependent effects or substantial safety limitations. Based on the nonclinical data, 10F4v3-DM1 exhibits an encouraging pharmacodynamic profile for the potential treatment of non-Hodgkin's lymphoma. [Table: see text]