bluuebunny/crossref_metadata_2025 huggingface dataset:
Predictive computer simulations of tumor drug response demonstrate that 3-D hypoxic gradients significantly increase drug resistance
Authors: Cristini V. , Frieboes H. , Fruehauf J.
Published: March 2020

2071

Background: We created a three-dimensional physiologically based computer (in-silico) model of cancer based on a description of biological events at the cellular scale with input variables determined from patient specific information, such as in-vitro drug response experiments and in-vivo tumor imaging, with the long term goal of individualized treatment selection. The central hypothesis is that such a model that incorporates basic tumor growth kinetics information is capable of representing and predicting tumor response to chemotherapy. Methods: We measured in-vitro tumor growth and drug response for Doxorubicin sensitive and resistant MCF-7 breast cancer cells through trypan blue exclusion counts, tridiated thymidine incorporation, and the XTT assay. We used these results of parameter-based statistics to define input variables to our in-silico model of cancer, and ran computer simulations to measure the drug response predicted by the model. Results: The computer model could accurately predict the in-vitro response of drug sensitive and resistant MCF-7 breast cancer cells. The model also predicted that gradients of oxygen and nutrient in a tumor microenvironment, whether naturally occurring or induced by treatment, and which in previous work we found could increase the invasive capability of tumor cells and destabilize tumor morphology, could also contribute to acquired drug resistance by increasing the population of quiescent cells. Conclusions: We demonstrated that a rigorously, experimentally calibrated computer model of cancer is accurately predictive of in-vitro tumor response to chemotherapeutic drugs, and established that this model offers a means to quantitatively study tumor drug response. We did this through a grounds-up physical representation of tumor biology, not by fitting to experimental data. This validation begins the path to computational modeling and more efficient prediction of in-vivo tumor response to chemotherapy.

No significant financial relationships to disclose.
Stromal cells extracted from ovarian cancer express functional multi drugs resistance proteins: ATP bindig casset and Major vault protein
Authors: Rafii A. , Mirshahi P. , Simon A. , Faussat A. , Ducros E. , Marie J. , Pujade-Lauraone E. , Soria J. , Mirshahi M.
Published: March 2020

2072

Background: Stromal cells play a central role for the growth of tumor cells. The functional contribution of these cells in cancer therapy is poorly understood. Here we studied the presenceofthe proteins ABC (ATP binding Cassette) and MVP (Major vault protein) implicated in the multi drugs resistance (MDR) phenomena in stromal cells isolated from ascitis of patients with ovarian carcinoma. Methods: Stromal cells were extracted from ascitis of patients with ovarian carcinoma. The expression of MDR proteins as p-gp (Permeability-glycoprotein), BCRP (breast cancer resistance protein) and MRPs (multidrug related proteins) as well as LRP (lung resistance protein that is a MVP) was studied by two different technique (immunocytochemistry and flow cytometry) using specific antibodies against these proteins. The functionality of the pumps or efflux, was studied by incorporation of fluorescent probes, Rhodamine 123 and JC1, substrate for p-gp, calcéine-AM substrate for p-gp and MRPs and at last Mitoxantrone substratum of BCRP, in the presence of specific inhibitors: as the cyclosporine HAS, the GG918 and the MK571 for the pumps Pgp, BCRP and MRPs respectively. Then the expression of the genes was assessed by RT-PCR. Results: 1) The expression of the proteins ABC is confirmed by immunocytochemistry and by flow cytometry. The Pgp and LRP proteins were strongly expressed and they are functional, the MRP-1, 2, 3 and BCRP proteins are weakly expressed and the MRP-5 protein is not detected. 2) The RNAm corresponding to all of these proteins is found by RT-PCR in the stromal cells. Conclusions: All of these results suggest that the MDR proteins are present on the cells surface of the tumour cell microenvironnement. The functionality of these proteins allows supposing their implication in the phenomena of multi drugs resistance to chemotherapy. The interaction between cancer cells and stromal cells should be targeted during specific chemotherapy.

No significant financial relationships to disclose.
Phase I dose-escalation study of novel oral multi-target tumor growth inhibitor (MTGI) ZK 304709 administered daily for 7 days of a 21-day cycle to patients with advanced solid tumors
Authors: Graham J. , Wagner K. , Plummer R. , Wiedenmann B. , Cassidy J. , Kowal K. , McCoy C. , Calvert H.
Published: March 2020

2073

Background: ZK304709 is a novel MTGI that selectively inhibits activity of Cyclin Dependent Kinases (CDKs) 1, 2, 4, 7, 9, and the tyrosine kinase activity of VEGF-R 1, 2, 3 and PDGF-βR. Methods: Adult patients (pts) with a good performance status (WHO PS ≤2) and a histologically or cytologically confirmed relapsed/refractory solid tumor were eligible. ZK304709 is administered, as a monotherapy, orally on days 1–7 of a 21-day cycle to fasting patients at a starting dose of 15 mg qd. Dose escalation has ranged from 33% - 100% of prior dose, depending on occurrence of drug-related toxicity ≥ grade (gr) 2 (CTC v2.0). Between 3 and 7 patients are to be enrolled per dose level, depending on DLTs that are observed. The primary objective is determination of the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of ZK304709. Secondary objectives include tolerability, pharmacokinetic (PK) profile, and preliminary efficacy. Results: Interim results are available for 22 pts (15 M/7 F, median age 60.5 yrs; range 37–71) treated with ZK304709 at 6 dose levels (15 - 180 mg qd). Patients completed a median of 2 cycles (range 0–8). Common AEs were nausea, vomiting, diarrhea, and lethargy. Two DLT were observed: supraventricular tachycardia and vomiting, but the MTD was not reached. The PK profile shows rapid absorption, with a Tmax of 2–4 hrs, and a dose-dependent increase in systemic exposure over the 15–90 mg dose range. Disease stabilization for ≥4 cycles has been observed. Conclusions: ZK304709 is rapidly absorbed and has been tolerated on this schedule at doses up to 180 mg qd. The MTD has not been reached, and enrolment is ongoing. These preliminary data demonstrate that oral delivery on this schedule of an agent that inhibits both cell cycle and angiogenesis is feasible.

[Table: see text]
Randomized, double-blind, vector-controlled study of targeted immunotherapy in patients (pts) with hormone-refractory prostate cancer (HRPC)
Authors: Kantoff P. W. , Glode L. M. , Tannenbaum S. I. , Bilhartz D. L. , Pittman W. G. , Schuetz T. J.
Published: March 2020

2501

Background: Therapeutic vaccines for prostate cancer have yielded encouraging data in uncontrolled Phase 1 and 2 studies. PROSTVAC-VF comprises 2 recombinant viral vectors each containing genes encoding the prostate-specific antigen (PSA) gene modified to optimize antigen presentation in HLA-A2+ pts and 3 T-cell costimulatory molecules (B7.1, LFA3, and ICAM-1 [TRICOM]). These vectors are administered in a heterologous prime-boost regimen with concurrent low-dose GM-CSF to enhance recruitment of antigen-presenting cells to the immunization site. Here we report results of a Phase 2 study in pts with metastatic HRPC. Methods: In this randomized, double-blind, controlled study, pts were randomized 2:1 to receive either PROSTVAC-VF plus GM-CSF or Control (empty vectors plus GM-CSF placebo) for 24 weeks. Eligible pts had rising PSA despite castrate testosterone levels and measurable, asymptomatic or non-narcotic-dependent metastases (positive bone scan or lymph node metastases on abdominal-pelvic CT scan). The primary endpoint is progression-free survival (PFS), with progression defined as appearance of new lesions on bone scan or RECIST-defined progression of nodal metastases. The planned sample size was 120 pts. The study was designed to detect a difference of 38% vs 12% PFS at Week 24 with a 2-sided α of 0.05 and 80% power. An independent Data Monitoring Committee evaluated safety data quarterly. Results: 125 pts were enrolled. Demographics are available for 122 pts (mean age, 73.3 years [range, 52–94]; ∼11% African American). Common adverse events (AEs) in 106 evaluable pts (blinded as of Jan 2006) included immunization site reactions (73%), fatigue (26%), fever (14%), and nausea (13%). The majority were of Grade 1/2 severity. Serious AEs attributed to immunization included 1 thrombotic thrombocytopenic purpura (TTP) event. Conclusions: A large, randomized, controlled study of therapeutic immunization with PROSTVAC-VF in 125 pts with metastatic HRPC has been completed. The therapy is well tolerated and findings are consistent with Phase 1 results, but also included a single case of TTP. Full efficacy data collection is ongoing.

[Table: see text]
A phase II study of the efficacy and toxicity of alemtuzumab for the therapy of human T cell lymphotrophic virus-1 (HTLV-1)-associated adult T-cell leukemia/lymphoma (ATL)
Authors: Sharma K. , Janik J. , O’Mahony D. , O’Hagan D. , Gao W. W. , Wharfe G. H. , Cranston B. E. , Waldmann T. A. , Morris J. C.
Published: March 2020

2535

Background: HTLV-1-associated ATL is an aggressive lymphoproliferative disorder with limited effective therapy. Alemtuzumab is a humanized monoclonal antibody directed against CD52. High levels of CD52 are expressed on the surface of ATL cells. Preclinical studies in the MET-1 mouse model of ATL showed alemtuzumab to be highly active. Methods: A single institution open-label phase II study examining the response and toxicity of alemtuzumab in patients with ATL. Eligibility criteria: HTLV-1-associated ATL (chronic, acute and lymphoma type), ≥10% CD52+ malignant cells, measurable disease, age ≥18 years, AGC ≥1000/μL, platelets ≥50,000/μL, adequate physiologic status and informed consent. Results: Ten (10) patients, 6 with leukemia, 4 with lymphoma, 8 Afro-Caribbean, 1 African-American and 1 Japanese, 7 women, 3 men, median age 49 years (range, 36–62), all having received previous treatments including CHOP (7), other monoclonal antibodies (5), radioimmunotherapy (2), and radiation (1), median WBC 48,500/μL (leukemia Pts.) received alemtuzumab standard induction followed by 30 mg 3 times weekly for a minimum of 4 weeks and maximum of 12 weeks. All patients experienced infusion reactions (grade, 1–3) including hypotension, fever, rigors, chills, pruritus and urticaria; however, no patient required discontinuation of treatment. All patients developed grade 4 lymphopenia, and transient cytomegalovirus (CMV) antigenemia. Four (4) patients with leukemia responded (1 CR, 3 PR). No patient with lymphoma responded. Conclusions: Alemtuzumab has antitumor activity in HTLV-1-associated adult T cell leukemia and is well tolerated. Lymphomatous ATL appears unresponsive to alemtuzumab. The reason for this is unknown; however, antibody levels achieved in lymph nodes may be suboptimal. Accrual continues.

No significant financial relationships to disclose.
An anti-CD40 activating antibody induces dendritic cell maturation and promotes autologous anti-tumor T cell responses in an in vitro mixed autologous tumor cell/lymph node cell model
Authors: Hunter T. B. , Gladue R. P. , Antonia S. J.
Published: March 2020

2537

Background: CD40-mediated interactions play an important role in the response to a variety of diseases, including cancer. Engagement of CD40 on antigen-presenting cells (APC) by CD40L leads to maturation and upregulation of co-stimulatory molecules, B7.1 and B7.2 (CD80 and CD86), which are requisite in the activation of T cells. Clinical trials involving immunologic interventions have shown clinical responses confirming that the immune system can be harnessed for the treatment of cancer. However, the clinical response rate has been low, signifying the need for new immunotherapeutic strategies. To this end, an agonist antibody specific for CD40 has been developed and is being evaluated as a potential anti-cancer agent. Methods: The activation capacity of anti-CD40 antibody CP-870,893 was analyzed by performing flow cytometric analysis of APC maturation markers following incubation of monocyte derived dendritic cells (DC) with the antibody. IL-12 and macrophage inflammatory protein-1α (Mip1 α) secretion were also analyzed. The effect of the antibody on anti-tumor T cell responses was tested in an autologous human model consisting of tumor cells as stimulator cells and tumor-draining lymph node cells as responders from a series of cancer patients. Results: Cultured DC treated with CP-870,893 consistently display a mature phenotype: robust upregulation of CD80, CD83, CD86 and HLA-DR expression, increased Mip1 α secretion, and the loss of antigen presenting capability. IL-12 secretion was not detected. CP-870,893 also promotes the responsiveness of lymph node derived T cells to autologous tumor, indicated by IFNγ and IL-2 ELISpot. Conclusions: These data demonstrate that CP-870,893 binds to and activates DC. A fully autologous mixed lymph node cell/tumor cell model was used to demonstrate that this activation promotes tumor-specific T cell responses. T cells from the tumor draining lymph node are not responsive to autologous tumor cells, however in the presence of CP-870,893 this unresponsiveness is reversed. These data indicate that CP-870,893 warrants further study as an immunotherapeutic agent in the treatment of cancer.

No significant financial relationships to disclose.
Efficacy of intraperitoneal treatment with the trifunctional antibody catumaxomab in patients with GI-tract cancer and peritoneal carcinomatosis: A matched-pair analysis
Authors: Stroehlein M. A. , Gruetzner K. U. , Tarabichi A. , Jauch K. W. , Bartelheim K. , Lindhofer H. , Von Roemeling R. , Heiss M. M.
Published: March 2020

2544

Background: Peritoneal carcinomatosis (PC) due to GI-tract cancer is an advanced tumor stage with poor survival. At present, no standard therapy has been recommended, as chemotherapy and surgery showed only limited efficacy in affected patients. When applied intraperitoneally (i.p.), the trifunctional antibody catumaxomab could be shown to destroy intraperitoneal tumor cells in patients with malignant ascites due to ovarian cancer. While binding simultaneously to EpCAM (on tumor cells), CD3 (T cells) and, via the Fc region, to Fc gamma receptor 1 and 3 on accessory cells, it induces a complex immunoreaction against epithelial tumor cells. The aim of this study was to investigate clinical efficacy of i.p. catumaxomab therapy in patients with PC compared to a matched control group. Methods: Between 2003 and 2005, 22 patients with PC due to cancer of colon (n=10), stomach (8), pancreas (3) and CUP (1) received treatment with catumaxomab within a phase I study. Treatment consisted of 3 to 4 i.p. applications (10–200 μg) of escalating catumaxomab doses. The survival was compared with patients receiving conventional therapies in a matched-pair analysis regarding sex, age, tumor surgery, chemotherapy, and extent of PC. Patients with existing ileus and clinically significant ascites were not included. Results: Follow up of patients receiving catumaxomab showed a median survival of 12.2 months (range 2–34) after first diagnosis of peritoneal carcinomatosis vs. 9.7 months (range 1–40) in patients with conventional treatment (p=0.005; log-rank). These data will be updated at presentation. Conclusion: Intraperitoneal treatment with the trifunctional antibody catumaxomab may be an attractive option for treatment of patients with peritoneal carcinomatosis due to GI-tract cancer. The convincing results have to be further investigated in clinical phase II/III trials.

[Table: see text]
Lovastatin enhances the antiproliferative effect of trastuzumab in HER2 over expressing breast cancer cells
Authors: Halaweh O. M. , Lobocki C. , Dumasia L. , Drelichman A.
Published: March 2020

2546

Background: Trastuzumab, a recombinant humanized anti-HER2 monoclonal antibody, has been found to have potent antiproliferative effects in HER2 overexpressing human breast tumors. Lovastatin, an HMG-CoA reductase inhibitor suppresses growth, and induces apoptosis in breast cancer cells. Both agents induce a G0/G1 arrest of cell cycle progression. The purpose of this study was to evaluate the antiproliferative effect of the novel combination of lovastatin and trastuzumab in human breast cancer cell lines. Methods: Increasing doses of lovastatin (0.16-40 μM) and trastuzumab (0.039-1 μg/ml) were tested alone and in combination. Three breast carcinoma cell lines were studied: two HER2 overexpressing lines (BT474 and SKBR3) and one cell line that expresses low levels of the receptor (MCF7). Inhibition of growth was assessed after 7 days of treatment by the MTT colorimetric assay, while apoptosis was detected using an in situ DNA Fragmentation Detection kit. Results: A dose-dependent growth inhibition was demonstrated in all three cell lines tested with lovastatin, while trastuzumab was only effective in the HER2 overexpressing cells. Trastuzumab (0.06 μg/ml) inhibited cell growth by 29.3% and 40.1%, while lovastatin (2.5 μM) caused an inhibition of 19.1% and 43% in the BT474 and SKBR3 cell lines, respectively. The combination of trastuzumab and lovastatin, at these doses, significantly inhibited growth in BT474 and SKBR3 cells by 45.4% and 68.9% (P < 0.001, oneway ANOVA) compared to either agent alone. Conclusions: Lovastatin plus trastuzumab treatment led to increased growth inhibition in HER2 positive breast cancer cell lines. Further studies in an animal model are warranted. This combination may also have important clinical therapeutic implications.

No significant financial relationships to disclose.
Saccharomyces cerevisiae as delivery vehicle for a NY-ESO-1 protein vaccine
Authors: Renner C. , Held G. , Neumann F. , Kleber S. , Thiel M. , Karbach J. , Jäger E. , Strahl S. , Wadle A.
Published: March 2020

2578

Background: Vaccine strategies that target or activate dendritic cells in order to elicit potent cellular immunity are currently the subject of intense research. Here we report that genetically engineered yeast expressing the full-length tumor associated antigen NY-ESO-1 are a versatile host for protein production eliciting MHC class I and II T-cell responses. Methods: The pYD1 yeast display vector was chosen for full length NY-Eso-1 protein (pNY-ESO-1) expression. NY-ESO-1 and SSX-2 (as control) protein were affinity purified on. IFN-g ELISPOT assays were performed in triplicates on nitrocellulose-lined 96-well plates. MHC class I cross-presentation of peptide epitopes was demonstrated by blocking T-cell responses against DCs. For this purpose, antigen or peptide pulsed DCs were labeled with different doses (100, 10, 1 μg/ml) of antibodies specific for HLA-A2/peptide complexes (HLA-A2/ NY-Eso-1157–165; 3M4E5) or an irrelevant antibody (specific for HLA-A2/IMP58–66) as control. Results: Highest level of NY-ESO-1 expression was detected on the cell wall of wt EBY100 strain with lower expression levels on PMT deficient strains PMT-2 and PMT-4. After protein feeding of immature DCs, NY-ESO-1 157–165 peptide cross-presentation was detected by 3M4E5 and an antigen-specific CD8+ T cell clone. There was a strong positive correlation between the amount of Aga2p-NY-ESO-1 protein (0–15μg/ml) and peptide presentation. Specific T-cell recognition of NY-Eso-1 157–165/HLA-A2 complexes was validated by blocking experiments with Fab 3M4E5. Pre-incubation of protein fed DCs with the antibody at different concentrations (0–100 μg/ml) resulted in a significant reduction (p< 0.05) of spot numbers. Efficient presentation and T-cell recognition of epitope 157–165 was only adequately detectable when protein produced by EBY100 wt yeast strain was used (p < 0.05). MHC class II presentation was studied in an autologous setting using a T-cell line recognising the NY-ESO-1 157–170 in HLA-DP4 context revealing that NY-ESO-1 protein produced in yeast was efficiently taken up and presented. Conclusions: Together, these data add further evidence that yeast expressing recombinant proteins can be used for vaccine purposes and that antigen uptake in APC depends on glycoslation of yeast expressed antigens.

No significant financial relationships to disclose.
Molecular correlates associated with a phase II study of temsirolimus (CCI-779) in patients with metastatic or recurrent endometrial cancer—NCIC IND 160
Authors: Oza A. M. , Elit L. , Biagi J. , Chapman W. , Tsao M. , Hedley D. , Hansen C. , Dancey J. , Eisenhauer E.
Published: March 2020

3003

Background: PTEN is a tumor suppressor gene and mutations in PTEN causing loss of protein expression/function may play a significant role in the pathogenesis of EC. Loss of PTEN protein expression has been reported in 26–80% of EC and leads to deregulated PI3K/Akt/mTOR signalling which may give neoplastic cells a survival advantage by enhancing angiogenesis, protein translation and cell cycle progression. Inhibition of mTOR, a protein kinase downstream of the PI3K/Akt pathway and target of rapamycins, inhibits proliferation of EC cell lines and formation of EC in PTEN−/+ heterozygous mice. We have evaluated temsirolimus (T) an ester derivative of rapamycin that inhibits mTOR given the frequent loss of PTEN in human EC. Methods: A two stage, phase II study has been conducted to evaluate single agent activity of T in women with recurrent or metastatic EC (chemotherapy naïve, upto 1 prior line of hormonal therapy). Treatment was 25mg i.v. weekly. One cycle is defined as 4 weeks of therapy. Thirty one patients (pts) have been registered; 23 are evaluable for toxicity and 19 for response. Results: Preliminary results have demonstrated encouraging activity and the trial fulfilled predefined criteria for activity. Of 19 pts evaluable for response, 5 have had a confirmed partial response (PR) (26%) and 12 have stable disease (SD) as best response (63%). Two pts had progressive disease (PD) (11%). PTEN, phosphorylated (p) mTOR and p-S6 protein (immunohistochemistry) results are available on 9 pts to date. The preliminary results indicate that responses and stable disease are seen in pts irrespective of PTEN status. Loss of p-mTOR was evident in tumor cells from all pts (range 75–99% loss) and did not correlate with response. Phosphorylated S6 was low in tumor cells in the one pt who had PD (5%), and levels were higher in pts with PR and SD (mean and median 30%). Conclusions: We conclude that Temsirolimus has encouraging single agent activity for in recurrent and metastatic EC, and the findings indicate this is irrespective of PTEN status. We are currently evaluating activity of T in pts previously treated with chemotherapy and molecular correlates in additional specimens.

No significant financial relationships to disclose.
A phase I clinical and pharmacokinetic (PK) trial of the aurora kinase (AK) inhibitor MK-0457 in cancer patients
Authors: Rubin E. H. , Shapiro G. I. , Stein M. N. , Watson P. , Bergstrom D. , Xiao A. , Clark J. B. , Freedman S. J. , Eder J. P.
Published: March 2020

3009

Background: The AKs are essential for mitotic progression, spindle formation, centrosome maturation, chromosomal segregation, and cytokinesis. Elevated expression occurs frequently in tumors. MK-0457 (VX-680) is a potent AK inhibitor, with Ki values of 0.66, 18 and 4.6 nM for AKs A, B and C, respectively. MK-0457 inhibits proliferation of transformed cells in vitro (IC50’s 15–113 nM), and induces colon and pancreatic cancer xenograft regressions. Methods: After IRB approval, consenting patients (pts) with refractory solid tumors (median 3 prior regimens, range 2–6) and adequate hematologic and organ function were enrolled using an accelerated dose escalation scheme with 1–2 pts/dose level until ≥ grade 2 toxicity, followed by 3–6 pts/level. MK-0457 was administered by continuous 5-day intravenous infusion every 28 days. Dose-limiting toxicity (DLT) was grade 3 non-hematologic or grade 4 hematologic toxicity ≥ 5 days, or grade 4 febrile neutropenia (FN) during cycle 1. PKs were collected pre-dose through 168 h and analyzed for MK-0457 and metabolites by HPLC/mass spec. Steady state volume of distribution (Vdss), clearance (CL), maximal concentration (Cmax) and terminal half-life (t1/2) were determined by WinNonLin. Results: 16 pts received MK-0457 dosed at 0.5, 1, 2, 4, 8, and 12 mg/m2/h. Median number of cycles was 2 (range 1–6). DLT was asymptomatic neutropenia ≥ 5 days at 12 mg/m2/h. At 8 mg/m2/h, 1 pt experienced FN in cycle 2; a second developed a grade 2 allergic reaction. Three pts achieved stable disease as best response, and two of them completed 6 cycles. Plasma concentrations reached steady state rapidly (i.e., within 24 h) and declined biexponentially after the end of infusion; after a rapid initial decay, a slower decaying terminal phase demonstrated a t1/2 ∼15 h. PK parameters include Vdss = 237 ± 107 (SD) L/m2 and CL = 517 ± 141 ml/min/m2. At 8 mg/m2/h, Cmax was ∼650 nM. Conclusion: MK-0457 is generally well tolerated and achieves plasma levels similar to those causing regressions in xenografts. CL is high and exposures achieved are roughly dose proportional. Because 8 mg/m2/h was well tolerated in heavily pre-treated pts, escalation to 10 mg/m2/h is underway. Baseline tumor samples will be assessed for predictive biomarkers at the recommended phase II dose.

[Table: see text]
Phase I evaluation of AZD2171, a highly potent, selective VEGFR signaling inhibitor, in combination with gefitinib, in patients with advanced tumors
Authors: Van Cruijsen H. , Voest E. E. , Van Herpen C. M. , Hoekman K. , Witteveen P. O. , Tjin-A-ton M. L. , Punt C. J. , Puchalski T. , Milenkova T. , Giaccone G.
Published: March 2020

3017

Background: AZD2171 is an oral, highly potent, vascular endothelial growth factor (VEGF) signaling inhibitor. This Phase I trial is evaluating the safety, tolerability, pharmacokinetics (PK) and efficacy of AZD2171, in combination with gefitinib (IRESSA), an inhibitor of EGF receptor tyrosine kinase. Methods: Patients with advanced solid tumors refractory to standard therapies received once-daily, oral AZD2171 (20, 25, 30 or 45 mg) and gefitinib 250 (Part A1) or 500 mg (Part B1) until dose-limiting toxicity was observed. The potential PK interaction of AZD2171 30 mg with gefitinib 250 mg was studied in an expanded cohort (Part A2). Part B2 follows the design of Part A2, with a gefitinib dose of 500 mg. Results: As of September 1, 2005, 70 patients (22–78 years) have received treatment ( Table ). Overall, the most frequently reported adverse events (AEs) were diarrhea, anorexia, fatigue and hypertension (91%, 64%, 51% and 51% of patients; respectively), with evidence of an AZD2171-related dose response for hypertension (reported in 36%, 75%, 47% and 75% of patients at AZD2171 20, 25, 30 and 45 mg; respectively). These were also the most commonly reported CTC grade ≥3 AEs, occurring in <13% of patients, in addition to increases in alanine aminotransferase (7%) and aspartate aminotransferase (4%). The steady-state PK parameters for AZD2171 (30 mg) and gefitinib (250 mg) are comparable with those seen previously with either agent alone. In total, 28 patients had a best RECIST response of stable disease (22 patients were non-evaluable). A patient with mesothelioma (45 mg AZD2171, Part A1) and a patient with renal cancer (20 mg AZD2171, Part B1) had confirmed partial responses. The second patient underwent surgery and is currently disease-free. Conclusions: No unexpected toxicities are associated with AZD2171 (20–45 mg) in combination with gefitinib (250 or 500 mg) and the preliminary response data are encouraging.

[Table: see text]

[Table: see text]
HKI-272, an irreversible pan erbB receptor tyrosine kinase inhibitor: Preliminary phase 1 results in patients with solid tumors
Authors: Wong K. K. , Fracasso P. M. , Bukowski R. M. , Munster P. N. , Lynch T. , Abbas R. , Quinn S. E. , Zacharchuk C. , Burris H.
Published: March 2020

3018

Background: HKI-272 is a potent, low molecular weight, orally active, irreversible pan erbB receptor tyrosine kinase inhibitor. It inhibits the growth of tumor cells that express erbB-1 (epidermal growth factor receptor, EGFR) and erbB-2 (HER-2) in culture and xenografts. HKI-272 also inhibits the growth of cultured cells that contain sensitizing and resistance-associated EGFR mutations (Kwak et al, Proc Natl Acad Sci USA 102:7665–70, 2005). We are conducting a phase 1 study in patients (pts) with advanced-stage tumors that express EGFR or HER-2 to assess HKI-272 for tolerability, safety, pharmacokinetics, and preliminary antitumor activity. Methods: Pts (3–6/cohort) received 40, 80, 120, 180, 240, 320, or 400 mg HKI-272 orally once on day 1 and then once daily beginning on day 8. Timed blood samples were collected on days 1 and 21 for pharmacokinetic analysis. Results: Enrollment of 73 pts is complete. Preliminary data for 51 pts as of 28 Nov 2005 are presented. Patients were a median 60 years and 26% men. The most frequently occurring tumor types at primary diagnosis were breast (23 pts), non-small cell lung (9), and colorectal, ovarian, and renal (3 pts each). Dose escalation ended when 2 pts who received 400 mg HKI-272/day had drug-related dose-limiting toxicity of grade 3 diarrhea. Thus, the maximum tolerated dose (MTD) was 320 mg HKI-272/day. HKI-272-related adverse events (AEs), any grade, that occurred in ≥10% of pts were diarrhea (84%), nausea (55%), asthenia (45%), anorexia (31%), vomiting (29%), chills (12%), and rash (10%). Grade 3 related AEs that occurred in >1 pt were diarrhea (11) and asthenia (4). HKI-272 Cmax and AUC increased in a dose-dependent manner. At steady state at the MTD, mean values were Cmax: 112±58 ng/mL, AUC: 1618±930 ng.h/mL, t1/2: 15±2.5 h. Day 1 and 21 AUC values were comparable. Tumor assessments (modified RECIST criteria) were made at baseline and at the end of alternate cycles (28 days/cycle). Two breast cancer pts had confirmed partial responses (PRs) and 2 had unconfirmed PRs. Conclusions: When HKI-272 was administered on a continuous, once-daily, oral treatment schedule, the MTD was 320 mg/day, with diarrhea as the most frequently occurring related AE. HKI-272 has antitumor activity in HER-2-positive breast cancer.

[Table: see text]
Phase I pharmacokinetic (PK) and pharmacodynamic (PD) evaluation of a small molecule inhibitor of Poly ADP-Ribose Polymerase (PARP), KU-0059436 (Ku) in patients (p) with advanced tumours
Authors: Fong P. C. , Spicer J. , Reade S. , Reid A. , Vidal L. , Schellens J. H. , Tutt A. , Harris P. A. , Kaye S. , De Bono J. S.
Published: March 2020

3022

Background: PARP is a DNA strand break and base damage repair enzyme. Ku inhibits PARP-1 and 2 with a mean IC50 of 2nM. Inhibition of PARP leads to defective DNA repair and induces selective cytotoxicity in cells with defective homologous recombination repair through, for example, loss of BRCA 1/2 function (Farmer et al, Nature 2005 Apr 14;434(7035):917–21). This is a first in man Phase I trial of Ku. PD studies included functional evaluation of PARP-1 activity in surrogate and tumor tissue. Methods: Ku was administered once a day for 14 of every 21 days to p with advanced solid tumors refractory to standard treatment. Cohorts of 3–6 p were treated, with a starting dose of 10 mg/day. The dose was doubled in the absence of drug related grade 2 CTC-AE toxicity. Drug related toxicity in cancer patients known to carry a BRCA mutation is being compared to toxicity in other patients. Results: To date 12 p (6 male; median age 55y, range 25–73) with solid tumours have received 25 courses (range 1–8), with 1 p being a known BRCA1 mutation carrier (dose level 40mg). Dose levels evaluated to date include 10, 20, 40, and 80mg per day. Minimal toxicity has been observed to date, with only intermittent grade 1 nausea being reported. PK data to date, up to 40mg per day, supports dose proportionality with a mean elimination half-life of 6.91 hours (Range: 5.3–9.5), a mean clearance of 4.1 L/h (Range: 1.3–9.4) and a mean volume of distribution of 39.8 L (Range: 16.3–86.9). PD studies indicate inhibition of PARP functional activity in peripheral blood mononuclear cells with increasing inhibition observed with increasing dose of Ku. Initial studies in tumor biopsies performed pre-treatment and on day 8 revealed PARP inhibition of >50% at 40 mg/day. A p with metastatic soft tissue sarcoma and progressing disease pretreatment achieved stable disease for 24 weeks. Conclusions: Dose escalation continues with more BRCA carriers planned. PARP inhibition in both surrogate and tumor tissue is achievable with minimal toxicity in cancer patients, and has not resulted in any short term toxicity in a BRCA mutation carrier.

[Table: see text]
Phase I, safety, pharmacokinetic and biomarker study of BAY 57–9352, an oral VEGFR-2 inhibitor, in a continuous schedule in patients with advanced solid tumors
Authors: Gelderblom H. , Verweij J. , Steeghs N. , Van Erkel A. , Van Doorn L. , Ouwerkerk J. , Rajagopalan P. , Matthys A. , Voliotis D. , Eskens F.
Published: March 2020

3040

Background: BAY 57–9352 is a potent competitive inhibitor of the VEGFR-2 (IC50: 6 nM), VEGFR-3 (IC50: 4 nM), PDGFR-β and c-KIT tyrosine kinases. BAY 57–9352 showed tumor efficacy in colon, breast, pancreatic and NSCLC models. Methods: Patients with advanced solid tumors received oral BAY 57–9352 on a continuous basis, in escalating doses. One cycle was defined as 21 days of treatment. Extensive PK and PD (dynamic contrast-enhanced MRI [DCE-MRI]) evaluations were performed. Plasma biomarkers (e.g. VEGF)were also evaluated. Results: Forty patients (median 54 yrs) were enrolled at seven dose levels from 20 mg solution once daily to1500 mg twice daily (bid; 150 mg tablets) for a total of 169 cycles (range 1–17). The most frequent drug-related adverse events were nausea, hypertension, headache, vomiting, hoarseness, rash, dry skin and anorexia. One patient treated at 600 mg bid had a dose-limiting toxicity defined by an increase from grade 2 to 3 hypertension, despite the addition of an ACE-inhibitor and Ca-antagonist on day 8 of cycle 2. Another patient at that same dose level and also on day 8 cycle 2, had grade 3 AST/ALT increase, however this was not assessed as dose-limiting. Both patients continued treatment after dose reductions. Treatment was well tolerated, even at the highest dose levels. One patient with a hemangio-endothelioma (600 mg bid) had a clinical response and one desmoid tumor patient (900 mg bid) had a 53% reduction in tumor volume. BAY 57–9352 AUC increased dose proportionally up to 900 mg bid. The target AUC, based on animal models (5 mg × h/L) was reached in all patients at 900 mg bid. Dose levels exceeding 900 mg bid had similar plasma VEGF biomarker levels. Conclusions: BAY 57–9352 was well tolerated in doses up to 1500 mg bid. Based on safety, PK, PD and biomarker assessments, the recommended dose level is 900 mg bid. A 300 mg tablet is being tested for patient convenience. Combination chemotherapy studies have been started.

[Table: see text]
A phase I dose-escalation and pharmacokinetic (PK) study of a novel spectrum selective kinase inhibitor, XL647, in patients with advanced solid malignancies (ASM)
Authors: Wakelee H. A. , Adjei A. A. , Halsey J. , Lensing J. L. , Dugay J. D. , Hanson L. J. , Reid J. M. , Piens J. R. , Sikic B. I.
Published: March 2020

3044

Background: XL647 is an orally bioavailable small molecule inhibitor of multiple receptor tyrosine kinases involved in tumor cell growth, angiogenesis, and metastasis, including EGFR (erbB1), erbB2, VEGFR2/KDR, and EphB4. Methods: Patients (pts) with ASM were enrolled in successive cohorts to receive XL647 orally as a single dose on day 1 with PK sampling, followed by 5 continuous daily doses starting on day 4 with additional PK sampling. Pts then continued to receive XL647 for 5 consecutive days, followed by a break, with cycles repeating every 14 days. Tumor imaging was conducted at baseline, after the first 3 or 4 cycles, and then after every 4 cycles. Pts were allowed to stay on-study in the absence of unacceptable toxicity until evidence of disease progression. Results: A total of 37 pts have been treated across 9 dose levels to date: 0.06, 0.12, 0.19, 0.28, 0.39, 0.78, 1.56, 3.12, 4.68, and 7.0 mg/kg. One pt at 3.12 mg/kg had a dose limiting toxicity (DLT) of asymptomatic QTc prolongation on electrocardiogram, resulting in expansion of that cohort. The first two pts who received 7.0 mg/kg experienced DLTs of grade 3 diarrhea, requiring dose reduction. Both pts from the 7.0 mg/kg cohort tolerated 4.68 mg/kg well. Expansion of the 4.68 mg/kg cohort to 6 pts occurred without further DLTs and this is considered the maximum tolerated dose (MTD). One serious adverse event, grade 4 pulmonary embolism, was considered possibly related to study treatment in a pt dosed at 0.28 mg/kg. PK analysis indicates that XL647 shows approximately dose-proportional exposure, a mean time to maximal concentration (tmax) of 6–9 hours and an elimination half-life of 50–70 hours. To date, 1 pt (non-small cell lung cancer [NSCLC]) from cohort 1 had a partial response and 7 others (NSCLC [2], chordoma [2], adenoid cystic carcinoma, adrenocortical carcinoma, colorectal) have had prolonged stable disease (>3 months). Conclusions: XL647 has been well tolerated. An MTD of 4.68 mg/kg oral dosing for 5 consecutive days every 14 days has been established. Exploration of additional dosing schedules is ongoing, including continuous daily dosing.

[Table: see text]
Response to neoadjuvant chemotherapy as measured by PET predicts outcome after liver resection for colorectal metastases
Authors: Akhurst T. J. , Gonen M. , Tuorto S. , Schwartz L. , Brody L. , Larson S. M. , Fong Y.
Published: March 2020

3056

Background: Patients with hepatic colorectal metastases are often treated with neoadjuvant chemotherapy prior to liver resection. FDG PET is a standard imaging modality for such patients. We have shown the amount of FDG uptake in liver metastases is reduced by recent chemotherapy (chemo) administration and this is associated with a reduction in FDG uptake mediated by a reduction in hexokinase activity. We sought to determine if the amount of FDG uptake in the hepatic colorectal metastasis post chemo correlates with survival and to compare the prognostic significance of this single biologic scan to standard clinical predictors of outcome. Methods: A group of 149 patients enrolled in a prospective clinical trial examining the efficacy of FDG PET imaging in patients undergoing hepatic resection of colorectal cancer metastases to the liver formed the dataset. The maximal SUV within the liver was recorded for each patient, and the median of those maximums was determined across the patient group. Patients were then stratified by the median SUV, by the presence or absence of any chemo within 6 months of PET and by the clinical risk score (CRS) (a standard score for prognosis based on five clinical parameter (nodal status of primary, disease-free interval before liver metastases, size of largest liver tumor, number of tumors, and CEA). Multivariate analysis (MVA) and hazard ratios of death (HRD) were assessed. Results: The median of maximal SUVs was 7.9. In MVA in the patients without recent chemo, the CRS≥3 was an excellent predictor of survival (HRD=2.53; p=0.008), while SUV>8 was not (HRD=1.02; p=0.96). Conversely, in patients who had chemo within 6 months, SUV>8 (HRD 3.34; p=0.03) was a much superior predictor of outcome than CRS≥3 (HRD=1.25; p=0.57). Conclusions: In those patients without recent chemo CRS is the best predictor of survival confirming the utility of this scoring system, In those patients who had had chemo within 6 months of PET prior to surgery PET SUV was the best predictor of survival.

No significant financial relationships to disclose.
SNS-595 demonstrates clinical activity and dose-proportional pharmacokinetics (PK) in two phase I clinical studies
Authors: Hurwitz H. , Gordon M. , Advani R. , Ebbinghaus S. , Mendelson D. , Wakelee H. , Hoch U. , Silverman J. , Havrilla N. , Adelman D.
Published: March 2020

3062

Background: SNS-595 is a novel naphthyridine analog with broad and potent activity in preclinical models. Methods: SNS-595 was administered to patients (pts) with advanced solid cancers as an IV infusion over 10 minutes on 2 schedules: (A) qwk x3/1 week off, and (B) q3wks. Pt eligibility included refractory solid tumors and adequate organ function. Results: In study A, 20 patients (pts) were treated in 6 cohorts (dose range 3–24 mg/m2/wk). In study B, 41 pts were treated in 9 cohorts (dose range 3–75 mg/m2/wk). After the MTD in heavily pretreated (HP) pts was found, dose escalation in minimally pretreated (MP) pts was evaluated. The median ages were 60.5 yrs (A) and 59.5 yrs (B), sex 12F/8M (A), 16F/25M (B). All pts had a ECOG PS 0–2. Neutropenia was the dose limiting toxicity (DLT) for both studies. The MTD for A was 15 mg/m2 for HP and MP pts; the MTD for B was 48 mg/m2 for HP and 60 mg/m2 for MP pts. For both studies 2 pts had grade 4 thrombocytopenia; non-hematological toxicities were all grade 1/2. In A, pharmacokinetics (PK) were assessed on Days 1 and 15 (after the 1st and 3rd doses); exposure increased linearly over an 8-fold dose range (1.6–15 mcghr/mL), CL, Vss and T1/2 averaged 2 L/hr/m2, 49 L/m2, 18 hr, respectively, and did not change from Day 1 to 15. In B, PK were assessed on Day 1 after the 1st dose; exposure increased linearly over the 24-fold dose range (1.1–46 mcghr/mL), CL, Vss, and T1/2 averaged 2 L/hr/m2, 53 L/m2, and 21 hrs, respectively. For A, best responses were 4 SD (range 13–22 wks); for B, best responses were 1 PR and 12 SD (range 14–56 wks). Conclusion: SNS-595 was well tolerated and showed clinical activity with both qwk and q3wk dosing. The DLT was non-cumulative neutropenia. SNS-595 demonstrated remarkably predictable PK, with low inter-and intra-patient variability. Based on these data, phase 2 studies of SNS-595 as monotherapy are ongoing, and are planned in combination therapy.

[Table: see text]
Frequency of potential therapeutic targets identified by immunohistochemistry (IHC) and DNA microarray (DMA) in tumors from patients who have progressed on multiple therapeutic agents
Authors: Von Hoff D. D. , Penny R. , Shack S. , Campbell E. , Taverna D. , Borad M. , Love D. , Trent J. , Bittner M.
Published: March 2020

3071

An important question that arises when caring for patients referred for phase I clinical trials is, if one studied the patients’ tumors carefully enough, would there be targets in those patients’ tumors for which a therapeutic agent might already be available. Perhaps treating the patient with that therapeutic agent would be better than trying the phase I agent. To address that issue we have performed IHC assays for up to 13 targets (e.g. Her2/neu, ER, c-kit, etc.) as well as a two color Agilent oligonucleotide microarray with 17, 085 unique probes, on tumors from patients with advanced cancer who have exhausted conventional therapy and who were undergoing a procedure for a cancer related matter (e.g. obstruction, ascites, etc.). Ninety-one patients had excess tissue submitted from the procedure, immediately frozen and subjected to microarray analysis and had IHC performed on sections obtained from the paraffin blocks prepared as part of their standard surgical workup. IHC was considered positive if ≥ 30% of tumor cells were scored as +1 or greater staining. For microarray studies the gene expressions were called significantly increased or decreased if the fold change in expression relative to the nominal tissue of origin reference was significant at p≤0.001. For the 91 patients where frozen tumor was submitted 89 (98%) of them had RNA that was of excellent quality. The findings were a surprise in that IHC identified an average of 1.2 targets (for which a conventional therapeutic agent is available) per patient (range 0 - 4 targets). The DMA identified an average of 3.3 targets per patient (range 0 - 8 targets). Overall, a target was found for 89 (98%) of the patients. This data indicates that using IHC and DMA one can consistently find a potential target for which we have a therapeutic agent in patients’ tumors even thought they have progressed on prior therapies. This has implications for patients’ planning on participating in phase I clinical trials. It is important to conduct a prospective clinical trial to determine whether the targets discovered using IHC and DMA can be used to select therapy which will further benefit the patient who would otherwise be participating in a phase I clinical trial.

[Table: see text]
UGT1A1 promoter genotype correlates with pharmacokinetics but not toxicity in patients receiving protracted irinotecan (IRN)
Authors: Stewart C. F. , Panetta J. C. , O’Shaughnessy M. , Throm S. , Liu T. , Billups C. , Gajjar A. , Furman W. L. , McGregor L. M.
Published: March 2020

3078

Background: Recent USFDA recommendations include a dosage adjustment for patients who are homozygous for the UGT1A1*28 allele (i.e., 7 TA repeats in the promoter) due to an increase in neutropenia when those patients receive IRN. However, this recommendation was based upon data from adults treated with high IRN dosage (e.g., 350 mg/m2). This study evaluates the relationship between UGT1A1 promoter genotype and phenotype (i.e., SN-38 glucuronidation and IRN toxicity) in patients treated with low-dose, protracted IRN. Methods: 31 children treated on 2 institutional protocols received low dosage (20 to 60 mg/m2) i.v. IRN daily for 5 days of 2 consecutive weeks. PK sampling and UGT1A1 genotyping were performed during cycle 1. Patients were designated as 6/6, 6/7, or 7/7 depending on the number of TA repeats in the UGT1A1 promoter region. All patients were evaluable for gastrointestinal and hematological toxicity, primarily grades 3 and 4 neutropenia and diarrhea. Results: The frequencies of 6/6, 6/7, and 7/7 genotypes were 9/31 (29%), 15/31 (48%), and 7/31 (23%), respectively. Patients with 7/7 genotype had a statistically greater baseline bilirubin than patients with 6/6 or 6/7 genotype (p<0.03), but the difference was not considered clinically significant. In females, the SN-38:IRN AUC ratio was greater in patients with 7/7 vs. 6/6 or 6/7 genotype (0.15 vs. 0.05 vs. 0.09;p<0.005). Similarly the SN-38G:SN-38 ratio was less in females with 7/7 vs. 6/6 or 6/7 genotype (1.5 vs. 4.1 vs. 3.5;p<0.03). Patients with 7/7 genotype did not have a greater incidence of diarrhea (0/7) or neutropenia (0/7) than patients with 6/6 (3/9 with diarrhea, 2/9 with neutropenia) or 6/7 (3/15 with diarrhea, 1/15 with neutropenia) genotype. Conclusions: Although female patients with a 7/7 genotype did have altered SN-38 disposition, toxicity was not increased in patients with the 7/7 genotype treated with a low dose protracted schedule of irinotecan. Therefore, no dosage adjustment for genotype is indicated with this IRN dosing schedule.

No significant financial relationships to disclose.