bluuebunny/crossref_metadata_2025 huggingface dataset:
Determination of human brain tumour therapy response using an ex vivo invasion assay provides a potential step toward individualized treatment
Authors: Costello P. C. , MacDonald D. , McDonald W. , Hammond R. , Sloby V. , Faubert B. , Megyesi J.
Published: March 2020

11509

Background: Malignant brain tumours are the 6th leading cause of pre-mature death in Ontario with over 10,000 potential years of life lost each year. Improved treatment for malignant brain tumours is needed. Models assessing chemotherapy response employ clonal malignant human tumour cells while patient responses are heterogeneous. Tumour spreading is dependent on tissue invasion and in this study, a surgical sample of each patient’s tumour was used to assess invasion and growth while exposed to a panel of clinically relevant chemotherapies. Methods: Tissue specimens were placed into a nutrient-rich collagen gel that mimics the tumour environment in the body. Chemotherapy treatments were suspended in the matrix surrounding the tumour. Growth and invasion in the presence of chemotherapies was assessed for 5 days following surgical removal in this 3 dimensional matrix and compared to control conditions using student t- test. Results: 12 patient’s individual tumour response was assessed. 4 patients tumours did not respond to any chemotherapy tested. Table 1 shows the number of responders to each therapy tested. Conclusions: Individual response to chemotherapy is highly variable both clinically and in our ex vivo assessment of tissue fragments. Several patients (8/12 or 67%) tumour assessment displayed significant (p<.05) response to one or more therapies. Results from this data will continue to be compared to patient response, The overall predictive value of the data obtained using this ex vivo model will be determined by continuing to collect information time to recurrence and survival at 3, 6, 12 and 24 months) from 90 solid tumour patients per year. Pre-assessment each patient’s responsiveness to chemotherapies could lead to more individualized and therefore more effective treatment.

[Table: see text]

[Table: see text]
Determination of expression of platelet derived growth factor receptors (PDGFR) in astrocitic tumors
Authors: Barrios C. H. , Viola F. S. , Coutinho L. M. , Paglioli E.
Published: March 2020

11518

Background: PDGF and its receptors (α and β) are frequently expressed together in gliomas raising the possibility that an autocrine/paracrine loop could contribute to the pathogenesis of these tumors. Studies with immunohistochemistry (IHC) and in situ hybridization have clarified that PDGF-α receptors (PDGF-R α) are preferentially expressed in tumor cells, whereas PDGF-β receptors (PDGF-R β) are preferentially expressed in proliferating endotelial cells within the tumor vasculature. Objective: Determine the expression of PDGF-R α and β in astrocitic tumors. Methods: Paraffin blocks samples from patients with a diagnosis of low-grade astrocitoma, anaplastic astrocitoma, and glioblastoma were obtained from the Neuro-Oncology Unit at Hospital São Lucas-PUCRS. These patients presented and were treated from 1996 through 2001. We collected a total of 130 cases: 57 Low-grade astrocitomas (LGA), 13 Anaplastic Astrocitomas (AA), and 60 Glioblastomas (GBM). All cases were studied with standard IHC techniques using antibodies for PDGFR α and β (Santa Cruz Biotechnology). Results: See table . Conclusion: The expression of PDGF-R α and β in low-grade tumors reflects the possible role these receptors may have in the evolution of these neoplasms. More importantly we documented that over 60% of high-grade gliomas (61% in AA; 65% in GBM) show expression of PDGF-R β predominantly in the endothelial cell compartment of the tumors. This is consistent with and reflects the extensive angiogenesis observed in these diseases. The level of expression we encountered identifies an attractive molecular target to explore.

[Table: see text]

No significant financial relationships to disclose.
Evaluation of the safety of C-1311 administered in a phase 1 dose-escalation trial as a 1-hour infusion once every 3 weeks in patients with advanced solid tumors
Authors: Thomas A. , Anthoney A. , Ahmed S. , Drouin M. , Major A. , Capizzi R. L. , Grieshaber C. , Loadman P. , Twelves C.
Published: March 2020

12005

Background: C-1311 (Symadex) is the most active member of a new series of anti-cancer agents, the imidazoacridinones, specially designed compounds developed from research on the structure-activity relationships of existing cancer therapies. This clinical trial was designed to assess the safety profile of ascending doses of C-1311 and to determine the recommended dose when administered every 3 weeks (Q3W). Methods: Patients with advanced solid tumors refractory to conventional therapy were enrolled. The dose escalation scheme was divided into 2 phases with different schedules. Initially, C-1311 was given as a 1-hour daily infusion over 5 consecutive days. Following review of pre-clinical data, coupled with preliminary results of a parallel weekly study, a day 1 only schedule was explored. The maximum tolerated dose (MTD) is defined as the dose at which 2/3 or 2/6 pts experience a dose-limiting toxicity (DLT). The recommended dose (RD) is defined as the dose level below the MTD, confirmed by expansion of the RD cohort to 9 pts. Results: The first 5 patients were treated at doubling doses of 6, 12, 24, 48 and 96 mg/m2 on a schedule of 1-hour daily infusions over 5 consecutive days, repeated every 3 weeks; no DLTs were seen. The 6th pt received the same total dose as the 5th (480 mg/m2) but on day 1 only, following which a modified Fibonacci design with cohorts of 3 pts and 33% dose increments was utilized. Subsequently, pts received C-1311 at doses of 640 mg/m2 (3 pts), 850 mg/m2 (3 pts) and 1100 mg/m2 (5 pts); 2/5 pts treated at 1100 mg/m2 experienced an identical DLT (grade 4 neutropenia for ≥7 days with grade 4 thrombocytopenia), defining this as the MTD. The 850 mg/m2 cohort was expanded to confirm this as the RD. Neutropenia, thrombocytopenia, anemia and fatigue have been reported as drug-related grade 3 or 4 adverse events (AEs). Grade 1 or 2 AEs most commonly described as drug-related are fatigue, nausea, vomiting and diarrhea. Stable disease was observed in two patients with advanced malignancy. A pt had a stable disease over 8 cycles and one over 6 cycles. Plasma drug concentrations are linear and proportional to dose. Conclusions: A C-1311 dose of 850 mg/m2 administered once every 3 weeks offers a predictable and tolerable safety profile.

[Table: see text]
Preclinical efficacy evaluation of ixabepilone (BMS-247550) in combination with cetuximab or capecitabine in human colon and lung carcinoma xenografts
Authors: Lee F. Y. , Camuso A. , Castenada S. , Flefleh C. , Ingio I. , Kan D. , McGlinchey K. , Menard K. , Rose W.
Published: March 2020

12017

Background: Ixabepilone belongs to a class of structurally novel, microtubule-stabilizing agents that exert their antimitotic action by binding to tubulin with a binding mode that is distinct from the taxanes. Preclinical findings that ixabepilone has antitumor activity in a broad spectrum of tumor types, including taxane-resistant tumors, is borne out by Phase II clinical trials where ixabepilone has demonstrated activities in multiple tumor types including breast, renal, pancreatic, prostate and lymphoma. The aim of this series of studies was to further characterize the therapeutic potential of ixabepilone in combination with currently approved chemotherapy agents. Methods: Antitumor activity was evaluated in the GEO human colon and L2987 human lung carcinoma xenografts. Therapeutic synergism of the combination was defined as the attainment of efficacy that was significantly better than the best response of the individual single agents administered at their maximum-tolerated dose (MTD) or optimal dose (OD). Results: In the GEO tumors, single-agent ixabepilone produced 1.1 log cell kill (LCK) at its MTD. Cetuximab at its OD yielded 0.8 LCK. The combination of ixabepilone and cetuximab produced 1.7 LCK which was significantly superior to ixabepilone alone (P=0.0173) and cetuximab alone (P=0.0002). Similar synergistic efficacy was observed in the L2987 tumors. The combined efficacy of capecitabine plus ixabepilone was evaluated in the GEO tumors. In this tumor, single-agent ixabepilone was modestly active (LCK = 0.8) at its MTD. Single-agent capecitabine was not effective (LCK = 0.4) at its MTD. However, the combination of the two agents produced therapeutic synergism, yielding antitumor efficacy (1.9 LCK) that was superior to either of the agents alone at their MTDs (P=0.035 and 0.0004, respectively). Conclusions: Ixabepilone demonstrates robust synergistic antitumor efficacy when used in combination with cetuximab or capecitabine in human xenografts providing a biologic rationale for these combinations in the treatment of cancer.

[Table: see text]
The efficacy of combination chemotherapy with cisplatin and gemcitabine in patients with advanced adrenal cortical carcinoma (ACC)
Authors: Menefee M. , Edgerly M. , Velarde M. , Herbert K. , Fojo A. T.
Published: March 2020

12033

Background: ACC is a rare, but highly lethal disease for which more effective systemic therapies are needed. Prior studies have concluded that cisplatin and doxorubicin have single agent activity and that combinations of these and other agents, most notably etoposide, may have additive or synergistic effects. However, the majority of responses are neither complete nor durable. Anecdotal evidence of activity by gemcitabine in patients with ACC motivated the present analysis, designed to assess the efficacy of cisplatin and gemcitabine in combination in patients with metastatic ACC. Methods: 18 patients with metastatic disease were evaluated. Patient’s ages ranged from 19 to 63 years with a median age of 46 years. 5 patients were treated at initial presentation, while 13 were treated after disease progression on or following a previous chemotherapy regimen. Among the latter, the median number of prior regimens was 1, with a median of 4 prior drugs. Sites of metastases included lung (10/18), liver (12/18), retroperitoneum/adrenal bed (5/18) and bone (2/20). The starting dosages were 100 mg/m2 of cisplatin and 1250 mg/m2 of gemcitabine. A total of 56 cycles were administered to 18 patients, with a range of 2 to 12 cycles and a median of 3. Results: The toxicity of this regimen in this patient population was similar to that reported with this regimen in other tumor types. The partial response rate was 11% with an additional 16% of patients demonstrating cytoreduction that did not meet the criteria for a partial response. Conclusions: We conclude that the combination of cisplatin and gemcitabine has activity in ACC. While the superiority of this combination over single agent platinum is not established, the combination does not appear to be superior enough to warrant its routine use, especially in patients with more indolent disease, where single agent platinum can be followed by single agent gemcitabine. An attribute this combination has over other regimens used in patients with ACC, notably those incorporating doxorubicin and/or etoposide, is that it can be given at full doses without excessive toxicity to patients with hormone producing tumors in combination with ketoconazole.

No significant financial relationships to disclose.
Gemcitabine and capecitabine synergism and biomodulation with dipridamole in a mouse tumor model
Authors: Demir G. , Klein H. O. , Yildirim S. , Esen I. , Altug T.
Published: March 2020

12034

Background and Aim: Gemcitabine and capecitabine are antimetabolites that are effective in the pyrimidine pathway of the DNA synthesis. Capecitabine through a 3-step activation process is transformed to 5-FU in the tumor cell by thymidine phosphorilase. On the other hand, gemcitabine interacts with the enzymes thymidine kinase, tymidine phosphorilase ve ribonucloetide reductase. Our hypothesis is based on a possible synergistic blockade by concurrent administration of these two antimetabolites. Additionally, dipridamole is an inhibitor of the nucleoside transport; and that can prolong the accumulation of antimetabolites within the tumor cell. In this study, combinations of these drugs are tested on an animal model. Methods and Results: 80 male balb-c mice were inoculated dorsally with 0.1 cc Ehrlich ascites tumor, and 10 days later the animals were separated into 5 groups having a similar tumor load. The control group received no treatment, while in the gemcitabine arm the animals received 50 mg/d gemcitabine on day 1. In the capecitabine arm, the animals received 1mg/day capecitabine administered in drinking water on days 1–4. In the gemcitabine + capecitabine combination arm, the animals received both treatments. In the gemcitabine + capecitabine + dipridamole arm, in addition to both of the drugs, dipridamole was also given 2mg/day in drinking water on days 1–4. In the control group (n=16) median survival was 17 days, while it was 33 days in gemcitabine arm (n=11), 35 days in capecitabine arm (n=14), and 44 days in the gemcitabine + capecitabine combination arm (n=22) which was significantly higher (p<0.007). Dipridamole added to this combination (n=17) did not prolong survival any further. Conclusion: combination of gemcitabine with capecitabine suggests favorable results in an animal model. Testing of this combination in clinical trials seems to be justified.

No significant financial relationships to disclose.
A phase I study of antisense Bcl-2 oligonucleotide (G3139) in combination with carboplatin (C) and paclitaxel (T) in patients with advanced solid tumors
Authors: Lalich M. , Wilding G. , Kolesar J. , McNeel D. G. , Schell K. , Leith C. , Chappell R. , Marnocha R. , Alberti D. , Liu G.
Published: March 2020

13006

Background: G3139 is an 18-mer oligonucleotide that targets the mRNA of Bcl-2, a protein that inhibits apoptosis conferring treatment resistance, and is synergistic with taxanes in studies using Bcl-2 over-expressing xenografts. Here we conduct a study combining G3139 with C + T in order to define the recommended phase II dose, as well as evaluate the direct biologic effect of G3139 on tumor. Methods: Patients with advanced solid tumors were treated with a dose escalation of G3139 (3–7 mg/kg/day) by continuous infusion days 1–7, with C (AUC 5) and T (150 mg/m2) given on day 4, repeated in 3 week cycles. At the planned expanded cohort (G3139 7 mg/kg/day dose), 12 patients underwent paired tumor biopsies (baseline and day 4 pre-chemotherapy) for assessment of Bcl-2/Bax expression by RT-PCR and IHC, as well as intratumoral G3139 levels using ELISA. Likewise, peripheral blood mononuclear cells (PBLs) were assessed using flow cytometry and RT-PCR for changes in Bcl-2/Bax expression. Results: 34 patients have been treated: 11 melanoma, 7 bladder, 3 prostate, 2 esophageal, 3 non-small cell lung, and 1 head/neck, kidney, breast, pancreas, liver, gastrointestinal stromal, biliary, and unknown primary cancers. G3139/C/T appeared well tolerated at the doses administered with the main toxicities observed being attributed to the C + T chemotherapy (myelosuppression and thrombocytopenia). The maximal tolerated dose is yet to be achieved. Assessment of paired tumor biopsies on 12 patients show decreases in Bcl-2 transcription in laser capture microdissected tumor using RT-PCR, with concordance observed using IHC. Likewise, decrease in Bcl-2 gene expression in PBLs was seen. 2 confirmed PRs were observed, including a bladder patient with baseline Bcl-2 tumor expression 10-fold greater than any other patient assessed. Conclusions: G3139/C/T is well tolerated, with main toxicities attributable to the chemotherapy alone. Bcl-2 is suppressed in tumor and PBLs supporting that a biologically active dose of G3139 is being achieved. Currently, the C + T is being escalated to define a MTD. Complete clinical data, G3139 pharmacokinetics, and Bcl-2/Bax data will be presented in detail.

No significant financial relationships to disclose.
A prospective pharmacogenetic study of thymidylate synthase (TS) polymorphisms in high risk stage II or stage III colon cancer patients treated with 5-fluorouracil (5-FU) and leucovorin (LV)
Authors: Mulder K. E. , Butts C. A. , Scarfe A. , Au H. , Koski S. , Fields A. , Hanson J. , Kuzma M. , Graham K. , Sawyer M. B.
Published: March 2020

13018

Background: Retrospective studies suggest TS polymorphisms predict toxicity from TS inhibitors as well as therapeutic response. The TS promoter has a variable number of tandem repeats (VNTR) polymorphism containing putative E-box binding sites that bind upstream stimulatory factor (USF) -1 and -2. One E-box binding site exists in TSER*2 and 2 binding sites exist in TSER*3. A single nucleotide polymorphism (SNP) at position 12 (G→C) in TSER*3’s 2nd repeat abolishes binding of USF-1/2. Combined effects of VNTR and SNP means individuals may have 2, 3 or 4 enhancer regions. We hypothesized that decreased enhancer numbers predicts for patients at risk for grade ≥3 mucositis, diarrhea, neutropenia, and overall toxicity and performed a prospective pharmacogenetic study of TS polymorphisms in adjuvant colon cancer patients treated with 5-FU/LV. Methods: High risk Stage II or Stage III colon cancer patients treated with 5FU/LV (425 mg/m2/ 20 mg/m2) daily for 5 days every 4 weeks had blood drawn for genotyping prior to starting therapy. Patients were assessed for toxicity using NCI CTC 2.0 in cycle 1. Three year disease-free survival will also be assessed. Results: 103 patients were enrolled and genotyped with 95 evaluable for toxicity. Patient characteristics: median age 61yrs (36–79): M 52%/F 48%; Stage III 77%, Stage II 23%. Frequency of genotypes containing 2 enhancers (TSER*2/ TSER*2, TSER*2 / TSER*3C, TSER*3C/ TSER*3C), 3 enhancers (TSER*2/ TSER*3G, TSER*3C/ TSER*3G) and 4 enhancers (TSER*3G/ TSER*3G) was 0.64, 0.31, and 0.05 respectively. No significant difference was seen in overall toxicity, mucositis, diarrhea and neutropenia based on TS polymorphism genotypes. Frequency of recurrence in 2 enhancer patients was 13% versus 26% in 3/4 enhancer patients but this did not reach statistical significance (p = 0.16). Conclusions: This prospective study does not confirm previously published retrospective studies suggesting that TS VNTR and SNP predict toxicity from TS inhibitors in patients treated with 5-fluorouracil for colon cancer. There is a trend for prediction of recurrence which requires further follow-up.

No significant financial relationships to disclose.
A phase I study examining weekly dosing and pharmacokinetics (PK) of a novel spectrum selective kinase inhibitor, XL999, in patients (pts) with advanced solid malignancies (ASM)
Authors: Cooper J. , Mita M. M. , Curtright J. , Ricart A. , Mita A. , Takimoto C. , Tolcher A. , Dowlati A. , Flick S. , Papadopoulos K. P.
Published: March 2020

13024

Background: XL999 is a small molecule inhibitor of multiple kinases involved in tumor cell growth, angiogenesis, and metastasis, including VEGFR2 (KDR), PDGFRα/β, FGFR1/3, FLT-3, and SRC. A phase I study of XL999 administered as a 4 hr infusion every 2 weeks in pts with ASM showed that the maximum tolerated dose (MTD) was 3.2 mg/kg and the plasma t1/2 was approximately 24 hrs. Three pts dosed at 0.2–1.6 mg/kg (anaplastic thyroid cancer [1], renal cell carcinoma [1], hepatic squamous cell carcinoma [1]) had partial responses and 9 pts had stable disease for 3 to 11 months. Based on these data, a weekly (wkly) dosing schedule with PK monitoring was explored. Methods: XL999 at 3.2 mg/kg was administered to pts as a 4 hr infusion on day (d) 1 and 8 with toxicity assessment. Pts received further doses of XL999 wkly in the absence of unacceptable toxicity, disease progression, or accumulation based on PK results. Results: Overall 15 pts were enrolled and 7 were initially dosed at 3.2 mg/kg. Two of these pts experienced severe drug related toxicities, including 1 pt with G3 fatigue who was able to continue wkly XL999 at 2.4 mg/kg and another pt who was discontinued after developing reversible cardiac dysfunction on d1. The next 8 pts were treated at 2.4 mg/kg and none of these has experienced any G2 or worse drug related adverse events. One asymptomatic pt with non-specific ECG changes after d1 was discontinued from study. Four of 11 evaluable pts had SD. In 7 evaluable pts treated at the 2.4 dose level, the mean Cmax was 519 ng/mL with moderate interpatient variability (coefficient of variation, CV) of 38%. Intrapatient variability in the Cmax values on d1 and d15 was moderate (≤3-fold); however, there was no evidence of drug accumulation on repeat dosing. Conclusions: XL999 administered wkly as a 4 hr infusion at a dose of 2.4 mg/kg appears to be well tolerated with no evidence of drug accumulation. The safety and PK data suggest that 2.4 mg/kg on a wkly schedule is appropriate for phase 2 studies.

[Table: see text]
Phase I trial of the oral histone deacetylase inhibitor MS-275 administered with food
Authors: Donovan E. A. , Sparreboom A. , Figg W. , Trepel J. , Maynard K. , Zwiebel J. , Melillo G. , Gutierrez M. , Doroshow J. , Kummar S.
Published: March 2020

13036

Background: The histone deacetylase (HDAC) inhibitor MS-275, a synthetic benzamide derivative, has demonstrated antitumor activity in vitro & in vivo. After determining maximum tolerable dose (MTD = 2 mg/m2) & dose limiting toxicity (DLT) for MS-275 given to fasting patients (pts) weekly ×4 q6 weeks, we explored toxicity profile, MTD, & pharmacokinetics (PK) of MS-275 when given po on the same schedule with food. Methods: MS-275 at 2, 4, or 6 mg/m2 was administered to pts with advanced malignancy & PS ≤2, LFTs ≤2.5 × normal, adequate hematopoietic & renal function, & normal resting MUGA. PK samples were analyzed by LC-MS. Data for pts in the fed state were compared to data obtained in previous cohorts of pts treated in the fasting state. Protein acetylation assessed by a novel flow cytometric assay & HDAC enzymatic activity were measured in peripheral blood mononuclear cells (PBMC). Results: 16 pts received a median of 2 cycles (1–5) of MS-275 2–6 mg/m2 with food. No DLT occurred on 2 or 6 mg/m2 (n = 3 each), while 1 pt on 4 mg/m2 (n = 10) had a DLT: grade 3 hypophosphatemia. For 2–6 mg/m2 other grade 3 toxicities were neutropenia & lymphopenia. Grade 1–2 toxicities in >1 pt were leucopenia, anemia, thrombocytopenia, fatigue, nausea, vomiting, headache, hypoalbuminemia, hypophosphatemia, hyponatremia, & hypocalcemia. MTD has not been reached; current dose level is 8 mg/m2. Comparing PK for fasting & fed pts on 2–4 mg/m2, there was no difference in Tmax (0.5h); average Cmax & AUC were 35% & 25% lower, respectively, in fed pts; this difference is not statistically significant. Interindividual variability in exposure to MS-275 increased from 52% in fasting pts to 100% in fed pts. PBMC protein acetylation & HDAC inhibition were seen at all dose levels (2–6 mg/m2) in fed pts. Of 9 pts evaluable for response (2–4 mg/m2), 2 of 6 pts on 4 mg/m2 had stable disease. Conclusions: MTD has not yet been established for MS-275 given with food on this schedule but is ≥4 mg/m2 weekly x4 q6 weeks. Interindividual variability in exposure increases with food. Whether intestinal absorption is decreased when MS-275 is given with food requires further evaluation with additional patients. Drug-related protein hyperacetylation & HDAC inhibition were observed.

[Table: see text]
Phase I study of the safety and efficacy of atiprimod, a novel azaspirine, for patients with advanced cancer
Authors: Braiteh F. S. , Yao J. , Camacho L. H. , Ng C. , Hong D. S. , Harris P. , Dhillon N. , Kurzrock R.
Published: March 2020

13050

Background: Atiprimod (N-N-diethl-8,8-dipropyl-2-azaspiro [4.5] decane-2-propanamine) is an oral cationic azaspirane that suppresses angiogenesis by inhibiting both bFGF and VEGF induced proliferation and migration. Atiprimod has been shown to down-regulate multiple growth factors involved in tumor progressions and metastases, including IL-6, TNF-α, and VEGF. Methods: This is an ongoing, single-center, open-label, ascending dose (modified Fibonacci) Phase I trial of oral atiprimod in patients with advanced cancers (3+3 design). Atiprimod was given orally for 14 days every 28-day cycle. The primary objectives are to identify the MTD and to evaluate the safety of atiprimod; the secondary objectives include measuring PK and describing efficacy. Data from these patients enrolled are presented here. Results: Fourteen patients have been treated to date with 60 mg tablets (N = 3), 60 mg capsules (N = 3), 90 mg capsules (N = 3) and 120 mg capsules (N = 5). The most common side effects, which occurred in over half the patients, were related to the gastrointestinal system, and include nausea (11), diarrhea (7), vomiting (4) abdominal pain (2) and dyspepsia (2). These events were generally low-grade, occurred primarily during days of active drug administration and tended to resolve during off-drug days. Less common adverse events were sinus headaches, and elevated serum transaminases, alkaline phosphatase and creatinine. One patient who received prolonged therapy (7 months) developed fever and multi-organ failure of unclear etiology. One patient with uterine leiomyosarcoma experienced a DLT (syncope and hypotension) at 120 mg/day, and that dose level is therefore being expanded up to 6 patients. One patient with midgut carcinoid tumor and liver metastasis achieved a partial remission lasting 2+ months (50% decrease in maximum diameter by RECIST). Three patients (carcinoid = 2 and thymoma = 1) had stable disease for four, four and six months, respectively. Conclusions: Preliminary data indicate that atiprimod was reasonably tolerated, with predominantly gastrointestinal side effects. There is early evidence of anti-tumor activity in carcinoid tumors. Dose escalation continues.

[Table: see text]
Safety and pharmacokinetics of intravenous VEGF Trap plus FOLFOX4 in a combination phase I clinical trial of patients with advanced solid tumors
Authors: Mulay M. , Limentani S. A. , Carroll M. , Furfine E. S. , Cohen D. P. , Rosen L. S.
Published: March 2020

13061

Background: VEGF Trap is a potent angiogenesis inhibitor comprising portions of human VEGF receptor VEGFR1 (Flt-1) and VEGFR2 (KDR) extracellular domains fused to the Fc portion of human IgG. VEGF Trap binds VEGF and neutralizes all VEGF-A isoforms plus placental growth factor. FOLFOX4 is an approved chemotherapy regimen for the treatment of colorectal cancer. This study was designed to evaluate the safety and pharmacokinetics (PK) of VEGF Trap plus FOLFOX4 administered intravenously. Methods: Successive cohorts of 3–6 patients (pts) with advanced solid tumors received intravenous VEGF Trap plus FOLFOX4 every 2 weeks. Study endpoints included safety, PK, and immunogenicity. Antitumor activity was assessed by CT scan. Results: Six pts (3 male/3 female), median age 55 (25–74), ECOG PS 0/1/2: 2/4/0, with a variety of advanced solid tumors, including 2 gastric and 2 neuroendocrine tumors, have received a total of 19 cycles of VEGF Trap plus FOLFOX4 across 2 VEGF Trap dose levels (2.0 mg/kg, 4.0 mg/kg) to date. Three of these 6 pts had grade 3 AEs (hypertension [n=2], neutropenia [n=2]), which were manageable and reversible. However, no dose-limiting toxicities or grade 4 AEs have been encountered so far. Preliminary mean free VEGF Trap clearance was 17.1 mL/kg/day. No pts have developed anti-VEGF Trap antibodies. Conclusions: VEGF Trap may be safely combined with FOLFOX4 at the dose levels studied. Preliminary free VEGF Trap clearance did not differ significantly from that seen with single-agent exposure; chemotherapy PK analysis is pending. The maximum tolerated dose has not yet been reached, and dose escalation continues. Updated safety, pharmacokinetic, and preliminary efficacy results from this ongoing study will be presented.

[Table: see text]
ABT-869, a novel multi-target receptor tyrosine kinase inhibitor (RTKI), combined with chemotherapy is synergistic in the therapy of acute myeloid leukemia cells with FLT3-ITD mutation (FLT3-AML)
Authors: Zhou J. , Pan M. , Loh S. , Xie Z. , Lim Y. , Lilly M. , Glaser K. , Albert D. , Davidsen S. , Chen C. S.
Published: March 2020

13064

Background: Internal tandem duplications (ITDs) of fms-like tyrosine kinase 3 (FLT3) receptor are identified in 20–25% of adult AML patients associated with poor prognosis. ABT-869 is active in FLT3-AML and is currently under clinical investigaton. We hypothesize that the combination of ABT-869 with chemotherapy can improve the therapeutic index in FLT3-AML. Methods: Using Calcusyn software, the additive, synergistic or antagonistic effect of ABT-869 with concurrent or sequential cytosine arabinoside (Ara-C) or doxorubicin (Dox) was measured in MV4–11 and MOLM-14 cells. The synergistic combination sequence was further tested in a MV4–11 xenograft model in four groups (10 mice/group) including control, Ara-C, ABT-869, and combination (Ara-C first for 4 days, then daily ABT-869). Cell cycle analysis and apoptosis and signal pathway assays were performed in vitro and in vivo. Results: ABT-869 induced dose- and time-dependent apoptosis on FLT3-AML cells resulting in down regulation of p-FLT3, p-STAT5, Bcl-XL and up regulation of p53 and BID. ABT-869 caused G1-phase arrest and the removal of cells in the S- and G2/M-phase mediated by reduction of cyclins D and E. We observed significant synergistic effect with Ara-C or Dox first, followed by ABT-869, as well as in concurrent treatment with ABT-869 and Dox. Simultaneous treatment with ABT-869 and Ara-C only achieved additive effect. Conversely, we found an antagonistic effect in the sequence of pretreatment of ABT-869 followed by chemotherapy. In a MV4–11 xenograft model, all mice succumbed to leukemia in the control and Ara-C groups (median survival = 53 and 55.5 days respectively). Combination therapy gave a faster reduction of tumor volume compared to ABT-869 treatment alone (p=0.03) without recurrence of leukemia in either group by day 67. In vivo immunohistochemistry (IHC) analysis revealed ABT-869 potently inhibited VEGF and phosphor-ERK. Conclusions: ABT-869 can be given after Ara-C or Dox to act synergistically. Our study suggests that combinations of RTKIs with chemotherapy should be carefully tested prior to clinical protocol development. A clinical trial of such combination therapy in FLT3-AML is warranted.

No significant financial relationships to disclose.
Perifosine (P) can be combined with docetaxel (T) without dose reduction of either drug
Authors: Cervera A. , Bernhardt B. , Nemunaitis J. J. , Ebrahimi B. , Birch R. , Richards D. A. , Smith G. B. , Allerton J. P. , Henderson I. C.
Published: March 2020

13066

Background: Perifosine is an alkylphospholipid that modulates several signal transduction pathways, including Akt, which is often activated in taxane resistant tumors and is thought to be one mediator of such resistance. The combination of T, 75 mg/m2 every 3 weeks, and prednisone (Pr), 5 mg bid has become standard therapy for patients (pts) with metastatic prostate cancer. The addition of P might decrease resistance to T in these patients who often have activated Akt because of PTEN mutations. This phase I trial is the first attempt to combine these agents. Methods: Between 12/04 and 9/05, 39 pts were enrolled. P was given either daily as a 50 mg tablet 1, 2 or 3 times per day on days 1–14 or weekly in doses of 300 mg every 4 - 6 hours 3, 4 or 5 times on days 1–2, 8–9 and 15–16 of each 21 day cycle. T, 75 mg/m2, was given on day 8 of a 21 day cycle with or without Pr. Results: Disease sites: prostate 11, NSCLC 9, ovary 4, head/neck 3, pancreas 3, breast 2 & other 7. Median age was 63 (range 37–80); 24 patients were male and median ECOG performance status was 1 (range 0–2). 34 pts had received prior chemotherapy including 24 previously given a taxane. Three patients were entered at each dose level for each schedule and the cohort expanded to 6 patients if 2 or more patients experienced a grade 3/4 non-hematologic toxicity (DLT) during the first cycle of therapy. A dose level was toxic if 4 or more patients experienced a DLT during cycle 1. The grade 3/4 toxicities for each perifosine dosing schedule are given in the table . Glucose values for the grade 3 toxicities were between 253 and 306. This was seen only in the Pr pts & has not been observed in other P trials. P dose reductions were required in 4% of cycles for daily P, 5% for daily P+Pr and 37% for weekly P. Conclusions: Daily doses up to 150 mg could be administered either with or without Pr but the maximum tolerated dose for the weekly regimen was 1200 mg It is concluded that daily P ± Pr is well tolerated with T 75 mg/m2 q 3 weeks and that daily doses are preferred for phase II studies to further define activity of the combination.

[Table: see text]

[Table: see text]
Pharmacogenetic influence of OATP1B1 variants *1b and *15 on irinotecan disposition in Asian and Caucasian cancer patients
Authors: Chowbay B. , Sparreboom A. , R Jada S. , Xiaoqiang X. , H Li H. , H Mathijssen R. , H van Schaik R. , Verweij J. , Goh B. C. , Lim R. , H Tan E.
Published: March 2020

13069

Background: The objective of this study was to evaluate the impact of OATP1B1 (SLCO1B1; OATP-C) functional variants on the disposition of irinotecan in Asian and Caucasian cancer patients. Methods: Irinotecan pharmacokinetic parameters and OATP1B1*1a, *1b, *5 and *15 genotyping data were obtained from Asian (N=71) and Caucasian (N=30) cancer patients receiving the drug as a 90-minute i.v. infusion. Genotypic-phenotypic correlations were assessed in cancer patients from each ethnic group. Results: The *1a/*1a genotype and the *15/*15 diplotype were absent in Caucasian cancer patients but present in Asians (*1a/*1a, N=6; *15/*15, N=1). Statistically insignificant differences were observed between patients carrying *1a/*1b and *1b/*1b genotypes and also between *1b/*15, *15/*15 and *15/*15 diplotypes. Compared to wild-type patients (N=6), total irinotecan clearance normalized by BSA was 2- and 3-fold lower in Asian patients carrying at least one *1b (*1a/*1b + *1b/*1b; N=54; P=0.055) and one *15 (*1b/*15 + *5/*15 + *15/*15; N=11; P=0.001) allele, respectively. Significant differences were also present between Asian patients carrying the *15 diplotype and wild-type patients with regard to exposure levels (Cmax/dose/BSA) to irinotecan (P=0.007), SN-38 (P=0.009) and SN-38G (P=0.004) as well as REC (P=0.005) and REG (0.001). The REG was 5-fold (P=0.022) and 27-fold (P=0.001) lower in Asian cancer patients carrying at least one *1b allele and at least one *15 haplotype, respectively, when compared with wild-type patients. No significant differences in pharmacokinetic parameters were found when comparing Caucasian cancer patients carrying at least one *1b allele and those carrying at least one *15 allele (P>0.05). Conclusions: The genotype and diplotype frequencies of the studied OATP1B1 variants were ethnically dependent, and OATP1B1 genotype status accounts, at least in part, for the observed differences in irinotecan disposition in Asian cancer patients. The lack of significant influence of OATP1B1 variants on irinotecan disposition in Caucasian cancer patients is not clear but may have resulted from the small patient population.

No significant financial relationships to disclose.
The combination of arsenic trioxide and rapamycin has potent inhibitory effects on acute myeloid leukemia (AML) cells
Authors: Altman J. K. , Yoon P. J. , Sassano A. , Smith J. , Mears H. , Tallman M. S. , Platanias L. C.
Published: March 2020

13101

Background: Arsenic trioxide (As2O3) exhibits potent growth inhibitory and pro-apoptotic effects against a variety of neoplastic cells, but the precise mechanisms by which it mediates such effects are not known. The mammalian target of rapamycin (mTOR) is a key cellular regulator of multiple signaling events that control initiation of mRNA translation in leukemia cells. We examined the effects of As2O3 on the activation of mTOR-dependent pathways that regulate initiation of mRNA translation in acute myeloid leukemia (AML) cells. We also determined the effects of the combination of As2O3 with the mTOR inhibitor rapamycin on the growth of AML cell lines. Methods: The human leukemia cell lines, KG-1, U937, and MM6, were incubated and cultured with increasing concentrations of As2O3, in the presence or absence of the mTOR inhibitor rapamycin. Cell lysates were immunoprecipitated with an anti-p70 S6 kinase antibody, and immune-complex kinase assays to detect p70 S6 kinase activity were performed. In addition, cell proliferation assays were carried out in cells treated with or without rapamycin (10 or 20 nM) and increasing concentrations of AS2O3 (0 to 5 uM). Results: As2O3-treatment of U937 cells resulted in strong induction of p70 S6 kinase activity, which was inhibited by concomitant treatment of cells with rapamycin. In cell proliferation assays, we found that rapamycin alone significantly inhibited the growth of U937, KG-1, and MM6 cells. The addition of As2O3 further enhanced the inhibitory effects of rapamycin, in a dose-dependent manner, indicating that the combination of these agents is more potent in inhibiting the growth of AML cell lines than each agent alone. Conclusions: During treatment of AML cell lines with As2O3, the p70 S6 kinase pathway is activated, apparently in a negative feedback regulatory manner. Pharmacological inhibition of mTOR with rapamycin has potent antileukemic properties, which are further enhanced by As2O3. Therefore, the use of As2O3 and rapamycin in combination may be a promising strategy for the treatment of AML.

No significant financial relationships to disclose.
Azurin, highly potent and selective anticancer agent for breast cancer
Authors: Yamada T. , Mehta R. , Majumdar D. , Chakrabarty A. M. , Das Gupta T. K.
Published: March 2020

13106

Background: The use of live or attenuated pathogenic bacteria in the treatment of cancer dates back to the late nineteen hundreds when William B. Coley first reported that inducing Streptococcal infection resulted in tumor regression. However, the hazards of using live bacteria are obvious. Similarly, the results of using attenuated bacteria have been spotty and enthusiasm for it has waxed and waned. Recently, we have shown that redox protein azurin (14 kDa) secreted by an opportunistic pathogen, Pseudomonas aeruginosa, is not only cytotoxic to cancer cells in vitro but also produces tumor regression in athymic mice without producing any toxicity (PNAS, 99, 14098–14103, 2002; Science’s STKE, 158, tw416, 2002). Methods: In this study, we show the effect of 1mg/kg of azurin injected i.p. starting 72 hours after inoculation of 5x107 MCF-7 breast cancer cells in estradiol pretreated nude mice for 28 days (n = 20, control = 10, azurin-treated = 10). Results: Univariate analysis of the data showed the difference in tumor growth rates between control animals and azurin-treated animals was significant. For instance, 22 days after the start of treatment, the mean tumor volume in azurin-treated animals was only 22% of the mean tumor volume in the control mice (i.e., 0.0267 cm3 + 0.124 cm3 respectively, P = 0.0179 Kruskal-Wallis test). At the end of the experiment on the 29th day there was a reduction in the tumor volume by 85% in the treated group. We used a multivariate model, where the tumor growth over time was taken to be exponential with coefficients that were subject specific mixed effect (For control, tumor volumes = exp (−4.23 + 0.06 time) while for the treated group it was tumor volume = exp (−4.23 + 0.03 time)). The difference is statistically significant (P = 0.0456). Taken together, this in vivo data shows azurin exerts an inhibitory effect in the growth and progression of MCF-7 tumor xenotransplants. During the 28 days of treatment, treated animals did not show any sign of toxicity. Conclusions: Bacterial redox protein azurin can be explored as a novel therapeutic agent for treatment of breast cancer. Recently, we have prepared a truncated version of azurin which has 28 amino acids. It appers that this chemically synthesized peptide (2.8 kDa) has similar properties as azurin.

No significant financial relationships to disclose.
A phase 1 study of daily oral perifosine (P) with weekly paclitaxel (T)
Authors: Ebrahimi B. , Nemunaitis J. J. , Shiffman R. , Birch R. , Diaz-Lacayo M. , Berdeaux D. H. , Rettenmaier M. A. , Goggins T. F. , Henderson I. C.
Published: March 2020

13117

Background: P is an oral signal transduction modulator with limited toxicity. P combined with 3-weekly T led to no toxicity beyond that expected with each drug alone. Weekly T is more effective than 3-weekly T in some settings (Seidman, ASCO 2004:512), so this study evaluated whether weekly T altered the tolerance to P. Methods: Twelve patients (pts) were enrolled. T was given at 80 mg/m2 on days 1, 8 and 15 of a 28 day cycle. P, 50 mg, was given 1, 2 or 3 times a day on days 1–21 of each cycle. Results: Tumor types were lung 2, breast 4, endometrium 3 and other 3. Median age was 55 (range 41–82). All pts had received prior chemotherapy (median 2.5, range 1–3 regimens) and 6 a prior taxane. Three pts were entered at each dose and the cohort expanded to 6 pts if 2 or more experienced a grade 3/4 non-hematologic toxicity (DLT) during cycle 1. A dose was toxic if 4 or more pts experienced a DLT during cycle 1. Since toxicity was not dose limiting in any cohort, the 150 dose was expanded to 6 pts. There were no grade 3/4 hematologic toxicities. The grade 3/4 non-hematologic toxicities at least possibly related to perifosine are given in the table below: The high glucose values were 276 and 277. A total of 38 cycles and a median of 2.5 cycles per pt (range 1–10+) were delivered. Full dose T was given in 85% of cycles (50 mg–100%, 100 mg–85%, 150 mg–86%). Dose reductions of T in 3 pts were related to neuropathy, suspected bronchitis and fatigue. One pt treated at 100 mg requested T be stopped after 6 cycles due to neurotoxicity and has received 6 additional cycles of perifosine alone. Perifosine dose reductions were required in 13% of cycles (50 mg - 0%, 100 mg - 21%, 150 mg - 9%). One pt each was reduced due to constipation, nausea and diarrhea. Five of 7 evaluable pts had stable disease (breast 2, cervix, endometrium, thyroid) for at least 3 months. Four remain stable at 3+ to 10+ months. Conclusions: The single agent doses of P (150 mg daily) & T (80 mg/m2 weekly) were given without increasing the toxicities expected from using each drug alone. Phase II studies are warranted to define the activity of the combination.

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A phase I study of thalidomide, capecitabine and temozolomide (TCT) in advanced cancer
Authors: Khan M. I. , Salvador C. , Schonard C. L. , Taft B. S. , Kloecker G. H. , Laber D. A.
Published: March 2020

13122

Background: The aim is to develop a novel oral immuno-chemotherapy regimen against advanced cancers. Methods: Patients were enrolled in cohorts of 3 or 6 in a standard phase I design. Thalidomide 100 mg was kept stable for all cohorts. If well tolerated after 1 week, capecitabine and temozolomide (TCT) were given daily without rest and escalated one at a time until dose limiting toxicity (DLT) occurred. If no DLT occurred within 28 days (1 cycle), the following group was enrolled into the next dose level. Results: Twenty-three patients with advanced cancers have been treated in this study. All patients have been evaluated for toxicity and response. Eighty cycles of TCT have been administered (1–13 cycles/patient). Patient characteristics: Median age 59 (31–79), PS ECOG 1 (0–2). Type of cancer: renal (7), bladder (2), pancreatic (2), prostate (2), colon (2), and lung, gastric, synovial sarcoma, angiosarcoma, anal, nasopharyngeal, breast, esophageal (1 each). Prior to TCT, all patients had objective documentation of progressive metastatic disease after a median of 2 therapies (range 0–4). Objective response: Four subjects (17%) achieved partial response (renal 1, gastric 1, prostate 2), and 4 patients (17%) had stable disease (renal 1, colon 1, pancreas 2), adding to a clinical benefit of 34%. Toxicity: Treatment was well tolerated. Common toxicities included grade 3 thromboses 17%; and grade 1–2: hand-foot syndrome, fatigue, sensory neuropathy, nausea, vomiting, and neutropenia. Based on DLT within the first 28 days, the MTD of daily TCT therapy was thalidomide 100 mg, capecitabine 2000 mg and temozolomide 100 mg. With long-term treatment, majority of the patients required dose interruptions due to fatigue, hand-foot syndrome, and neutropenia. Dose level 2.5 was implemented: daily thalidomide and 3-weeks-on 1-week-off capecitabine and temozolomide. Six patients were treated at dose level 2.5 without toxicities. Conclusions: TCT is an effective palliative oral chemo-immunotherapy for patients with advanced cancer. The recommended dose for a phase II trial is dose level 2.5, including thalidomide 100 mg daily, capecitabine 2000 mg/day and temozolomide 100 mg/day three-weeks on and one-week off regimen.

[Table: see text]
Hepatic expression of CYP3A4 and CYP3A5 genes in Asians and implications for pharmacokinetic variations during chemotherapy
Authors: R Jada S. , Xiang X. , Zhou Q. , H Li H. , L Ooi L. , Chowbay B.
Published: March 2020

13124

Background: Hepatic expression of CYP3A4 and CYP3A5 enzymes are important determinants of interindividual variability in chemotherapy. The objective of this study was to genotypically quantitate expression of CYP3A4 and CYP3A5 genes in healthy hepatic tissues from Asian cancer patients undergoing hepatectomy. Methods: Healthy Asian hepatic tissues (Chinese: N = 27; Malay: N = 1; Indian: N = 3) were obtained from the institution’s central tissue repository bank. Messenger RNA was isolated from each tissue sample and reversed transcribed to cDNA followed by real time PCR experiments. Results from these gene expression experiments were normalized against GAPDH transcripts. DNA was also extracted from the hepatocytes and genotyped for four single nucleotide polymorphisms in the CYP3A4 gene (CYP3A4*1B, *4, *5 and *6) and three in the CYP3A5 gene (CYP3A5*1, *3 and *6). Results: CYP3A4 variant forms were absent in all Asian patients. CYP3A5 was polymorphic and genotyping analysis showed that the *1/*1, *1/*3 and *3/*3 genotypes were present in 6%, 52% and 42% of the Asian liver samples, respectively. Liver tissues harbouring the *1/*1 and *1/*3 genotypes showed insignificant CYP3A5 expression pattern (P=0.160). The CYP3A5 mRNA expression levels were approximately 6-fold lower in *3/*3 samples compared with samples carrying at least one *1 allele (*1/*1 + *1/*3). Non-parametric analysis using Kruskal-Wallis test showed that the hepatic expression of CYP3A5 mRNA between liver tissues that harboured at least one *1 allele (*1/*1 + *1/*3) and those carrying homozygous *3/*3 genotype to be highly significantly different (P < 0.007). Conclusions: These results show that polymorphic CYP3A4 isoforms are probably rare in Asians compared with CYP3A5 polymorphisms. This study also suggest that CYP3A5, rather than CYP3A4 could be important for interindividual variations in pharmacokinetics of CYP3A4/5 substrates during chemotherapy in Asians.

No significant financial relationships to disclose.