bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase IIa study of light-activated talaporfin sodium in patients with primary or recurrent glioblastoma multiforme
Authors: Keltner L. , Chen J. C. , Wang S. , Rakic M. L.
Published: August 2020

e13026

Background: Preclinical studies have shown that talaporfin sodium (LS11) can concentrate in brain-tumor cells and be activated by red light (664nm wavelength) from light-emitting diodes (LEDs). Singlet oxygen is released that induces blood-vessel occlusion and apoptosis in target tumor cells, which results in direct tumor-cell death and a potential antitumor immunogenic effect on untreated tumors. Preferential talaporfin uptake in tumor and clearance from normal surrounding brain occur by 24 hours after injection. A single center, open label phase IIa study was conducted to establish safety and acute antitumor effect of light-activated drug therapy in glioblastoma patients. Methods: Nine patients (Karnofsky score >90) with operable glioblastoma, four of which were recurrent in the right frontal or temporal lobe, were recruited at a neurosurgical center in Belgrade, Serbia. Tumor diameter ranged 4–9 cm. Treatment consisted of IV injection of 1mg/kg of LS11 with subsequent craniotomy after a 24-hour wait. A single LED device was inserted into the tumor center followed by different light doses, 250 joules in six patients and 500 joules in three patients. Treated tumors were then resected. Patients were assessed for 4 weeks with serial CT imaging, intracranial pressure monitoring, and clinical, neurologic, and lab examination. Results: No dose-limiting toxicity was noted at the higher light-dose level. Seven adverse events (2 neurologic) occurred in four patients, none treatment related. Apoptosis was evident by TUNEL stain, and vessel closure was seen histologically. No acute inflammatory changes or cerebral edema were noted; normal brain was unaffected. No adverse neurologic sequelae were ascribable to the therapy, and no post-operative ICP elevation was noted. At 4 weeks, all patients were alive; two patients progressed and died shortly thereafter. Conclusions: Treatment of glioblastoma with this light-activated drug therapy was safe and tolerable in this study. An antivascular effect and tumor-cell apoptosis were seen histologically and confined to tumor.

[Table: see text]
Impact of extent of resection of glioblastoma multiforme (GBM) in the era of chemoradiation
Authors: Slotman B. J. , Eppinga W. S. , Reijneveld J. C. , Noske D. P. , Buter J. , Braam L. M. , Lagerwaard F. J.
Published: August 2020

e13029

Background: Controversy remains regarding the impact of the extent of resection (EOR) on survival in patients with GBM (Sanai 2008). The main reason for this is the fact that most studies were based on the surgeon's estimate of the EOR, which is known to be unreliable, rather than early postoperative MRI scans (po-MRI). Data for the current standard of postoperative chemo-radiotherapy (CTRT) have recently been reported, but suffer from the same limitation (Gorlia 2008). We studied the prognostic impact of the EOR using early (<72 hours) po-MRI scans in a cohort of GBM patients treated with CTRT in a single center. Methods: The results of 48 consecutive patients (35 male, 13 female; age 18–73 yrs) treated with surgery, followed by concurrent CTRT (60 Gy plus temozolomide) and adjuvant temozolomide were assessed with respect to survival and relapse patterns. EOR was determined by both the surgeon's estimation and early po-MRI scans that were available in all but two patients. EOR was categorized as biopsy (N = 3), partial resection (N = 24), major resection (N = 11; i.e., total resection according to the surgeon's report, but residual tumor on po-MRI), and total resection (N = 10; i.e. no residual tumor on po-MRI). Results: Median overall survival of the entire cohort was 18.9 months, and EOR was the only significant prognostic factor (p = 0.02) on multivariate analysis, which also included age, gender, performance, and radiotherapy target volume. 2-year survival rates improved significantly with increasing EOR, with 0%, 18.9%, 68.6%, and 100% for biopsy, partial-, major-, and total resection, respectively. In-field progression was the predominant pattern of failure in 27 out of 30 patients (90%) with a recurrence. Time to neurological progression (TNP) was significantly correlated with EOR (p < 0.001). Median TNP was 3.0 months for biopsy, 7.0 months for partial resection, 20.5 months for major resection, and was not reached for total resection. Conclusions: With the use of more effective local therapy in the form of surgery and CTRT, the prognostic impact of the EOR on survival appears to be higher than previously reported. This should be accounted for in future trials.

No significant financial relationships to disclose.
Patterns in the care of oligodendrogliomas and oligoastrocytomas: A single center experience
Authors: Kizilbash S. H. , Nadeau L.
Published: August 2020

e13034

Background: Although rare, oligodendrogliomas (ODs) and oligoastrocytomas (OAs) have established a unique identity due to their sensitivity to chemotherapy, especially if they exhibit combined loss of heterozygosity (LOH) of 1p and 19q. However, optimal management is still controversial and data is lacking on actual practice patterns. This study describes the epidemiology of ODs/OAs at a community based hospital in Michigan and evaluates the management of these tumors, especially with respect to 1p/19q LOH. Methods: A retrospective review was conducted of all cases of OD and OA that were managed at our institution from 1975 to 2007. 135 patients were isolated. Of these, 48 patients had already been evaluated for 1p/19q LOH. This latter subset underwent data collection and analysis. Results: 31 patients had low-grade tumors (either ODs or OAs) while 17 had high grade tumors (anaplastic ODs or anaplastic OAs). Of the low grade tumors, 35% had combined 1p/19q LOH. 71% underwent surgical resection, 35% received chemotherapy, and 26% received radiation therapy. As for the high grade tumors, 47% had combined 1p/19q LOH. 88% underwent surgical resection, 76% received chemotherapy, and 59% received radiation therapy. At a mean of 29 months of follow up, eight patients had tumor progression while 12 died. Median progression free survival (MPFS) for patients receiving chemotherapy was increased in patients with combined 1p/19q LOH, for both low-grade tumors (34 vs. 20 months) and high-grade tumors (14 vs. 8 months). Also, significantly more patients with low-grade tumors and combined 1p/19q LOH were offered chemotherapy when compared to those without 1p/19q LOH (64% vs 20%, p = 0.04, Fisher exact). However, in patients with high-grade tumors, knowledge of 1p/19q LOH did not significantly impact the choice to administer chemotherapy (88% vs. 67%, p = 0.67). Conclusions: Patients with ODs/OAs and combined 1p/19q LOH who have been treated with chemotherapy demonstrate increased MPFS when compared with those without this genotype. Despite this, determination of 1p/19q LOH significantly affects physician choice to offer chemotherapy only in patients with low-grade tumors, but not in those with high-grade tumors. A future study is in development to determine 1p/19q LOH status for the remaining 87 patients.

No significant financial relationships to disclose.
Addition of temozolomide to radiotherapy for treatment of newly diagnosed anaplastic gliomas
Authors: Simonelli M. , Banna G. , Navarria P. , Di Ieva A. , Zucali P. , De Vincenzo F. , Gaetani P. , Condorelli R. , Rodriguez y Baena R. , Scorsetti M. , Santoro A.
Published: August 2020

e13037

Background: Anaplastic astrocytoma (AA), oligodendroglioma (AOD), and oligoastrocytoma (AOA) are rare tumors showing variable outcome due to their histological heterogeneity and different chemo- and radio-sensitivity. The presence of an oligodendroglial component is associated with LOH 1p/19 and a prolonged survival. Currently, the addition of chemotherapy to radiotherapy (RT) for newly diagnosed anaplastic gliomas is not sustained by available data. We evaluated the addition of temozolomide (TMZ) to radiotherapy for newly diagnosed anaplastic gliomas in terms of tolerability, progression-free survival (PFS), and overall survival (OS). Methods: Since September 2004, following initial surgery, patients (pts) with histologically confirmed anaplastic glioma, Karnofsky Performance Status (KPS) ≥40, adequate organ function, no prior chemotherapy, were treated with RT to limited fields once daily at 2 Gy per fraction, 5 days a week, for a total of 60 Gy with concomitant TMZ (75 mg/m2 for 7 days a week) followed by 6 cycles of maintenance TMZ at 200 mg/m2 on days 1–5 every 28 days. LOH 1p/19q was assessed by fluorescence in situ hybridization (FISH). Results: Twenty-eight pts were treated, 20 males, 8 females, median age 51 (range, 22–75), median KPS 90 (range, 40–100). Eleven pts had AOD (39%), 10 AA (36%), 6 AOA (21%), 1 pt gliosarcoma (4%). Nine pts (32%) underwent tumor complete resection, 10 partial resection (36%), and 9 (32%) tumor biopsy. In 1 patient with AOD RT and concomitant TMZ were interrupted at 44 Gy because of cerebral oedema, while in 1 patient with AA maintenance TMZ was suspended due to cumulative myelosuppression. Other severe toxicities included one spondilodiscitis, and a cutaneous G3 rush. Frequent mild toxicities were grade 1–2 nausea/vomiting (17 pts-63%), and grade 1–2 asthenia (8 pts-30%). With a median follow-up of 18 months (range, 4–53), median PFS, and 1-year PFS were 14.8 months and 72.6%, respectively; 1-year OS was 84.3%, median OS was not reached yet. Data on LOH 1p-19q available on 16 pts will be presented. Conclusions: The addition of temozolomide to radiation therapy for newly diagnosed anaplastic gliomas is well tolerated and seems active; efficacy needs confirmation in a randomized clinical trial.

No significant financial relationships to disclose.
First-in-human, first-in-class, phase I study of a human monoclonal antibody CNTO 888 to the CC-chemokine ligand 2 (CCL2/MCP-1) in patients with solid tumors
Authors: Sandhu S. K. , Fong P. C. , Frentzas S. , Patnaik A. , Papadopoulos K. , Tromp B. , Puchalski T. , Berns B. , Tolcher A. W. , De-Bono J. S.
Published: August 2020

e13500

Background: The chemokine CCL2 promotes angiogenesis, tumor proliferation, migration and metastasis through PI3K and NFkB signaling. CNTO 888 is a human IgG1κ monoclonal antibody with high binding affinity for CCL2 and documented preclinical antitumor activity. Methods: Patients were administered a 90 minute infusion of CNTO 888 on day 1, day 28 and subsequently on a q14 schedule. Exploratory PD assessments include diffusion contrast enhanced CT, circulating tumor and endothelial cells, free and bound CCL2 levels, bone markers and paired tumor biopsies. Results: 21 patients in cohorts of 3–6 patients received repeated CNTO 888 infusions at 5 dose levels (0.3mg/kg, 1mg/kg, 3mg/kg, 10mg/kg, 15 mg/kg). A further 23 patients are currently being evaluated in 2 expansion cohorts; 10mg/kg (n=12) and 15mg/kg (n=11). No dose limiting toxicities were seen up to 15 mg/kg q14. Preliminary pharmacokinetic (PK) data for doses ≤ 10 mg/kg showed linear kinetics with a bi-exponential decline and a t1/2 of 4.4 - 8.7 days. The 10 mg/kg dose level resulted in steady-state minimum concentrations above that needed to inhibit chemotaxis and calcium mobilization in preclinical studies. Dose-dependent increase in bound CCL2 levels of > 1000-fold seen following treatment, supports target modulation. 2 patients demonstrated stable disease (SD) > 6 months at 15mg/kg CNTO 888 (ocular melanoma and neuroendocrine tumor). Another patient at 0.3mg/kg CNTO 888 with ovarian cancer had 50% CA125 decline and SD for 10 months. Conclusions: CNTO 888 is well tolerated with no DLTs when administered up to 15mg/kg q14. Preliminary evidence of antitumor activity is reported.

[Table: see text]
A phase I trial of liposomal doxorubicin (D), bevacizumab (A), and temsirolimus (T) in advanced malignancy
Authors: Moroney J. W. , Coleman R. L. , Hong D. S. , Wheler J. J. , Ng C. , Bodurka D. C. , Falchook G. , Naing A. , Helgason T. , Kurzrock R.
Published: August 2020

e13508

Background: Liposomal doxorubicin (D) and bevacizumab (A) are active drugs in multiple malignancies. Unfortunately, resistance mechanisms have been described for each that limit their efficacy following repeated exposure. These include aberrant activation of alternate signaling pathways, such as PI3K/AKT/mTOR and upregulation of hypoxia inducible factor (HIF-1α). We therefore added temsirolimus (T), an agent known to inhibit mTOR and to downregulate HIF-1α, to the combination of D and A. The objectives of this trial were to assess the safety of this combination, obtain preliminary efficacy data and to identify biologic correlates for treatment response. Methods: D, A and T were administered intravenously on a 21 day cycle. D, A and T were given day 1, and T was administered alone weeks 2 and 3. A standard 3+3 trial design was used for dose escalation; 6 dose levels are planned. Patient serum and biopsies were also collected pre- and post-treatment for batched analysis to assess biologic response correlates. Results: 6/12 treated patients are evaluable (remaining patients have not yet completed 1st restaging). 5 patients are male; median age (all patients) 53, range 12 to 59. Median number of prior treatments = 5, range 2 - 8. At first restaging, 2/2 patients with endometrial cancer were found to have ≥ 25% decrease in tumor size (RECIST), and one patient with colorectal carcinoma had a 15% decrease. 1 patient had stable disease. One of the patients with endometrial cancer and extensive intra-abdominal disease who showed rapid tumor regression (≥ 25% decrease at 2 months) developed an entero-colonic fistula, and chose hospice care. Grade 2 stomatitis and fatigue (CTCAEv3)have also been seen. The current doses being used are 20mg/m2 of D and 5mg/m2 of A every 21 days, and 25mg of T every 7 days (dose level 3). Conclusions: Preliminary data indicate that the combination of D, A and T has anti-tumor activity and is well tolerated at the doses used. Patients with intra-abdominal disease who experience rapid tumor regression may be at risk for fistula formation. Biomarker analysis for modulation of the mTOR signal (via PI3K mutations or other aberrations) and the HIF-1α pathway is ongoing.

No significant financial relationships to disclose.
Results of a phase I study to evaluate the feasibility, safety, and biological effects of intravenous administration of wild-type reovirus with docetaxel to patients with advanced malignancies
Authors: Rudman S. M. , Comins C. , Mukherji D. , Coffey M. , Mettinger K. , Protheroe A. , Harrington K. J. , Pandha H. , Spicer J. F.
Published: August 2020

e13524

Background: Reovirus has minimal pathogenicity in humans but selectively replicates in cells with activated Ras. Wild- type reovirus serotype 3 Dearing strain (Reolysin) has selective antitumor activity in vitro, in murine models, and after systemic delivery in humans in phase 1 trials. Synergistic tumour kill has been observed combining reovirus with taxanes in a range of cancer cell lines and in vivo. Methods: Patients were treated in an open-label, dose-escalating, phase I trial and received 3- weekly 75mg/m2 docetaxel i.v. and reovirus i.v. (day 1–5 of first week inclusive). Reovirus was administered at a starting dose of 3x109 tissue culture infectious dose (TCID50) and then increased to 1 x 1010 and 3 x 1010 TCID50. Primary endpoints were to determine the maximum tolerated dose (MTD), dose limiting toxicity (DLT) and to recommend a dose and schedule for future investigation. Secondary endpoints were to evaluate pharmacokinetics, neutralizing antibody development, cell- mediated immune response and anti-tumour activity. Results: 17 patients were treated (15 males, median age 60 years). No MTD has been reached. DLT's observed were G4 neutropenia (and a recurrent perianal abcess) and G3 rise in AST. Other toxicities observed were fatigue, hypotension and neutropenic sepsis. At present, 5 patients remain on treatment. We have observed 2 partial responses (breast and gastric carcinoma) and 10 patients had stable disease as best response. Conclusions: Reovirus is well tolerated when administered in combination with intravenous docetaxel, with predictable toxicity observed. The recommended dose has been defined at 3x1010 TCID50 and phase II studies are planned. Objective radiological evidence of anticancer activity for this combination has been observed.

[Table: see text]
Dose finding study of the combination of satraplatin and gemcitabine in patients with advanced solid tumors
Authors: Donato Di Paola E. , Alonso S. , D’Alessio A. , Giuliani R. , Calabrò F. , Messina C. , Zivi A. , Squilloni E. , De Marco S. , Sternberg C.
Published: August 2020

e13534

Background: The potential advantage of combining satraplatin (S) a novel oral platinum with Gem is attractive. MTD and DLT of combination S and Gem in patients (pts) with advanced solid tumors was evaluated. Methods: Cohorts of 3–6 pts (modified Fibonacci) received escalating doses of i.v. Gem on days (d) 1, 8 and 15 Q 28 d followed by oral S on d 1–5. Seventeen pts with metastatic solid tumors were separated into 2 groups: A) Pts that had progressed following cytotoxic therapy and B) Pts who had received no prior chemotherapy. Starting dose was Gem 800 mg in both groups, S 40 mg and 60 mg for A and B respectively. Results: Group A. 6 previously treated pts with 1 or 2 regimens (3 prostate, 1 hepatocarcinoma, 1 bladder and 1 thymic ca) received 25 cycles, median 2 (2–12). 2 DLTs (G3 transaminases) were observed in 6 pts treated at level 1. Other G3 major toxicities were: thrombocytopenia (1 pt) and diarrhea (1 pt). 2 pts had PSA declines, with TTP of 630 days in 1 of them. Group B. 11 pts with no prior chemotherapy (4 hepatocarcinoma, 4 pancreas, 1 renal, 1 unknown origin and 1 gallbladder), received 38 cycles, median 2 (1–12). 1 DLT (G3 diarrhea) was observed in 8 pts treated at level 1 (2 not evaluable; received Gem d1 only), DLT (G3 thrombocytopenia) was observed in 3 pts treated at level 2 (Gem 1000, S 60). Other G3 toxicities were: thrombocytopenia (3 pts) and neutropenia (3 pts). 1 CR (pancreas) and 1 PR (gallbladder) were observed. Gem d8 or d15 was omitted in 11 of 17 pts during the 1st cycle. Conclusions: In this study the combination of S and Gem showed a clinically acceptable toxicity profile with promising antitumor activity. However, since in cycle 1, it was not possible to administer Gem on both d8 and d15 on 11 occasions, a 2nd study was initiated with S d1–3 and Gem d1 and 8 given on a Q 21 d schedule. Sponsored by GPC Biotech

No significant financial relationships to disclose.
Phase I study of gemcitabine, docetaxel, and imatinib in refractory and relapsed solid tumors
Authors: Saraiya B. , Karantza-Wadsworth V. , Stein M. N. , Chugh R. , Mehnert J. , Moss R. , Lin Y. , Poplin E.
Published: August 2020

e13538

Background: The combination of the tyrosine kinase inhibitor imatinib with cytotoxic chemotherapy targets multiple pathways of tumor progression. In a previous phase I study, the combination of gemcitabine and imatinib was tolerable and had broad activity. The maximally tolerated dose (MTD) was gemcitabine 1500 mg/m2/150 minute and imatinib 400 mg days 1–5, 8–12, and 15–19. Given the activity seen when combining gemcitabine and docetaxel in some solid tumors, this phase I trial studied the addition of docetaxel to gemcitabine/imatinib. Methods: Twenty patients with relapsed/refractory solid tumors were enrolled in this IRB-approved study at the Cancer Institute of New Jersey and University of Michigan. The mean age was 64, mean ECOG PS 1. Five patients had lung cancer; 5, sarcoma; 3 ampullary-biliary tumors; 2 mesothelioma and bladder, 3, other. Imatinib was administered at 400 mg daily on days 1–5, 8–12 and 15–19. Gemcitabine was started at 600 mg/m2 at the fixed dose infusion of 10 mg/min on days 3 and 10 and docetaxel at 30 mg/m2 on day 10. Results: Because of unexpectedly severe hematological toxicities seen with escalating either gemcitabine or docetaxel, the protocol was amended to eliminate days 15–19 of imatinib. The MTD is gemcitabine 600 mg/m2, on days 3 and 10, docetaxel 30 mg/m2 on day 10, and imatinib 400 mg PO given on days 1–5 and 8–12. The dose limiting toxicities were neutropenic fever, pleural and pericardial effusion after cycle 1 of chemotherapy. The best response achieved was stable disease at 6 cycles in one patient each with mesothelioma and non small cell lung cancer (NSCLC) at the MTD. Two other patients with NSCLC had stable disease at 4 cycles. Discussion: An unexpectedly low MTD for this triplet was identified, an outcome different from prior experience with the doublets gemcitabine/imatinib or gemcitabine/docetaxel where much higher dosages are tolerated. Our results suggest possible drug-drug interactions that amplify toxicities with little initial evidence of improved tumor control. Given the unexpectedly high toxicity of the combination of gemcitabine, docetaxel and imatinib at low dosages, further development of this regimen is not indicated.

[Table: see text]
Scalp cooler efficacy to reduce anthracycline-induced alopecia and its QOL impact in breast cancer
Authors: El-saka R. O. , El-Husseiny G. , Rostom Y. , Salama A.
Published: August 2020

e13539

Background: Hair loss is a common, unavoidable, and stressful side effect of chemotherapy. This work was performed to evaluate the role of scalp cooling in reducing anthracycline-induced hair loss and its impact on Quality of life (QOL). Methods: The study was conducted from July 2007 to August 2008. It included 120 females with breast cancer, treated in adjuvant setting. Patients were chosen according to certain criteria (age ≤ 70 years, WHO performance status 0–1, no cardiac disease, no serious psychiatric conditions, no previous chemotherapy). Patients were divided randomly into 2 groups according to whether scalp cooler was used or not during chemotherapy. Chemotherapy consisted of doxorubicin (50 mg/m2), 5-FU (500 mg/m2) and cyclophosphamide (500 mg/m2) for 6 cycles. Paxman Scalp Cooler was used. The cap was applied 20 minutes before, during and 2 hours after infusion. Hair loss was assessed using WHO criteria at each cycle and after 6 cycles of chemotherapy. QOL was assessed using EORTC QLQ-C30 and BR23. Results: After 4 cycle, 61.7 % of patients in scalp cooling group had grade 4 hair loss compared to 81.7 % of patients in control group. After 6 cycles, 85% of patients in scalp cooling group experienced grade 4 hair loss compared to 100% of patients in the control group. Only 9 patients (15%) in the scalp cooling group developed grade 1–2 hair loss. No significant relation was found between the degree of hair loss and the liver function tests. Most patients (73.3%) were comfortable during cooling. QOL scores were comparable between the two groups except for emotional functioning and body image. In the hair loss group, 71.2% of patients showed severe disturbance of emotional functioning and 54.1% of patients had moderate disturbance in body image. In hair preservation group (9 patients), 77.8% developed moderate disturbance of emotional functioning and all patients had mild disturbance in the body image. Conclusions: The role of scalp cooling is limited at the total dose of 300 mg/m2 doxorubicin. It may be more effective with fewer cycles or less aggressive drug combination. Hair loss affects various aspects of QOL, especially emotional functioning and body image. More time is needed to assess the long term effect of hair loss on QOL and the incidence of scalp metastasis in the two study groups.

No significant financial relationships to disclose.
Antitumor activity of a new cholesterol derivative (24-ethyl-cholestane- 3β, 5α,6α-triol) in solid tumors
Authors: Habib N. , Daaboul H. , Hajj G. , Jabbour A. , Kassem N.
Published: August 2020

e13541

Oxysterols are oxygenated derivatives of cholesterol. They have nuclear receptors and have been shown to pass cell membranes and the blood-brain barrier at a faster rate than cholesterol itself. In addition, oxysterols have been ascribed a number of important roles in connection with cholesterol turnover, atherosclerosis, apoptosis, and necrosis. Oxysterols have been shown to have antitumor effects on experimental models. These compounds however may be toxic and to our knowledge, although some derivatives have been tested in animals, none have reached the clinical level. 24-ethyl-cholestane- 3β,5α,6α-triol is a new oxysterol developed in our lab. An oral form of this compound has been tested in mice and rats and has shown neither acute nor chronic toxicity. It has also been tested on animal tumor models and on human cancer xenografts. The results of these tests were very promising showing an anti-tumor activity on a panel of tumor cell lines. Our experiments on humans have shown no toxicity for this drug. Many patients with a variety of solid tumors all of whom have received many lines of chemotherapy and considered refractory to any conventional therapy have received this new drug. We observed in most of these patients a rapid and dramatic improvement in their quality of life and a fast pain control. Some patients could stop taking high doses of opioids within 1 or 2 days. A high rate of clinical benefit has also been observed in a variety of solid tumors including lung, breast, pancreatic, ovarian and uterine cancers, associated in some cases with a sharp decrease in tumor markers. Some patients with brain tumors (glioblastomas) have also responded to this therapy.

No significant financial relationships to disclose.
The comparison of epirubicin-treated MCF-7 mammosphere cells to the treated monolayer cells
Authors: Huang M. , Zhang F. , Xu Y. , Wang H. , Lin S. , Zhang Y.
Published: August 2020

e13542

Objective: To explore the different effects of epirubicin on the MCF-7 mammosphere cells and the monolayer cells. Methods: MCF-7 cells were cultured in suspension to generate primary mammospheres. The inhibitory effects of epirubicin on MCF-7 mammosphere cells and the monolayer cells by were measured by MTT assay. The change of CD44+CD24- expression and cell cycle distribution in MCF-7 mammosphere cells and the monolayer cells under epirubicin condition was analyzed by flow cytometry. Results: The cell inhibition was lower in MCF-7 mammosphere cells than that in the monolayer cells when induced by the same concentration of epirubicin (>100 ng/ml),(P<0.01). The CD44+CD24- expression was significantly higher in MCF-7 mammosphere cells than that in the monolayer cells under 400 ng/μl epirubicin for 72 h, (22.8% ± 4.8% Vs 3.3% ± 0.8%),(P<0.01). The cell cycle indicated that MCF-7 mammosphere cells had higher proportion of G0/G1 phase than the monolayer cells, (74.33% ± 3.20% Vs 53.40% ± 3.45%) (P<0.01). Epirubicin had little effect on the G0/G1 phase of MCF-7 mammosphere cells and the monolayer cells, but the S phase and G2 phase was not the case. Conclusion: Epirubicin had lower inhibitory effects on MCF-7 mammosphere cells and it can be used to enrich breast cancer stem cell. Epirubicin had lower effect on the G0/G1 phase of MCF-7 mammosphere cells as compared with control.

No significant financial relationships to disclose.
Clinical benefit of catumaxomab in malignant ascites in patient subpopulations in a pivotal phase II/III trial
Authors: Parsons S. , Hennig M. , Linke R. , Klein A. , Lahr A. , Lindhofer H. , Heiss M.
Published: August 2020

e14000

Background: Parsons et al. (ASCO 2008) reported the results of a pivotal phase II/III trial in patients with malignant ascites due to epithelial cancer. Treatment with the trifunctional antibody catumaxomab resulted in a clinically relevant prolongation of puncture-free survival, defined as the time to the next therapeutic puncture or the time to death, whichever occurred first. Malignant ascites is a typical late-stage manifestation of cancer associated with a poor prognosis and survival. Effective treatment options are limited. It is thus of special interest if all patient subgroups derive objective benefit from treatment. Methods: A post-hoc analysis was performed on the 258 patients with epithelial tumors treated with catumaxomab + paracentesis or paracentesis alone (control) in the pivotal trial to investigate any association between the primary endpoint (puncture-free survival) and the primary tumor, metastases, or other prognostic parameters. Results: Puncture-free survival was lower in patients with non-ovarian vs ovarian tumors and those with a poor prognosis (metastases vs no metastases, elderly vs younger, or low vs serum protein level). However, there was always a statistically significant treatment effect for catumaxomab compared with the respective control group (p≤0.0001, log rank test, for all comparisons) (see table). Conclusion: Catumaxomab demonstrated a significant clinical benefit in patients with malignant ascites independent of the primary tumor or other prognostic factors. Therefore, catumaxomab could be considered as a treatment option for patients with a poor prognosis.

[Table: see text]

[Table: see text]
Association of copy number variants in colorectal liver metastases with 5-fluorouracil resistance
Authors: Watson R. G. , Muhale F. , Thorne L. , Yu J. , O’Neil B. , Hoskins J. M. , Myers M. O. , McLeod H. L. , Auman J. T.
Published: August 2020

e14502

Background: Resistance to 5-fluorouracil (5-FU) represents a major contributor to cancer-related mortality in advanced colorectal cancer patients. Previous work has shown that thymidylate synthase (TYMS) copy gains were associated with significantly shorter survival, while increased expression of thymidine phosphorylase (TP) led to greater sensitivity to 5-FU in vitro. We assessed TYMS and TP copy number in colorectal liver metastases from untreated patients and patients treated with 5-FU in an effort to elucidate the underlying molecular mechanisms for 5-FU resistance. Methods: Liver metastases were procured from 59 patients who had received 5-FU within 6 months preceding liver resection (treated samples) and from 46 patients who had received no 5-FU treatment in the 6 months prior to their liver resections (untreated samples). DNA copy number of TYMS and TP was evaluated in frozen colorectal liver metastases using quantitative real time PCR. Results: For TYMS, 8.9% of the treated samples showed copy number gain, as compared to 4.8% of the untreated samples. Loss of TYMS was rare, with only 1 and 2 occurrences seen in the treated and untreated samples, respectively. For TP, both groups exhibited similar copy number gains (25% for treated, 29% for untreated); however, a greater proportion of the treated samples exhibited loss of TP (20% vs. 10%). Collectively, the treated samples have a much higher incidence of genetic alterations potentially associated with resistance (TYMS gain or TP loss) than untreated samples (30% vs. 10%, p = 0.03 Fisher exact test). Conclusions: Colorectal liver metastases treated with 5-FU exhibit DNA copy variants that may reduce 5- FU's efficacy. Our data suggest that these genetic alterations may have important implications for the management of advanced colorectal cancer patients with recurrent disease.

No significant financial relationships to disclose.
A phase I trial using patupilone (epothilone B) and concurrent radiotherapy for CNS malignancies
Authors: Fogh S. E. , Machtay M. , Werner-Wasik M. , Curran W. , Bonanni R. , Mallon G. , Axelrod R. , Andrews D. , Dicker A.
Published: August 2020

e14504

Background: Based on pre-clinical data indicating the radiosensitizing potential of Epothilone B, this study was designed to evaluate the toxicity and response rate of patupilone (EPO906), an anti-microtubule stabilizing agent, with concurrent radiotherapy in the treatment of patients with CNS malignancies. Methods: This phase I study evaluated the toxicities associated with patupilone in combination with radiotherapy for the treatment of CNS malignancies in order to establish maximum tolerated dose (MTD). Eligible patients had recurrent gliomas (10), primary (5), or metastatic (17) brain tumors. Dose escalation occurred if no dose limiting toxicities (DLT) defined as any Grade 4–5 toxicity or Grade 3 toxicity requiring hospitalization or interruption of radiation therapy. Results: A total of 32 patients were enrolled. Five patients were treated with weekly patupilone at 1.5 mg/m2, 4 patients at 2.0 mg/m2, 4 patients at 2.5 mg/m2 and one patient at 4mg/m2. Based on sponsor recommendations, the protocol was changed to a q-3 week dosing schedule with a starting dose of 6 mg/m2. Seven patients were treated in the 6 mg/m2 group, 6 patients in the 8 mg/m2 cohort and 5 patients in the 10 mg/m2 group. Radiation treatment was determined by the patient's diagnosis. Primary CNS malignancies received a median dose of 60 Gy in 1.8–2.0 Gy fractions. CNS metastases received whole brain radiation with a median dose of 37.4 Gy in 1.8–2.5 Gy fractions and patients with recurrent gliomas received stereotactic radiotherapy with a median dose of 37.5 Gy in 2.0–3.5 Gy fractions. No DLTs were observed in patients who received weekly patupilone or in the 6 mg/m2 q3wk cohort. One DLT (pneumonia/infection without neutropenia) was observed at the 8 mg/m2 q3wk group. In the subsequent dose level (10 mg/m2), two grade 4 DLTs occurred (renal failure and pulmonary hemorrhage) making 8 mg/m2 q3wk the MTD and recommended phase II dose. Median overall survival was 12 months for recurrent gliomas, 15 months for primary brain tumors and 4 months for CNS metastasis. Conclusions: Combined with a variety of radiation doses and fractionation schedules, concurrent patupilone is well tolerated and safe with a MTD of 8 mg/m2 q3wk. A phase II study to characterize efficacy should be considered.

No significant financial relationships to disclose.
Phase I/II trial of oncolytic reovirus (Reolysin) in combination with carboplatin/paclitaxel in patients (pts) with advanced solid cancers
Authors: Karapanagiotou E. , Pandha H. S. , Hall G. , Chester J. , Melcher A. , Coffey M. , de Bono J. , Gore M. E. , Nutting C. M. , Harrington K. J.
Published: August 2020

e14519

Background: Reolysin, a wild type reovirus (Dearing strain), replicates preferentially in Ras-activated cancer cells. Preclinical data have demonstrated synergistic tumor kill when reolysin is combined with standard chemotherapies including platinum agents and taxanes, justifying the clinical evaluation of this drug combination. Methods: Pts were initially treated in an open-label, dose-escalating, phase I trial and received iv reolysin, d1–5, iv carboplatin (AUC5), d1, and paclitaxel (175mg/m2), d1, qw3. Reolysin was administered at a starting dose of 3x109 TCID50 and then increased to 1x1010 and 3x1010 TCID50 in cohorts of 3 pts. Primary endpoints for the dose escalation trial were to determine the maximum tolerated dose, dose limiting toxicity (DLT) and to recommend a dose for phase II studies. Secondary endpoints were to evaluate pharmacokinetics, immune response and anti-tumour activity. The primary endpoint for the phase II expansion cohort in head and neck (H&N) pts is to characterize response rate. Results: 17 heavily pre-treated pts (11 M, median age 55 yrs) with advanced cancer: H&N (10), melanoma (4), peritoneal/endometrial cancer (2), and sarcoma (1) have received 82 cycles of treatment to date; 4 pts are still on study. There were no DLTs in the dose escalation. Toxicities were mainly grade 1 and 2 and included: nausea, fatigue, vomiting, myalgia, fever, neutropenia, lymphopenia, thrombocytopenia and hypotension. This combination resulted in a blunting of antiviral immune response as compared to monotherapy virus. Response rates in 15 evaluable patients were partial response (PR) (4 pts), stable disease (SD) (6 pts) and progressive disease (5 pts). Of note, all PRs and 4/5 SDs were in H&N disease. Conclusions: The combination of reolysin and carboplatin/paclitaxel was well tolerated and resulted in disease control in the majority of pts. Significant responses in refractory H&N pts recommended this combination for phase II evaluation. Enrollment is ongoing and randomized studies are planned.

[Table: see text]
Development of radiolabeled mapatumumab and imaging in solid tumor patients who are treated with gemcitabine, cisplatin, and mapatumumab
Authors: Oldenhuis C. , Dijkers E. C. , Duiker E. W. , Fox N. L. , Klein J. L. , Gietema J. A. , Brouwers A. H. , Lub-de Hooge M. N. , de Vries E. G.
Published: August 2020

e14521

Background: Mapatumumab is a fully human agonistic monoclonal antibody (mAb) to the tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1). Mapatumumab combined with gemcitabine and cisplatin increased cytotoxicity in preclinical models and was safe in a phase 1 study. To study its biodistribution, 111Indium (111In) labeled mapatumumab was developed for γ-camera imaging and tested in mice. Subsequently, 111In-mapatumumab scintigraphy was performed in patients (pts). Methods: Mapatumumab was labeled with 111In. Labeling efficiency, radiochemical purity, stability and binding properties were determined in vitro. Biodistribution was studied at multiple time points in nude mice bearing human xenografts (SKBR3 or SW948). Tissue activity was expressed as % injected dose/gram tissue (%ID/g). In a feasibility study, gemcitabine 1250 mg/m2 IV on days 1 and 8, cisplatin 80 mg/m2 IV and mapatumumab 20 mg/kg on day 1 was administered to advanced solid tumor pts every 21 days. In cycles 1 and 3, pts underwent γ-camera imaging directly, and at day 1, 3, and 6 after 150 MBq 111In-mapatumumab IV (planar and single-photon emission computed tomography (SPECT)). Results: Labeling efficiency was 92.0% and radiochemical purity 96.0%. 111In-mapatumumab was stable in serum for 1 week at 37°C and specific TRAIL-R1 binding was maintained after labeling. In mice, high uptake was seen in liver (8.14 ± 0.75 %ID/g), kidneys (16.30 ± 1.75 %ID/g), spleen (7.25 ± 2.64 %ID/g) and bone (5.68 ± 1.31 %ID/g), with a maximum 24–72 hours (h) after tracer injection. Maximum uptake in the xenografts was observed after 72 h (7.55 ± 3.54 %ID/g for SKBR3 and 6.21 ± 2.03 %ID/g for SW948). Five pts have been enrolled in the ongoing clinical study. Known tumor lesions (by CT-scan) showed variable tracer uptake in 3 pts, while within pts not all known tumor lesions were positive on SPECT. Conclusions: Mapatumumab can be efficiently radiolabeled for clinical use. Preliminary results show that mapatumumab scintigraphy identifies some but not all tumor lesions in pts. This is the first demonstration that mAb targeting a TRAIL-R distributes to tumor tissues in patients and could potentially guide mapatumumab therapy.

[Table: see text]
Population pharmacokinetic (PK)/pharmacodynamic (PD) modeling and simulations for exposure‐;tumor response relationships: Motesanib in a phase II thyroid cancer (TC) trial
Authors: Lu J. , Claret L. , Sutjandra L. , Kuchimanchi M. , Stepan D. , Bruno R. , Melara R. , Sun Y.
Published: August 2020

e14528

Background: Motesanib is a highly selective, oral inhibitor of VEGF receptors 1, 2, and 3; PDGFR; and Kit that is being investigated for its antitumor activity. In a phase 2 monotherapy study, a response rate of 14% (per RECIST) was observed in patients (pts) with differentiated thyroid cancer (DTC; NEJM 359:31–42, 2008) compared with 1% in pts with medullary TC (MTC; Endocr Soc Ann Meeting 2007, abstract OR39–3). We evaluated the relationship between motesanib PK and tumor response, investigated whether differences in PK between MTC and DTC pts contributed to the observed difference in response, and simulated tumor response with different dose regimens in pts with TC. Methods: Data from the phase 2 TC trial were used for PK/PD modeling. The study enrolled 93 DTC and 91 MTC pts who received motesanib 125 mg once daily (QD). Motesanib concentrations were fitted to a 2- compartment population PK model. Estimates of pts’ PK parameters were used to calculate concentration and steady-state area under the curve values for motesanib, which were used as the exposure measures in population PK/PD modeling (ie, longitudinal exposure-tumor response modeling of drug effect on tumor growth dynamics). Monte Carlo simulations were used to evaluate the potential effect of doses other than 125 mg QD (75 mg and 100 mg QD) on tumor response in TC pts. Results: Clearance in MTC pts was 40% faster than in DTC pts (74 vs 44 L/h). The fit was significantly improved (P<0.001) when exposure instead of dose was used in the model. The exposure-tumor response model that incorporated the difference in exposure described change in tumor size well in both MTC and DTC populations. Clinical trial simulations using the preliminary model based on week 24 data predicted that DTC pts would achieve 19.7%, 15.7%, and 11.3% reductions in tumor size at week 24 following doses of 125 mg QD, 100 mg QD, and 75 mg QD, respectively. The actual change in median tumor size at week 24 following 125-mg QD dosing in DTC pts included in the PK/PD analysis was 17.9%. Conclusions: The use of 125 mg QD motesanib in DTC pts was supported by PK/PD modeling and Monte Carlo simulations. Differences in PK may explain the difference in tumor response observed in MTC and DTC patient populations.

[Table: see text]
A modeling framework to simulate motesanib efficacy in thyroid cancer
Authors: Claret L. , Lu J. , Sun Y. , Stepan D. , Bruno R.
Published: August 2020

e14553

Background: Motesanib is a highly selective, oral inhibitor of VEGF receptors 1, 2, and 3; PDGFR, and Kit with antiangiogenic and direct antitumor activity. A modeling framework that simulates clinical endpoints, including objective response rate (ORR; per RECIST) and progression-free survival (PFS), was developed to support clinical development of motesanib. This study evaluated the framework using results from a trial of motesanib in thyroid cancer (TC). Methods: Models for tumor growth inhibition (J Clin Oncol 24[18S]:abstract 6025, 2006) with drug effect driven by area under the curve (AUC) (as predicted by a population pharmacokinetic model), overall survival, and probability and duration of dose reductions were developed based on data from 93 differentiated TC (DTC) and 91 medullary TC patients who received motesanib monotherapy (125 mg once daily [QD]) in a phase 2 study (Horm Res 68[suppl 3]:28–9, 2007; NEJM 359:31–42, 2008). The full simulation framework was assessed in predicting dose intensity (starting dose of 125 mg QD), tumor size over time, ORR, and PFS. Dose-response simulations were performed in DTC patients. Results: Survival times followed a Weibull distribution with ECOG performance status, baseline tumor size, and change in tumor size from baseline at week 7 as predictors. The probability of dose reductions was dependent on time and AUC. Time to event Weibull models predicted the duration of dose reductions and dose interruptions. The models correctly predicted median daily exposure intensities up to week 24. The predicted ORR in DTC patients was 15.0% (95% prediction interval [PI], 7.5%-23.7%) compared with the observed ORR of 14.0%. Predicted median PFS was 40 weeks (95% PI, 32–49 wk) compared with the observed median PFS of 40 weeks. Dose- response simulations confirmed the appropriateness of 125-mg QD dosing in DTC: the modeling framework predicted no clinically relevant improvement in PFS would be obtained by dose intensification. Conclusions: This modeling framework (dose reduction/tumor growth inhibition/survival) will be an important tool to simulate clinical response and support clinical development decisions. Further evaluation of the model using additional datasets will be required.

[Table: see text]
LX1032: A potential new therapy for carcinoid syndrome (CS)
Authors: Pappas C. , Turnage A. , Frazier K. S. , Liu Q. , Brown P.
Published: August 2020

e14555

Background: Patients with metastatic CS experience a variety of symptoms due to increased serotonin (5-HT) produced by metastatic GI tumor cells. The enzyme tryptophan hydroxylase (TPH) catalyzes the rate-limiting step in the synthesis of 5-HT. Reducing 5-HT synthesis by TPH inhibition represents a new mechanism for potentially managing symptoms associated with CS. LX1032 is a novel, orally bioavailable TPH inhibitor designed to afford systemic exposure without affecting 5-HT synthesis in the CNS. Preclinical studies of LX1032 in multiple species confirmed systemic inhibition of 5-HT synthesis without changes in brain 5-HT levels. Methods: Single (n=47 subjects) and multiple (n=40 subjects) ascending dose studies with LX1032 were completed in normal volunteers; 24-hr urinary 5-HIAA and blood 5-HT were measured as biomarkers of 5-HT metabolism. Results: LX1032 produced a significant dose-dependent reduction in urinary 5-HIAA and blood 5-HT levels, with maximal reductions observed at doses at or above 500 mg, once daily, in the 14 day multiple ascending dose (MAD) study; the mean change from baseline in blood 5-HT was -30% for the 1500 mg (500 mg TID) dose group. Single doses up to 500 mg were well tolerated with no evidence of dose limiting toxicity or tolerability; GI related adverse events (nausea, emesis, and diarrhea) started to emerge at the 1,000 mg dose level and became dose-limiting at the 1,500 mg single dose level. Multiple doses were well tolerated at all dose levels up to 1.500 mg (500 mg TID). Adverse events (AEs) were mild to moderate and no serious AEs occurred; a dose-dependent, mild increase in hepatic transaminase levels was observed in the MAD study. Conclusions: Inhibiting TPH, and thereby reducing peripheral 5-HT production, represents a potential new approach for managing symptoms in CS patients. LX1032 is a novel, orally bioavailable TPH inhibitor that significantly reduced 5-HT production at well tolerated dose levels. The favorable safety profile and observed decrease in urinary 5-HIAA and blood 5-HT levels indicate that LX1032 could be used to lower 5-HT as a potential new approach for managing hyperserotoninemia-related complications of CS, and support studies of the compound in CS patients.

[Table: see text]