bluuebunny/crossref_metadata_2025_split huggingface dataset:
Involvement of compensatory CD44+ stem cells following BCL-2 suppression by antisense oligonucleotides.
Authors: Rubenstein Marvin , Hollowell Courtney M.P. , Guinan Patrick 
Published: March 2020

2590 Background: Gene therapy is in theory specific but encounters difficulties in practice. Suitable targets are found in many pathways and tumors do express altered patterns of expression. However the actual activity of most regulatory genes are similar to normal. Resistance develops because biochemical pathways are complex, regulated by stimulatory and inhibitory factors, each possibly affected by therapy. It’s suggested that tumors alter dependence on targeted gene products for growth by relying upon others, through compensation. Antisense oligos have targeted regulatory proteins in both in vivo and in vitro prostate cancer models. Cells treated with antisense directed against bcl-2 compensated by suppressing caspase-3 (an apoptosis promoter) and enhancing androgen receptor (AR), (co-activating) p300 and IL-6 expression. This suggests that in LNCaP a progression to increased androgen sensitivity accompanies bcl-2 suppression with a pattern of co-activation associated with more advanced prostate tumors. Methods: We evaluated mono- and bispecific oligos which targeted and equally suppressed bcl-2 expression in LNCaP cells. To further evaluate compensatory mechanisms related to tumor resistance we evaluated the level of CD44 expression employing RT-PCR and agarose gel quantification. Bands representing pcr product were photographed, converted to black and white and assessed by MIPAV software. Results: Comparable amounts of RNA from LNCaP cells treated with either mono- or bispecific oligos directed against bcl-2 (and EGFR in the bispecifics) were evaluated by RT-PCR using primers directed against CD44. When background intensity was subtracted, the relative intensity of the bands corresponding to CD44, and representing cells treated with MR4, MR24 and MR42 (compared to controls) were respectively increased 3.0% ± 33.6 (NS), suppressed 16.4% ± 49.1 (NS) and suppressed 9.2% ± 26.5 (NS). These results were pooled from both duplicate PCR runs and gels, and indicate no significant changes in CD44 expression was produced by any oligo type. Conclusions: Stem cells expressing this marker were unaffected by treatment, suggesting this population is not altered by suppressive bcl-2 therapy.
Trastuzumab (T) and everolimus (E) pharmacokinetics (PK) in HER2 positive (+) primary breast cancer (BC) patients (pts): Unicancer RADHER trial results.
Authors: Bernadou Guillemette , Rezai Keyvan , Merlin Jean-Louis , Campone Mario , Lokiec Francois , Bachelot Thomas Denis , Delaloge Suzette , Dieras Veronique , Jimenez Marta , Ternant David , Paintaud Gilles 
Published: March 2020

2599 Background: T has greatly modified the prognosis of HER2+ BC, but few studies have analyzed its PK. The RADHER study evaluated the interest of adding E to T as preoperative therapy for primary HER2+ BC. It also aimed at describing the PK of T and studying the impact of E with T in primary BC. Methods: Eligible pts with HER2+ operable primary BC were randomized to receive T alone (loading dose 4 mg/kg, then 2 mg/kg/week (W)) or T + E (10 mg/day (D)) for a 6-W pre-operative treatment. Blood samples were collected to measure T and E concentrations. For T, plasma samples were collected in all pts before each infusion, and at Hour (H) 1, D1, D3, W1, W2, W4, W8 and W12 after the last infusion. E concentrations were determined on whole blood collected at H0, H0.5, H1, H2, H4, H6, H12 and H24 after the first T infusion, and again after the last E intake. T and E PK were described using population compartment analyses. Results: From 82 pts randomized, 79 were evaluable for T and 22 for E PK. Mean estimated PK parameters of T were (interindividual coefficient of variation %): central (Vc) and peripheral (Vp) volumes of distribution = 2 L (24%) and 1.3 L (39%), systemic (CL) and intercompartment (Q) clearances = 0.22 L/day (19%) and 0.36 L/day, respectively. Vc increased with body weight and decreased with age, while CL increased with body weight and with tumor volume. Elimination half-life was 11 days, a value lower than that previously reported in metastatic BC (28 days). E PK was best described by a two-compartment model. Mean estimated PK parameters (RSE%) of E were: CL = 3.96 L/h (22%), Q = 29.1 L/h (7%), Vc = 119 L (11%), Vp = 1530 L (24%). E did not influence T PK. E PK was similar to that previously reported in other indications. Conclusions: This is the first study describing the PK of T and E in primary BC. Notably, T CL increases with tumor volume and the elimination half-life is only 11 days, lower than expected from previous results in metastatic BC. The differences in PK between primary and metastatic BC might lead to take a second look at trastuzumab dose regimen in primary BC. Clinical trial information: NCT00674414.
Phase I clinical trials attrition related to central molecular prescreening.
Authors: Boni Valentina , Garralda Elena , Cubillo Antonio , Diaz-Padilla Ivan , Calles Antonio , Gomez-Martin Carlos , Cerdá Sara , Puerta Sonia , Ordonez Esther , López-Ríos Fernando , Olmos David , Hidalgo Manuel , Calvo Emiliano 
Published: March 2020

2600 Background: The increasing trend to incorporate molecular assays as part of selection assessment in Ph1 trials is based on the potential to observe early antitumor activity. Nonetheless, its impact has been almost negligible to date and might affect time to achieve a recommended dose. We assessed the impact on recruitment of pursuing central mandatory molecular assessment of tumor samples on a state-of-the-art Ph1 unit. Methods: Two first-in-human Ph1 studies, requiring central laboratory biomarker assessment as inclusion criterion (DS6 IHC and FGFR mut/ampl, respectively), and a consecutive series of pts in our program for central tumor mutation screening (OncoCarta Panel v1.0) to participate in molecularly-driven Ph1 studies, were reviewed. Results: 13 (4.8%) out of 267 pre-screened pts were able to receive treatment within a targeted Ph1 trial. Conclusions: A vast majority of pts trying to participate in molecularly-driven trial central biomarker screening are not included due to negative results. Still 71.1% pts who were initially eligible and were positive in the central review fail to participate due to clinical and/or analytical deterioration during the time of central molecular assessment. New strategies including local sample pre-screening allowance, as well as anticipated massive molecular profiling in the conventional setting, are needed to reduce this time and improve feasibility of these trials. The derived current “impoverishment” of studies with non-targeted drugs (that lack patients with tumors with “hot” mutations) and of those with targeted drugs (that miss patients with nonmutated tumors) within the same Ph1 Programs, and the need of a joint approach to co-finance for wide-spectrum molecular profiling for different studies, would be discussed as well. [Table: see text]
Pharmacokinetics and safety of an oral ALK inhibitor, ASP3026, observed in a phase I dose escalation trial.
Authors: Patnaik Amita , LoRusso Patricia , Ball Howard A. , Bahceci Erkut , Yuen Geoffrey , Papadopoulos Kyriakos P. , Kittaneh Muaiad , Tolcher Anthony W. 
Published: March 2020

2602 Background: ASP3026 (3026) is a selective, potent, ATP-competitive, small molecule oral inhibitor of ALK receptor tyrosine kinase that has not previously been tested in humans. A Phase 1 dose-escalation trial, using a 3+3 design, evaluating 3026 as an oral single agent was conducted to investigate PK (Day 1 and Day 28), safety and clinical activity in patients (pts) with advanced malignancies (excluding leukemias) of ECOG PS 2 or less. Methods: 3026 was administered under fasting conditions on a continuous schedule to pts in successive dose-escalating cohorts at doses ranging from 25 mg QD to 800 mg QD. Results: Thirty pts were enrolled into the dose escalation part of the study. The MTD was determined based on DLT data from cycle 1. Three DLTs were observed: grade 2 nausea and vomiting leading to dose reduction at 525 mg QD; grade 3 rash leading to dose reduction, and grade 3 ALT/AST increase leading to study withdrawal at 800 mg QD. The most common AEs were constipation, vomiting, diarrhea, nausea and abdominal pain, and all AEs were manageable and reversible. Median AUC and Cmax increased proportionally with dose from 25 mg QD to 800 mg QD. There was no evidence of non-linear PK at ASP3026 doses >25 mg QD. The median terminal half-life was approximately 10 - 41 hours. Overall, A3026 appears well absorbed with median Tmax around 3 hours for both Day 1 and Day 28. Terminal T1/2 appears adequate for one daily dosing with median values ranging from approximately 18 to 34 hours. Based on visual inspection of pre-dose (trough) values from Days 8, 15, 22, and 28 it appears that steady-state conditions are achieved by day 28. Conclusions: The MTD of 3026 is 525 mg QD. Treatment with 3026 resulted in a promising safety and PK profile in pts with advanced malignancies. Further evaluation of 3026 in pts with tumors harboring gene mutation or ALK fusion genes in the cohort expansion phase at the MTD is ongoing. Clinical trial information: NCT01401504.
Phase I study of margetuximab (MGAH22), an FC-modified chimeric monoclonal antibody (MAb), in patients (pts) with advanced solid tumors expressing the HER2 oncoprotein.
Authors: Burris Howard A. , Giaccone Giuseppe , Im Seock-Ah , Bauer Todd Michael , Trepel Jane B. , Nordstrom Jeffrey L. , Li Hua , Carlin David A , Baughman Jan E. , Stewart Stanford , Bang Yung-Jue 
Published: March 2020

3004 Background: The anti-HER2 MAb, trastuzumab (H), has proven effective for HER2+ breast cancer (BC) and gastroesophageal cancer (GEC). H’s mechanism of action is incompletely understood, but evidence indicates ADCC is important. MGAH22 is an Fc-modified chimeric MAb which preserves the antigen binding properties of H, and exhibits enhanced binding to the activating low affinity Fcg receptor, CD16A, and diminished binding to the inhibitory low affinity Fcg receptor, CD32B. Preclinical data indicate MGAH22 is more potent than H. Methods: 34 pts with HER2 positive (2+ or 3+ by IHC) tumors have been treated: 19 in 5 dose-escalation cohorts (0.1 - 6.0 mg/kg qw x 4); 15 in 6.0 mg/kg expansion. Tumor types include: BC (10), GEC (13), colon (5), lung (2), salivary (1), ampulla of Vater (1), endometrium (1), bladder (1). Results: MGAH22 was well tolerated. Most common adverse events (AEs) were Grade 1-2 constitutional symptoms and infusion-related reactions. Related AEs ≥ Grade 3 were limited to a single infusion reaction, 2 episodes of brief lymphopenia confounded by steroids, and transient worsening anemia. No cardiac toxicities were observed. Dose escalation was halted at 6 mg/kg, well above the preclinically predicted minimally effective dose (0.1 mg/kg). Antitumor activity has been observed at all dose levels, including partial responses (PRs) and long times to progression (≥ 5 mo). Two PRs lasting 3.5 and 5.5 mo were observed among the 10 BC pts (both had failed prior H and lapatinib). 4/13 GEC pts experienced stable disease lasting a median of 3.6 mo (range 1.5–5.3), all but one previously failing anti-HER2 treatment. Conclusions: Margetuximab is well tolerated with promising activity in pts with BC and GEC who have failed prior HER-2 therapies and in pts with HER2+ tumors for which H is considered ineffective. A phase II trial in relapsed or refractory HER2 2+, nonamplified BC is underway. Clinical trial information: NCT01195935. [Table: see text]
Novel cancer vaccines in combination with oxaliplatin-based chemotherapy as first-line therapy in advanced colorectal cancer: A randomized phase II study.
Authors: Tanaka Hiroaki , Hazama Shoichi , Tahara Ko , Shimizu Ryoichi , Sugiura Fumiaki , Okuno Kiyotaka , Takumi Furuya , Nishimura Taku , Sakata Koichiro , Yoshimatsu Kazuhiko , Inoue Yuka , Kanekiyo Shinsuke , Yoshino Shigefumi , Shindo Yoshitaro , Yoshida Koji , Shinozaki Hirokazu , Furukawa Hiroyuki , Hirakawa Kosei , Nakamura Yusuke , Oka Masaaki 
Published: March 2020

3006 Background: A phase I cancer vaccination trial using five novel HLA-A24-binding peptides derived from not only three oncoantigens, RNF43 (ring finger protein 43), TOMM34 (34 kDa translocase of the outer mitochondrial membrane), and KOC1 (IMP-3; IGF-II mRNA binding protein 3) but also antiangiogenic cancer vaccine targeting VEGFR1 (vascular endothelial growth factor receptor 1) and VEGFR2 had revealed safety and immunogenicity in advanced colorectal cancer (CRC) as presented at 2011 ASCO Oral Abstract Session (No. 2510). We further performed a phase II trial to evaluate the benefit of the cancer vaccination in combination with oxaliplatin-based chemotherapy as first-line therapy. Methods: Ninety-six chemotherapy naïve CRC pts were enrolled to evaluate primarily response rates (RR), and secondarily OS and PFS. Each of the five peptides (3 mg each) was mixed with 1.5 ml of IFA and subcutaneously administered weekly for 12 weeks and after then biweekly. Chemotherapy was performed simultaneously as mFOLFOX6 or XELOX with/without bevacizumab. All enrolled pts had received the therapy without knowing HLA-A status double-blindly, and the HLA genotype were key-opened at analysis point and then, the endpoints are evaluated between HLA-A*2402 positive and HLA-A*2402 negative group. Results: Between February 2009 and November 2012, a total of 96 pts were enrolled in this study. The cutoff date for the main analysis was January 31, 2013 (median duration of follow-up of 26.5months). mFOLFOX6 and XELOX were administered to 93 and 3 pts, respectively. Bevacizumab was used for 5 pts. RR, the primary study end point, was 61.5% (CR 1, PR 58, SD 33, PD 4). It seemed superior as compared to other reports. The median duration to reach the best responses (14 weeks; range 8-69) was surprisingly long and indicated the delayed effect of vaccination. PFS and OS were 8.2 m and 20.7 m, respectively. The HLA genotype will be key-opened at March 2013 and the endpoints will be presented between HLA-A*2402 positive and negative group at the meeting. Conclusions: The phase II cancer vaccine therapy demonstrated the promising response, and warrants further clinical studies. Clinical trial information: UMIN000001791.
Targeting CD137 to enhance the antitumor efficacy of cetuximab by stimulation of innate and adaptive immunity.
Authors: Kohrt Holbrook Edwin , Houot Roch , Weiskopf Kipp , Goldstein Matthew , Lund Peder , Lira Ruth R , Troutner Emily , Richards Lori , Rajapaksa Amanda , Ostashko Anton , Weng Wen-Kai , Chen Lieping , Czerwinski Debra , Colevas A. Dimitrios , Sunwoo John , Levy Ronald 
Published: March 2020

3015 Background: Cetuximab therapy results in beneficial, yet limited, clinical improvement for patients with KRAS wildtype (WT) colorectal (CRC) and head and neck (HN) cancer. The efficacy of cetuximab, an IgG1 monoclonal antibody against EGFR, is due in part to antibody-dependent cell-mediated cytotoxicity (ADCC) by natural killer (NK) cells. CD137 is a costimulatory molecule expressed following activation on NK and memory, antigen-specific, CD8 T cells. Methods: We investigated the hypothesis that the combination of cetuximab with anti-CD137 mAb will enhance innate and adaptive immunity, thereby improving cetuximab’s anti-tumor efficacy in preclinical models and a prospective trial, NCT01114256. Results: NK cells increased their expression of CD137 by a factor of 30-40 when exposed to cetuximab-coated, EGFR-expressing HN and CRC cell lines. An agonistic anti-CD137 mAb enhanced NK cell degranulation and cytotoxicity 2-fold (~45 to 90% tumor lysis assayed by chromium release). The combination of cetuximab and anti-CD137 mAbs was synergistic in a syngeneic, human-EGFR-transfected murine tumor leading to complete tumor resolution and prolonged survival. NK cell depletion, significantly, and CD8 T cell depletion, partly, abrogated the anti-tumor efficacy of this combination. A series of HN and both KRAS WT and mutant CRC xenotransplant models demonstrated synergy with cetuximab and anti-CD137 mAbs. In our clinical trial, 54 patients with HN cancer receiving cetuximab therapy, circulating and intratumoral NK cells upregulated CD137 with amplitude influenced by duration post-cetuximab and host FcyRIIIa polymorphism. Interestingly, in 10 HLA-A2+ patients, following cetuximab, an increase in EGFR-specific, CD137-expressing, CD8 T cells directly correlated with the percent increase in CD137-expressing NK cells. Conclusions: Our results demonstrate the synergy of combining an agonistic mAb, anti-CD137, augmenting ADCC and T cell memory following a tumor-targeting mAb, cetuximab, in HN and KRAS mutant and WT CRC cancer. These results support a novel, sequential antibody approach by targeting first the tumor and then the host innate and adaptive immune system. Clinical trial information: NCT01114256.
Effect of anti-CTLA-4 antibody treatment on T-cell repertoire evolution in treated cancer patients.
Authors: Cha Edward , Hou Yafei , Klinger Mark , Cummings Craig , Faham Malek , Ribas Antoni , Fong Lawrence 
Published: March 2020

3020 Background: CTL-associated antigen 4 (CTLA-4) is an immune checkpoint expressed by T cells. While treatment with anti-CTLA-4 antibody can induce clinical responses in advanced cancer patients, its effects on the breadth of the T cell response is unknown. Methods: We used a sequencing-based method, LymphoSIGHT, to assess T cell repertoire diversity in 46 patients with metastatic castration resistant prostate cancer or metastatic melanoma. Peripheral blood mononuclear cells were obtained from patients prior to and during treatment with anti-CTLA-4 antibody. mRNA was amplified using locus-specific primer sets for T cell receptor (TCR) beta, and the amplified product was sequenced. Sequence reads were used to quantitate absolute TCR frequencies using standardized clonotype determination algorithms with normalization by spiked reference TCR sequences. Following clonotype quantitation, repertoire differences between serial samples were assessed by the Morisita index, a statistical measure of population dispersion. Results: 97 paired samples were assessed, of which 46 (47%) had increases and 22 (23%) had decreases in TCR diversity by more than 2-fold. By comparison, none of 9 untreated sample pairs underwent more than a 2-fold change in diversity (P = 0.005, Fisher’s exact test, two tailed). TCR repertoire differences between monthly samples were markedly higher than for time-matched controls. After the first treatment, median Morisita index between samples was 0.197 for treated samples versus 0.039 for untreated (P = 0.0005, Mann-Whitney U test). The median number of clones that significantly changed in abundance was 421 for treated versus 45 for controls. In patients with multiple time points, this rapid clonotype evolution continued through treatment. Despite this global turnover in repertoire, a subset of high frequency clones, including CMV-specific T cells, remained relatively constant over the course of the study. Conclusions: CTLA-4 blockade increases the global rate of T cell clonotype turnover and influences TCR diversity. This evolution of the TCR repertoire may reflect a mechanism by which CTLA-4 blockade enhances tumor-specific T cells over time.
A phase I open-label study of Ad-RTS-hIL-12, an adenoviral vector engineered to express hIL-12 under the control of an oral activator ligand, in subjects with unresectable stage III/IV melanoma.
Authors: Linette Gerald P. , Hamid Omid , Whitman Eric D. , Nemunaitis John J. , Chesney Jason , Agarwala Sanjiv S. , Starodub Alexander , Barrett John A , Marsh Andrew , Martell Lori A. , Cho Angela , Reed Thomas D. , Youssoufian Hagop , Vergara-Silva Andrea 
Published: March 2020

3022 Background: IL-12 is a pleiotropic cytokine with known antitumor activity; however, clinical use was limited by toxicity when delivered systemically. Ad-RTS-hIL-12 is an adenoviral vector engineered for controlled expression of IL-12 with the RheoSwitch Therapeutic System (RTS) and an oral activator, INXN-1001. Methods: In a phase I, 3+3 dose escalation study, subjects with unresectable stage III/IV melanoma were administered 1e12 viral particles (Ad-RTS-hIL-12) intratumorally on the first day of up to six 21-day cycles, and INXN-1001 (5, 20, 100, and 160 mg) orally on days 1-7 of each cycle. Results: Dose escalation is complete with 14 subjects treated. Median prior therapeutic agents was 3 (range 1-4). Common related adverse events included chills (11, 78.6%), pyrexia (11, 78.6%), fatigue (10, 71.4%), and nausea (10, 71.4%). With a biologically effective dose of 160 mg, MTD for INXN-1001 was not reached. One death unrelated to study drug was secondary to septicemia. Clinical activity was observed in 5 of 7 subjects treated at doses of INXN-1001 ≥100 mg, but not at <100 mg, and included prominent inflammatory responses in injected and non-injected lesions, decreases in size of injected and non-injected lesions, and reduction in tumor-associated pain. One subject at the 160-mg dose had stable disease for 20 weeks. Clinical activity in dose cohorts ≥100 mg coincided with a 4-fold median increase from baseline in peak serum levels of IL-12 and IFN-γ compared with lower dose cohorts. Flow cytometric analyses of PBMCs revealed 7-fold (≥100 mg dose cohorts) median increases from baseline in peak levels of absolute numbers of CD3+ and CD8+ T cells. ELISPOT and T-cell proliferation assays for antigen-specific responses are ongoing. Conclusions: Intratumoral delivery of IL-12 via an adenoviral vector with RheoSwitch enabled finely-controlled expression of IL-12 levels by an oral ligand. Ad-RTS-hIL-12 plus INXN-1001 (160 mg) was well tolerated and induced biological and clinical activity in subjects with advanced melanoma. Phase II studies are ongoing at the biologically effective dose. Clinical trial information: NCT01397708.