bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimal circadian time of vinorelbine (V) combined with chronomodulated 5-FU in pretreated metastatic breast cancer patients. EORTC 05971 randomized multicenter study
Authors: Coudert B. , Focan C. , Genet D. , Giacchetti S. , Lentz M. , Marreaud S. , Baron B. , Gorlia T. , Lévi F.
Published: March 2020

2066

Background: Chronotherapy is an aim to increase efficacy/toxicity ratio. Objectives: to define the dosing least toxic time (DLTT) of V (30 mg/m2/d at D1 and D6), combined with chrono 5-FU (10 pm-10 am) (850 mg/m2 D2-D5) over 3 courses q3w. Methods: A logistic regression model (LRM) estimated the DLTT assuming a sinusoidal distribution over time (i.e. over the 8 different arms) of the toxicity rate observed in each arm. The associated 90% confidence limits (CL) has been obtained by bootstrap method. Results: 90 patients were recruited. Toxicity in 46 pts led to the V dosage reduction to 25 mg/m2/d. 40 and 43 pts were assigned the V30 and the V25 regimen. 12% pts went off for toxicity, 5% for PD, 1% for refusal, 1% for unrelated death. 224 cycles were analyzed . V and 5FU relative dose intensities were 79.4% and 78.2% in the V30 while 88.1% and 87.4% in the V25 pts. Over the 3 cycles, toxicity by cycle was: Grade (G) 3 and G4 leucopenia in 47% and 29%, G3 and G4 neutropenia in 12% and 77%. G3 febrile neutropenia in 34%. G2 thrombopenia and anemia in 4% each. Other G3 and G 4 toxicity were stomatitis (12%), alopecia (7%), and less than 5%: cardiovascular, lethargy, diarrhea, constipation, other gastrointestinal, infection, sensory, pulmonary. LRM could not demonstrate a DLTT for the neutropenia G3–4 incidence, the primary endpoint. However, based on the stratified by dose analysis, a 90% CI of less than 6 hours width was observed: - around 17H17 [14H04–20H03] for the incidence of leucopenia G3–4. - around 8H16 [06H04–10H39] for tolerability (dose reduction, dose delay or treatment interruption for toxicity reason). This suggests that treatment tolerability was influenced by other factors beside leucopenia nadir. No other 90% CI of less than 6 hours width could be observed for other toxicity endpoints. Conclusions: Using a novel time finding study design with ad hoc statistics, this first randomized multicenter study has determined a DLTT for Vinorelbine in 90 women with MBC. Additional studies are ongoing to further assess the relevance of this trial design method that could prove useful for improving the safety of anticancer drugs during their clinical development. Support Pierre Fabre Oncology, Ligue Bourguignonne contre le Cancer

No significant financial relationships to disclose.
A phase I dose escalation study of BIBW 2992, an irreversible dual EGFR/HER2 receptor tyrosine kinase inhibitor, in a continuous schedule in patients with advanced solid tumours
Authors: Agus D. B. , Terlizzi E. , Stopfer P. , Amelsberg A. , Gordon M. S.
Published: March 2020

2074

Background: BIBW 2992 is a novel, potent, orally bioavailable irreversible inhibitor of both EGFR and HER2 receptor tyrosine kinases with IC50 values of 0.5 and 14 nM, respectively. Methods: BIBW 2992 was administered orally as a continuous once daily dose starting at 10 mg daily and doubled in successive cohorts until observation of drug-related adverse events (AE) ≥ CTC grade 2. Thereafter, escalation steps of no more than 50% were allowed. All pts underwent pharmacokinetic sampling. The enrolled patient population included a variety of advanced solid malignancies, historically known to express EGFR and/or HER2. After reaching DLT, the MTD dose group was expanded to a total of 18 treated at that dose level. Results: To date in this continuing study, twenty-two patients have been included (13 M/ 9 F). Median age: 61.5 (range: 34–80). Administered doses (patients) were 10 (5), 20 (3), 40 (11), and 60 (3) mg in a once daily schedule. Ten pts who completed the initial 28 treatment days were eligible to continue treatment beyond the first treatment cycle. Duration of treatment is up to 7 cycles so far in this ongoing study. A total of three dose-limiting toxicities (DLT) were observed. DLT events were diarrhea (CTC grade 3) and patients recovered fully upon cessation of the drug. The 60 mg dose level was considered dose-limiting with the occurrence of two DLT. The dose level below (40 mg) was expanded to a total of 18 patients. A pharmacokinetic interim analysis (9 pts) showed, in general, increasing exposure to BIBW 2992 with increasing doses at steady state. A high inter-patient variability in all PK parameters was detected. Conclusions: BIBW 2992, in an oral once daily administration of 40mg, is well tolerated with an acceptable toxicity profile. The further evaluation of BIBW 2992 in Phase II clinical trials is warranted.

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Cellular immunotherapy redirected by bispecific antibodies in primary ovarian cancer cells: A preclinical study
Authors: Chan J. K. , Hamilton C. A. , Cheung M. K. , Schulz S. , Thorne S. H. , Anderson E. M. , Baker J. , Husain A. , Teng N. N. , Contag C. H. , Negrin R. S.
Published: March 2020

2518

Background: Cytokine induced killer cells (CIKs) are ex-vivo activated and expanded CD8+ natural killer T cells that have been shown to have cytotoxic activity against cancers in randomized clinical trials. This preclinical study demonstrates the enhanced effect of CIK killing in primary ovarian carcinoma using bispecific antibodies (BSAbs) and the potential of translating our findings to a clinical trial. Methods: Primary ovarian cancer cells and autologous CIKs were collected and cultured under IRB approval. Cytotoxicity enhancing BSAbs against CA125 (BSAbxCA125) and Her2/neu (BSAbxHer2) were designed using chemical conjugation methods. Tumor cell lysis of ovarian primary ovarian cancer cells was quantified using 51Cr release assays. Anti-NKG2D monoclonal antibodies were used in antibody blocking assays. Using a SCID mouse model of minimal residual disease, tumor progression was monitored using the bioluminescence imaging (BLI) system. Three-color immunofluorescence analysis was performed on pathologic specimens to localize CIK migration to tumor cells. Results: The mean percent lysis with an Effector:Target (E:T) ratio at 100:1 was 22.2% (±2.0) in primary cells in 4-hour killing assays. Redirection with BSAbxCA125 significantly enhanced cytolysis to 65.7% (±0.6). Adding BSAbxHer2 significantly enhanced cytolysis of cell lines to 89.4% (±1.3). Anti-NKG2D antibodies significantly attenuated the CIK activity by 54%. In vivo BLI studies in SCID mice showed that CIK treatment at a 10:1 E:T ratio was well-tolerated and effective in reducing tumor burden by 80% after 21 days post-treatment compared to untreated mice (p<0.0001). Immunofluorescence staining clearly depicted the in vivo infiltration of CIK (CD8+NKG2D+) cells into Her2-expressing tumor targets. Conclusions: Bispecific antibodies effectively enhanced the cytotoxicity of autologous CIK cells against fresh ovarian tumors. Our in vivo studies suggest that CIK cells may ultimately prove to be efficacious immunotheraputic modality in the treatment of resistant ovarian cancer.

No significant financial relationships to disclose.
A phase I, pharmacokinetic (PK) and pharmacodynamic (PD) study of MDX-214, a novel immune-mediated mechanism agent targeting the epithelial growth factor receptor (EGFR), in patients with advanced solid tumors
Authors: Mita C. A. , Papadopoulos K. , Mita M. M. , Ricart A. , Sarantopoulos J. , Berg K. , Uritz B. , Levy E. , Lowy I. , Tolcher A. W.
Published: March 2020

2523

Background: MDX-214 is a recombinant fusion protein between human EGF and the Fab′ fragment of a fully human anti-CD89 (IgA FcR) MAb. MDX-214 is designed to block EGFR and activate neutrophils via CD89 stimulation, and promotes EGFR+ cell killing in vitro by both mechanisms. Methods: The objectives of this study were to evaluate the safety and tolerability, to determine the maximum tolerated dose (MTD), to characterize the PK, to assess PD markers and to explore the antitumor activity of MDX-214 administered intravenously weekly for 4 weeksin EGFR+ malignancies. PD studies included monitoring immune cell trafficking to tumors by paired In111 WBC scans at the final dose level, MDX-214 saturation of CD89+ neutrophils in blood, as well as EGFR signaling in skin. Pts were permitted only 1 course of therapy. Results: To date, 18 pts (median age 61, range 48–83, 10 M/8 F) have been treated over 4 dose levels at 0.4, 1, 4 and 10 mg/m2, respectively. Tumor types included renal (4), colorectal (2), pancreatic (2), head/neck (2), tracheal, parotid, esophageal, breast, anal, thyroid, hepatocellular, and skin carcinomas. DLT was encountered at 10 mg/m2 with one grade 3 reversible infusion reaction of rigors, erythema and transient hypoxemia. In the 6 pts treated at this dose level, 2 additional pts experienced grade 2 infusion reactions despite premedication, and one grade 2 hypotension. The MTD was therefore 4 mg/m2. Other grade 1–2 toxicities included nausea/vomiting (9), diarrhea (2), fatigue (4), headache (4). There were 7 pts with stable disease at 6 weeks. The serum half-life was < 30 min but neutrophil-bound MDX-214 was detectable for 24 h. In111 WBC scans are under analysis. Conclusion: Weekly administration of MDX-214, a novel immune mediated therapeutic strategy targeting EGFR is feasible with an MTD of 4 mg/m2. This dose results in neutrophil labeling with MDX-214 for over 24 hours, and may permit activated neutrophil localization at tumor sites. Accrual at the MTD is ongoing.

[Table: see text]
Open label phase II studies of modified vaccinia ankara expressing the tumor antigen 5T4 given in conjunction with IFL and FOLFOX chemotherapy regimens: Final analysis of safety and immunogenicity of MVA 5T4 given before, during and after chemotherapy
Authors: Harrop R. , Hawkins R. , Anthoney A. , Steven N. , Habib N. , Griffiths R. , Melcher A. , Wassan H. , Naylor S.
Published: March 2020

2527

Background: 5T4 is a tumour associated antigen that is widely expressed on the surface of most human adenocarcinomas, including colorectal, but rarely in normal cells. Modified Vaccinia Ankara (MVA) has been employed as a vaccine vector to deliver 5T4. Previously, MVA-5T4 has been evaluated in a phase I/II clinical trial in stage IV colorectal cancer patients. MVA-5T4 was shown to be safe and well tolerated and induced 5T4 specific immune responses in most patients. Furthermore, 5T4 specific antibody titres correlated with clinical benefit. Methods: Two open label phase II clinical trials were initiated in which patients with advanced colorectal cancer received MVA-5T4 in conjunction with either 5-FU/leukovorin and irinotecan (TV2-IFL; n=19 patients) or 5-FU/leukovorin and oxaliplatin (TV2-FOLFOX; n=17 patients). MVA-5T4 was administered up to 6 times, 2 prior to, 2 during and 2 post-chemotherapy. The primary objectives were to assess the safety and immunogenicity of MVA-5T4 given in combination with chemotherapy. Results: Recruitment to both trials is complete and MVA-5T4 was well tolerated in all ITT patients, with no serious adverse events being associated with MVA-5T4. 5T4-specific cellular and humoral immune responses were monitored before, during and after chemotherapy in all 23 per protocol patients (n=12 for TV2-IFL and n=11 for TV2-FOLFOX). Following vaccination, all 23 patients mounted 5T4 cellular and/or humoral responses. Immune responses were detectable during chemotherapy in the majority of patients. IFNγ ELISPOT responses to 5T4 peptides revealed precursor frequencies as high as 1 in 1000 PBMCs. Assessment of clinical responses in all PP patients demonstrated an overall response rate of 65% across both trials. Conclusions: MVA-5T4 is safe and well tolerated when administered in conjunction with IFL and FOLFOX chemotherapy regimens. Furthermore, 5T4 specific immune responses are induced in all per protocol patients and can be boosted or maintained during chemotherapy. Encouraging clinical responses have been observed and 5T4 immune responses shown to correlate with clinical benefit.

[Table: see text]
Phase I pharmacokinetics (PK) of humanized anti-MUC-1 antibody R1550
Authors: Pegram M. D. , Borges V. , Fuloria J. , Ibrahim N. , Shapiro C. L. , Perez E. S. , Wang K. , Schaedeli Stark F. , Yeon C. , Courtenay-Luck N.
Published: March 2020

2533

Background: MUC-1 glycoprotein establishes a molecular barrier at the epithelial surface, and engages in morphogenetic signal transduction. A 20 amino acid MUC-1 core tandem repeat is aberrantly glycosylated in >90% of epithelial tumors, exposing peptide sequence PDTRP. Humanized IgG1 κ monoclonal antibody R1550 binds PDTRP (Kd∼1nM) and induces potent antibody-dependent cellular cytotoxicity. Methods: R1550 clinical tolerability and PK was determined in advanced, PDTRP-expressing (by IHC), breast cancer patients progressing after anthracyclines and taxanes. Key eligibility: informed consent, WHO PS 0–1, life expectancy >4 mos, non-inflammatory histology, and no CNS metastasis. R1550 was infused IV over 1–3 hrs: cohort 1 (N = 3) 1 mg/kg; cohort 2 (N = 9) 3 mg/kg; cohort 3 (N = 6) 9 mg/kg; cohort 4 (N=3) 16 mg/kg, with repeat dosing every 1–2 weeks (patient-individualized PK assessment) until disease progression. Plasma [R1550] was measured by quantitative ELISA. PK parameters were analyzed by a non-compartmental model, and a 2-compartment population PK model. Results: 21 patients (mean age 54, median # of prior chemotherapy agents = 4) have been dosed. Safety data (n=18): R1550 is generally well tolerated with fatigue (28%), gastrointestinal symptoms (22%), skin rash (17%), pyrexia (11%), and elevated liver function tests (11%) as the most frequently reported adverse events (AEs). Two grade 4 AEs were reported: elevated AST, and hyperglycemia, both in cohort 2. Neither have been observed in expanded or subsequent cohorts. Median number of doses received per patient = 3 (range, 3–4), 4 (1–13) and 6 (4–21), in cohorts 1, 2, and 3, respectively. No anti-humanized antibodies were detected. PK parameters of cohorts 1–3 are shown below. Conclusions: R1550 is well tolerated, with MTD exceeding 9 mg/kg. PK parameters using non-compartmental, and 2-compartment population PK models are in agreement. R1550 half-life suggests weekly dosing. Plasma exposure and dose relationships are linear within 1–9 mg/kg dose range. Accrual to cohort 4 is ongoing.

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Treatment of non-small cell lung cancer (NSCLC) patients with the trifunctional antibody catumaxomab (anti-EpCAM x anti-CD3): Results of a phase I/II study
Authors: Passlick B. , Schmittel A. , Friccius-Quecke H. , Kanniess F. , Wiewrodt R. , Lindhofer H. , Jaeger M. , Sebastian M.
Published: March 2020

2540

Background: Catumaxomab is a trifunctional monoclonal antibody with binding specificities to human EpCAM, human CD3 and Fc gamma receptor I/III-positive accessory cells leading to induction of cell mediated, tumor specific cytotoxicity. As EpCAM is overexpressed in NSCLC patients (pts.) the present study was conducted in order to evaluate safety and tolerability of intravenous (i.v.) treatment with catumaxomab. Methods: Patients with NSCLC (UICC stage IB - IV) with at least one prior therapy were included into this trial. Escalating doses of 2–7,5 μg catumaxomab were given as a single i.v. infusion. Various doses of dexamethasone premedication (10 and 40 mg) were investigated at five different dose levels (level: catumaxomab (μg)/dexamethasone (mg)/number of pts. treated: I: 2/40/3, II: 2/0/1, III: 5/40/4, IV: 5/10/5, V: 7,5/40/2, respectively). Primary objectives were toxicity and definition of the maximum tolerated dose (MTD). In addition, time to progression (TTP) and survival were evaluated. Results: 24 pts. were included into this trial; 15 pts. were evaluable for safety analysis, 13 pts. for follow up. 13/15 pts. experienced a total of 68 AEs, of which 55 were reported as drug related and 9 defined as critical AEs. The majority (77%) of AEs were mild (CTC grade 1 and 2), 19% were grade 3 and 4% grade 4. 73% of the AEs were elevation of liver enzymes (gamma-GT, AST and ALT). Other toxicities were increase of blood ALP, dizziness, lymphopenia and pyrexia. Dose limiting toxicity (DLT) was a transient grade 3 and 4 elevation of ALT, AST and gamma-GT, observed at dose levels IV and V. Maximum tolerated dose (MTD) was defined at dose level III. Remarkably, follow up data showed 4/4 pts. stage IIIB and 1/4 pts. stage IV still alive at 26–28 months after catumaxomab treatment. Conclusion: 5 μg of catumaxomab can safely be administered intravenously with 40 mg dexamethasone as premedication. Based on the current results we recommend this regimen as first dose in a future study consisting of multiple catumaxomab infusions in pts. with locally advanced NSCLC.

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Ex vivo blood stimulation assay as a translational research tool in the development of the ticilimumab (CP-675,206)
Authors: Millham R. , Pavlov D. , Canniff P. , Guyot D. , Hanson D. , Ribas A. , Camacho L. H. , Gomez-Navarro J.
Published: March 2020

2542

Background: Cytotoxic T Lymphocyte-associated Antigen 4 (CTLA4) is an activation-induced T lymphocyte negative costimulatory receptor which down-regulates cellular immune responses. CTLA4 blockade may break peripheral immunological tolerance, leading to an effective immune response to cancer. Tools for assessing the effects of such a blockade are limited, as CTLA4 is not constitutively expressed on circulating T cells, and because activated lymphocytes are difficult to access in vivo. Therefore, we have employed ex vivo blood stimulation assays to define pharmacodynamic properties of the anti-CTLA4 antibody, ticilimumab. Methods: Ex vivo blood stimulation assays employed staphylococcal enterotoxin A (SEA) to stimulate isolated peripheral blood mononuclear cells (PBMC) or whole blood. Stimulation was monitored by production of interleukin 2 (IL-2). This assay was used preclinically to predict in vivo responses in animal models and in samples from cancer patients, as a batch release assay for production runs of ticilimumab, and clinically as a pharmacodynamic measurement in clinical trials of ticilimumab. Results: Screening experiments using the SEA assay allowed us to identify the lead candidate mAb with optimal CTLA4 blockade activity, ticilimumab. Dose-dependent increases in IL-2 production were observed in PBMC and whole blood samples up to an in vitro concentration of 100 ug/mL of ticilimumab, with 10 ug/mL identified as the minimum predicted efficacious concentration (Ceff). This functional potency assay was adapted for qualification of production lots of ticilimumab. Whole blood taken from cynomolgus monkeys dosed with ticilimumab demonstrated significant enhancement of IL-2 production at the same magnitude observed in in vitro experiments. Additionally, longitudinal samples taken from healthy volunteers and cancer patients suggested that an enhancement of 2.8 fold would be indicative of a pharmacodynamic effect of ticilimumab. Conclusions: The SEA assay provides a functional assessment of ticilimumab activity and can be used to guide the clinical development of this agent. Our data suggest that T cell reactivity is enhanced in the presence of ticilimumab in vitro, in primate models and in humans.

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SOX2 antibody responses in patients with various tumor types and SCLC with and without paraneoplastic neurologic syndromes
Authors: Chen L. , Narayanan S. , Posner J. , Ozbek U. , Ritter E. , Gnjatic S. , Chen Y. , Old L. , Gure A.
Published: March 2020

2562

Background: SOX2, a member of the SOX Group B family of transcription factors, is expressed in normal adult brain, testis and prostate as well as in many SCLC cell lines. Spontaneous antibody responses to SOX2 have previously been shown to be detectable in SCLC patients. We undertook a retrospective study to determine whether antibody responses were detectable in patients with other malignancies and in patients with paraneoplastic neurologic syndromes (PND/PNS). Methods: Previously obtained serum samples from patients with no known disease (n = 84), breast and ovarian cancer (n = 35 each), melanoma (n = 42), NSCLC (n = 150), and SCLC patients, 90 from Turkey and 68 patients studied for PND, were tested by ELISA using serial 4-fold dilutions for anti-SOX2 and anti-HuD antibody. Results: Preliminary data shows SOX2 reactivity in 5/84 (6%) normal volunteer sera, 8/35 (23%) in both breast and ovarian cancer patients, 4/42 (9%) melanoma patients, 20/150 (13.3%) NSCLC patients, and 56/158 (35.4%) SCLC patients. Compared to controls, there was a statistically significant difference in SOX2 immunoreactivity in breast, ovarian (p = 0.007 for both) and SCLC patients (p < 0.001), and a trend was noted in NSCLC patients (p = 0.080). No breast, ovarian, melanoma or normal patient had SOX2 antibody titers ≥1:6400, compared with 32/56 (57.1%) of SCLC (p < 0.01) and 6/20 (30%) NSCLC patients (p < 0.16). Nine SCLC patients had neurologic symptoms and were previously found to have anti-HuD antibodies, associated with a diagnosis of PND. This was confirmed in 8/9 patients in our assay. However, none of the nine patients displayed anti-SOX2 reactivity. Eleven additional SCLC patients were found to be HuD positive by our ELISA. Conclusions: Anti-SOX2 responses are found in a significant proportion of patients with SCLC, breast and ovarian cancer, but not in melanoma patients compared to normal controls. Patients with SCLC have higher titer antibodies when compared with the other groups, and anti-SOX2 antibodies do not appear to associate with anti-HuD responses, supporting the hypothesis that SOX2 immune responses are not associated with PND and may be useful as a vaccine target. Supported by the Cancer and Leukemia Group B/Aventis Oncology Award and the Steps for Breath Foundation.

No significant financial relationships to disclose.
A multicenter phase I study of adenoviral p53 in Japanese patients with advanced non-small cell lung cancer
Authors: Kagawa S. , Fujiwara T. , Saijo Y. , Nukiwa T. , Yoshimura K. , Nakamura H. , Kato H. , Chada S. , Tanaka N.
Published: March 2020

2564

Adenovirus expressing p53 gene, Advexin (A), has shown antitumor activity in a variety of human cancer in preclinical and clinical studies. The goals of this study were to determine the feasibility, safety, humoral immune response, and biological activity of multiple intratumoral injections of A and to characterize the pharmacokinetics of A in Japanese patients with advanced non-small cell lung cancer (NSCLC). Fifteen patients with histologically confirmed NSCLC and p53 mutations were enrolled into this phase I trial. Nine patients received escalating dose levels of A (1 × 109 to 1 × 1011 plaque-forming units [PFU]) as monotherapy once every 4 weeks. Six patients were treated on a 28-day schedule with A in combination with intravenous administration of cisplatin (80 mg/m2). Patients were monitored for toxicity, tumor response, antibody formation, and vector distribution. Fifteen patients received a total of 63 intratumoral injections of A without dose-limiting toxicity. The most common treatment-related toxicity was a transient fever. Thirteen of 15 patients were assessable for efficacy; one patient had a partial response (squamous cell carcinoma at the carina), 10 patients had stable disease, with three lasting > 9 months, and 2 patients had progressive disease. Distribution studies revealed that the vector was detected in the gargle and plasma, but rarely in the urine. Despite of the presence of neutralizing anti-adenovirus antibody, specific p53 transgene expression was detected in biopsied tumor tissues throughout the period of treatment using reverse-transcriptase polymerase chain reaction We conclude that multiple courses of intratumoral A injection alone or in combination with intravenous administration of cisplatin were feasible and well tolerated in advanced NSCLC patients, and appeared to provide clinical benefit.

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A vaccinia-based vaccine (TroVax) targeting the oncofetal antigen 5T4 administered before and after surgical resection of colorectal cancer liver metastases: Phase II trial
Authors: Dangoor A. , Burt D. , Harrop R. , Drury N. , Hamer C. , Andrews D. , Sherlock D. , Stern P. , Hawkins R.
Published: March 2020

2574

Background: Oncofetal antigen 5T4 is expressed by most colorectal cancers. Administration of a vaccine combining a Modified Vaccinia Ankara (MVA) vector with 5T4 elicits immune responses in late-stage colorectal cancer patients. This trial seeks to investigate the immunological effects of the vaccine both in peripheral blood and locally in tumour tissue resected during potentially curative surgery for colorectal liver metastases. Some patients may have micrometastatic disease, a potential target for immunotherapy. Methods: Colorectal cancer patients selected for resection of liver metastases were eligible. Recruitment of up to 20 patients was planned. Following screening they received 2 vaccinations prior to, and 2 after, surgery. Primary endpoint was assessment of the immune response at time of surgery. Blood was taken for analysis at screening and 2 weeks after each vaccination. A tumour biopsy was obtained at surgery. T-cell responses were assessed using proliferation and gamma-interferon ELISPOT assays; ELISA used to assess serological response. Immunohistochemical analysis was used to confirm tumour antigen expression and the nature of T-cell infiltration into the liver. If 5T4-specific immune responses were demonstrated patients were offered further vaccinations at 20 and 28 weeks post surgery. Results: Of 20 patients recruited, 16 were eligible for assessment, 4 excluded, 1 due to hepatocellular carcinoma, 3 with inoperable disease. There was no grade III/IV toxicity related to vaccination. Tumour expression of 5T4 was confirmed in all cases, local T-cell infiltration consisted predominantly of CD4 cells. According to proliferation assays, 8 of 16 patients had T-cell responses at time of surgery and 12 of 16 in total to date. 14 patients have developed 5T4-specific antibody responses. At median follow up of 8.4 months 7 of 16 patients have disease recurrence. Conclusions: The MVA-5T4 vaccine (TroVax) was safe and well tolerated in all patients undergoing resection of colorectal liver metastases. 5T4 specific cellular and/or humoral immune responses were induced in the majority of patients following vaccination with TroVax.

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Durable clinical responses in patients with metastatic melanoma vaccinated with dendritic cells loaded with killed allogeneic melanoma cells
Authors: Fay J. W. , Ueno H. , Connolly J. , Banchereau J. , Palucka K.
Published: March 2020

2576

Background: We demonstrated that DCs loaded with killed allogeneic tumors can cross-prime tumor-specific naïve CD8+T cells in vitro. Clinically this approach would overcome HLA restriction inherent to peptide vaccines and allow diversification of immune responses including priming of many clones of CD8+ and CD4+ T cells. Methods: Twenty (20) patients with metastatic melanoma were vaccinated with autologous monocyte-derived DCs loaded with killed allogeneic Colo829 melanoma cell line. A total of 8 vaccines were administered at monthly intervals. DCs were generated from monocytes by culturing with GM-CSF and IL-4 and activated by additional culture with TNFα and CD40 ligand. KLH was used as a control antigen. The first patient was accrued December, 2002 and the last November, 2003. Results: DC vaccinations induced durable objective clinical responses in two patients who had progressive metastatic disease after previous cytotoxic chemotherapy. One patient experienced a CR and one patient a PR both remissions have lasted ≥ 20 months. Fourteen patients were alive at 12 months and 9 patients are alive at the end of 2005. The estimated median overall survival is 22 months with a range of 2–31 months. DC vaccination led to elicitation of CD8+T cell immunity specific to MART-1 tissue differentiation antigen, suggesting that cross-priming/presentation of melanoma antigens by the DC vaccines had occurred in vivo. Vaccinations were safe and tolerable. There were no significant adverse events. Conclusions: The present results justify the design of larger follow-up studies to assess the immunological and clinical response to DC vaccines in patients with metastatic melanoma and other malignant diseases.

No significant financial relationships to disclose.
Vaccination of stage IV melanoma patients with dendritic cells generated ex vivo with type I interferon and loaded with heat-treated killed allogeneic melanoma cells—Preliminary report from the phase II clinical trial
Authors: Palucka A. , Nemunitis J. , Weber J. , Ueno H. , Auditore-Hargreaves K. , Fay J. , Banchereau J.
Published: March 2020

2582

Background: We have previously demonstrated in phase I clinical trial treating 20 patients with metastatic melanoma that dendritic cells (DCs) loaded with killed allogeneic tumor cells can elicit immune and clinical responses. In that study DCs were generated from monocytes with GM-CSF and IL-4 and activated with a combination of TNF and soluble CD40 ligand. Two patients who had failed previous therapy including DTIC, achieved durable objective clinical responses, one CR and one PR lasting ≥ 20 months. We describe here the development of a high-throughput method for generating DC vaccines with improved immunogenicity and preliminary data from their evaluation in a Phase II trial in metastatic melanoma. Methods: We have initiated a phase II clinical trial (IRB #005–065; BB-IND #12339) enrolling patients with stage IV melanoma who failed first line therapy with DTIC and/or temozolomide with or without IL-2. Patients will receive seven injections of an autologous DC vaccine generated from monocytes by culturing with GM-CSF and Type I interferon and loaded with heat-treated and killed allogeneic Colo829 melanoma cells. Vaccine is generated in a closed system and stored frozen. Patients are vaccinated over 18 weeks. The trial is based on an initial toxicity evaluation in the first 10 patients on top of a 2-stage response rule - 1/19 to continue and 5/30 to accept. The trial is expected to accrue a total of 32 subjects. The primary end-points of this trial are the rate of objective clinical response and the safety/feasibility of the vaccination preparation. Results: To date seven patients were enrolled and begun vaccinations. Vaccine has been successfully generated for all enrolled patients. Thus far, a total of 20 vaccinations have been administered. Vaccinations were safe and tolerable.

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Multi-targeted inhibition of the epidermal growth factor (EGFR) and vascular endothelial growth factor receptor (VEGFR) pathways: A phase I study of cetuximab (C), erlotinib (E), and bevacizumab (B) in patients with solid tumors
Authors: Preston G. G. , Calvo E. , Papadopoulos K. , Patnaik A. , Mita A. , Sarantopoulos J. , Mita M. , O’Rourke P. , Takimoto C. , Tolcher A.
Published: March 2020

3005

Background: Complex interrelationships exist between the EGFR and VEGFR pathways. EGFR activation elicits cell proliferation, and downstream effects increase expression of VEGF. In renal cell carcinoma, mutations increase hypoxia inducible factor-1alpha, stimulating VEGF and transforming growth factor expression. Moreover, there is additive tumor inhibition from combined EGFR targeting with C, and a tyrosine kinase inhibitor. To maximally inhibit EGFR, and then inhibit downstream VEGFR activity, this phase I study was initiated to determine the maximum tolerated dose (MTD) of E with a fixed dose of C, and then the MTD of B with combined E and C in patients with advanced malignancies. Methods: Patients with advanced malignancies likely to express EGFR were entered in part 1 to daily oral E (starting at 100mg, planned initially to increase to 150 mg), with fixed dose C (400 mg/m2 loading and 250 mg/m2 IV weekly). Once the MTD was determined for E in combination C, part 2 incorporated the addition of escalating doses of B (5 mg/kg IV every 2 weeks, to increase to 10 mg/kg) to the combination of E and C. Results: 27 patients were entered and received 84 courses over 3 dose levels. In part 1 grade 3 rash occurred in 2 patients at E at 100 mg daily, and the MTD of E for this combination was 50 mg daily with standard dose C (12 patients treated). Other adverse events included rash, diarrhea, hypomagnesemia, and nausea. Part 2: B at 5 mg/kg IV q14 days can be added to the MTD of E with C, with additional non-dose limiting toxicities of headache, proteinuria, and hypertension. Durable stable disease has been observed in 4 patients with metastatic disease for 7 (sqaumous cell); 10+, 12, and 12+ (renal cell) months. Conclusions: The MTD for E combined with standard C is 50 mg daily. B at 5mg/kg can be combined safely with this combination and dose escalation is ongoing.

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HGS-ETR2—A fully human monoclonal antibody to TRAIL-R2: Results of a phase I trial in patients with advanced solid tumors
Authors: Patnaik A. , Wakelee H. , Mita M. , Fitzgerald A. , Hill M. , Fox N. , Howard T. , Ullrich S. , Tolcher A. , Sikic B.
Published: March 2020

3012

Background: HGS-ETR2 is a fully-human high-affinity monoclonal antibody that is agonistic to the Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Receptor 2 (TRAIL-R2, DR5). TRAIL-R2 is expressed more widely on the surface of tumor cells than normal cells; binding of HGS-ETR2 to TRAIL-R2 leads to activation of the extrinsic apoptosis pathway. HGS-ETR2 shows anti-tumor activity at doses ≥ 0.3 mg/kg in xenograft models, both as a single agent and in combination with chemotherapeutic agents. Methods: This phase 1, dose-escalation study assessed the safety, tolerability, pharmacokinetics and immunogenicity of HGS-ETR2 administered IV every 14 days in patients with advanced solid tumors. Patients received HGS-ETR2 until disease progression or unacceptable toxicity. Tumor measurements were repeated every 2 months. Results: To date, 31 patients have received 167 courses of HGS-ETR2 over 5 dose levels: 0.1, 0.3, 1.0, 3.0 and 10.0 mg/kg q14 days. The majority (26 of 31) received at least 4 courses. One patient experienced a dose-limiting toxicity of grade 3 hyperamylasemia at the 10 mg/kg dose level. The event was determined to be possibly related to HGS-ETR2 and also possibly related to a nutritional supplement. Stable disease was achieved in 10 patients for 4 to 16 cycles. One patient with chemotherapy-refractive Hodgkin’s disease had a tumor regression of abdominal disease. HGS-ETR2 pharmacokinetics were linear up to 10 mg/kg. At the 10 mg/kg dose, the pharmacokinetics were characterized by a mean (SD) t1/2β of 11 (4) days, CL of 6.0 (0.7) mL/day, and V1 of 47 (8) mL/kg, slightly larger than the plasma volume. The 1.8-fold larger Vss of 85 (27) mL/kg indicates that HGS-ETR2 distributes outside the plasma compartment. Human anti-human antibody formation has not been detected. Conclusions: HGS-ETR2 can be safely administered every 14 days at doses up to and including 10 mg/kg. Further evaluation of HGS-ETR2 is planned, including studies of HGS-ETR2 in combination with chemotherapeutic agents.

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A phase I safety and pharmacokinetic (PK) study of recombinant Apo2L/TRAIL, an apoptosis-inducing protein in patients with advanced cancer
Authors: Herbst R. S. , Mendolson D. S. , Ebbinghaus S. , Gordon M. S. , O’Dwyer P. , Lieberman G. , Ing J. , Kurzrock R. , Novotny W. , Eckhardt G.
Published: March 2020

3013

Background: Recombinant human Apo2L/TRAIL (rhApo2L) is the only dual pro-apoptotic receptor agonist that directly activates both pro-apoptotic receptors (DR4 & DR5). RhApo2L selectively induces apoptosis (programmed cell death) in a variety of cancer cells, while sparing most normal cells in preclinical models. RhApo2L is being co-developed by Genentech and Amgen as a targeted therapy for solid tumors and hematologic malignancies. The present study was designed to assess the safety and PK of intravenous rhApo2L administered for the first time to humans, comparing safety in patients with liver metastasis to those without. Methods: RhApo2L was administered to patients with advanced solid tumors or NHL for 5 consecutive days every three weeks up to 8 cycles at dose levels of 0.5, 1.5, 4, 8, and 15 mg/kg. Patients without liver metastasis were treated before patients with liver metastasis in a staggered fashion. Results: Fifty-one adult patients have currently been enrolled and treated through 15 mg/kg. Of 36 patients with available data, the most common diagnoses were colorectal, melanoma, lung, and ovarian cancers. After 586 administered doses, there were no dose-limiting toxicities or clearly attributable toxicities. Thirty-two patients had at least one post-baseline tumor assessment with 17 (53%) having stable disease, and 13 (41%) with progression. One patient with a chondrosarcoma had a confirmed, objective partial response at 8 mg/kg. No anti-Apo2L antibodies have been detected. PK results will be presented separately. Conclusions: RhApo2L is safe and well tolerated up to 15 mg/kg. Enrollment is continuing at 8 mg/kg for expanded safety data and further dose optimization. Contribution to the standard treatment of advanced solid tumors and hematologic malignancies should be evaluated in randomized trials.

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Safety and antitumor activity of AMG 706 in patients (pts) with thyroid cancer (TC): A subset analysis from a phase 1 dose-finding study
Authors: Boughton D. , Rosen L. , Van Vugt A. , Kurzrock R. , Eschenberg M. , Wiezorek J. , Ingram M. , Wang D. , Stepan D. , Herbst R. S.
Published: March 2020

3030

Background: AMG 706 is an investigational, oral, small molecule multi-kinase inhibitor with both antiangiogenic and direct antitumor activity that selectively targets VEGF, PDGF, and Kit receptors. From a phase 1 study (Rosen ASCO 2005; Herbst EORTC 2005), encouraging antitumor activity was seen in pts with TC. In this analysis, we report on the TC subset from the study. Methods: Pts with refractory solid tumors received oral AMG 706 QD (50, 100, 125, 175 mg) or BID (25 mg) intermittently or continuously for 28-day cycles. Study objectives were to assess safety, establish the maximum tolerated dose (MTD), and generate pharmacokinetic profiles of AMG 706 in these pts. Tumor response (modified RECIST) was evaluated at wk 8 and Q12W thereafter. Data from Oct 2005 were analyzed. Results: In this study, 7 of 71 pts enrolled had TC. Baseline demographics for this subset were 4 W/3 M, median (range) age of 58 (41, 78) yrs, ECOG 1 (71%), and all had stage IV disease. Histologies were papillary (3: PTC), follicular (1; FTC), Hürthle cell (1), anaplastic (1), and medullary TC (1; MTC). All pts received prior external radiotherapy, radioiodine, chemotherapy, and/or surgery. Initial doses of AMG 706 were 125 mg and 175 QD and 25 mg BID. The MTD for the study was 125 mg QD. Median (range) time on treatment for the TC pts was 141 (14, 564) days. Treatment-related adverse events are summarized ( table ). Best objective responses were 3 pts with partial response (PR), 3 with stable disease (SD), and 1 with progressive disease. PR was seen in pts with MTC, PTC and FTC. Two pts with PR did not have confirmation of response (1 had a PR during the last assessment). The 3 pts with PR received AMG 706 for 338, 366, and 564 days; 2 pts are still receiving AMG 706. Time to response for these 3 pts were 210, 217, and 304 days. Conclusion: In patients with TC, AMG 706 appears to be relatively well tolerated and displays promising antitumor activity for some pts. Based on these favorable findings, a phase 2 study of AMG 706 for the treatment of advanced TC is ongoing.

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VEGFR2 blockade in patients with solid tumors: Mechanism of hypertension and effects on vascular function
Authors: Steeghs N. , Hovens M. M. , Rabelink A. J. , Op ’t Roodt J. , Matthys A. , Christensen O. , Gelderblom H.
Published: March 2020

3037

Background: Hypertension is the most common side effect in trials with inhibitors of vascular endothelial growth factor (VEGF) signaling, although the underlying pathophysiology is unclear. As the use of anti-VEGF therapy is increasing, hypertension and related serious adverse events are likely to become more important. Methods: To better understand this pathophysiology,blood pressure and vascular function parameters were assessed in this substudy of a phase I trial in patients with advanced solid tumours treated with BAY 57–9352, an oral VEGF receptor 2 (VEGFR2) inhibitor. Blood pressure, flow-mediated dilatation (FMD), nitroglycerin-mediated dilatation (NMD) and pulse-wave velocity (PWV) were measured at baseline and after 5 weeks of daily treatment in 10 patients. Patients were spread out over different cohorts, taking different dosages of study drug. Results: Mean systolic blood pressure increased from 129.0 mm Hg to 139.4 mm Hg after 5 weeks of treatment (difference 10.4 mm Hg; 95% confidence interval (CI) 5.0–15.7 mm Hg; p=0.002). Mean diastolic blood pressure increased from 80.9 to 87.4 mm Hg (difference 6.5 mm Hg; 95% CI 1.7–11.3; p=0.013). Endothelium-dependent vasodilatation (FMD) decreased from 5.6% to 3.0% (95% CI 1.1–3.9%; p=0.003). NMD, indicating endothelium-independent vasodilatation, also decreased from 12.9% to 7.7% (95% CI 2.7–7.6%; p=0.001). Arterial stiffness (PWV), increased from 9.4 m/s to 10.3 m/s (p=0.07). Conclusions: Inhibition of VEGFR2 significantly increases systolic and diastolic blood pressure. As VEGF enhances endothelial nitric oxide (NO) synthetase activity, the clear decrease in FMD could be explained by reduced bioavailability of NO. The decrease in NMD may be a direct effect of VEGFR2 inhibition on vascular smooth muscle cells. However, a more likely hypothesis for these profound vascular effects is a reduced number of microvessels (i.e. rarefaction). As the microcirculation is largely responsible for peripheral resistance, the rarefaction associated with VEGFR2 inhibition is likely to increase peripheral resistance and lead to hypertension.

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Phase I study of an anti-angiogenic agent with a novel mechanism of action E7820: Safety, pharmacokinetics (PK) and pharmacodynamic (PD) studies in patients (pts) with solid tumors
Authors: Mita M. M. , Mita A. C. , Ricart A. , Rodon J. , Till E. , Okereke C. , Desai P. , Zang E. , Rowinsky E. K. , Takimoto C.
Published: March 2020

3048

Background: E7820 is a first-in-class oral antiangiogenic sulfonamide that inhibits alpha-2 integrin expression, endothelial cell proliferation and is active against human breast and pancreatic cancer xenografts. Methods: The objectives of the study were to evaluate the safety, tolerability, to determine the maximum tolerated dose (MTD) to characterize the PK behavior, to assess PD markers and to explore the antitumor activity. Results: Thirty pts (18 male/12 female; age range 40–83) received E7820 at doses ranging from 10 to 200 mg daily continuously, in a 28 day cycle. A total of 93 cycles were administered (range 1–15); 4 pts underwent intrapatient dose escalation. Dose-limiting toxicities (DLT) at 100 mg/day included grade (gr) 3 elevated liver enzymes and gr 3 hemoptysis. At the 200 mg dose level, 2 pts experienced hematological toxicity, including gr 4 thrombocytopenia and neutropenia. One of these patients with cervical cancer and a vaginal fistula had gr 4 thrombocytopenia, neutropenia and gr 3 anemia with a fatal bleed from her pelvic tumor. Other gr 3/4 adverse events included: nausea, vomiting, fatigue, hypoxia, chest pain, abdominal pain, ileus, anemia, neutropenia, hypoalbuminemia, elevated transaminases and alkaline phosphatases. Disease stabilization beyond cycle 4 was observed in 6 pts, with 3 lasting for 6+ months. Tmax ranged from 1.3–5.3 hr and the t1/2 is 5.7 to 11.9 hr. Cmax and AUC increased dose proportionaly up to 70 mg, however accumulation was seen at 200 mg. At higher doses (70–200 mg) plasma concentrations exceed levels active in preclinical models in vivo. Preliminary analysis of alpha-2 integrin expression showed marked (∼50%) and sustained decreases beyond day 28 in 3 of 4 pts at 200 mg, while moderate (<30%) and less consistent decreases were observed in 2/3 and 3/6 pts at 70 mg and 100 mg dose levels, respectively. No changes in integrin levels were observed at E7820 doses < 40 mg. Conclusions: Up to 100 mg/day E7820 has a good safety profile in pts with solid malignancies. MTD was established at 100 mg/day. Patient treatment and PD analyses are ongoing.

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Myocardial HER2 expression with 111In-DTPA-trastuzmab scan in patients shortly after anthracycline treatment
Authors: Perik P. J. , Lub-De Hooge M. N. , Jager P. L. , De Korte M. A. , Gietema J. A. , Van der Graaf W. T. , Van Veldhuisen D. J. , Sleijfer D. T. , De Vries E. G.
Published: March 2020

3057

Background: The monoclonal antibody trastuzumab, apart from antitumor effect, can induce cardiotoxicity, particularly when combined with anthracyclines. Myocardial HER2 upregulation may serve, transiently, as a compensatory mechanism induced by cardiac stress. Previously we showed in a xenograft model that 111In-DTPA-trastuzumab scintigraphy can detect HER2 positive lesions (Br J Pharmacol 2004;143:99–106) but that myocardial 111In-DTPA-trastuzumab uptake was found in only 1 of 17 anthracycline-pretreated HER2-positive metastatic breast cancer patients (ESMO 2004#50). This low number may be related to the long interval between anthracycline administration (median 11 months) and performed scan in these patients. To evaluate whether myocardial HER2 expression is induced by anthracyclines, we performed 111In-DTPA-trastuzumab scans in patients shortly after anthracycline treatment. Methods: Patients who completed 4–6 cycles of anthracycline-based chemotherapy (< 3 weeks after last dose) underwent gammacamera imaging 48 and 96 h after iv administration of 150 MBq 111In-DTPA-trastuzumab (5mg). Results: 10 anthracycline-treated patients, 8 as adjuvant breast cancer treatment and 2 for metastatic sarcoma have been enrolled. Myocardial 111In-DTPA-trastuzumab uptake was observed in 5/10 anthracycline-treated patients who all were without symptomatic cardiac dysfunction. Conclusions: Shortly after completion of anthracycline treatment myocardial HER2 overexpression was detectable in 50% of the patients. This may be a transient phenomenon. 111In-DTPA-trastuzumab scan after anthracycline treatment prior to adjuvant trastuzumab may identify patients more susceptible for trastuzumab-induced cardiotoxicity. This important observation may add to optimal timing of trastuzumab therapy i.e. when HER2/neu expression in the heart is negative (again).

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