bluuebunny/crossref_metadata_2025 huggingface dataset:
Tumor-specific peptide vaccination in newly-diagnosed patients with GBM
Authors: Heimberger A. B. , Hussain S. F. , Aldape K. , Sawaya R. , Archer G. A. , Friedman H. , Reardon D. , Friedman A. , Bigner D. , Sampson J. H.
Published: March 2020

2529

Background: Despite multimodality approaches, survival with GBM is dismal. Induction of immune responses to suppress the infiltrative, residual component with an easily manufactured and administered immunotherapy has been a theoretical ideal. The epidermal growth factor receptor variant III (EGFRvIII) is a tumor-specific cell surface protein expressed on approximately 40% of GBMs. Methods: Newly-diagnosed GBM patients with a gross-total resection, a KPS ≥70, and EGFRvIII+, after undergoing radiation with concurrent temozolomide without tumor progression, were eligible to receive EGFRvIII peptide vaccination i.d. with GM-CSF. Primary endpoint was safety. Results: Accrual began in 06/14/2004 and is now complete. 19 patients were enrolled. Median follow-up is 18 months. Toxicity was minimal and without evidence of autoimmunity. Humoral and cellular immune responses were generated. Median TTP from surgery in vaccine-treated patients is 12 months (n = 12), comparing favorably with a historical matched unvaccinated cohort (gross total resection without progression during radiation, KPS≥70, EGFRvIII+) that had a median TTP of 7.1 months (n = 39) (p = 0.0058). These results also compared favorably with those reported for concurrent temozolomide and radiation followed by adjuvant temozolomide, with a median TTP of 6.9 months. Median survival in this trial has exceeded 18 months which compares favorably to all published analyses accounting for all known prognostic indicators. Among recurrent tumors evaluated by immunohistochemistry, 100% no longer expressed the EGFRvIII, suggesting immunological activation that eliminated EGFRvIII-expressing cells, as well as one potential mechanism of treatment failure. Conclusions: EGFRvIII peptide vaccination warrants further investigation in a larger randomized clinical trial in patients with EGFRvIII-expressing tumors.

No significant financial relationships to disclose.
Autologous tumor cell vaccination with PF-3512676 (CPG 7909) and GM-CSF followed by subcutaneous PF-3512676 and IFN-alpha for patients with metastatic renal cell carcinoma
Authors: Van Den Eertwegh A. J. , Lensen R. J. , Scheper R. J. , Giaccone G. , Meijer C. J. , Bontkes H. J. , Gruijl T. D. , Hooijberg E.
Published: March 2020

2530

Background: Metastatic renal cell carcinoma (RCC) has a poor prognosis with a 5-year survival of less than 10%. Non-specific immunotherapy, e.g. IL-2 and IFN-α achieves responses in 10–30% of patients at the cost of relatively high toxicity. Tumor vaccination has shown great promise in a variety of cancers, particularly in the adjuvant setting. Studies in metastatic setting are suitable to identify the best adjuvants and to optimize vaccination schedules. CpGs are synthetic oligonucleotides that have been shown to have superior immunogenicity in animal and human vaccination studies (Hepatitis B). Besides its positive effect on the specific immune response, CpGs also stimulate the innate immune system. We initiated a phase I/II trial to investigate the potentials of CpG in the treatment of metastatic RCC. Methods: Nephrectomized patients with progressive metastatic RCC were vaccinated with autologous tumor cells (ATC) derived from the primary tumor or metastases. Vaccines consisted of irradiated ATC, PF-3512676 and GM-CSF. The first three induction vaccinations were given weekly followed by subcutaneous administration of IFN-α (6 MIU, TIW) and PF-3512676 (8 mg bi-weekly). After 3 months tumor evaluation was performed and in case of a remission or stable disease patients continued with 3 monthly vaccinations and PF-3512676 /IFN-α. Blood was collected for immunomonitoring and DTH responses against ATC were measured before and after vaccination. Results: Preparation of vaccines was successful in 88% of the patients. Twelve patients were included and treated according to the protocol. Treatment was well tolerated. At the vaccination site we observed erythema and induration. Some patients experienced flu-like symptoms, including fever and fatigue. In all patients we observed only after vaccination a DTH response (> 10 mm) against ATC, suggestive for a specific antitumor response. Three patients (25%) achieved a partial response (durations 6, 4+, 4+ months) and 2 patients (17%) stable disease (3 months). Conclusions: This new combined immunotherapy is tolerable, safe, and immunogenic. Moreover, it can produce tumor responses in advanced RCC.

No significant financial relationships to disclose.
Impact of antibody Fc carbohydrate fucosylation on antibody-dependent cellular cytotoxicity by HuMax-EGFr —A fully human epidermal growth factor receptor antibody
Authors: Dechant M. , Lammerts van Bueren J. , Peipp M. , Bleeker W. , Beyer T. , Van Berkel P. , Parren P. W. , Van de Winkel J. G. , Valerius T.
Published: March 2020

2543

Background: HuMax-EGFr - a human IgG1 EGF-R antibody in phase II clinical trials - was demonstrated to block EGF binding, to interfere with cellular signaling and to efficiently recruit effector cells for ADCC. Triggering of ADCC requires antibody binding to cellular Fc receptors which can be modulated by antibody glycosylation. Here, we investigated whether the glycosylation profile of HuMax-EGFr altered effector functions, and compared the contribution of mononuclear (MNC) and polymorphonuclear (PMN) cells for ADCC in human blood. Methods: Varying concentrations of two HuMax-EGFr batches, differing in the level of fucosylation of the complex-type oligosaccharides present in the Fc fragment, were compared in their capacity to kill EGF-R expressing tumor cells. Antibody binding and inhibition of proliferation was analyzed by flow cytometry and measuring vital cell mass, respectively. ADCC by isolated PMN, MNC and human whole blood was analyzed by chromium release assays. Results: Both batches of HuMax-EGFr bound similarly to target cells, and inhibited their proliferation to a similar extent. Low-fucosylated HuMax-EGFr demonstrated higher affinity for recombinant FcγRIIIa than fully fucosylated antibody. As expected, low-fucosylated antibody was significantly better in mediating ADCC by MNC (EC50 obtained at 10-fold lower antibody concentrations, p<0.05). In contrast, PMN-mediated ADCC was unaffected by the antibody fucosylation level. Importantly, whole blood ADCC assays also revealed little differences between both batches. ADCC was significantly enhanced by blood from G-CSF-primed patients, but again both high- and low-fucosylated antibody performed similarly. Conclusions: Both HuMax-EGFr batches were equally potent in inhibiting cell proliferation, and were highly active in triggering ADCC by MNC and PMN. Differences in fucosylation of Fc carbohydrate affected MNC-mediated lysis, whereas PMN- and whole blood-mediated cell killing were only minimally affected. Thus, fucosylation of antibody Fc may only prove critical for therapeutic antibodies which predominantly recruit NK cells for ADCC, while it may be less relevant for PMN-recruiting antibodies.

[Table: see text]
Nonmyeloablative allogeneic blood stem cell transplantation (NMBSCT) ± donor lymphocyte infusion (DLI) for chemorefractory advanced nasopharyngeal carcinoma (NPC)
Authors: Toh H. C. , Tan E. H. , Thng C. H. , Yap S. P. , Lee K. M. , Phoon Y. P. , Chua S. , Soe Y. , Hee S. W. , Sun L.
Published: March 2020

2549

Background: There is emerging clinical evidence for T cell immunotherapy in NPC. We report a NMBSCT regimen that induced mixed chimerism for DLI to potentially achieve a graft-versus-tumour effect (GVT) in NPC. Methods: 15 patients with advanced pretreated NPC were accrued to this prospective clinical trial. Our regimen comprised IV cyclophosphamide 50 mg/kg on day-5,-4,-3 and IV thymoglobuline on day-1, +1, +2 and +3 (n = 9) and then revised to IV thymoglobuline day-1, +1, +2, +3 (n = 6). Thymic radiation was given on day-1. G-CSF mobilized HLA-matched (n = 14) and 1-antigen-mismatched (n = 1) sibling PBSC were infused. DLI was initiated following taper of prophylactic cyclosporine (CyA). Results: Median age (n =15) was 49 yrs, median no. of metastatic organ sites was 3, mean no. of prior chemotherapy was 4 (range 2 - 8) and 14/15 had prior radiation. Median time to engraftment was 13 days and hospital stay was 17 days. Complete removal of prophylactic CyA was achieved for all patients at a median of day +28. DLI was given in 14 patients (median = 2, range 1 to 6). 4 patients were later re-started on GVHD immunosuppressive therapy. Two (13.3%) patients had acute GVHD (one Grade II and one fatal case who died on day+91). 3 patients developed chronic GVHD (20%), all controlled with short courses of standard immunosuppressive treatment. 11/15 died of PD, and 2/15 died from sepsis. 100-day TRM was 6.6%. 3/9 patients had donor graft loss. 6/6 patients on the revised protocol had stable and/or full donor chimerism. CMV antigenemia was 9/9 for the first regimen and 3/6 for the revised regimen (p = 0.044). Tumor response (RECIST) confirmed 40% PR, 33.3% SD and 40% PD, for a disease control rate of 73.3%. > day+100 anti-tumor response were observed in 5/15 patients (33.3%), implicating a GVT effect. 1 patient achieved a delayed PR on day+111 with stable donor chimerism of 19%. The longest surviving patient (36.5 mths) with multiple nodal, bone and lung metastasis achieved full donor chimerism and further tumor shrinkage at 8 mths post-NMBSCT. Conclusions: GVT is achievable with NMBSCT ± DLI in Stage IV NPC patients with a high disease control rate and acceptable GVHD. Early complete removal of prophylactic CyA was possible in all 15 patients.

No significant financial relationships to disclose.
Metronomic cyclophosphamide regimen electively depletes CD4+ CD25+ regulatory T cells in patients with advanced solid tumors
Authors: Ghiringhelli Esq. F. , Ladoire S. , Zitvogel L. , Chauffert B.
Published: March 2020

2561

Background: CD4+CD25+ regulatory T cells (Treg) are involved in the prevention of autoimmune diseases and in tumor-induced tolerance. We previously demonstrated in tumor-bearing rodents that low doses of cyclophosphamide (CPM) could significantly decrease both number and suppressive functions of Treg, facilitating vaccine-induced tumor rejection. Repeated low doses of cyclophosphamide, referred to as metronomic treatment aiming at reducing tumor angiogenesis, are used in patients with advanced, chemoresistant tumors. Methods: Six patients with metastatic solid tumors were treated after informed consent with metronomic CPM - 50 mg orally twice a day, with one week on, and one week off, until progression or limiting toxicity. Peripheral blood mononucleated cells (PBMC) were sampled before and after 4 weeks of treatment. Occurrence of blood leucocyte subpopulation and capacity of Treg to inhibit NK and T cells patients functions were measured. Results: metronomic CPM induced a profound and selective reduction of circulating Treg, both in percentage (7.7 ± 0.8 % before versus 3.3 ± 0.8 % after, p < 0.005) and absolute number (25.2 ± 7.5 cells/mm3 before versus 6.1 ± 3.3 cells/mm3 after, p < 0.0006). Inhibitory functions of Treg on conventional T cells and NK cells lead to a restoration of peripheral T cell proliferation - i.e. PBMC from cancer patients exhibited 17 ± 3% T cells proliferation capacity after CD3 CD28 stimulation versus 44 ± 5% (p < 0.01) 1 month after the beginning of the treatment, and versus 45 ± 6% in healthy volunteers- and innate NK killing activities - i.e. PBMC from cancer patients exhibited 9 ± 1% NK killing capacity against K562 target versus 26 ± 5% (p < 0.005) after 4 week treatment. Conclusions: Metronomic CPM has not only effect on tumor angiogenesis, but also strongly curtail immunosuppressive Treg, which could favor a better control of tumor progression.

No significant financial relationships to disclose.
Adjuavnt tyrosinase peptide vaccination in patients with resected stage III/IV melanoma
Authors: Letsch A. , Scheibenbogen C. , Fluck M. , Asemissen A. , Nagorsen D. , Thiel E. , Keilholz U.
Published: March 2020

2570

Background: This phase II study was undertaken to evaluate the immunogenicity and clinical efficacy of vaccination with tyrosinase peptides as adjuvant treatment in melanoma patients after multiple relapses. Methods: Stage III/IV melanoma patients after complete resection of relapses were vaccinated with tyrosinase peptides together with GM-CSF and KLH. Vaccination was given bi-weekly times 4, followed by monthly times 8 in absence of relevant disease progression. Tyrosinase-specific T cells were quantitated and characterized ex vivo by intracellular cytokine flow cytometry. Results: 44 patients were accrued with a median of 5.8 (range 2–25) previous relapses at cutaneous /s.c. only (n = 11), ln (n = 30) and/or visceral sites (n = 7). 11 patients received less than 6 vaccinations due to rapid progression. Of 32 patients evaluable for immunological response 16 (50%) displayed pre-vaccine spontaneous tyrosinase-specific T cells (median 0.32%). In 7 of the 15 patients without pre-existing T cells tyrosinase-specific T cells were induced after 6 vaccinations (median 0.08% CD3+CD8+ T cells) and in 10 of 12 patients after 12 vaccinations (median 0.36%, p = 0.03 compared to 6 vaccinations). Similarly, in 9 of the 16 patients with pre-existing T cell responses the frequency of tyrosinase-specific T cells did increase after 6 cycles (median 0.43 %), but in none of 10 patients with pre-existing T cells an increase was observed after 12 vaccinations (median 0.20%). Both, the spontaneous and the vaccine-induced T cells were predominantly of effector and effector-memory phenotype. With respect to clinical efficacy vaccination was terminated after 3 to 9 cycles due to disease progression in 19 of 44 patients. Of the remaining 25 patients receiving all 12 vaccinations 7 (16% of all 44 enrolled) had a favourable clinical course with cessation of recurrences. Conclusions: Taken together, this study shows high immunogenicity of the vaccine in patients with limited tumor burden associated with clinical efficacy. In case of a spontaneous pre-existing T cell response to the vaccine peptides, however, this could not, or only transiently be augmented.

No significant financial relationships to disclose.
Identification of predictive markers of clinical activity from a phase II trial of single agent pertuzumab (rhuMab 2C4), a HER dimerization inhibitor, in advanced ovarian cancer (OC)
Authors: Amler L. , Gordon M. S. , Strauss A. , Rabbee N. , Derynck M. K. , Krueger K. , Eberhard D. A. , Matei D. , Karlan B. Y.
Published: March 2020

3001

Background: Pertuzumab (P), a humanized HER2 antibody, represents a new class of targeted agents called HER dimerization inhibitors (HDIs). P inhibits dimerization of HER2 with EGFR, HER3 and HER4, and subsequently inhibits signaling through MAP and PI3 kinases. Interim data from a phase II trial suggested that P has activity in OC, especially in a subset of tumors with activated HER2 (Abstract #5051 ASCO 2005). Methods: 123 pts with relapsed OC were treated with P. Cohort 1 was treated with 840mg followed by 420mg and cohort 2 with 1050mg every 3 weeks. Fresh tissue biopsies were mandated from Cohort 1, and archival formalin fixed paraffin tissue (FFPET ) were obtained from both cohorts. Molecular expression studies from FFPET and fresh tissue were conducted. Results: From final data of 117 evaluable pts, 5 pts had objective partial responses (RR = 4.3%). Eight pts (6.8%) had SD for ≥ 6 months, and an additional 4 pts (3.4%) had SD with CA-125 reduction of ≥50%. Overall rate of activity = 14.5%. Of the 65 fresh tumor biopsies, 28 were evaluable and 8 (28.6%) were positive for phosphorylated HER2 (pHER2) by ELISA. Among pts who had pHER2 status determined, TTP was 20.9 weeks for pHER2+ pts (n=8), compared to 5.8 weeks for pHER2- (n = 20). Data from microarray expression profiling were analyzed with respect to pHER2 status from the same tumors. The expression levels of HER2, EGFR and HER3 in combination with the expression of certain HER ligands may be predictive of pHER2 status. We have extended these analyses to qRT-PCR from macrodissected FFPET of HER receptors and ligands. This was analyzed with respect to clinical outcome. Preliminary analyses of expression data suggest that HER receptors and ligands may be promising candidates for diagnostic markers. Updated data in 78 OC pts will be presented. Conclusions: Clinical activity was observed in 14.5% of pts with heavily pretreated OC (PRs, SD ≥ 6 months, and SD with CA-125 reductions of ≥50%). This study suggests that P may be active in OC, and that specific HER receptors and ligands may be promising diagnostics for identifying tumors responsive to P.

[Table: see text]
A phase I study of YM155, a novel survivin suppressant, administered by 168 hour continuous infusion to patients with advanced solid tumors
Authors: Tolcher A. W. , Antonia S. , Lewis L. D. , Mita A. , Mahany J. , Reddy N. J. , Till E. , Buell D. , Keating A. T.
Published: March 2020

3014

Background: Survivin is one of the family of inhibitor of apoptosis proteins (IAP) that suppresses apoptosis through inhibition of caspases and procaspases. Survivin is selectively expressed in most solid tumors but not normal tissues. In a PC-3 cell model YM155 inhibited survivin mRNA transcription and survivin protein expression and showed potent (nM) anti-proliferative activity in preclinical models including tumor regressions. Methods: The objectives were to determine the maximum tolerated dose (MTD) of 168 hour continuous infusion of YM155 every 3 weeks, to evaluate toxicity, characterize the pharmacokinetics and observe anti-tumor activity. Standard 3+3 dose escalation scheme was utilized. Additional pts were added to fully characterize toxicities at the MTD. Pharmacokinetic sampling was performed during cycles 1 and 2. Results: 41 pts (M/F: 31/10, median age 61, range 28–78) with performance status of 0–2 were enrolled into 4 dose cohorts [1.8 mg/m2/day (N = 8), 3.6 (6), 6.0 (2) and 4.8 (25)]. Most common tumor types were prostate (9), NHL (5), and colorectal (5). 2/2 pts experienced DLTs at 6.0 (renal tubular necrosis with grade 3 mucositis and increased serum creatinine), thus the MTD was 4.8 mg/m2/day. The most frequent AEs were: pyrexia, arthralgia, nausea, fatigue and diarrhea. The most common grade 3 or 4 drug related AEs were: mucosal inflammation (N = 2, 4.9%) and increased INR (N = 2, 4.9%). At MTD, the median clearance was 47 L/hr with a median steady state concentration of 7.5 ng/mL and a median terminal half-life of 22 hours. Two pts with chemotherapy refractory intermediate grade NHL had marked reduction of lymph nodes including one that was durable (PR reviewed independently). This pt went onto BMT and was in remission at the time of this submission. Two HRPC pts exhibited PSA response (> 50% reduction). Conclusions: YM 155, the first survivin inhibitor, was well tolerated, had a MTD of 4.8 mg/m2/day × 7 days and exhibited provocative anti-tumor activity in 4 pts that warrant broad phase II evaluation.

No significant financial relationships to disclose.
VEGF, sVEGFR-2, bFGF, and IL-8 as biomarkers of the pharmacological activity of BAY 57–9352, an oral VEGFR-2 receptor tyrosine kinase inhibitor, in patients with solid tumors
Authors: Zuehlsdorf M. , Christensen O. , Strumberg D. , Mross K. , Eskens F. , Gelderblom H. , Verweij J. , Rajagopalan P. , Voliotis D. , Wensing G.
Published: March 2020

3035

Background: BAY 57–9352 (BAY) is a potent anti-angiogenic drug that inhibits VEGFR-2, as well as VEGFR-1, VEGFR-3, PDGFR-β, and c-Kit tyrosine kinases. Molecular biomarkers of angiogenesis (VEGF165, soluble VEGFR-2 [sVEGFR-2], basic FGF [bFGF], and interleukin-8 [IL-8]) were used to assess the pharmacodynamic effects of BAY. Methods: Patients with advanced solid tumors from two Phase I studies received oral BAY on either an intermittent 21 day cycle (14 days on drug, 7 days off drug) or continuous schedule (21 day cycle). Doses were escalated from 20 mg once daily (od) to 1500 mg twice daily (bid). Molecular biomarkers were measured at baseline, pre-dose, and 8 hours post-dose on Days 1 and 14 of each cycle. Pharmacokinetic parameters of BAY were also assessed. Results: Plasma samples from 130 patients were analyzed for angiogenic biomarkers. Increased VEGF165 and decreased sVEGFR-2 clearly correlated with the dose of BAY, respectively. All clinical responders (as shown by tumor shrinkage) were located within the upper 10% of the total response distribution for these markers. Subgroup analysis in the three more prevalent tumors showed that patients with colorectal, renal cell, and hepatocellular carcinoma all showed biomarker responses exceeding the mean overall responses. Biomarker levels reached a plateau at daily doses of approximately 900 mg bid or 1800 mg, suggesting a saturated pharmacodynamic effect. There were no consistent changes in bFGF and IL-8. Conclusions: Both VEGF and sVEGFR-2 demonstrated a dose-dependent change with BAY 57–9352. VEGF and sVEGFR-2 may be appropriate biomarkers of the therapeutic effects of BAY, and may be useful as potential predictors of early response.

[Table: see text]
Sunitinib-related thyroid dysfunction: A single-center retrospective and prospective evaluation
Authors: Schoeffski P. , Wolter P. , Himpe U. , Dychter S. S. , Baum C. , Prenen H. , Wildiers H. , Bex M. , Dumez H.
Published: March 2020

3092

Background: Sunitinib is a multi-target tyrosine kinase inhibitor with anti-angiogenic and anti-proliferative activity mediated by signal blockade of VEGFR1/2, KIT, PDGFRα/β, and FLT-3. Phase II/III trials have demonstrated efficacy of the oral agent in Imatinib-resistant GIST and advanced renal cell cancer (RCC). We observed several cases of thyroid dysfunction in GIST during treatment with sunitinib suggesting that the drug may be associated with hypothyroidism. We therefore assessed the incidence and severity of thyroid dysfunction in cancer patients treated with sunitinib. Methods: Thyroid function (serum TSH, T3 and free thyroxin index) and thyroid antibodies (anti-TPO, -Tg and TSH-R-Ab) were evaluated retrospectively in a cohort of patients with GIST in a Phase III trial and in an expanded access program (1st part of the investigation) and in a prospective cohort of RCC and GIST patients treated in the framework of expanded access programs (2nd part). Sunitinib was given at a daily oral dose of 50 mg 4 weeks on, 2 weeks off. Thyroid parameters were assessed on days 1 and 28 of each treatment cycle in the prospective cohort. We report here the first TSH results, the full data set will be available at ASCO. Results: We identified a total of 46 patients who received sunitinib, and 33 of these patients were evaluable for thyroid function. 14 patients were analyzed retrospectively (all GIST), 19 patients prospectively (8 GIST, 11 RCC). 7 of these 19 patients (37%) showed an elevated TSH (>5 mIU/L) during treatment. In the retrospective analysis of 14 patients with a median treatment duration of 44 weeks, 8 patients (57%) had developed hypothyroidism. All patients with GIST in randomized Phase III trial remaining under active treatment with sunitinib for 58–80 weeks show an increased TSH (up to 83 mIU/L) during the course of treatment, requiring hormone substitution. In a cohort of 11 patients with RCC, after 6 weeks of treatment, 3 patients already have an increased TSH. Conclusions: Sunitinib is associated with a high incidence of thyroid dysfunction which requires further study. The mechanism by which Sunitinib induces thyroid dysfunction is yet unclear.

No significant financial relationships to disclose.
Preliminary results of a phase I study of bevacizumab (BV) in combination with everolimus (E) in patients with advanced solid tumors
Authors: Zafar Y. , Bendell J. , Lager J. , Yu D. , George D. , Nixon A. , Petros W. , Beci R. , Arrowood C. , Hurwitz H.
Published: March 2020

3097

Background: BV is a potent inhibitor of vascular endothelial growth factor (VEGF) with broad clinical activity. E is an mTOR (mammalian target of rapamycin) inhibitor in development for cancer and solid organ transplant therapy. VEGF and mTOR inhibitors have anti-tumor and anti-angiogenesis effects alone and in combination in preclinical models. As a combination anti-angiogenesis therapy, we evaluated BV + E in a phase I, pharmacokinetic (PK), biomarker study. Methods: BV was dosed at 10mg/kg IV q14d. E was dosed at 5mg PO QD, escalating to 10mg QD. Cycle length was 28 days. DLT was defined as any grade 4 heme or grade 3/4 non-heme event in Cycle 1 related to treatment. Pts had advanced solid tumors, adequate organ function, and no increased risks for class-related toxicities. Serial blood samples were collected for PK studies of E. Dermal wound angiogenesis assays were performed pre and on treatment for phospho VEGFR2, AKT, mTOR, and S6K. Results: 14 pts have been enrolled (8 F, 6 M), 12 evaluable for toxicity, 14 for efficacy. Median age is 58y (range 29–73). At dose level 1 (BV 10mg/E 5mg) there were no DLT’s in 5 pts. At dose level 2 (BV 10mg/E 10mg), no DLT’s were noted in the initial 3 pts and the cohort was expanded to 9 pts. Side effects were primarily grade 1–2: pain (10/14), mucositis (9/14), anorexia (8/14), rash (7/14), bleeding (7/14), hyperlipidemia (6/14), fatigue (6/14), and HTN (4/14). 1 pt had a myocardial infarction at day 72 and one pt developed nephrotic syndrome at day 70. 7/14 pts had stable disease as best response (70–278d). Conclusions: BV + E is generally well-tolerated. Preliminary clinical activity and class-related side effects were noted. The recommended phase II dose is BV 10mg/kg IV q14d and E 10mg PO QD.

[Table: see text]
Percutaneous radiofrequency ablation of inoperable pulmonary metastases from colorectal cancer
Authors: Yan T. D. , King J. , Glenn D. , Steinke K. , Morris D. L.
Published: March 2020

3502

Background: This current study was an open, prospective and nonrandomized phase II study, which critically evaluated the prognostic parameters for local disease-free survival (DFS) and overall survival (OS) in patients who underwent percutaneous radiofrequency ablation (RFA) for inoperable colorectal pulmonary metastases (CRPM). Methods: The inclusion criteria were patients who had inoperable CRPM, due to number, distribution, poor performance status or patients’ refusal to accept surgery. The exclusion criteria were lesions > 6 per hemithorax; diameter of metastases > 5 cm; bleeding diathesis; and/or significantly compromised lung function. All patients underwent percutaneous RFA with a radiological clear margin of at least 2 cm. The end-points of this study were local DFS and OS, determined from the time of RFA intervention. Ten clinical and six treatment-related prognostic parameters were assessed in univariate and multivariate analyses. All patients were reviewed at one week, one month and every three months thereafter with chest CT. Fifty-five patients entered into the study. The follow-up was complete and the median follow-up was 24 months (6 to 40). Results: The median local DFS was not reached and 2-year local DFS was 57%. Univariate analysis demonstrated that largest size of lung metastasis, location of lung metastases, post-RFA CEA at 1 month and 3 months were significant for local DFS. In multivariate analysis, largest size of lung metastasis of ≤ 3 cm and post-RFA CEA of ≤ 5 ng/ml at 1 month were independently associated with an improved local DFS. The median OS was 33 months (4 to 40), with 1-, 2-, and 3-year survival of 85%, 64% and 46%, respectively. Univariate analysis demonstrated that interval between the diagnoses of colorectal cancer and pulmonary metastasis; largest size of lung metastasis and location of lung metastases were significant for OS. In multivariate analysis, only size of lung metastasis of ≤ 3 cm was independently associated with an improved OS. Conclusions: Percutaneous RFA of inoperable CRPM may have a useful role in patients with a lesion of ≤ 3 cm.

No significant financial relationships to disclose.
Safety and efficacy of oxaliplatin/fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer (mCRC): Final analysis of the TREE-Study
Authors: Hochster H. S. , Hart L. L. , Ramanathan R. K. , Hainsworth J. D. , Hedrick E. E. , Childs B. H.
Published: March 2020

3510

Background: The addition of bevacizumab (bev) to fluorouracil-based combination chemotherapy results in statistically significant improvement in survival among patients (pts) with mCRC. This randomized, multicenter trial was designed to assess the safety, tolerability and efficacy of each of three oxaliplatin (OX) plus bolus (b), infusional, or oral fluoropyrimidine (FP) regimens without (TREE1 cohort) or with (TREE2 cohort) bev for 1st line tx of mCRC. Methods: Eligibility included age ≥ 18 years, measurable, untreated mCRC, ECOG performance status ≤1. Primary endpoint: incidence of grade (gr) 3–4 toxicities (tox) on each arm during the 1st 12 weeks of therapy; secondary endpoints: ORR, TTP, OS. Regimens TREE-1: FOLFOX: OX 85mg/m2, leucovorin (LV) 350mg, 5-FU bolus 400mg/m2 and 2400mg/m2 CIV over 46 hours ; bFOL : OX 85mg/m2 days (d) 1&15, LV 20 mg/m2 and bolus 5-FU 500mg/m2 d 1,8,15 q 4 wks; CapeOx: OX 130 mg/m2 d 1, Capecitabine 1000–850 mg/m2 bid for 14 d. In TREE-2 bev 5 mg/kg q14 or 7.5 q 21 d was added. Results: 147 pts were treated in TREE1 and 213 treated in TREE2. Overall, incidence of any gr 3–4 toxicity (TREE1 vs. TREE2 respectively) = FOLFOX 75% vs. 66%, bFOL 42% vs. 59%, CapeOx 73% vs. 54%. Addition of bev in TREE2 caused more gr 3–4 hypertension, impaired wound healing, and bowel perforation in each arm. Confirmed ITT ORR (TREE1 vs TREE2 respectively) = FOLFOX 41% vs.52%, bFOL 20% vs.39%, CapeOx 27% vs. 46%. Median TTP (months) + 95% CI (TREE1 vs TREE2 respectively) = FOLFOX 8.7 (6.5, 9.8) vs. 9.9 (7.9, 11.7), bFOL 6.9 (4.2, 8.0) vs. 8.3 (6.6, 9.9), CapeOx 5.9 (5.1, 7.4) vs.10.3 (8.6, 12.5). Probability of survival at 18 months (TREE1 vs. TREE2 respectively) = FOLFOX 53% vs. 63%, bFOL 50% vs. 63%, CapeOx 49% vs. 68%. As of January 9, 2006, 56 TREE1 pts (38%) and 122 TREE2 pts (57%) are alive. Conclusions: These data demonstrate these three Ox/FP regimens to be tolerable and effective. Addition of bev to Ox/FP regimens improves response rate and TTP with acceptable tolerability, and no unexpected toxicity.

[Table: see text]
Local recurrence after rectal cancer resection is strongly related to the plane of surgical dissection and is further reduced by pre-operative short course radiotherapy. Preliminary results of the Medical Research Council (MRC) CR07 trial
Authors: Quirke P. , Sebag-Montefiore D. , Steele R. , Khanna S. , Monson J. , Holliday A. , Thompson L. , Griffiths G. , Stephens R.
Published: March 2020

3512

Background: The MRC CR07 trial compared routine short course pre-operative radiotherapy (PRE) with selective post-operative chemo-radiation if there was involvement of the circumferential resection margin (CRM) (POST) and included a prospective pathological assessment of the quality of resection of the surgical specimen. Methods: A total of 1350 patients were randomised from 52 centres between March 1998 and August 2005. Median follow-up is 3 years. Trial pathologists were trained in histopathological assessment and reporting of the involvement of the CRM and plane of surgery (PoS) according to pre-set criteria describing the plane of dissection (Grade 1-muscularis plane: 2-intramesorectal plane: 3-mesorectal plane). 1232 patients were prospectively assessed for CRM and 1119 for PoS. Results: The CRM was involved (tumour ≤1mm) in 139 (11%) of resected specimens, and for these patients the 3-year local recurrence (LR), disease-free survival (DFS) and overall survival rates were 18%, 50% and 57%. For the 1093 patients with CRM-ve the respective rates were 7%, 81% and 84%. LR and DFS rates were associated with PoS (log-rank test p=0.0019 and p=0.0506 respectively), and in addition there was clear evidence of a reduction in LR and improvement in DFS rates in favour of PRE for all grades of quality of surgical assessment as shown in the table . Conclusions: The results indicate a strong association between the quality of surgery and the rates of local recurrence and disease-free survival, as well as a clear benefit from the addition of PRE to all grades of surgical dissection. Thus for patients with rectal cancer short-course pre-operative radiotherapy and good quality surgery can almost completely eliminate local recurrence.

[Table: see text]

No significant financial relationships to disclose.
Capecitabine, oxaliplatin, radiotherapy, and excision (CORE) in patients with MRI-defined locally advanced rectal adenocarcinoma: Results of an international multicenter phase II study
Authors: Rutten H. , Sebag-Montefiore D. , Glynne-Jones R. , Rullier E. , Peeters M. , Brown G. , Van Cutsem E. , Ricci S. , Van de Velde C. J. , Quirke P.
Published: March 2020

3528

Background: The addition of chemotherapy to preoperative radiotherapy (RT) may reduce distant recurrence and increase tumor resectability. The CORE study evaluated oxaliplatin, capecitabine, and RT (XELOX-RT) followed by total mesorectal excision (TME), then adjuvant XELOX in patients (pts) with MRI-defined locally advanced rectal cancer. Methods: MRI inclusion criteria: tumor beyond mesorectal fascia, tumor ≤2 mm from mesorectal fascia, or T3/4 tumor <5 cm from anal verge. Chemoradiation (CRT) was 45 Gy RT (1.8 Gy/dose) 5 days/wk for 5 wks, weekly oxaliplatin 50 mg/m2, and twice-daily capecitabine 825 mg/m2 on each day of RT. Surgery was 6–8 wks after completing XELOX-RT. Pts with R0-R1 resection were to receive XELOX for 6 cycles. Central radiologic and histopathologic review were key study components. Processes to determine histopathologic response and circumferential resection margin (CRM) were predefined. The primary endpoint was pCR rate (planned n=70 evaluable pts). Results: Between July 2003 and Dec 2004, 87 pts were enrolled; 85 pts received XELOX-RT and 79 had TME. Seventy pts (82%) had R0-R1 resection, with a 67% R0 rate (n=57) by Quirke methodology (CRM >1 mm). The pCR rate was 13% (10/78 pts assessable for tumor response; 95% CI, 5.46–20.34%). Tumor regression grading showed excellent response in 35% and poor response in 64% of pts. Of 60 pts evaluated by central MRI review for response by RECIST, the overall response rate was 70% (7% complete; 63% partial response). Preoperative grade (G) 3/4 adverse events (% of pts; evaluable n=85) included diarrhea 16% (12% G3), sensory neuropathy 1% (G3), neutropenia 1% (G3), and hand-foot syndrome 1% (G3). More than 90% of pts received full dose radiotherapy. Conclusions: Significant tumor regression and a high R0 resection rate were achieved using a CRT regimen of preoperative oxaliplatin, capecitabine, and 45 Gy RT, with acceptable toxicity. Central histopathologic and radiologic review data, together with safety and efficacy results for both preoperative CRT and postoperative chemotherapy, will be presented.

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Patient-reported neurotoxicity with FULV versus FLOX in patients with stage II or III carcinoma of the colon: Results of NSABP Protocol C-07
Authors: Land S. R. , Kopec J. , Cecchini R. , Ganz P. A. , Wieand H. , Colangelo L. , Sharif S. , Kuebler J. P. , Costantino J. , Wolmark N.
Published: March 2020

3564

Background: NSABP Phase III Protocol C-07 compared the efficacy of FULV versus FLOX in patients with stage II or III colon cancer. The definitive analysis revealed an increase in 3-year disease-free survival from 71.6% to 76.5% (HR=0.79, p=0.004) in favor of FLOX. The present study compares patient-reported neurotoxicity between the treatment groups. Methods: Patients were randomized to either FULV (5-FU, 500 mg/m2 iv bolus weekly x 6; LV, 500 mg/m2 iv weekly x 6, each 8-week cycle x 3) or FLOX (FULV with oxaliplatin 85 mg/m2 iv administered on weeks 1, 3 and 5 of each 8-week cycle x 3). A subset of patients (planned sample size 400) at select institutions completed the validated FACT/GOG Oxaliplatin-Specific Neurotoxicity Scale (NTX-12) at baseline, week 4 of cycle 2, and at 6, 12 and 18 months. Mean NTX-12 scores were compared between treatments at 18 months using a t-test and longitudinally with mixed effects modeling. Item responses were compared between treatments with logistic regression. Results: From February 2000 to July 2001, 395 patients with follow-up (206 FULV, 189 FLOX) were enrolled in the neurotoxicity study. They were comparable by disease stage and site, age, and sex to the 759 concurrently accrued C-07 patients not in the sub-study (data not shown). NTX-12 form submission rates were high (with a low of 77% at 12 months). Mean neurotoxicity was higher in the oxaliplatin arm throughout the period of study (p<0.0001) and remained higher at 18 months (p=0.009). During therapy, FLOX patients experienced significant increases in hand/foot neuropathy and overall weakness, and an improvement in hearing ( Table ). At 18 months, hand neurotoxicity resolved, but patients who received oxaliplatin experienced ringing in the ears and continued foot discomfort. Conclusions: This presentation provides the first public review of the severity and persistence of neurotoxicity associated with oxaliplatin in this study.

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Final safety findings from a randomized phase III trial of capecitabine + oxaliplatin (XELOX) vs. bolus 5-FU/LV as adjuvant therapy for patients (pts) with stage III colon cancer
Authors: Schmoll H. J. , Tabernero J. , Nowacki M. , Maroun J. , Price T. , Lim R. , Van Cutsem E. , De Braud F. , Haller D.
Published: March 2020

3569

Background: Adjuvant capecitabine results in at least equivalent disease-free survival (DFS) to i.v. bolus 5-FU/LV in stage III colon cancer [Twelves et al. 2005]. Early phase III data in 1st-line metastatic colorectal cancer suggest that XELOX is as safe as oxaliplatin + infusional 5-FU ± LV [Sastre et al. 2005; Ducreux et al. 2005]. The XELOXA study compared safety and efficacy of XELOX vs. bolus 5-FU/LV (the standard regimen at study start) as adjuvant therapy for stage III colon cancer. Methods: Pts with resected disease were randomized to receive either XELOX (capecitabine 1000 mg/m2 bid d1–14 + oxaliplatin 130 mg/m2 d1, q3w for 8 cycles) or i.v. bolus 5-FU/LV (Mayo Clinic, LV 20 mg/m2 + 5-FU 425 mg/m2 d1–5, q4w for 6 cycles; or Roswell Park [RP], LV 500 mg/m2 + 5-FU 500 mg/m2 d1, w1–6 in 8w cycles x4). Centers’ preferred 5-FU/LV regimen was selected at study start and used in all pts. Results: 1861/1886 pts randomized between Apr 03 and Oct 04 are evaluable for safety. The rate of related grade 3/4 adverse events (AEs) was 54% for XELOX and 45% for 5-FU/LV ( table ). 60-day all cause mortality was 1.0% in both arms. Treatment-related death rate within 28 days from last dose was 0.7% for XELOX and 0.5% for 5-FU/LV. Conclusions: XELOX causes less myelosuppression and stomatitis but more skin toxicity than 5-FU/LV. The inclusion of oxaliplatin adds neurosensory toxicity. Cross-study comparison of grade 3/4 AEs in the current and MOSAIC trials suggests that XELOX safety is similar to FOLFOX4, with the advantage of an oral fluoropyrimidine-based regimen. Final safety data will be presented at the meeting, and efficacy data will be available in 2007.

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A dose attenuated schedule of irinotecan and capecitabine in combination with celecoxib in advanced colorectal cancer
Authors: El-Rayes B. F. , Shields A. F. , Vaishampayan U. , Heilbrun L. K. , Zalupski M. M. , Philip P. A.
Published: March 2020

3584

Background: The cyclooxygenase-2 (COX-2) enzyme is overexpressed in the majority of colorectal cancers. Inhibition of the COX-2 enzyme can sensitize colorectal cancer cells to the apoptotic effects of chemotherapeutic agents and block angiogenesis. This phase II study was undertaken to determine the effects of adding celecoxib to a dose attenuated irinotecan and capecitabine regimen. Methods: The primary objective was to estimate the objective response rate of patients with metastatic colorectal cancer treated with irinotecan, capecitabine, and celecoxib. Previously untreated patients, except for adjuvant therapy, with metastatic colorectal adenocarcinoma were eligible for this study. Patients received irinotecan 70 mg/m2 (over 30 minutes) on days 1 and 8, and capecitabine 2,000 mg/m2/day from day 1 to 14 of a 21-day cycle. Celecoxib was administered at a dose of 400 mg twice-daily starting on day -7 until termination from study. Results: A total of 51 patients (median age 58 years) have been enrolled on the study. The results presented are for the first 48 patients registered to the study. Median performance status was 1. A median number of 5.5 cycles (range 0- 18) were administered. In an intention to treat analysis, objective response rate was 50%. The median progression free survival was 6.9 months (90%CI; 4.7–8.2). Median survival is ≥19.4 months. No treatment related deaths were observed. The only grade 4 toxicity was diarrhea in 2 (4%) patients. Grade 3 toxicities were diarrhea (33%), hand-foot syndrome (8%), nausea (13%), vomiting (8%) and neutropenia (12%). Conclusion: Lowering the dose intensity of irinotecan in this study did not appear to compromise the treatment outcome and markedly improved the therapeutic index of this combination. Celecoxib can be safely administered in combination with irinotecan and capecitabine. Based on the observed progression free survival and response rate, the regimen has promising activity.

No significant financial relationships to disclose.
Phase II trial of DJ-927, an oral tubulin depolymerization inhibitor, in the treatment of metastatic colorectal cancer
Authors: Moore M. R. , Jones C. , Harker G. , Lee F. , Ardalan B. , Saif M. W. , Hoff P. , Coomes J. , Rollins C. , Felt K.
Published: March 2020

3591

Background: DJ-927, a novel oral tubulin depolymerization inhibitor, causes apoptosis and DNA cell division arrest. It is not a substrate for the MDR and has excellent activity in preclinical colorectal cancer models. Methods: We are conducting a two-stage, multi-center, phase II trial to assess the efficacy of DJ-927 administered initially as second-line therapy following failure of irinotecan or oxaliplatin based therapy (n= 39). DJ-927 is given as a single oral dose on day 1 of a 21-day cycle at a dose range of 27 - 35 mg/m2. Results: Thirty-nine patients were enrolled, including 14 with prior irinotecan based therapy and 25 who had received prior oxaliplatin therapy. The median age was 56 years (range: 30–87) and the median ECOG PS at baseline was 1 (range: 0–2). A total of 155 courses (range: 1–24) have been administered with a median of 2 courses. Nine patients required dose reduction due to toxicity. Thirty-seven patients were evaluable for efficacy. There were 2 CRs and 2 PRs (10.3%) reported that were confirmed as per RECIST criteria. Fourteen patients (35.9%) had SD, including 6 patients (15.4%) with SD >12 weeks. The most common Grade 3 or 4 AEs were neutropenia (48.7%), fatigue (10.3%), neuropathy (7.8%), and nausea (5.0%).Six patients experienced febrile neutropenia, all requiring hospitalization but tolerated treatment with subsequent dose reduction. There were 13 episodes (33.3%) of peripheral neuropathy reported; however, only 3 (7.8%) were grade 3 or 4. Six patients withdrew due to adverse events. Conclusions: The results of this study indicate activity of DJ-927 as second line therapy in patients with metastatic colorectal cancer. Severe toxicity was generally limited to reversible neutropenia and peripheral neuropathy. This novel oral agent is well tolerated and warrants further evaluation in combination with other active agents.

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Pretreatment COX-2 protein expression is a predictor of tumor regression in rectal cancer treated with preoperative short-term chemoradiotherapy
Authors: Kobayashi H. , Hashiguchi Y. , Ueno H. , Shinto E. , Kajiwara Y. , Lenz H. , Danenberg K. D. , Danenberg P. V. , Mochizuki H.
Published: March 2020

3610

Background: Neoadjuvant chemoradiotherapy (CRT) followed by total mesorectal excision has become a standard therapy for patients with rectal cancer. However, not all patients have a good response to CRT. Therefore, it is useful to know what the predictor of chemoradiotherapeutic response is. Cumulative evidence has shown that COX-2 has an important role in the progression of colorectal cancer. The aim of this study was to clarify whether pretreatment COX-2 protein expression was a predictor of histopathologic response in patients with rectal cancer treated with preoperative short-term chemoradiotherapy. Methods: Fifty-two patients with lower rectal cancer received short-term preoperative chemoradiotherapy (20 Gy given in 5 daily doses of 4 Gy and administration of Tegafur/Uracil 400mg/day during the same period), followed by total mesorectal excision at National Defense Medical College from 2001 to 2005. COX-2 expression before and after CRT was measured by immunoshistochemistry. The specimens were graded based on the intensity and extent of staining. Tumor regression grading (TRG) was also evaluated (TRG 4, complete regression; TRG 3, regression > 50%; TRG 2, 25% to 50%; TRG 1, < 25%; and TRG 0, no regression). The correlation between COX-2 expression and tumor regression was analyzed. Results: The patient characteristics were as follows: the male:female ratio was 36:16; median age was 62. The Median postoperative follow-up period was 30 months. Two patients had pathological complete response. Good response (TRG 3 + 4) was found in 57.7% of the resected specimens. COX-2 was positive in 80.8% of patients before CRT while in 100% after CRT. The rates of good response (TRG 3 + 4) in patients with and without COX-2 expression were 50% and 90%, respectively (p = 0.021). Conclusions: Patients without pretreatment COX-2 expression were more likely to demonstrate good response to treatment than those with COX-2 expression. Pretreatment COX-2 protein expression can predict response of CRT in patients with rectal cancer.

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