bluuebunny/crossref_metadata_2025 huggingface dataset:
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.
Adoptive T-cell therapy (ACT) with TILs for metastatic melanoma: Clinical responses and durable persistence of anticancer responses in peripheral blood.
Authors: Donia Marco , Andersen Rikke , Ellebaek Eva , Iversen Trine Zeeberg , Andersen Mads Hald , thor Straten Per , Svane Inge Marie
Published: March 2020

3028

Background: TIL treatment holds the promise to introduce a new treatment paradigm into oncology practice. To demonstrate the logistical feasibility of this complex approach in Europe, at Herlev Hospital, Denmark, we have initiated a trial for patients with metastatic melanoma and evaluated the melanoma-specific immunity in the peripheral blood. Methods: We present the updated results of trial NCT00937625. The study takes place in a medium-size academic center (30 in-patient oncology beds) equipped with a 36 square meters cGMP cell production lab integrated in a hematopoietic stem cell transplantation unit. Patients were treated with autologous TILs preceded by standard lymphodepleting chemotherapy but followed by attenuated regimens of IL-2 (n=6 low-dose s.c. for 14 days; n=9 i.v. intermediate decrescendo dose). Melanoma-specific responses were assessed with intracellular cytokine staining. Results: We have generated TILs from 28/31 patients, with 15 patients treated so far and many TILs cryopreserved for future use. Patients were treated with an average of >50x109 CD4+, CD8+and a small but consistent fraction of γδ TILs. The lower doses of IL-2 have significantly decreased the classical toxicity of the treatment associated with more harsh IL-2 regimens, and response evaluation showed the achievement of three CR lasting > 1 year and four PR. Clinical responses were associated with high numbers of tumour reactive T-cells infused. Importantly, in most responding patients we observed induction and durable persistence (up to 1 year) of anti-melanoma T-cell responses in the peripheral blood. Conclusions: A high response rate including durable complete responses can be induced after treatment with TILs followed by an attenuated regimen of IL-2, which significantly reduced the occurrence of severe side effects. Effective TIL treatment is associated with induction and long-term persistence in the blood of T cells producing in vitro anticancer responses. By showing that TIL-based ACT is logistically feasible and accessible to medium-size academic centers, we open the possibility for testing this treatment in a large randomized setting in Europe. Clinical trial information: NCT00937625.
Allogeneic dendritic cell (DC) vaccination as an “off the shelf” treatment to prevent or delay relapse in elderly acute myeloid leukemia patients: Results of phase I study.
Authors: van den Loosdrecht Arjan A , Santegoets Saskia , Wetering Sandra van , Singh Satwinder Kaugh , Koppes Malika , Hall Anthony , de Gruijl Tanja D. , Ossenkoppele Gert J. , Kruisbeek Ada M
Published: March 2020

3029

Background: Vaccines against tumor-associated antigens represent an appealing strategy for preventing tumor recurrence. A novel immunotherapy platform is represented by the DCOne cell line, which originates from a human myeloid leukemia cell line, endogenously expresses a range of tumor associated antigens and can be differentiated into mature dendritic cells. Methods: A phase I study enrolled 12 AML patients (age range 58-71) who were either in CR1/CR2 (n=5) or had smouldering disease (n=7), at high risk of relapse and ineligible for available post-remission therapies, in a 3+3 design, starting with 4 bi-weekly intradermal DCOne DC vaccinations of 10E6 cells (n=3), 25E6 (n=3) or 50E6 (n=6). Patients were monitored for clinical and immunological responses for 126 days and surviving patients were followed up after study completion. Results: Treatment was well tolerated in all patients, with expected toxicities of injection site reactions (< grade 2). During the study 3 patients died: 2 from infections and 1 from leukemia. Patients who survived more than 6 months post-vaccination showed remarkable survival (22 mo after the first patient was recruited, 3 patients have been alive for 22, 20 and 16 months respectively). One patient with smouldering AML at entry achieved CR2 after vaccination; one patient who was in CR2 at entry, relapsed 8 mo after vaccination and entered CR3 following a single low dose of 5-AZA. Remarkably, 1/5 patients that were evaluable by IFNg ELIPOTs showed vaccination-induced specific T cell responses to WT-1 and PRAME, antigens present in DCOne DC. In addition, increased post vaccination delayed type hypersensitivity reactions were observed in all cohorts. Furthermore, induction of systemic immune responses, with increases in CD4+ and CD8+ T cell proliferative responses and/or seroconversion to DCOne DC and/or AML blasts was seen in 5 out of 9 patients. Conclusions: Vaccination with DCOne derived DC is feasible in AML, generated cellular and humoral immune responses, and interesting clinical responses. The hypothesis that immune responses correlate with clinical benefit will be investigated in a randomised phase II trial. Clinical trial information: NCT01373515.
Risk of HCC recurrence with cellular immunotherapy following radiofrequency ablation.
Authors: Cui Jiuwei , Li Wei , Wang Nanya , Zhao Hengjun , Jin Haofan , Niu Chao , Wang Guanjun
Published: March 2020

3031

Background: Although radiofrequency ablation (RFA) has brought promising therapeutic outcome in hepatocellular carcinoma (HCC) treatment, the curative rate was compromised by high recurrence and metastasis after RFA. Immunosupression in patients with HCC is an important factor leading to its recurrence and metastasis. This study was designed to observe the efficiency and safety of application of cellular immunotherapy (CIT) after RFA for HCC patients. Methods: Sixty-two patients with HCC who were treated with radical RFA were divided into two groups: RFA alone (32 patients) and RFA/CIT (30 patients). Autologous mononuclear cells were collected from the peripheral blood and separated by apheresis, and then induced into natural killer cells, γδT cells, cytokine-induced killer cells. These cells were identified by flow cytometry with their specific antibodies and then were infused intravenously to RFA/CIT patients for 3 or 6 courses. The tumor recurrent status of these patients was evaluated with computed tomography (CT) every 3 months after RFA. Progression-free survival (PFS), liver function, viral load, and adverse effects were examined. Results: The median PFS in RFA group was 12.0 (9.1-14.8) months while median PFS in RFA/CIT group has not yet been reached. It indicated that sequential RFA/CIT significantly reduced the risk of HCC recurrence [hazard ratio (HR) = 0.136]. In RFA/CIT group, six courses had better survival prognosis than three courses (P <0.05). Viral load of hepatitis C decreased in two of three patients without antiviral therapy in RFA/CIT group, but was increased in RFA alone group. The RFA/CIT group maintained the hepatic function at the level before CIT. The hepatic function in 28.1% (9/32 cases) patients in RFA group was deteriorated. Only one developed fever (38.5 °C) after one infusion and recovered 2 hours later. Otherwise, there was no toxic effect in the RFA/CIT group. Conclusions: These preliminary results suggested that combination of sequential CIT with RFA for HCC patients was efficient and safe, and may be helpful in the prevention of the recurrence for the patients with HCC after RFA. It also suggested that the CIT may reduce the risk of recurrence by dual effects of anti-tumor and anti-virus.
Correlative biomarker analysis of sequential tumor biopsies in a ph I mode of action (MoA) study in neoadjuvant head and neck squamous cell carcinoma (HNSCC) patients (pts) treated with RG7160 (GA201), a novel dual-acting, monoclonal antibody (mAb) designed to enhance antibody-dependent cellular cytotoxicity (ADCC), with cetuximab (C) as reference.
Authors: Mancao Christoph , Di Scala Lilla , Delmar Paul , Temam Stéphane , Soria Jean-Charles , Spicer James F. , McGurk Mark , Delord Jean-Pierre , Sarini Jerome , Halama Niels , Evers Stefan , Passioukov Alexandre
Published: March 2020

3035

Background: GA201 is a novel humanized anti-epidermal growth factor receptor (EGFR) mAb with a dual MoA: glycoengineered to enhance ADCC on top of inhibition of EGFR signaling. In an open-label, multi-center trial of pts with HNSCC, an exploratory biomarker analysis of sequential tumor biopsies was performed to investigate the single/duplex marker correlation structure. Methods: Pts received 2 doses of 700 or 1,400 mg GA201 or C (day 1, 8). Tumor biopsies were taken at baseline (BL) and pre-surgery (day 15). Immunohistochemistry immune-cell counts (single/duplex markers), EGFR-pathway markers and intra-tumoral cytokines (LUMINEX) were assessed. Advanced exploratory statistical methods were used to analyse inter-relationship between BL and on treatment markers, and with response (as determined by FDG-PET). Results: All immune markers (single and duplex) presented highly heterogeneous median values at BL, but cluster analysis emphasized their strong inter-correlation. These markers were unrelated to the BL tumor EGFR and pERK expression. Strongest bivariate correlation was seen between (CD16, CD68), (CD3, 4, 8) and (CD4, NKp46). GA201 treatment induced positively correlated dynamic changes (chg) between (CD8, CD68), while C did so for (CD4, CD16) and (CD16, CD68). Strong and negative correlation between (CD56chg, PETchg) was seen only in pts treated with 1,400 mg GA201. Intra-tumoral cytokines like CXCL12 showed good correlation with BL CD3, 16 and 68 infiltration. Principle component analysis also confirmed a good association between most BL immune markers and was able to differentiate strongest PET responders in the 700 mg GA201 cohort. Conclusions: Multivariate statistical methods were used to demonstrate strong interdependencies between immune-effector markers and to highlight their promising associations with response to GA201 treatment, likely due to ADCC processes in the tumors. Clinical trial information: NCT01046266.
Relationships of peripheral blood lymphocyte counts (PBLC) with antitumor activity of NGR-hTNF given in combination with chemotherapy (CT).
Authors: Bulotta Alessandra , Gregorc Vanesa , Rossoni Gilda , Todisco Gabriele , Viganò Maria Grazia , Ammannati Cristina , Mazzola Giulia , Lambiase Antonio , Bordignon Claudio
Published: March 2020

3038

Background: Antitumor effects of NGR-hTNF (N), a tumor-targeted antivascular agent, are driven at low dose by an early vessel stabilization that greatly enhances both intratumoral CT uptake and T-cell infiltration. Synergism with CT was shown in immunocompetent mice, but not in nude mice lacking functional T cells. Methods: By an individual patient pooled analysis of 396 patients (pts) from 7 ph II trials in 6 tumor types, we estimated the effects of baseline PBLC on the antitumor activity of N (with or without CT) and CT alone. Low dose N (0.8 μg/m2) was given in combination with CT in 171 pts. Control groups of 140 and 85 pts receiving N and CT alone, respectively, were also analyzed. CT was doxorubicin or a platinum-based regimen. In all trials, response to therapy was assessed every 6 weeks by RECIST. Endpoints of interest were response rate (RR, complete plus partial response), disease control rate (DCR, RR plus stable disease), duration of response (DOR) and progression-free survival (PFS). In logistic and Cox regression analyses, PBLC data were dichotomized in high or low levels by the median cutpoint (1.5/mL; 95% CI, 1.4-1.6). Multivariate models included age, sex, PS and tumor type as covariates. Results: In both N-alone and CT-alone groups, there was no statistically significant difference in treatment effect according to baseline PBLC. Conversely, high PBLC were related to better treatment outcome in the N plus CT group, compared to low PBLC. In this N plus CT group, high PBLC (vs low) were associated with higher RR (OR=2.8; 95% CI, 1.2-6.3; p=.01) and DCR (OR=2.6; 1.3-4.9; p=.004), and with longer DOR (HR=0.39; 0.16-0.96; p=.04) and PFS (HR=0.60; 0.43-0.85; p=.004). For high vs low PBLC, RR was 29% vs 14%, DCR 76% vs 57%, median DOR 8.2 vs 6.3 months, and median PFS 5.0 vs 3.0 months, respectively. On multivariate analyses, high PBLC remained an independent predictor of increased RR (OR=2.7; p=.01) and DCR (OR=2.6; p=.005), and improved DOR (HR=0.36; p=.04) and PFS (HR=0.60; p=.005). Conclusions: Consistently with preclinical data, these results highlight the potential value of PBLC in predicting tumor response to NGR-hTNF in combination with CT, which merits further clinical validation Clinical trial information: NCT00994097-NCT00484432-NCT00484276-NCT00484211-NCT00483509-NCT00483080-NCT01358071.
Effect of vaccination with autologous tumor-loaded dendritic cells on intratumoral regulatory T cells in metastatic melanoma patients.
Authors: Guidoboni Massimo , Granato Anna Maria , Ancarani Valentina , Pancisi Elena , Petrini Massimiliano , Riccobon Angela , Fiammenghi Laura , Drago Francesco , Ridolfi Laura , De Rosa Francesco , Nanni Oriana , Valmorri Linda , Lanza Giovanni , Serra Luigi , Verdecchia Giorgio Maria , Migliori Giuseppe , Amadori Dino , Ridolfi Ruggero
Published: March 2020

3040

Background: Vaccination with dendritic cells (DC) is still a valid experimental option for metastatic melanoma (MM). However, only a few patients experience long-lasting objective responses and the majority of clinical responders afterwards relapse and die. Which mechanisms are actually responsible for this “secondary resistance” to whole tumor antigens-loaded DC vaccines is largely unknown. It has been hypothesized that suppressive immune cell subpopulations, regulatory T cells in particular, may progressively accumulate in tumor tissues thus hampering therapy-induced antitumor immune responses along time. To elucidate this issue we evaluated changes induced by immunologically effective DC vaccination in the composition of tumor-associated T cell subpopulations. Methods: 12 patients with MM previously enrolled in a phase I/II DC vaccine trial and for which tumor tissue taken before and after at least 4 induction vaccine doses were available, were included in the study. Intratumoral lymphocytes were evaluated by CD3, CD4, CD8, FoxP3 and GrB immunostainings, and quantified by a computer-assisted method. A nonparametric two-tailed Wilcoxon signed-rank test was utilized for evaluating differences in the distribution of the number of cell positive for each marker on the total cell counts in pre- and post-vaccine biopsies. Results: Our data showed a considerable and statistically significant decrease of intratumoral FoxP3+regulatory T cells in melanoma tissues after DC vaccination. In addition, the concurrent increase of intratumoral activated cytotoxic T lymphocytes, as shown by CD8 and Granzyme B stainings, indicated that this decrease has likely a functional relevance. Conclusions: Our findings that vaccination with DC loaded with autologous tumor lysate strongly reduces the intratumoral content of regulatory T cells add strength to the rationale for the development of potentially more effective combination schedules where whole tumor antigen-loaded DC vaccine prime and partially activate tumor-specific low-affinity T cells in a first tumor antigen-focusing step, followed by boosting with non-maximal doses of anti-CTLA-4 antibodies.
T-regulatory cell function analysis in locally/regionally advanced melanoma patients treated with ipilimumab.
Authors: VanderWeele Robert Alan , Butterfield Lisa H. , Lin Hui-Min , Cunningham Diana E. , Lin Yan , Kirkwood John M. , Tarhini Ahmad A.
Published: March 2020

3041

Background: We conducted an immunogenicity and biomarker analysis in stage IIIB-C melanoma patients treated with neoadjuvant ipilimumab (ipi) and reported a significant increase in the frequency of circulating T-regulatory cells (T-reg) (CD4+CD25hi+ Foxp3+; p=0.02 CD4+CD25hi+CD39+; p=0.001) from pre-ipi (baseline) to post-ipi (6 weeks) in treated patients (Tarhini et al., ASCO 2012). Also, increases in T-reg were associated with improved PFS (p=0.034; HR=0.57). We hypothesized that ipi induces its clinical activity in part through its effect on T-reg, and despite the observed increase in circulating T-reg frequency; their suppressor function is reduced. Methods: Patients were treated with ipi (10 mg/kg IV q3weeks x 2doses) bracketing definitive surgery. PBMC were collected at baseline and at 6 weeks. T-reg were isolated from pre-ipi (baseline) and post-ipi (6 weeks) PBMC samples utilizing Miltenyi Biotec T regulatory isolation kit (CD4+CD25+CD127dim/-). Isolated T-reg were incubated with OKT3/IL-2/CD28-stimulated and CFSE-labeled CD4+CD25- responder T-cells from the same patient time point at 1:1, 1:2 and 1:5 ratios. Flow cytometery was used to evaluate the number of cell divisions of CFSE labeled responder cells and, therefore, the degree of T-reg proliferation suppression. Results: Thirty-five patients were enrolled in the study; of those, 18 patients had adequate PBMC samples with sufficient T-reg isolated for T-reg functional analysis. Preliminary analysis of the first 13 patients shows a trend toward decreased suppressive function of T-reg after treatment with ipi. Expressed as “percent of maximum inhibition”, pre- vs. post-ipi T-reg showed 61% vs. 47% suppressive activity (p=0.15) at the 1:1 ratio. Conclusions: There was a trend toward decreased suppressive function of T-reg after treatment with ipi, supporting the function modulation hypothesis. T-reg functional analysis for the remaining 5 patients is ongoing and we will perform comparative studies of changes in T-reg function with changes in T-reg frequency and clinical outcomes in the entire cohort.
A trial of autologous ex vivo expanded NK cell-enriched lymphocytes with docetaxel in patients with advanced NSCLC as second- or third-line treatment: Phase IIa study.
Authors: Park Suk-Young
Published: March 2020

3045

Background: Cancer immunotherapy has been attractive for a long time with diverse clinical attempts and results. In particular, NK cells have received considerable attention because of their potential role in immune surveillance in vivo. MICA/B on tumor cells, known as the representative ligand for NKG2D receptor on NK cell, has been reported to be modulated by a variety of stresses including some chemotherapeutic agents and it is anticipated that enhancing MICA/B expression is contributory to anti-cancer treatment. With recent development of expanding autologous ex-vivo NK cell enriched lymphocytes (NKL), we designed a trial to augment the anti-cancer effect by co-administering NKL and docetaxel (D), one of the second-line agents in patients with advanced NSCLC. Methods: We first identified some chemotherapeutic agents, such as cisplatin and D, that induce peak MICA/B expression on HeLa cell during the 24-36 hours and designed a trial of combination of NKL with D administered within the same day. Eligible patients were 20-75 years old, ECOG PS 0-2, previously received one chemotherapy, and had stage IIIB/IV histologically proven NSCLC with measurable lesions. NKL were prepared and provided from NKBIO CO. Feasibility, adverse effect, and PFS were evaluated and compared with historical control of weekly D. Results: 19 patients were enrolled before early closure. NKL production and administration were feasible in all cases even with disseminated disease. No additional AE was observed in addition to that reported in D alone. PFS 3M and RR 10.5% with 2 PR were observed and similar to historical control (PFS 2.9M, RR 8.8%). Conclusions: To our knowledge, it seems to be the first report on the combination of NKL with D in patients with advanced NSCLC. Autologous NKL production and co-administration with D were feasible without further toxicity or complication. Benefit in PFS and RR, as compared with historical control, was not detected in this study population with advanced NSCLC, but further study to see whether the combination of NKL and chemotherapy has anti-cancer effect is desirable to be performed in low tumor burden state, such as less advanced or remission induced state.
Double-loaded mature dendritic cell (DC) therapy for non-HLA-restricted patients with advanced ovarian cancer: Final results of a clinical phase I study.
Authors: Imhof Marianne , Lipovac Markus , Angleitner-Boubenizek Lukas , Barta Johannes , Gomez Ivan , Hrdina Astrid , Krupa Ewa , Lafleur Judith , Lang Istvan , Pieta Katharin , Rottmann Heike , Imhof Martin ,   Hospital Korneuburg Gynecology Nurses
Published: March 2020

3052

Background: Prognosis of ovarian cancer remains poor after initial responsiveness to surgery and chemotherapy followed by high recurrence and mortality rates and new experimental approaches are warranted. Our goal was to evaluate a novel DC-based vaccine, which exploits a unique dual loading strategy to amplify specific anti-tumor short- and long-term immune responses to delay or even prevent recurrent and metastatic disease. Methods: Monocytes were collected via apheresis, matured into DCs and pulsed with two universal tumor associated antigens (uTAA) in our GMP facility. DCs were loaded with TERT and Survivin via two different pathways (mRNA and peptide) to elicit CD8+ and CD4+T cells directly. Endpoints of the study were tolerability and safety, immunological and clinical responses. T cell responses against the IMP and loaded antigens were evaluated by cytokine bead array (CBA) and intracellular staining assays. Results: 15 non HLA-restricted patients with advanced ovarian cancer were enrolled 8 weeks after standard treatment (surgery and chemotherapy). Each patient was vaccinated intradermally on a weekly or fortnightly basis with a maximum of 8 doses of 13*106 double loaded DCs. The majority of treatment related side effects were grade 1 fever and erythema. Overall the therapy was well tolerated. Immune response data is available for 14/15 patients, 1 was withdrawn after the first administration. The IMP leads to strong immune responses with high frequency (>90%), which is proven for both uTAAs in CD8+ as well as CD4+ T cells. A clear positive trend in progression free survival is demonstrated compared to matched historical control. Conclusions: Therapy with our unique double loaded DC vaccine was feasible, safe and well-tolerated by patients. The vaccine was highly immune stimulatory and elicited both, long-term and short-term anti-tumor immune responses, establishing a promising platform for immune therapy for ovarian cancer and all solid tumors in general. The first two authors contributed equally. Clinical trial information: NCT01456065.
A phase Ib dose-escalation study of TRC105 (anti-endoglin antibody) in combination with capecitabine for advanced solid tumors (including patients with progressive or recurrent HER2-negative metastatic breast cancer).
Authors: Levine Ellis Glenn , Forero Andres , O'Connor Tracy , Seon Ben K. , Jivani Manoj A , Adams Bonne J. , Theuer Charles P.
Published: March 2020

3057

Background: CD105 (endoglin) is an endothelial cell membrane receptor highly expressed on angiogenic tumor vessels that is essential for angiogenesis and upregulated by hypoxia and VEGF inhibition. TRC105 is an anti-CD105 monoclonal antibody being studied in phase II trials that potentiates chemotherapy in preclinical models. Methods: Pts with advanced solid tumors (for purposes of dose escalation) or pts with metastatic HER2-negative breast cancer (following completion of dose escalation), ECOG PS 0-1, and normal organ function were treated with intravenously administered TRC105 wkly plus capecitabine at 1,000 mg/m2 BID for 14 of every 21 days, and assessed for safety, PK, and response. Results: Fourteen patients (median age = 52; M:F 4:10; median of 3 prior regimens; 10 with breast and 4 with colorectal cancer) were enrolled. Dose escalation proceeded from 7.5 mg/kg TRC105 to the recommended single agent phase II dose of 10 mg/kg of TRC105 in combination with capecitabine, without development of dose limiting toxicity. Fourteen pts were treated at 7.5 mg/kg (n=4) or 10 mg/kg (n=10) TRC105 wkly + 1,000 mg/m2 BID/14d capecitabine of repeating 21 day cycles. Patients experienced expected TRC105 related adverse events of grade 1 or grade 2 infusion reaction, epistaxis, gingival bleeding, telangiectasia, headache, rash, and fatigue. Grade 3 headache and grade 3 vomiting were each seen in one patient. Adverse events characteristic of each individual drug were not increased in frequency or severity when the two drugs were administered together. Mucocutaneous telangiectasia, a marker of TRC105 target modulation, was observed at both dose levels. A heavily pretreated male breast cancer patient remained on study for 9 months with a RECIST-defined partial response. Stable disease beyond 9 weeks was observed in three patients. Conclusions: The recommended single agent phase II dose of 10 mg/kg TRC105 wkly was well tolerated in combination with capecitabine. The combination treatment could be advanced in HER2-negative breast or colorectal cancer. Clinical trial information: NCT01326481.
A phase Ib dose-escalation study of TRC105 (anti-endoglin antibody) in combination with bevacizumab (BEV) for advanced solid tumors.
Authors: Rosen Lee S. , Robert Francisco , Matei Daniela , Goldman Jonathan Wade , Mendelson David S. , Chiorean E. Gabriela , Strother Robert Matthew , Seon Ben K. , Alvarez Delia , Adams Bonne J. , Theuer Charles P. , Gordon Michael S.
Published: March 2020

3059

Background: CD105 (endoglin) is an endothelial cell membrane receptor highly expressed on angiogenic tumor vessels that is essential for angiogenesis and upregulated by hypoxia and VEGF inhibition. TRC105 is an anti-CD105 monoclonal antibody that potentiates VEGF inhibitors in preclinical models. This study assessed safety, PK and preliminary efficacy of TRC105 in combination with BEV. Methods: Pts with advanced solid tumors, ECOG PS 0-1, and normal organ function were treated with escalating doses of IV TRC105 (3, 6, 8 or 10 mg/kg/wk) plus bevacizumab (BEV) at 15 mg/kg q3wk or 10 mg/kg q2wk. Results: Thirty one pts (median age = 62; M:F 14:17; median 4 prior regimens; primarily metastatic colorectal or ovarian cancer) were treated with TRC105 wkly + BEV. TRC105 3 mg/kg wkly + 15 mg/kg q3wk BEV was well tolerated. Concurrent administration of TRC105 6 mg/kg wkly + 15 mg/kg BEV q3wk resulted in headaches in 4 of 5 pts on cycle 1 day 1 (two grade 3). Dose escalation to the recommended single-agent phase II dose of 10 mg/kg TRC105 weekly + BEV (10 mg/kg q2wk) was tolerated when the initial TRC105 dose was introduced one week after BEV dosing and administered over 2 days. Headache was the only serious adverse drug reaction observed. Adverse events characteristic of each individual drug were not increased in frequency or severity. Target TRC105 serum concentrations were achieved at 6 mg/kg. Mucocutaneous telangiectasia, a marker of TRC105 target modulation, was observed beginning at 6 mg/kg and was dose proportional. Five of 19 heavily pretreated, BEV or VEGF receptor tyrosine kinase inhibitor (TKI) refractory pts with colorectal and ovarian cancer, each with marked tumor burden, experienced radiographic reductions in tumor volume (10-17%). Three of these patients remained on study longer than the prior VEGF inhibitor treatment and two are ongoing. Seven ongoing patients have been treated for 2-8 months. Conclusions: TRC105 10 mg/kg wkly was well tolerated with BEV 10 mg/kg q2wk. The combination demonstrated activity in BEV and VEGF TKI refractory pts. Randomized phase II trials of BEV +/- TRC105 have commenced in renal cell cancer and glioblastoma. Clinical trial information: NCT01332721.
Prognostic factors for the efficacy of catumaxomab in patients (pts) with malignant ascites (MA): Meta-analysis from two phase III studies.
Authors: Friccius-Quecke Hilke , Heiss Markus M. , Lordick Florian , Parsons Simon L. , Wimberger Pauline , Bokemeyer Carsten
Published: March 2020

3078

Background: Data from two phase III studies (IP-REM-AC-01 and CASIMAS) were used for a meta-analysis to identify factors with a potential impact on the efficacy of catumaxomab (CATU) in pts with MA. Methods: 389 pts treated with CATU plus paracentesis and 88 control pts (paracentesis only) were included. Efficacy parameters were overall survival (OS), puncture-free survival (PuFS) and time to first puncture (TTPu). The impact of the prognostic factors Karnofsky Index (KI), total serum protein (protein) and presence/absence of distant metastases (metastases) at inclusion was analysed for these parameters. Results: Pts treated with CATU showed a significant prolongation of PuFS (44 vs 11 d, HR 0.34, p<0.0001), TTPu (88 vs 13 d, HR 0.26, p<0.0001) and OS (88 vs 68 d, HR 0.62, p=0.007) compared to control pts. Pts treated with CATU and a KI of 80–100 at inclusion had significantly better OS compared to those with a KI of 60–79 (120 vs 57 d, HR 0.55, p<0.001) and improved PuFS (55 vs 27 d, HR 0.61, p<0.001) but not improved TTPu (88 vs 96 d, HR 0.80, p=0.186). Linear Cox regression of KI as a co-variable showed a significantly positive impact of high KI on catumaxomab efficacy for OS (HR 0.97, p<0.001) and PuFS (HR 0.98, p<0.001) but not TTPu (HR 0.99, p=0.054). Cox regression analysis of the presence of distant metastases and low (< normal) total serum protein on CATU efficacy showed a negative impact on OS (metastases: HR 1.43; p<0.001; protein: HR 1.39, p=0.002), PuFS (metastases: HR 1.37, p=0.003; protein: HR 1.45, p<0.001) and TTPu (metastases: HR 1.28, p=0.069; protein: HR 1.41, p= 0.011). Treatment effects on PuFS and TTPu were observed in all subgroups for all factors but the effect on OS compared to controls was only found in pts with KI 80–100 and in those with no distant metastases and with normal/high total serum protein. Conclusions: Karnofsky Index, distant metastases and total serum protein at screening were identified as factors having a significant impact on OS in CATU-treated pts and better prognostic pts compared to controls. In contrast, the effect of CATU on ascites control (PuFS, TTPu) was observed in all subgroups irrespective of whether the pts were in the good or poor prognostic group.
Phase III randomized, placebo (PL)-controlled, double-blind study of intravenous calcium/magnesium (CaMg) to prevent oxaliplatin-induced sensory neurotoxicity (sNT), N08CB: An alliance for clinical trials in oncology study.
Authors: Loprinzi Charles L. , Qin Rui , Dakhil Shaker R. , Fehrenbacher Louis , Stella Philip J. , Atherton Pamela J. , Seisler Drew K. , Qamar Rubina , Lewis Grant Carlton , Grothey Axel
Published: March 2020

3501

Background: Cumulative neurotoxicity commonly leads to early discontinuation of oxaliplatin-based therapy. In a relatively small, prematurely-discontinued, randomized study, IV CaMg was associated with reduced oxaliplatin-induced sNT (Grothey, JCO, 2011). N08CB was designed to definitively test whether IV CaMg significantly decreases cumulative oxaliplatin-related sNT. Methods: 353 pts with colon cancer undergoing adjuvant therapy with FOLFOX were randomized to 3 arms: IV CaMg (1g calcium gluconate, 1g magnesium sulfate) before and after oxaliplatin vs PL before and after vs CaMg before and PL after. The primary endpoint was cumulative sNT repeatedly measured by the sensory subscale of the EORTC QLQ-CIPN20. Secondary endpoints, using CTCAE 4.0 and an oxaliplatin specific neurotoxicity scale, were also assessed. Acute neuropathy data were also collected for 5 days following each oxaliplatin dose. The area under the curve (AUC) of the sensory subscale during the treatment cycles was used as summary measures for comparison. The Wilcoxon rank-sum tests were conducted for each treatment versus placebo arm, at 2.5%, adjusting for multiplicity using Bonferroni’s approach. Results: CaMg did not reduce cumulative sNT. Primary and secondary analyses data are summarized in the Table. In addition, there were no significant differences between arms regarding oxaliplatin administered doses or chemotherapy discontinuation rates. Also, there were no substantial differences in acute neuropathy scores or side-effects between study arms. Conclusions: This study does not demonstrate any activity of IV CaMg as a neuroprotectant against oxaliplatin-induced neurotoxicity. Clinical trial information: NCT01099449. [Table: see text]