bluuebunny/crossref_metadata_2025 huggingface dataset:
Correlation of PDL1 tumor expression and outcomes in renal cell carcinoma (RCC) patients (pts) treated with pazopanib (paz).
Authors: Figueroa David J , Liu Yuan , Gagnon Robert C. , Carpenter Christopher , Dar Mohammed , Bartlett-Pandite Arundathy N.
Published: March 2020

3021

Background: The interaction between PDL1 (B7H1) and its receptor PD-1 on activated T cells plays an important role in the inhibition of T-cell responses and contributes to suppression of antitumor immune responses. Tumor PDL1 expression has been associated with poor outcomes in RCC. This study investigates the correlation between PDL1 tumor expression and outcomes in RCC pts treated with paz. Methods: Using IHC, we retrospectively analyzed baseline FFPE tumor samples for PDL1 from 2 paz RCC studies: a single arm phase II trial and randomized placebo (pbo)-controlled phase III study. PDL1 expression was analyzed by MedTox Laboratories using the anti-PDL1 MouseIgG1 clone 5H1 (Thompson) on the Leica automated IHC platform. Additional dual PDL1/CD68 staining was carried out to delineate tumor and macrophage PDL1 expression. Tumor PDL1 expression was quantified by H-Score (HS) and PDL1+ macrophages were assessed semi-quantitatively. Association between PDL1H scores and PFS was investigated by Kaplan-Meier analysis using optimal cutoff of PDL1tumor HS (minimum p value, log rank test). Results: The optimal cut-point of PD-L1 tumor HS, relative to PFS, was identified as HS > 3. In the phase II study (46 available samples out of 225), HS range was 0-150 and most samples had negative (HS = 0, n = 34, 74%) or low (HS 1-3, n=4, 9%) PDL1 expression. Pts with HS > 3 (n = 8, 17%) had significantly shorter PFS (2.6 mo) than those with HS ≤ 3 (12 mo; p = .0005). In the phase III study (N = 160 available samples: paz, 113 of 290; pbo, 47 of 145), HS range was 0-280. Most patients had negative (n = 122/160, 76%) or low (n = 9/160, 6%) PD-L1 expression, with 18% (29/160) having HS > 3. Pbo-arm pts with HS > 3 (n = 6/47, 13%) had shorter PFS (2.3 vs 5.5 mo p = .0207). Paz-arm pts with HS > 3 (n = 23/113, 20%) trended toward shorter PFS (7.3 vs 11 mo, p = .1405). Conclusions: PDL1 appears to be a prognostic marker with PDL1 HS > 3 associated with shorter PFS. Limitations of the study include the retrospective nature of the analysis with limited pt samples available, low or negative PDL1 expression in the vast majority of pts, and use of archival samples that may not accurately reflect PDL1 status at study entry. Additional results (tumor volume, OS) will be presented.
Phase I study of the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of the oral inhibitor of indoleamine 2,3-dioxygenase (IDO1) INCB024360 in patients (pts) with advanced malignancies.
Authors: Beatty Gregory Lawrence , O'Dwyer Peter J. , Clark Jason , Shi Jack G , Newton Robert Charles , Schaub Richard , Maleski Janet , Leopold Lance , Gajewski Thomas
Published: March 2020

3025

Background: INCB024360 is a potent, selective inhibitor of IDO1. As the catabolism of tryptophan (Trp) to kynurenine (Kyn) by IDO1 inhibits immune responses and IDO1 expression is elevated in many human cancers, IDO1 inhibition may potentiate effective antitumor immune responses. Methods: This dose-escalation study in adult pts with advanced malignancies used a 3+3 design to determine MTD, toxicity, PK, PD, and tumor response rate. Daily doses of INCB024360 were evaluated in 28-day cycles in 8 cohorts (50 mg once daily; 50 mg, 100 mg, 300 mg, 400 mg, 500 mg, 600 mg, or 700 mg BID). Treatment continued until disease progression or unacceptable toxicity. PK and PD samples were drawn on days 1 and 15. Results: 52 pts have been treated. Tumor types included colorectal (56%), melanoma (12%), and other (33%). The most common adverse events (≥20%) were fatigue, nausea, decreased appetite, vomiting, constipation, abdominal pain, diarrhea, dyspnea, back pain, and cough. The most common grade 3 or 4 adverse events were abdominal pain, hypokalemia, and fatigue (9.6% each). One DLT each was observed at 300 mg BID (grade 3 radiation pneumonitis) and 400 mg BID (grade 3 fatigue); no DLTs were observed in the 18 pts treated with 600 mg or 700 mg BID. There were no objective responses. At 56 days, stable disease was seen in 15 patients and lasted ≥112 days in 7 patients. Significant dose-dependent reductions in plasma Kyn/Trp ratios and Kyn levels were detected at all doses and in all pts. Maximal effects were observed at doses ≥300 mg BID. With repeat dosing, 700 mg BID provided an average plasma concentration ~5-fold the projected IC90. Overall, doses ≥300 mg BID achieved greater than 90% inhibition of IDO1 throughout the dosing period. Conclusions: INCB024360 was generally well tolerated at doses of up to 700 mg BID and there appears to be no correlation of dose with toxicity. Doses ≥300 mg BID were capable of >90% inhibition of IDO1 activity and found to effectively normalize plasma Kyn levels. The recommended dose as monotherapy is 600 mg BID. Clinical trial information: NCT01195311.
Recombinant adenoviral human p53 gene infusion in treatment of malignant pleural effusions and malignant ascites.
Authors: Hu Kaiweng
Published: March 2020

3027

Background: Malignant pleural or peritoneal effusions are frequently developed in the late-stage malignant tumors in chest or abdominal cavity. Various drainage methods and intra-cavity chemotherapy have transient and limited benefits. Here we evaluated the role of recombinant adenoviral human p53 gene (rAd-p53) infusion for patients with malignant pleural or peritoneal effusions. Methods: Thirty-two patients with historically diagnosed malignant pleural (18 cases) or peritoneal (14 cases) effusions, 19 males and 13 females with an average age of 61 years old (37–80 years), were included this study. The malignant pleural effusions were caused by primary lung cancers (8 cases), lung metastatic tumors (4 cases), breast cancers (3 cases), pleural mesothelioma (2 cases), lymphoma (1 cases), and the peritoneal effusions were caused by ovarian cancers (5 cases), primary liver cancers (4 cases), liver metastatic tumors (2 cases), colon cancer (1 case), gastric cancer (1 case), and prostate cancer (1 case). After draining most of the fluids, 4×1012 viral particles (VP) of rAd-p53 diluted into 1,000 ml of saline solution for intra-abdominal cavity infusion and 2×1012VP of rAd-p53 diluted into 500 ml of saline solution for intra-chest cavity infusion, were given weekly for 4 weeks. The response rate was evaluated. The complete response is defined as the complete disappearance of pleural or peritoneal fluid and negative cytologic findings for >4 weeks, and the partial response is defined as a decrease over 50% of the fluid without the need of drainage and negative cytologic findings for >4 weeks. Results: The pleural effusion showed a complete response in 6 patients (33.3%) and a partial response in 6 patients (33.3%). The peritoneal effusion had a complete response in 3 patients (21.4%) and a partial response in 7 patients (50.0%). The overall response rate was 68.8% (22/32). The symptoms associated with the malignant effusion relieved in 27 patients (84.4%). There were no serious side effects observed except for self-limited fever found in all the cases. Conclusions: Intra-abdominal or chest cavity infusion of rAd-p53 is a safe and effective treatment for some malignant pleural or peritoneal effusions.
Awareness and understanding of cancer immunotherapy in Europe.
Authors: Mellstedt Hakan , Gaudernack Gustav , Gerritsen Winald R. , Huber Christoph , Melero Ignacio , Parmiani Giorgio , Scholl Suzy , Thatcher Nick , Wagstaff John , Zielinski Christoph
Published: March 2020

3053

Background: Use of immunotherapies in the treatment of cancer is growing and a range of new immunotherapeutic strategies are being evaluated. It is important that healthcare providers (HCP) understand these treatments and how they compare with and may complement established therapies. As part of the activities of the POINT expert group, we commissioned a survey of current awareness, attitudes and perceptions of cancer immunotherapy in Europe. Methods: From August-September 2011, 426 healthcare professionals (HCPs: oncologists, surgeons and oncology nurses) from France, Germany, Italy, Spain and the UK (~85 respondents/country) completed online interviews. Representatives of patient advocacy groups (PAGs) in each country were surveyed by telephone interview. Results: Nearly all (98%) HCPs were aware of cancer immunotherapy. While 68% of HCPs indicated a high level of interest, knowledge levels were lower. Only 24% of the HCPs had direct experience with cancer immunotherapies, while others reported they knew a lot (12%), a reasonable amount (28%) or little (34%) about immunotherapy strategies but had not used them (76%). Overall perceptions of cancer immunotherapy among HCPs were largely positive (60%) and rarely negative (3%). The key advantages of cancer immunotherapy were perceived to be good safety and tolerability (75%), a targeted mechanism of action (61%) and good efficacy (48%). The leading barriers to use of immunotherapies were costs of treatment (58%), past clinical trial failures (45%) and access/formulary restrictions (44%). Most (75%) HCPs had already discussed cancer immunotherapy with their patients and 70% of patients were reported as being receptive to the concept. The majority of PAGs indicated they were currently unable to advise patients about cancer immunotherapy due to a lack of or confusing information and poor understanding. Conclusions: Awareness of cancer immunotherapy in Europe is high and it is generally perceived as a positive addition to established treatment options. However, the understanding varies and the direct experience is limited. There is a clear need for further educational activities concerning cancer immunotherapy, as well as further clinical data on long-term efficacy and safety.
Antitumor activity of concurrent blockade of immune checkpoint molecules CTLA-4 and PD-1 in preclinical models.
Authors: Selby Mark , Engelhardt John , Lu Li-Sheng , Quigley Michael , Wang Changyu , Chen Bingliang , Korman Alan J.
Published: March 2020

3061

Background: Interaction of immune checkpoint molecules PD-1 and CTLA-4 and their respective ligands attenuates antitumor T cell responses. In clinical studies, PD-1 blocking antibody (Ab) nivolumab (BMS-936558) or the CTLA-4 blocking Ab ipilimumab result in durable responses in multiple human malignancies. We describe the evaluation of concurrent treatment with anti-PD-1 and anti-CTLA-4 mAbs in preclinical models. Methods: Antitumor activity of treatment with murine homologs of anti-PD-1 (4H2-mIgG1) and anti-CTLA-4 (9D9-mIgG2b) was evaluated in MC38, a murine colon adenocarcinoma model. The effects of concurrent treatment on T cell infiltration of tumors, tumoral expression of PD-L1 and cytokine levels were explored. The preclinical safety profile of concurrent nivolumab + ipilimumab was assessed in a cynomolgus macaque model. Results: Concurrent treatment of MC38 tumors with 4H2-mIgG1 + 9D9-mIgG2b (10 mg/kg Q3d x 3) results in synergistic antitumor activity whereas efficacy with sequential dosing was similar to either agent alone. With concurrent treatment, dose reductions of one Ab relative to a fixed dose of the other resulted in retention of some antitumor activity. Anti-PD-1 enhanced CD8+ T cell infiltration of MC38 tumors and increased tumor PD-L1 expression. Anti-CTLA-4 treatment increased intratumoral CD8+ T cells and reduced intratumoral T regulatory cells. While concurrent treatment did not result in further increases in T cell infiltration, it increased expression of intratumoral cytokines. Anti-PD-1 resulted in down regulation of cell surface and intracellular levels of PD-1 in CD8+ T cells. In cynomolgus macaques, concurrent nivolumab + ipilimumab resulted in dose-dependent gastrointestinal toxicities (diarrhea; body weight loss) not observed in earlier cynomolgus studies with nivolumab and rarely with ipilimumab. These preclinical observations provided the rationale for a dose escalation trial (NCT01024231) of combined nivolumab + ipilimumab in advanced melanoma. Conclusions: Concurrent treatment with anti-PD-1/anti-CTLA-4 resulted in synergistic antitumor activity in preclinical models and supports the evaluation of the combination in clinical studies.
Use of an antibody-drug conjugate targeting tissue factor to induce complete tumor regression in xenograft models with heterogeneous target expression.
Authors: Breij Esther CW , Satijn David , Verploegen Sandra , de Goeij Bart , Schuurhuis Danita , Bleeker Wim , Houtkamp Mischa , Parren Paul
Published: March 2020

3066

Background: Tissue factor (TF) is the main initiator of coagulation, that starts when circulating factor VII(a) (FVII(a)) binds membrane bound TF. In addition, the TF:FVIIa complex can initiate a pro-angiogenic signaling pathway by activation of PAR-2. TF is aberrantly expressed in many solid tumors, and expression has been associated with poor prognosis. TF-011-vcMMAE, an antibody-drug conjugate (ADC) under development for the treatment of solid tumors, is composed of a human TF specific antibody (TF-011), a proteaseEcleavable valine-citrulline (vc) linker and the microtubule disrupting agent monomethyl auristatin E (MMAE). Methods: TF-011 and TF-011-vcMMAE were functionally characterized using in vitro assays. In vivo anti-tumor activity of TF-011-vcMMAE was assessed in human biopsy derived xenograft models, which genetically and histologically resemble human tumors. TF expression in xenografts was assessed using immunohistochemistry. Results: TF-011 inhibited TF:FVIIa induced intracellular signaling and efficiently killed tumor cells by antibody dependent cell-mediated cytoxicity in vitro, but showed only minor inhibition of TF procoagulant activity. TF-011 was rapidly internalized and targeted to the lysosomes, a prerequisite for intracellular MMAE release and subsequent tumor cell killing by the ADC. Indeed, TF-011-vcMMAE efficiently and specifically killed TF-positive tumors in vitro and in vivo. Importantly, TF-011-vcMMAE showed excellent anti-tumor activity in human biopsyEderived xenograft models derived from bladder, lung, pancreas, prostate, ovarian and cervical cancer (n=7). TF expression in these models was heterogeneous, ranging from 25-100% of tumor cells. Complete tumor regression was observed in all models, including cervical and ovarian cancer xenografts that showed only 25-50% TF positive tumor cells. Conclusions: TF-011-vcMMAE is a promising new ADC with potent anti-tumor activity in xenograft models that represent the heterogeneity of human tumors, including heterogeneous TF expression. The functional characteristics of TF-011-vcMMAE allow efficient tumor targeting, with minimal impact on coagulation.
Novel heteroclitic XBP1 peptides evoking antigen-specific cytotoxic T lymphocytes targeting various solid tumors.
Authors: Bae Jooeun , Carrasco Ruben , Daley John , Dranoff Glen , Anderson Kenneth Carl , Munshi Nikhil C.
Published: March 2020

3067

Background: Activation of the unfolded protein response (UPR) allows for tumor cells to survive prolonged endoplasmic reticulum stress and hypoxic conditions. XBP1 is an upstream element and a critical transcriptional activator of the UPR, and its up-regulation in a variety of human solid tumor cancers makes it as a promising immunotherapeutic target. The purpose of these studies was to evaluate immunogenic HLA-A2 XBP1-specific peptides for their ability to elicit cytotoxic T lymphocytes (CTL) against a variety of solid tumor cell lines. Methods: Upon the validation of XBP1 peptides for their strong HLA-A2 bindings and stabilities, peptide-specific CTL were generated ex vivo by repeated stimulation of CD3+ T lymphocytes obtained from HLA-A2+normal donors with XBP1 peptides-pulsed antigen-presenting cells, either dendritic cells or T2 cells. Results: A cocktail of heteroclitic XBP1 US184-192 (YISPWILAV) and heteroclitic XBP1 SP367-375 (YLFPQLISV) peptides with significantly improved HLA-A2 affinity and stability from their native counterparts were used to evoke XBP1 antigen-specific CTL. The CTL were predominantly CD3+CD8+ T cells (>80%) containing a high percentage of Effector Memory (EM; CCR7-CD45RO+) cells, which were distinctively evoked by repeated stimulation with the XBP1 peptides. In addition, the XBP1-CTL displayed a high level of cellular activation (CD69+/CD3+CD8+). The XBP1-CTL demonstrated effective anti-tumor responses including cell proliferation and IFN-g production, as well as degranulation (cytotoxic activity) against HLA-A2+breast cancer (MB231, MCF7), colon cancer (LS180, SW480) and pancreatic cancer (8902, Panc1, PL45) cell lines, which over-express both unspliced and spliced XBP1 antigens. Importantly, the specific anti-tumor activities were detected primarily in the EM CTL subset. Conclusions: These results suggest the immunotherapeutic potential of a cocktail of heteroclitic XBP1 US184-192 and XBP1 SP367-375 peptides to elicit effective anti-tumor responses against various solid tumors, and provide the framework for clinical development of vaccine trials to improve patient outcome.
Anti-60S ribosomal protein L29 antibody: New anticancer agent discovered from human sera.
Authors: Miyake Yasuhiro , Matsushita Hiroshi , Yamamoto Kazuhide
Published: March 2020

3071

Background: Incidence of hepatocellular carcinoma (HCC) is lower in autoimmune hepatitis (AIH) than chronic viral hepatitis. In AIH, serum immunoglobulin G (IgG) levels are associated with the clinical features. In this study, we searched IgG showing anti-tumor effect in sera of AIH patients. Methods: Total IgG was extracted from sera of AIH patients by using protein G. Anti-tumor effects of the total IgG were evaluated by MTT assay using human HCC Huh7 cells and PLC/PRF/5 cells. Autoantigens in membrane proteins of Huh7 cells were screened by immunoprecipitation followed by liquid chromatography-mass spectrometry (LC-MS) shotgun analysis. Results: In one AIH patient without any cancers, addition of total IgG extracted from her serum to the culture inhibited the proliferation of Huh7 cells and PLC/PRF/5 cells, and decreased intracellular levels of β-Catenin and Cyclin-D1. In this patient, autoantigens in membrane proteins were screened, and 60S ribosomal protein L29 (RPL29) was identified from the MS/MS spectra and the SwissProt database using the Mascot Search engine. RPL29 expression in human HCC cell lines including Huh7, PLC/PRF/5, Hep3B, HepG2, HLE, HLF and SK-Hep-1 were identified by Western blot. Next, in the other 25 AIH patients, we investigated the correlation between serum anti-RPL29 levels by indirect ELISA using recombinant RPL29 and anti-tumor effects of total IgG extracted from their sera. Serum anti-RPL29 levels were significantly correlated with anti-tumor effects of total IgG extracted from their sera (P <0.0001). On the other hand, addition of recombinant RPL29 to the culture canceled anti-tumor effects of total IgG extracted from sera of AIH patients showing higher serum anti-RPL29 levels. Additionally, these anti-tumor effects of total IgG extracted from sera of AIH patients were shown by MTT assay using human pancreatic cancer AsPC-1 cells and Panc-1 cells. Conclusions: Anti-RPL29 antibodies showing anti-tumor effect were discovered from human sera. Anti-RPL29 inhibits cancer cell proliferation via down-regulation of Wnt/β-Catenin signaling pathway. Serum anti-RPL29 may be one of immune systems by which the human does not develop cancers.
Novel murine anti-HER2 monoclonal antibodies to induce apoptosis and regulate miR-21 in breast cancer cell.
Authors: Kim Alice Y. , Zer Cindy , Williams John C. , Press Michael F. , Park Jinha Mark
Published: March 2020

3081

Background: MicroRNAs play critical roles in biological and pathological processes. Of these, miR-21 is frequently observed to be overexpressed in various cancers. However, treatment of breast cancer cells with trastuzumab enhances the level of miR-21 by a relative fold of 2.26 (Ichikawa, PLos ONE, 2012, p.5). In this study, we demonstrate that two murine anti-HER2 mAbs, 10H8 and 8H11, while inhibiting cell proliferation and inducing apoptosis, do not perturb the level of miR-21 in the same way as trastuzumab. To understand the differential effects of trastuzmab and the two mAbs, epitope mapping studies were also conducted. Methods: SKBR3 cells were used to confirm HER2 binding and determine the antibodies’ impact on proliferation, apoptosis, and miRNA expression. Cell proliferation upon a 3-day antibody treatment (10 to 15 μg/ml) was measured using MTS and Crystal Violet Assays. Apoptotic cells were identified using Annexin V-FITC flow cytometry. To determine their epitope mapping, cells were grown on coverslips overnight, fixed, blocked, and incubated in AF488-mAb or AF555-mAb, and images were captured with IX81. QRT-PCR was used to measure the relative levels of miR-21, using miR-16 as the endogenous control Results: Cell proliferation assays showed that the treatment of 10H8 resulted in a better growth inhibition in SKBr3 cells than that of trastuzumab (ex: 80.2% vs 84%, respectively). Combining 10H8 and 8H11 produced less viable cells and more early- and post-apoptotic cells than those treated with trastuzumab alone. In addition, whereas trastuzumab increased the relative quantity of the known oncogene, both 10H8 and 8H11 maintained a steady level of miR-21 (0.99 and 1.2, respectively). Conclusions: Initial results indicate that 10H8 and 8H11 inhibit cell proliferation and induce apoptosis in HER2-overexpressing cells. However, unlike trastuzumab, 10H8 and 8H11 do not involve miR-21 up-regulation. Moreover, the three mAbs do not have overlapping epitopes on HER2. Further investigations of the antibodies’ impact on intracellular signaling pathways and the structural determination of the HER2 binding sites would provide further understanding of the therapeutic potentials of these two mAbs.
NfP2X7, a novel target for immune therapeutic approaches in cancer treatment.
Authors: Nesselhut Jan , Barden Julian , Marx Dagmar , Cillien Nicole , Goebel Wiebke , Herrmann Michael , Chang Raymond Y. , Nesselhut Thomas
Published: March 2020

3094

Background: P2X7 receptor, a ligand-gated channel, is activated by extracellular ATP and mediates ATP induced apoptosis. Several polymorphisms leading to loss of function of P2X7 have been described. Overexpression of non-functioning P2X7 receptor (nfP2X7), able to form a Ca2+channel but not an apoptotic pore, is found on every type of cancer cell but no normal cells, making it a perfectly selective target for immune therapy approaches. Methods: Samples from various tumor types were analyzed for the expression of nfP2X7 using immunohistochemistry. MoDC from n=6 patients with advanced metastatic sarcoma (2 osteosarcoma, 4 soft tissue sarcoma) with disease progression after failure of extensive standard therapies were primed against the nfP2X7using a specific peptide. MoDC were harvested, analyzed by flow cytometry and applied to the patient intradermaly. Specific T-cell response was analyzed by IFN-gamma Elispot. Results: nfP2X7 is overexpressed in essentially all analyzed tumor samples from all cell types: epithelial, mesenchymal, neural, germinal examined in large numbers (n = 5 to >1,000). The uniquely displayed epitope associated with the ATP binding site exposed on nfP2X7 but hidden in P2X7 was found on the cancer cell surface but not on the surface of any normal cells. MoDC primed with a specific peptide against nfP2X7 show a distinct DC morphology and an up-regulation of the maturation marker CD83. Patients are 6-9 months (onset June 2012) under treatment at time of abstract submission. 2 patients have a disease stabilization. One further patient with a metastatic, rapidly growing osteosarcoma showed a mixed response. IFN-gamma Elispot, which was exemplarily performed, shows a nfP2X7-specific T-cell response. Conclusions: Efficient inductions of an antitumor response by dendritic cell therapy require the definition and choice of an optimal target, being expressed in almost all kinds of tumors. nfP2X7, a set of non-functioning forms of the P2X7 receptor unable to initiate apoptosis but maintaining channel activity, could therefore be an optimal universal candidate. The efficacy of dendritic-cell based therapy may be improved by priming the MoDC against nfP2X7 and thus may improve the clinical outcome.
Risk factors for development of delayed urticarial reactions in the phase II trial of HER2 peptide vaccines plus GM-CSF versus GM-CSF alone in high-risk breast cancer patients to prevent recurrence.
Authors: Trappey Alfred F , Berry John S. , Vreeland Timothy J , Hale Diane F. , Sears Alan K. , Ponniah Sathibalan , Perez Sonia A. , Clifton Guy T. , Papamichail Michael , Shumway Nathan M. , Mittendorf Elizabeth Ann , Peoples George Earl
Published: March 2020

3097

Background: We are monitoring the incidence of delayed urticarial reactions (DURs) in our phase II trial evaluating adjuvant HER2-specific vaccines (AE37 and GP2) for the prevention of breast cancer recurrence. Here, we characterize DURs and analyze risk factors for their development. Methods: After completion of standard of care therapy, disease-free node-positive or high-risk node-negative patients (pts) were randomized to receive either a peptide+GM-CSF (VG) or GM-CSF (CG). Pts receive 6 monthly intradermal inoculations during the primary vaccine series (PVS) then four boosters (B) every 6 mos. Immune response is measured by delayed type hypersensitivity (DTH) pre- (R0) and post-PVS (R6) and local reaction (LR) at R1 – R6. Results: Twenty-four (6.1%) of 393 initiated patients report a DUR; 13 VG (vDUR), and 11 CG (cDUR); vDUR - 9 AE37, 4 GP2. Time to onset of symptoms is 9±5 days (d) and is similar in vDUR/cDUR (p = 0.27). DURs manifest as hives/pruritis in all patients. Average duration of symptoms is 32.6 d ± 8.8 d (no difference in vDUR/cDUR [p = 0.23]). Episodes have resolved with antihistamines or IV/oral steroids. Ten (4 cDUR, 6 vDUR) patients have had recurrent episodes that have resolved similarly. 75% of first episodes occur between R6-B3. For DUR patients v. those who have not had a DUR (noDUR), there are no differences in demographics. DTH response is similar in vDUR pts v. noDUR VG pts (R0- p = 0.34; R6- p=0.40). cDUR pts had a greater DTH response v. CG noDUR pts at R6 (13.2 v 4.7 mm, p=0.01). LRs are greater in DUR pts compared to noDUR pts after the second vaccination (R2 – 66.2 v 48.2 mm, p=0.02). LR for DUR pts decrease and are less than noDUR at R6 (45.4 v 57.4 mm, p=0.09). Relative risk for developing DUR for LR > 100 mm at R2 is 3.49 (1.58-7.68, 95% CI [p=0.004]). At 29.9 months median follow-up, there have been no recurrences in VG and CG DUR v. 75.9% DFS for noDUR (p=0.05). Conclusions: DURs occur infrequently and without long-term sequelae. Pts at risk for developing DUR are identified early in the vaccine series using LR. Robust immune response in DUR may explain the survival benefit demonstrated here. Clinical trial information: NCT00524277.
Economic analysis of pharmacokinetic (PK) studies in phase I clinical trials.
Authors: El Osta Badi Edmond , Falchook Gerald Steven , Schaub Diane , Subramanian Harihara , Daneshmand Maryam , Harleaux Dina , Karp Daniel D.
Published: March 2020

3103

Background: Although PK evaluation is a prevalent and critical component of cancer drug development, optimization of the cost-value relationship of PK studies has not been evaluated. Methods: We reviewed 26 phase I protocols that were activated and performed in the Clinical & Translational Research Center at U.T. MD Anderson Cancer Center from 2010 to 2012. 23 protocols met the residual analysis criteria of a normal and independent distribution. We collected protocol-specific data including medication, route, frequency, mechanism of action, number of enrolled patients, number of PK time points, and PK charges. Results: All 23 protocols were funded by industry sponsors. During 2010-2012: the total number of patients was 560; the median number of patients enrolled per protocol at our site was 18 (range 3-84); the median number of total PK studies per patient performed on each protocol was 19.46 (4.11-36.92); the median charge of PK time points was $42.33 (35.02-80.00); the median charge of all PK time points per patient on a protocol was $813.00 (329.00-1676.00); the median number of total PK studies per patient on a protocol during cycle 1 was 15.20 (2.40-27.47); the median charge of PK studies during cycle 1 was $43.24 (36.93-80). The number of PK time points and the amount of PK charges did not significantly correlate with monotherapy vs. combination regimens, oral vs. parenteral route, or small molecules vs. other (cytotoxic, vaccine, monoclonal antibodies). However, protocols (all cycles combined) with small molecules had a trend of lower PK time point median charges (41.97 vs. 52.67; p=0.09). Analysis of PKs in cycle 1 demonstrated that protocols with small molecules had a trend of higher PK time point median charges (61.33 vs. 42.38; p=0.08). Conclusions: The number and charges of PK studies was independent of the study drug or route. Future studies comparing budgeted vs. performed PKs and industry vs. investigator-initiated trials are warranted.
FOLFOXIRI/bevacizumab (bev) versus FOLFIRI/bev as first-line treatment in unresectable metastatic colorectal cancer (mCRC) patients (pts): Results of the phase III TRIBE trial by GONO group.
Authors: Falcone Alfredo , Cremolini Chiara , Masi Gianluca , Lonardi Sara , Zagonel Vittorina , Salvatore Lisa , Trenta Patrizia , Tomasello Gianluca , Ronzoni Monica , Ciuffreda Libero , Zaniboni Alberto , Tonini Giuseppe , Buonadonna Angela , Valsuani Chiara , Chiara Silvana , Carlomagno Chiara , Boni Corrado , Marcucci Lorenzo , Boni Luca , Loupakis Fotios
Published: March 2020

3505

Background: Doublets plus bev are a standard option for the first-line treatment of mCRC. First-line FOLFOXIRI demonstrated superior RR, PFS and OS compared to FOLFIRI. A phase II study of FOLFOXIRI/bev showed promising activity and manageable toxicities. The objective of the TRIBE trial was to confirm the superiority of FOLFOXIRI vs FOLFIRI when bev is added to chemotherapy (CT). Methods: Eligibility criteria included: measurable and unresectable mCRC, age 18-75 years, no prior CT for advanced disease. Pts were randomized to either FOLFIRI/bev (arm A) or FOLFOXIRI/bev (arm B). Both treatments were administered for a maximum of 12 cycles followed by 5FU/bev until progression. Primary endpoint was PFS. Results: Between July 2008 and May 2011 508 pts were randomized. Pts characteristics were (arm A/arm B): median age 60/61, ECOG PS 1-2 11%/10%, synchronous metastases 81%/79%, multiple sites of disease 74%/70%, liver-only disease 18%/23%, prior adjuvant (adj) 12%/12%. At a median follow-up of 26.6 mos 424 pts progressed and 244 died. Median PFS and OS in the intention to treat (ITT) population were 10.9 and 30.9 mos. FOLFOXIRI/bev significantly increased PFS (median 9.7 vs 12.2 mos, HR 0.73 [0.60-0.88] p=0.0012). Subgroup analyses based on stratification factors (PS, prior adj) and baseline characteristics (site of primary, liver only disease, resection of primary, Kohne score) did not evidence significant interactions between treatment and analyzed factors. A trend toward a more consistent effect of FOLFOXIRI/bev was reported in no prior adj (HR 0.68 [0.55-0.83]) compared to prior adj group (HR 1.18 [0.67-2.08], p for interaction=0.071). Response rate (RECIST) was also significantly improved (53% vs 65% p=0.006). FOLFOXIRI/bev did not increase the R0 secondary resection rate in the ITT population (12% vs 15%, p=0.327), or in the liver-only subgroup (28% vs 32%, p=0.823). Conclusions: FOLFOXIRI/bev compared to FOLFIRI/bev, significantly increases PFS and response rate. Subgroup analysis suggests a possible interaction between prior adj CT and PFS benefit. Secondary resection rate does not differ between treatment arms. Clinical trial information: NCT00719797.
Pharmacodynamic and efficacy analysis of the BRAF inhibitor dabrafenib (GSK436) in combination with the MEK inhibitor trametinib (GSK212) in patients with BRAFV600 mutant colorectal cancer (CRC).
Authors: Corcoran Ryan Bruce , Falchook Gerald Steven , Infante Jeffrey R. , Hamid Omid , Messersmith Wells A. , Daud Adil , Kwak Eunice Lee , Ryan David P. , Kurzrock Razelle , Atreya Chloe Evelyn , Luan Jennifer , Sun Peng , Schaeffer Megan , Motwani Monica , Bleam Maureen R , Moy Christopher H , Patel Kiran , Orford Keith W. , Kopetz Scott , Venook Alan Paul
Published: March 2020

3507

Background: TheBRAF V600 mutation occurs in 5-10% of metastatic CRC, predicts poor prognosis, and may predict lack of response to standard therapy. The combination of inhibitors of BRAF (dabrafenib; D) and MEK (trametinib; T) has shown significant efficacy in BRAF-mutant melanoma. The safety, efficacy, and pharmacodynamic effects of this combination were studied in BRAF-mutant CRC patients (pts). Methods: BRAF mutant CRC pts were enrolled to an initial efficacy cohort of 26 pts and a subsequent pharmacodynamic (PD) expansion cohort that included biopsies of 15 pts at screening and at steady state. So far, 36 pts have enrolled, including 10 in the PD cohort. Eligible pts had previously-treated BRAFV600E mutant stage IV CRC. Pts were treated with D (150mg BID) and T (2mg QD). Additional analyses were performed on available archival tissues. Results: Data are available for 36 pts: ECOG performance status 0 (58%) or 1 (42%), 81% had received ≥ 2 prior chemotherapy regimens, 36% had received prior EGFR inhibitor treatment, and 83% had ≥ 1 biologic therapy. Among 34 pts with >1 restaging assessment as of November 2012, 1 (3%) achieved a complete response (confirmed, on study >12m), 3 (9%) achieved a partial response (1 confirmed to date), and 18 (53%) had stable disease (SD). Minor responses were seen in 7/18 pts (39%) with SD. Median PFS was 3.5 mo (95% CI: 1.8-4.9); overall duration on study range: 0.03–15.2 mo 7 pts (24%) remained on study for ≥6 cycles with 9 pts still on study. The most frequent AEs, any grade, included pyrexia (67%), nausea (56%), fatigue (53%), chills (47%), vomiting (39%), headache (31%), peripheral edema (31%), anemia (28%), and decreased appetite (28%). 2 pts (6%) discontinued due to AEs. Decreased pERK staining vs pre-dose samples was seen in all post-dose samples leading to absolute (49% ±29%) and relative (69% ±28%, normalized to total ERK) reduction in pERK. Conclusions: Further investigation is needed, as this combination is tolerable at full monotherapy doses of each drug, with manageable toxicities, and has activity in a subset of BRAF mutant pts. Updated safety, efficacy, and correlative data will be presented. Clinical trial information: NCT01072175.
A randomized, placebo-controlled, phase I/II study of tivantinib (ARQ 197) in combination with cetuximab and irinotecan in patients (pts) with KRAS wild-type (WT) metastatic colorectal cancer (CRC) who had received previous front-line systemic therapy.
Authors: Eng Cathy , Hart Lowell L. , Severtsev Aleksey , Gladkov Oleg , Mueller Lothar , Kopp Mikhail V. , Vladimirov Vladimir Ivanovich , Langdon Robert M. , Kotiv Bogdan , Barni Sandro , Hsu Ching , Bolotin Ellen , Von Roemeling Reinhard , Schwartz Brian E. , Bendell Johanna C.
Published: March 2020

3508

Background: Tivantinib (ARQ 197) selectively inhibits the MET receptor tyrosine kinase, which is implicated in tumor cell migration, invasion, and metastasis. Resistance to EGFR inhibitors has been associated with activation of alternative pathways including MET. Methods: Pts with advanced KRAS WT CRC that progressed on or after 1 prior line of chemotherapy and no previous treatment with an EGFR inhibitor were eligible. Pts were randomized 1:1 to receive cetuximab (500 mg/m2) and irinotecan (180 mg/m2) on days 1 and 15 every 28 days, plus oral tivantinib (360 mg twice daily [BID]) or placebo. The primary endpoint was progression-free survival (PFS); additional endpoints include safety, objective response rate, overall survival (OS) and exploratory biomarker analyses. Results: Between Jul 2010 and Feb 2012, 122 pts were randomized; 117 pts were eligible for analysis (60 tivantinib, 57 placebo). Mean age was 57 years (range, 27-79 years); ECOG PS 0/1 55%/45%; and 81% received prior oxaliplatin. Median PFS was 8.3 months in the tivantinib arm vs 7.3 months in the placebo arm (hazard ratio [HR] = 0.85; 95% CI, 0.55-1.33; P = 0.38). Objective response rate (95% CI) was 45% (33%-58%) in the tivantinib arm and 33% (23%-46%) in the placebo arm. Median OS has not yet been reached but is trending in favor of tivantinib vs placebo (HR = 0.67). Among pts with prior oxaliplatin therapy, median PFS was 8.4 months for tivantinib and 7.2 months for placebo (HR = 0.67; 95% CI, 0.44-1.00; P= 0.1). The most common grade 3/4 adverse events (≥ 10%) were neutropenia, diarrhea, and nausea. Correlation of clinical outcomes with additional factors including mutation status and immunohistochemical analysis of tumor MET expression will be presented. Conclusions: Outcomes in this trial trended towards improvement with tivantinib (360 mg BID) plus cetuximab and irinotecan, particularly in the subgroup who had previous oxaliplatin. Further studies are needed to identify the CRC population most likely to benefit from addition of tivantinib to standard therapy. Clinical trial information: NCT01075048.
Analysis of plasma protein biomarkers from the CORRECT phase III study of regorafenib for metastatic colorectal cancer.
Authors: Lenz Heinz-Josef , Van Cutsem Eric , Sobrero Alberto F. , Siena Salvatore , Falcone Alfredo , Ychou Marc , Humblet Yves , Bouche Olivier , Mineur Laurent , Barone Carlo , Adenis Antoine , Tabernero Josep , Yoshino Takayuki , Goldberg Richard M. , Sargent Daniel J. , Cihon Frank , Wagner Andrea , Laurent Dirk , Jeffers Michael , Grothey Axel
Published: March 2020

3514

Background: In the CORRECT phase III trial, the multikinase inhibitor regorafenib (REG) demonstrated significant improvement in overall survival (OS) and progression-free survival (PFS) vs placebo (Pla) in patients with metastatic colorectal cancer (mCRC) whose disease had progressed on other standard therapies. An exploratory biomarker subanalysis was conducted to identify protein biomarkers with potential predictive or prognostic value. Methods: Fifteen proteins of interest, many of which are involved in angiogenesis, were quantified by multiplex immunoassay or ELISA in baseline plasma samples collected at study entry from 80% (611/760) of patients. Potential predictive and prognostic effects were evaluated. Results: The biomarker subpopulation was representative of the overall study population in terms of OS and PFS. Using OS as the clinical endpoint, Tie-1 was the only protein whose level demonstrated significant correlation with efficacy (low protein group: REG/Pla, HR 0.87; high protein group, HR 0.56; interaction, p=0.035). Using PFS as the clinical endpoint, von Willebrand factor (VWF) was the only protein whose level demonstrated significant correlation with efficacy (low protein group: REG/Pla, HR 0.39; high protein group, HR 0.60; interaction, p=0.02). Following correction for multiple testing, neither Tie-1 nor VWF data retained statistical significance. Baseline levels of IL-8 and placental growth factor (PlGF) were found to have prognostic value for OS (IL-8: high/low protein levels, HR 3.48, p<0.001; PIGF: HR 1.81, p=0.002). IL-8 was also prognostic for PFS (high/low protein levels: HR 1.63, p<0.001). Conclusions: None of the plasma proteins examined showed significant predictive value for REG efficacy after multiple testing correction. The association between baseline levels of Tie-1/VWF and REG efficacy may be a hypothesis to be tested in further trials. Clinical trial information: NCT01103323.
Treatment outcome according to tumor ERCC1 expression status in OPUS study patients with metastatic colorectal cancer (mCRC) randomized to FOLFOX4 with/without cetuximab.
Authors: Bokemeyer Carsten , Köhne Claus-Henning , Bondarenko Igor , von Heydebreck Anja , Grote Hans Juergen , Stroh Christopher , Lenz Heinz-Josef
Published: March 2020

3537

Background: The OPUS study showed that the addition of cetuximab to infusional 5-fluorouracil/folinic acid + oxaliplatin (FOLFOX4) significantly improved progression-free survival (PFS) and response in the first-line treatment of patients (pts) with KRAS wild-type (wt) mCRC. High level expression in tumors of ERCC1, a protein involved in nucleotide excision repair, has been associated with resistance to platinum-based chemotherapy in a range of tumor types. This analysis assessed outcome according to ERCC1 expression level and treatment group in OPUS study pts. Methods: ERCC1 expression level was assessed by immunohistochemistry (IHC) in all available formalin-fixed paraffin-embedded tumor samples from OPUS study pts. An ERCC1 IHC score on a continuous scale of 0–300 was calculated for each tumor, based on the intensity of nuclear staining and proportion of positive cells. The median IHC score was used to define low (<median) and high (≥median) ERCC1 expression levels and outcome was assessed in low vs high expression groups in both treatment arms. Results: Of 337 OPUS study intention to treat pts, 97 (29%) were evaluable for ERCC1 expression. Pts in the FOLFOX4 arm in the high ERCC1 expression group (n=27) had shorter PFS (median 5.8 vs 9.2 months; hazard ratio, HR 1.63, 95% CI 0.80–3.34) and overall survival (median 11.5 vs 18.5 months; HR 1.75, 95% CI 0.90–3.40) and a lower response rate (33.3% vs 39.1%) compared with those in the low ERCC1 expression group (n=23). To assess the effect of adding cetuximab to FOLFOX4 according to ERCC1 expression level, outcome was assessed in the KRAS wt subgroup of pts. Although low pt numbers precluded the drawing of definitive conclusions, PFS in the high ERCC1 expression group was longer in the FOLFOX4 + cetuximab arm (n=14) compared with the FOLFOX4 arm (n=13; median 7.7 vs 5.8 months), survival was longer (median 19.7 vs 12.0 months) and the response rate was higher (71.4% vs 30.8%). Conclusions: High tumor ERCC1 expression was associated with poor outcome in pts with mCRC receiving first-line platinum-based chemotherapy. The addition of cetuximab to FOLFOX4 may mitigate this effect in those with KRAS wt tumors. Clinical trial information: NCT00125034.
Proof-of-concept study of Sym004, an anti-EGFR monoclonal antibody (mAb) mixture, in patients (pts) with anti-EGFR mab-refractory KRAS wild-type (wt) metastatic colorectal cancer (mCRC).
Authors: Dienstmann Rodrigo , Tabernero Josep , Van Cutsem Eric , Cervantes-Ruiperez Andres , Rosello Keranen Susana , Benavent Viñuales Marta , Kjær Ida , Pedersen Mikkel W , Skartved Niels Jorgen Ostergaard , Flensburg Mimi F , Horak Ivan David , Garcia-Carbonero Rocio
Published: March 2020

3551

Background: KRAS wt mCRC pts progressing on chemotherapy and anti-EGFR mAbs have limited treatment options. Sym004 is a first-in-class drug mixture of two mAbs targeting non-overlapping epitopes on the EGFR, causing its internalization and degradation. With this unique mechanism of action, Sym004 overcomes acquired resistance to anti-EGFR mAbs in preclinical studies. Methods: Open-label, multicenter trial assessing safety (primary endpoint) and efficacy of 2 dose levels of Sym004 in KRAS wt mCRC pts with prior clinical benefit to anti-EGFR mAbs and subsequent progression during or within 6 months after treatment cessation. Sym004 was administered until disease progression or unacceptable toxicity. Tumor responses were evaluated centrally according to RECIST criteria. Paired skin and tumor biopsies were obtained at baseline and week 4. Results: In total, 42 pts were enrolled at 9 mg/kg (13) and 12 mg/kg (29). Median age was 66 years and median number of prior treatment lines 3. Central radiology review was performed in 12/13 (92%) pts at 9 mg/kg and 27/29 (93%) pts at 12 mg/kg. Tumor shrinkage > 10% was documented in 4/12 (33%) pts at 9 mg/kg, with partial response (PR) in 1/12 (8%) and stable disease (SD) in 9/12 (75%). At 12 mg/kg, 7/27 (26%) pts had > 10% tumor shrinkage, with PR in 3/27 (11%) and SD in 15/27 (56%). Median progression-free survival was 13.6 weeks (95% CI: 5.3-23) and 13.7 weeks (95% CI: 5.9-18.6), respectively. Duration of response for pts with PR was 5.6-17.6 weeks. Grade 3 or higher toxicity included skin rash in 26/42 (62%), hypomagnesemia in 16/42 (38%) and diarrhea in 2/42 (8%). Adverse events were manageable with dose reduction and supportive medication. There were no indications of immunogenicity. Pharmacodynamic analysis in serial tumor samples showed profound down-regulation of EGFR and reduction in proliferation marker Ki67. Conclusions: Sym004 at weekly doses of 9 and 12 mg/kg showed significant clinical activity in anti-EGFR treatment-refractory KRAS wt mCRC pts, clearly demonstrating proof-of-concept. Serial biopsies confirmed its mechanism of action. No unexpected adverse events were observed. Clinical trial information: NCT01117428.
Regular statin users and colorectal cancer (CRC) prognosis.
Authors: Ma Wei-li , Shao Yu Yun , Hsu Chih-Hung , Yeh Kun-Huei , Chen Ho-Min , Yeh Yi-Chun , Lai Chiu-Lin , Lin Zhong-Zhe , Cheng Ann-Lii , Lai Mei-Shu
Published: March 2020

3554

Background: Statins are frequently used for the control of hyperlipidemia. Statins have multiple anti-cancer properties and may be associated with lower CRC risks among their users. This study tries to go a step further and explores whether statin use affects the prognosis of curatively resected CRC. Methods: We established a population cohort with patients (age ≥ 40 y) who were diagnosed as having stage I or II CRC from 2004 to 2008 and received curative surgery from the database of Taiwan Cancer Registry. Data of medication prescription and co-morbidities were retrieved from the database of National Health Insurance, Taiwan. Regular statin use was defined as taking statins for > 180 days within the observation period from one year before the cancer diagnosis to one year afterward. The database of National Death Registry was used for survival outcomes. Another similar cohort consisting of patients with hepatocellular carcinoma (HCC) was used for comparison. Results: In total, 10762 patients with CRC were enrolled; 891 (8%) patients were regular stain users, 812 (8%) patients took statins but were not regular users, and 9059 (84%) patients never used statins. Regular statin users, compared to never users, were more likely to be female (p < 0.001), older (p < 0.001), have stage I disease (p < 0.001) and co-morbidities such as diabetes, coronary artery disease, and renal disease. Adjuvant therapy was less frequently administered in regular statin users. In univariate analysis, cancer-specific survival (CSS) of regular stating users was significantly longer than that of never users (5-y CSS, 87% vs. 84%, p = 0.022), but overall survival (OS) was not significantly different (5-y OS, 80% vs. 77%, p = 0.156). In multivariate analysis adjusting for age, gender, stage, adjuvant therapy, co-morbidities, and the use of aspirin, regular stating use was an independent predictor both for better CSS (hazard ratio [HR] 0.72, p < 0.001) and for better OS (HR 0.71, p< 0.001). In contrast, no associations were found between statin use and CSS or OS in the HCC comparison cohort. Conclusions: Regular statin use was associated with better prognosis in CRC patients who received curative therapy. (This study was supported by grants DOH-101-TD-B-111-001 and DOH-102-TD-B-111-001).