bluuebunny/crossref_metadata_2025 huggingface dataset:
Final results of a phase I study using oral temozolomide (TMZ) daily for 14 days with weekly paclitaxel in patients (pts) with advanced malignancies
Authors: Figueroa J. A. , Tafur I. , Close D. , Cardona P. , Cruz J. , Quick D. , Shalaby I. , Dinunno L. , Ortiz P.
Published: March 2020

12020

Background: TMZ is an alkylating agent with activity in a variety of neoplasms. The optimal schedule of administration for TMZ has not been established and only a few studies have studied it in combination with other agents. Repair of TMZ-induced DNA damage is associated with the activity of O-6 alkylguanine-DNA-alkyl transferase (AGT). Preclinical and clinical data indicate that prolonged exposure to TMZ results, not only in enhanced DNA alkylation, but also in depletion of AGT. This serves as the rationale to study TMZ using protracted schedules. Methods: The aim of this study was to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of oral TMZ given daily for 14 days with weekly paclitaxel in pts with advanced cancers. Forty-five pts received 136 cycles of TMZ at escalating doses (50, 75, 100, 125 and 150 mg/m2/day × 14 days) plus paclitaxel at 80 mg/m2 on days 1, 8, and 15. Pts were stratified as lightly (LP) or heavily (HP) pretreated and MTD defined as the dose level (DL) at which 1/6 patients developed DLT. Results: Twenty-four LP patients were treated at 5 DLs with all but one evaluable for toxicity. Febrile neutropenia and grade 3 thrombocytopenia were the DLTs. MTD in this group was the 125 mg/m2/day level. Twenty-six HP were treated at 5 DLs and 21 were evaluable for toxicity. Febrile neutropenia and grade 3 thrombocytopenia were the DLTs. MTD for this group was also 125 mg/m2/day. Thirty-eight (84%) pts were evaluable for response after 2 cycles of therapy. Three (8%) pts had a partial response (lung, lymphoma, ependymoma), 20 (53%) remained stable and 15 (39%) developed disease progression. Six (16%) pts remained stable for 6 cycles or more (2 sarcomas, 2 lung, 1 pancreas, 1 glioblastoma). Conclusions: We concluded that combining oral TMZ at a dose of 125 mg/m2/day for 14 days with standard-dose weekly paclitaxel is safe in both HP and LP pts.

[Table: see text]
The influence of partial hepatectomy (PH) on pharmacokinetics of docetaxel (D) in sprague-dawley rats (SDR) with experimental mammary neoplasm models (EMNM)
Authors: Demirkan H. B. , Yilmaz O. , Çoker C. , Gümüstekin M. , Batu J. , Bülbül M. , Canda T. , Alakavuklar M.
Published: March 2020

12021

Background: Docetaxel (Taxotere-Aventis) is used in the treatment of breast, lung, head and neck, prostate and ovarian cancers. Recently, PH for isolated hepatic metastases of breast cancer has been reported in Japan and France. PH is an experimental model of hepatic insufficiency. Therefore we aimed to study the influence of PH on pharmacokinetics of D in SDR with EMNM. Methods: After the approval of Local Ethical Commitee on Laboratory Animal Researches, 40 female 50-day-old SDR were injected with 50 mg/kg body weight N-nitroso-N-methylurea (NMU) in 09% NaCL solution intraperitoneally. 5 female 50-day-old SDR were only injected with 09% NaCL solution intraperitoneally. After 6-months follow-up period for the formation of EMNM, 8 rats in the Group D+H were hepatectomized partially. Baseline venous blood samples were taken. 24 hours after PH, 6 rats were alive. There were 8 rats in the Group D (without hepatectomy). Before chemotherapy and 1 hour after intravenous infusion of 5 mg/kg body weight D, blood samples were taken for biochemical analyses from both groups. 5., 15., 30. minutes and 1., 2., 4., 5. hours after D infusion, arterial blood samples were taken for pharmacokinetic analyses. Biochemical and Pharmacokinetic tests (BPT) were done by auto-analyzer Hitachi Modular Analytic and HPLC (High Performance Liquid Chromatography) respectively. Area under the concentration-time curve [AUC (0–60)] was determined for each group. Statistical analyses were done by SPSS 11.0 for Windows at the 5% significance level. Results: PH affected liver functions and serum albumin levels negatively (p = 0.028). Although D infusion didn’t affect serum ALT and bilirubine levels, low serum albumin was detected 1 hour after chemotherapy in both groups (p= 0.028 and p= 0.030). AUC(0–60) of plasma D in hepatectomized rats were greater than the other group (p = 0.015). Conclusion: During the treatment of cancer patients in posthepatectomy period with taxanes (D), dose adjustment must be done. In both groups, statistically significant low serum albumin after D infusion may be as a result of decreased intertitial fluid pressure, albumin extravasation and edema formation caused by taxanes. Physiological and preventive studies are needed.

No significant financial relationships to disclose.
Implication of clinical and paraclinical covariates in the pharmacokinetics of high dose MTX (HD-MTX) in patients with osteosarcoma
Authors: Dupuis C. , Mercier C. , Salas S. , Yang C. , Deville J. , Balti M. , Ciccolini J. , Iliadis A. , Baciuchka M. , Duffaud F. , Favre R.
Published: March 2020

12022

Background: Methotrexate (MTX) is a mainstay in the treatment of ostosarcoma. MTX is characterized by a narrow therapeutic window, combined with high intra- and inter-patient variabilities. In our institute, safe administration of high dose MTX is ensured by using bayesian, adaptive dosing with feedback strategy. In patients with osteosarcoma, up to 20g/patient MTX is administred following an 8h infusion. From the 6th hour, the dose is tailored according to individual pharmacokinetics parameters, determined in real-time from two early sampling times (T3.5, T4.5) and a reference population. This method enables accurate adjustment of most patients around a target Cend of 10−3 M/L. Still, 15–20% of the patients show reduced MTX elimination rate, thus leading to an overlasting hospitalization time with folate rescue required to prevent severe toxicities. In this work, we studied the relevance of clinical or pareaclinical covariates likely to be associated with the MTX clearance so as to identify patients at risk of impaired elimination with subsequent increase in iatrogeny. Methods: This retrospective study was performed on 49 patients treated with HD-MTX. Population PK parameters were computed using Apis and NonMem routines. The second objective was to predict for how long MTX plasma concentration would remain above 0.2 μM/L, the threshold associated with toxicity, upper which folinic acid is required. Finally, simplified sampling strategy for folate rescue protocol was developed. Results: two covariates (creatinemia and ALAT) have been identified as being correlated with MTX clearance. Besides, simulation of the 0.2μM/L threshold reaching showed that it was possible to predict accurately the time most patients can leave the hospital safely. This, would have led to reduce the hospitalization stay by at least one day in 25% of the patients, thus optimizing their life quality while being cost-effective. Conclusions: in this study, we showed that high dose MTX can be administred safely using an adaptive dosing with drug monitoring strategy. Besides, modelling of MTX PK parameters leads to an accurate estimation of the elimination pattern of this drug, thus enabling a planification of the time patients leave the hospital.

No significant financial relationships to disclose.
Phase II study of docetaxel (T), carboplatin (C), and gemcitabine (G), in advanced tumors of unknown primary site
Authors: Mel Sr. J. R. , Provencio M. , Balañá C. , López-Vega J. M. , Casado A. , Segura A. , Cervera J. M. , Martí J. L. , Munárriz J. , Arranz F.
Published: March 2020

12028

Background: Treatment of tumors of unknown primary site is still a challenge nowadays. D, C and G have shown high activity in solid tumors. We designed this study to evaluate activity and toxicity profile of a combination of these three drugs, according a protocol previously tested in lung cancer (Pectasides D, et al. J Clin Oncol 1999). Methods: Patients with histological diagnosis of solid tumor of unknown primary site, age ≥ 18 years old, ECOG PS ≤ 2 and adequate bone marrow, renal, hepatic and cardiac functions, were included. Treatment consisted in (d1): C AUC = 5 and G 800 mg/m2 IV; and d8): D 75 mg/m2 and G 800 mg/m2 IV, with G-CSF support. Courses were repeated every 28d for a maximum of 8 cycles, unless progression, unacceptable toxicity or consent withdrawal, whichever comes first. Results: Sixty-three patients have been included: median age was 66 years old (28–90), 89.6% of patients had ECOG PS 0–1. Tumor histology included adenocarcinoma (65.1%), undifferentiated (17.5%) and carcinoma (7.9%) or large-cell carcinoma (1.6%). Main metastatic sites were lung (49%), liver (44%), lymph nodes (41%) and bone (25%). Previous treatments included surgery (20.6%), chemotherapy (1.6%) and radiotherapy (12.7%). Treatment: 296 cycles (median 6, range 1–11) were administered. Median relative dose intensity was 96% for D, C and G. Efficacy: 8 patients achieved CR and 15 PR, resulting in an overall response rate of 36.5% (95% CI: 24.6–48.4%). Main grade III/IV toxicity per patient were asthenia (19%), diarrhea (18%), mucositis (11%), vomiting (10%), nausea (6%), thrombocytopenia (38%), neutropenia (24%), leucopenia (19%) and anemia (13%). Febrile neutropenia was observed in 2 patients (3%). Fourteen patients (22.2%) experienced severe toxicity: 9 of them were dropped out and 5 were toxic deaths (2 sepses, 2 pancytopenia and 1 pulmonary thromboembolism). Median time to treatment failure was 6.0 months (95% CI: 4.8–7.1), median TTP was 10.8 months (95% CI: 8.6–13.0) and median OS was 11.8 months (95% CI: 9.4–12.3), with a median follow up of 10.8 months. Conclusions: Despite the combination of D, C and G shows high activity in tumors of unknown primary site, its toxic death rate is > 5%. Thus, our group is working no longer with such a triplet combination.

No significant financial relationships to disclose.
Immunological effects after an adoptive cellular immunotherapy with reactivated autologous memory T-Cells from bone marrow
Authors: Schuetz F. , Rom J. , Ehlert K. , Schirrmacher V. , Schneeweiss A. , Sohn C. , Beckhove P.
Published: March 2020

12502

Tumor-reactive CD4 and CD8 memory T cells (MTC) can be found in bone marrow (BM) of the majority of primary and metastatic breast cancer patients. In xenotransplant mouse models these cells, upon specific re-activation ex vivo, mediated efficient rejection of autologous breast tumors suggesting that the polyclonal natural MTC repertoire possesses therapeutic potential. In order to clinically exploit these anti-tumor capacities we treated 11 advanced metastasized breast cancer patients with autologous, tumor-reactive, reactivated MTC of BM in a phase-1 trial. Activation of T cells was done by MCF-7 lysate pulsed dendritic cells (DC). After reactivation both, T cells and pulsed DC were injected once intravenously. Peripheral blood was drawn on day 0, 1, 7, 14, 28. BM-re-aspiration was done on day 28 and 84. While TAA-reactive memory T cells were absent in the peripheral blood (PB) before therapy, 5 from 11 patients (=responders) showed TAA-specific PB T cell reactivity 7 days after therapeutic cell application suggesting a massive proliferation and mobilization into the blood of TAA-reactive T cells in these patients. A comparison of responders to adoptive cellular immunotherapy with non-responders revealed differences in the numbers of therapeutic cells that could be generated ex vivo and in the decreased frequency of tumor-reactive MTC in responders’ BM on days 28 and 84 which could be expained by a mobilization due to in situ activation by co-transferred DCs or due to local or systemic cytokine signals by transferred, activated T lymphocytes. Such effect might have contributed to the high numbers of circulating TAA-reactive T cells observed 7 days after the transfer. Furthermore we observed different concentrations of IL-4, IL-10, TNF-α, and INF-γ in PB and BM between the two groups leading to the hypothesis of a polarization in T cell responses (T1 type in responders vs T2 type in non-responders).

No significant financial relationships to disclose.
Tandem HD-chemotherapy and myeloablative radioimmunotherapy with 131I-anti-CD20 rituximab in relapsed and refractory B-cell lymphoma: Results of a phase II study of the German RAIT Study Group
Authors: Hohloch K. , Wulf G. , Jung W. , Stitz E. , Meller J. , Glass B. , Truemper L. , Griesinger F.
Published: March 2020

13007

Background: Radioimmunotherapy has been shown to be effective in CD20 + B-cell lymphomas. Both non-myeloablative as well as myeloablative regimens have been employed for low grade and high grade lymphomas with impressive response rates and remission durations. Recently, the Press group and our group published data on myeloablative 131-I-anti-CD20 RAIT with high response rates and favourable long term survival especially in follicular lymphomas and transformed FL. Therefore, a phase II study is currently being done within the German Radioimmunotherapy Group, interim analysis data are presented. Methods: Patients were to receive R-Dexa-BEAM, followed by BEAM and HD-RAIT 2–6 months after BEAM. 131-I-Rituximab was administered with a maximum kidney and lung dose of 25 Gy. Sample size was calculated to be 16 to evaluate toxicity and feasibility of the tandem approach as primary endpoint. Results: 16 pts with relapsed (14) or primary refractory (2) B-cell lymphomas (FLI,II: 4pts; DLBCL: 4pts (all early relapses); transformed FL: 6 pts; MCL:1 pt, marginal zone lymphoma: 1 pt) were treated with 1 (15 pts) or 2 cycles (1 pt) of R-Dexa-BEAM. 13/16 pts achieving PR (5) or CRu (8) were treated with BEAM, 2 pts with PD and 1 with subdural hematoma were drop outs. After BEAM, 9/13 pts were in CR, 3/13 PR, 1/13 PD. Of 12 responding pts, 6 received HD-RAIT (1 pancytopenia, 1 hepatic, 2 pulmonary toxicity, 3 too early). After HD RAIT, 5/6 pts were in CR, 1 in PR. 4/6 pts (3 CR, 1 PR) are alive for 22–31 months, 2 pts died in CR, 1 of interstitial lung disease 2 months after HD-RAIT, 1 pt of pneumonia 8 months after HD-RAIT. Conclusions: Myeloablative RAIT is a feasible and effective treatment modality for relapsed poor prognosis CD20+ B-NHL not having severe toxicity due to the salvage regimen and HD-chemotherapy. HD RAIT offers the potential for long term relapse free survival. Final analysis of toxicity and outcome of this phase II study will be presented at the meeting.

No significant financial relationships to disclose.
Erlotinib-associated rash correlates with plasma levels at steady state
Authors: Strother R. M. , Jones D. R. , Skaar T. , Huh W. S. , Porter J. , Foster A. , Sweeney C.
Published: March 2020

13008

Background: Erlotinib is a small molecule epidermal growth factor receptor tyrosine kinase inhibitor that is approved for non-small cell lung cancer as a single agent and for pancreatic cancer in combination with gemcitabine. Significant inter-individual variation in drug exposure may explain differential patient outcomes. Genetic polymorphisms of metabolizing enzymes of erlotinib may explain this variability in exposure. Biotransformation assays have implicated cytochrome 3A4/5 (CYP3A4/5) as the predominant metabolizing enzyme. Methods: Patients were enrolled onto a phase-1 dose-escalation study of weekly docetaxel with fixed oral daily dosing (150 mg) of erlotinib. Pharmacodynamic data regarding grade of rash per CTCAE v. 2 were recorded on all 23 patients. Samples for erlotinib pharmacokinetics were obtained after 28 days of continuous daily dosing. Pharmacokinetic (PK) data was attained in 21 patients using LC/MS/MS and analyzed using noncompartmental analysis. Genomic DNA was available for analysis in all 23 patients. Analysis for single nucleotide polymorphisms CYP3A5*3 and CYP2D6*4 were performed by real-time polymerase chain reaction and confirmed by restriction fragment length polymorphism analysis when needed. Results: Average age of patients was 56 (34–76). Nine patients had grade 0–1 rash and 12 had grade 2 rash. As summarized in the table below, the AUC for patients exhibiting grade 2 rash was approximately twice that of patients with grade 0–1 rash. No significant association was found between PK parameters and either CYP3A5 or CYP2D6 polymorphisms. Conclusions: In patients treated with erlotinib the pharmacodynamic endpoint of rash, which has been previously linked with improved patient outcomes, is significantly correlated to the degree of exposure to the drug at steady state. Preliminary data in this small study analyzing pharmacogenetics of erlotinib found no significant correlation between CYP3A5*3 and CYP2D6*4 polymorphic status in either PK or pharmacodynamic measures.

[Table: see text]

[Table: see text]
First-in-human phase-I pharmacokinetic trial of NS-9, a liposomal poly(I):poly(C), in patients with liver metastases from various primary cancers
Authors: Perez R. P. , Lewis L. D. , Cohen G. I. , Hwang J. , Malik S. , Marshall J. L. , Baker J. , Phan A. T. , Yao J. C. , Ajani J. A.
Published: March 2020

13016

Background: NS-9 is a complex of poly-inosinate [poly(I)] and poly-cytidylate [poly(C)] in a cationic liposome and is active in vitro and in vivo. Objectives: to determine the tolerability, safety, and maximal tolerated dose (MTD), and pharmacokinetics of NS-9 by 1 hr IV infusion, given daily x5 q 28 days. Methods: A phase I dose escalation study was undertaken in patients with liver metastases from solid tumors. Eligible patients were adults with ECOG PS 0–1 and no recent chemotherapy (≥ 4 wks prior). Dose cohorts studied were 0.1, 0.15, 0.2, 0.3 and 0.4mg/m2. Results: 18 patients were enrolled (13M:5F) median age 58 (range 21 to 77 yrs). Tumor types included neuroendocrine (8), and ocular melanoma (1), gastric (1), GE junction (1), esophageal (2), and colorectal (5) carcinomas. Two of three patients treated at the first dose level (0.4 mg/m2) had grade 3/4 reversible lipase elevation with or without acute pancreatitis, a dose limiting toxicity (DLT). De-escalation to doses ranging from 0.1 to 0.2 mg/m2/day was with no DLT. At 0.3 mg/m2 two of three patients treated had a DLT (neutropenia and thrombocytopenia). The MTD was determined at 0.2 mg/m2. Common toxicities included pyrexia, chills, nausea, fatigue, abdominal pain, myalgia, anorexia, sweating, neutropenia, thrombocytopenia, and elevated glucose, amylase, and LFTs. Pharmacokinetics showed rapid elimination (T1/2 ranged from 2.4 to 5.0 hours) without accumulation after multiple doses. 1 patient (esophageal Ca) had a PR in the target lesions in the liver. Conclusions: The MTD is 0.2 mg/m2/day with a hint of antitumor activity. NS-9 should be pursued in phase-II studies.

No significant financial relationships to disclose.
A phase I-II and pharmacodynamic (PD) study of the combination of the proteasome inhibitor bortezomib (B) and paclitaxel (P) in patients with taxane-sensitive solid tumors
Authors: Gallerani E. , Cresta S. , Tosi D. , Sessa C. , Capri G. , Catapano C. V. , Bertoni F. , Marsoni S. , Tursi J. , Gianni L.
Published: March 2020

13029

Background: Proteasome inhibition blocks the chemotherapy-induced activation of NF-кB increasing chemosensitivity to anticancer agents due to increased apoptosis. NF-кB is frequently aberrantly activated in primary human carcinomas and over-expressed in aggressive breast cancer lines1 supporting the rationale for combining B with P. We designed a phase I-II and PD trial to determine the recommended dose (RD) of the B&P combination, to screen for antitumor activity in patients with potentially taxane-sensitive tumors, to search for drug-induced changes and to identify potential surrogate markers of drug activity and toxicity in peripheral blood mononuclear cells (PBMC). Methods: Eligibility included ECOG performance status < 2, neurotoxicity < 2 and adequate organ functions. Treatment was given Q21 days: B on days 1,4, 8 and 11 and P on days 1 and 8. PBMC for gene expression profiling have been collected on day 1 and 4 before and after therapy. RECIST for response was applied. Results: Twenty-nine patients (20 female, median age 60 yrs) were accrued and 25 are evaluable (breast cancer: 13, ovarian cancer: 7, prostate cancer 1, other 4) ; 16 pts were treated in 4 escalation levels and the RD defined respectively at 1.3 mg/m2/dose & 100 mg/m2/dose for B&P. Neurotoxicity was the main toxicity (G1 36%, G2 20% and 1 case G3) requiring treatment discontinuation in 2 pts at cy 6 & 7. Other toxicities (all grades) were nausea and vomiting (68%), diarrhea (56%, G3 12%), alopecia (52%), asthenia (36%, G2 4%), and myalgia (32%, G2 8%). Antitumor activity consisted of 3 PR in pts with ovarian cancer lasting respectively 14, 8+ and 16 wks; 2 PRs in pts with breast cancer (12+ wks,14+ wks) and 1 PR in a pt with prostate cancer. Conclusions: Thus far the regimen has acceptable toxicity with evidence of antitumor activity. The trial will continue until accrual of four additional patients as planned. Footnotes 1 Adams J Current Opin Oncol 2002, 14:628–634.

[Table: see text]
Using hapmap tools to predict oncology-related phenotypes: TPMT activity vs hapmap SNPs
Authors: Jones T. , Yang W. , Evans W. , Relling M.
Published: March 2020

13035

Background: Thiopurine S-methyltransferase (TPMT) is a cytosolic enzyme responsible for the S-methylation of thiopurines. There are several functional genetic polymorphisms in TPMT activity, which can lead to drug toxicities; however, among individuals with high TPMT activity, a substantial portion of enzymatic variability remains unexplained. B-lymphoblastoid CEPH cell lines have been genotyped at over 2 million single nucleotide polymorphisms (SNPs) as part of the International HapMap project. Therefore, extensive phenotype-genotype association studies can be conducted in these cell lines by systematic determination of cancer-related phenotypes. Methods: We measured the phenotype of TPMT activity in 82 CEPH cell lines. Of these, 53 had expression data available on over 8000 genes from Affymetrix Focus Array technology. We evaluated whether TPMT activity was associated with HapMap SNPs in TPMT (cis SNPs), genome-wide HapMap SNPs (trans SNPs), and level of gene expression using Kruskal-Wallis test and Spearmans rank correlation. Results: We found associations of TPMT activity with four SNPs (p < 0.05) in TPMT (± 100K bp), one of which (rs1142345, p = 0.009) is a known functional SNP responsible for TPMT deficiency. Two other significant SNPs are in linkage disequilibrium with rs1142345. Associations were also found with 1598 trans SNPs across the genome (p < 0.001). TPMT activity was associated with the expression of eight genes (p < 0.0001, FDR <20%). The only overlapping trans gene is PACSIN2, whose expression most significantly correlated with TPMT activity and also contains two significantly predictive trans SNPs. Conclusions: The CEPH cell lines were useful in that a known functional variant, rs1142345, (serving as a positive control) was associated with TPMT activity, and that additional polymorphisms in TPMT and in potentially important trans-acting factors have been identified as possible additional genomic determinants of TPMT activity. Similar experiments with other phenotypes can likewise capitalize on this publicly available resource. With further validation, these studies may lead to discovery of additional candidate polymorphisms that can lead to further optimization of thiopurine therapy in the clinic.

No significant financial relationships to disclose.
A phase II trial of docetaxel, thalidomide, bevacizumab, and prednisone in patients (pts) with metastatic androgen-independent prostate cancer (AIPC)
Authors: Ning Y. M. , Arlen P. M. , Gulley J. , Latham L. , Retter A. , Wright J. , Parnes H. , Pinto P. , Figg W. D. , Dahut W. L.
Published: March 2020

13037

Background: Angiogenesis plays a vital role in progression of prostate cancer. Antiangiogenic agents’ thalidomide (Td) and bevacizumab (Bv) have been shown in Phase II trials to enhance docetaxel (Doc) activity in metastatic AIPC. Td plus Doc also improved median overall survival as compared to Doc alone. Td and Bv have different antiangiogenic mechanisms. Td appears to affect bFGF, alter circulating endothelial cells and inhibit TNF expression; yet Td does not affect the target of Bv (VEGF). Since tumor angiogenesis is a complex interplay of multiple angiogenic factors, we reasoned that combination of mechanistically different antiangiogenic agents Td and Bv with Doc might be associated with an adequately high and durable PSA response to merit further study. Methods: Pts have progressive, metastatic AIPC, with no prior chemotherapy for AIPC, or prior Td or Bv. Treatment consists of Doc 75 mg/m2 plus Bv 15 mg/kg day 1, q 21 days as a cycle (C), plus Td 200 mg qhs and prednisone10 mg qd. Enoxaparin 1 mg/kg/d sq is used for thrombosis prevention. PSA is assayed q C and radiographic studies are performed at C 0, C 2, & then q 3 Cs. Results: To date, 22 of planned 60 pts have been enrolled, median age 65 [54–79], Gleason score 8 [Gs 6∼7: 32%, Gs 8∼10: 68%], on-study PSA 111 ng/ml [7.7–4399], & pre-treatment PSA doubling time 1.7 months [0.8–18.2]. I) All 22 pts are actively on trial without progression, with median treatment 6 Cs [1–12]. II) 20 pts treated ≥ 2 Cs, 17 (85%) had PSA declines of >50%, 2 declines of >20%, and 1 stable; median duration of >50% PSA decline is 5 Cs [0∼11]. III) 14 pts (of the 20) treated ≥ 5 Cs, 13 (93%) had >50% PSA declines; 6 of them also had measurable disease: 1 CR, 2 PR, & 3 SD (50% RR). IV) Significant toxicities include grade 4 neutropenia (11/22), grade 3 febrile neutropenia (3/22), syncope (2/22), & colon perforation (1/22). No thrombosis was seen. Conclusions: This trial tests a novel strategy of improving conventional treatment of metastatic AIPC. Our data show that the combination of two mechanistically different antiangiogenic agents Td and Bv with Doc does result in a high durable response in PSA (85∼93%) with acceptable toxicities, suggesting that further studies with the combination are warranted. Accrual is continuing.

No significant financial relationships to disclose.
A phase I clinical study of safingol followed by cisplatin: promising activity in refractory adrenocortical cancer with novel pharmacology
Authors: Carvajal R. D. , Merrill A. H. , Dials H. , Barbi A. , Schwartz G. K.
Published: March 2020

13044

Background: Safingol (L-threo-dihydrosphingosine), originally identified as a competitive inhibitor of protein kinase C, has been re-identified as an inhibitor of sphingosine kinase (SK). Inhibition of SK induces apotosis and autophagy by increasing intracellular conversion of sphingosine to ceramide. In vivo, safingol enhances the antitumor activity of cisplatin in a sequence dependent manner (safingol→cisplatin). Methods: We designed a phase I trial of escalating doses of safingol (60→120→240→ 360→480→600 mg/m2) followed 1 hr later by fixed-dose cisplatin 75 mg/m2 given q21 days in pts with advanced solid tumors. Standard phase I eligibility critieria apply. Prior cisplatin is allowed. Results: 13 evaluable pts have been enrolled: 5 male/8 female, median age 54 (range 36–68), median KPS 90% (range 80–100%), mean number of priors 2.8 (range 1–6). 2 dose limiting toxicities (DLT) were observed with escalation of safingol to 240 mg/m2 (gr 3 fatigue, gr 3 hyponatremia), both felt to be due primarily to cisplatin. The protocol was amended to reduce cisplatin to 60 mg/m2, given with 240 mg/m2 of safingol. We observed 1 DLT (persistent gr 3 thrombocytopenia) at this dose level. Pharmacokinetic (PK) analysis by mass spectroscopy shows nearly complete clearance of safingol from circulation within 24 hours of treatment with a 10-fold greater amount of safingol in whole blood than in plasma. An increase in sphingosine and dihydroceramide levels were observed with therapy, and N-acyl- and N-methyl- metabolites of safingol were detected. We observed 1 PR (4+ months) in a pt with cisplatin-refractory adrenocortical cancer metastatic to the liver and lung after only 1 cycle of therapy. 1 additional pt with adrenocortical cancer has SD (2+ months) on therapy. Conclusions: Escalating doses of safingol can be safely administered with a fixed dose of cisplatin. PK data reveal acyl- and methyl-safingol for the first time in human plasma, with a significant fraction of safingol bound to human blood cells. We observed unusual activity in pts with adrenocortical cancer. Further dose escalation of safingol with cisplatin 60 mg/m2 is ongoing, and additional PK data and complete sphingolipid profiles will be presented. (Supported by NCI R21-CA112910).

No significant financial relationships to disclose.
NGRhTNF, a new vascular targeting agent with a dual mechanism of action: preliminary clinical results
Authors: Bordignon C. , Caligaris Capio F. , Toma S. , Manenti L. , Rizzardi P. , Curnis F. , Gallo Stampino C. , Corti A.
Published: March 2020

13052

Background: NGRhTNF is a vascular targeting agent (VTA) exploiting a tumour homing peptide (CNGRCG) selectively binding solid tumor (lung, renal, and colorectal) neovasculature. NGRhTNF specific binding relies on dynamic interactions with TNF-receptors, aminopeptidase N (CD13) and a specific integrin: a combination of receptors expressed by the tumor neovasculature endothelium, but not on normal vessels. This combination provides NGRhTNF with unique biological properties: at low dose, increased tumor vascular permeability, and massive tumor necrosis at high dose. Mouse preclinical data confirmed these properties, revealing also strong synergy between low dose NGRhTNF and cytotoxic agents (antracyclines, platinum based compounds, etc.). Methods: Based on these data, a series of studies were designed. A multicentre phase I study with NGRhTNF as single agent -still in progress- aims at defining MTD and preliminary anticancer activity, within the EORTC network (EORTC 16041). A single center phase I study exploiting the low dose range (0.2–1.6 μg/m2) aims at defining safety and NGRhTNF activity on the tumor vascular permeability using DCE MRI (HSR NGR002). Results: Twelve advanced neoplastic patients were enrolled in the HSR NGR002 study. Up to the dose of 1.6 μg/m2, the only common toxicity was represented by constitutional symptoms such as infusion-associated chills (40%) of mild to moderate intensity. At the tested doses, NGRhTNF increased vascular permeability, as shown by changes in DCE MRI parameters (Ktrans and Kep), and modulated the expression of chemokines possessing antiangiogenic activity. NGRhTNF achieved stable disease in about 45% of highly refractory treated patients, and still ongoing long lasting disease control in 2 cases (7 and 9 months along with sharp decline of CA125 and VEGF). Conclusions: NGR-hTNF, a VTA with a unique mechanism of action, combines activity on tumor vascular permeability and direct anti-cancer effect. Preliminary data in humans confirm its favourable safety profile along with remarkable anticancer activity, thus rendering the agent suitable for a development program alone or in combination with chemotherapeutics. Phase II low dose combination studies will begin in 2006.

[Table: see text]
ERCC1 expression as a predictor for chemosensitivity in recurrent colorectal cancer patients receiving cisplatinum (CDDP) plus S-1 chemotherapy
Authors: Uchida K. , Hayashi K. , Kuramochi H. , Kudo K. , Miyakura S. , Fujita I. , Yamamoto M. , Danenberg K. D. , Danenberg P. V. , Takasaki K.
Published: March 2020

13065

Background: To test the hypotheses of whether the relative mRNA expression of excision cross complement-1 (ERCCI) are associated with response to CDDP+S-1 chemotherapy in recurrent colorectal cancer (CRC). We assessed the relationship between ERCC1 mRNA expression levels and the response. Methods: Thirty four patients with relapsed CRC were treated with cisplatin 30 mg/m2 on Day 1 and Day 8, and S-1 twice daily (BSA = 1.5 m2, 60 mg/day) for 21 days, followed by a 2-week period of no treatment. cDNA was derived from paraffin-embeded tumor specimens to determine ERCC1 mRNA expression relative to the internal reference gene beta-actin using fluorescence-based, real-time reverse transcriptase polymerase chain reaction (Taqman) system. Results: Among 34 CRC patients, 4 patients were evaluated as CR, 13 as PR, and 17 as NC/PD. Relative ERCC1 mRNA gene expression level showed significant difference by the response with median expression levels of 0.70/1.33/1.80 in CR/PR/NC+PD patients respectively (P = 0.04). Conclusions: These data suggest that intratumoral ERCC1 mRNA expression levels are independent predictive markers of response to CDDP+S-1 chemotherapy in colorectal cancer.

No significant financial relationships to disclose.
Mechanisms of resistance to low-dose metronomic cyclophosphamide
Authors: Emmenegger U. , Chen L. , Shaked Y. , Francia G. , Kouri A. , Mutsaers A. J. , Ebos J. M. , Man S. , Kerbel R. S.
Published: March 2020

13079

Background: It has been postulated that antiangiogenic therapies are less susceptible to acquired resistance compared to conventional treatment strategies, which target genetically unstable tumor cells. However, resistance is commonly seen (pre)clinically. A better understanding of the underlying mechanisms is clearly needed to improve such therapies. Methods: We studied mechanisms of acquired resistance to low-dose metronomic (LDM) cyclophosphamide (CTX), the continuous or frequent administration of comparatively low doses of CTX with no extended breaks resulting primarily in antiangiogenic effects, by using LDM CTX relapsed/resistant variants obtained during prolonged in vivo therapy from the human prostate cancer cell line PC-3, which initially is highly responsive. The variants were analyzed for their growth characteristics, angiogenic “phenotype” and impact on circulating endothelial cells (CEC)/endothelial cell progenitors (CEP). Furthermore, we obtained microvessel density (MVD) counts of corresponding xenografts and analyzed in vitro resistance to 4-hydroxycyclophosphamide (4-OH-CTX), hypoxia, acidosis, and glucose as well as serum deprivation. Results: The resistant variants did not show consistent changes in their angiogenic “phenotype”. The decrease in MVD upon LDM CTX treatment was comparable to that obtained in xenografts from parental PC-3, which was reflected by similar changes in the number of CEC and CEP. Despite in vivo resistance to LDM CTX, there was no evidence of in vitro resistance of the variants to 4-OH-CTX. However, they exhibited increased tolerance to microenvironmental stress resulting from sustained antiangiogenic activity. Conclusions: In this model, resistance to LDM CTX develops despite sustained antiangiogenic activity. This provides further evidence that reduced vascular dependence of the tumor cell population may be a basis for the observed resistance. The administration of CTX in a LDM manner does not result in tumor cell CTX resistance, supporting the notion that LDM protocols target primarily the tumor vasculature. If confirmed in ongoing clinical metronomic chemotherapy trials, our results will have major implications for the management of patients that progress under such treatment.

No significant financial relationships to disclose.
A phase 1 study of daily oral perifosine (P) and weekly gemcitabine (G)
Authors: Weiss S. , Nemunaitis J. J. , Diaz-Lacayo M. , Birch R. , Ebrahimi B. , Berdeaux D. H. , Allerton J. P. , Gardner L. R. , Henderson I. C.
Published: March 2020

13084

Background: Miltefosine (M) has been shown to be synergistic with gemcitabine (G) in vitro (Georgieva Cancer Letters 182: 163–174, 2002). Perifosine (P) is a derivative of M with less GI toxicity. Methods: Twenty-two patients (pts) were enrolled on a phase 1 study to determine if G could be given at a dose of 1000 mg/m2 on days 1 and 8 of a 21-day cycle with 50 mg of P given orally 1, 2 or 3 times a day on days 1–14. Three pts were entered at each dose and the cohort expanded to 6 if 2 or more experienced a grade 3/4 non-hematologic toxicity (DLT) during the first cycle. A dose was toxic if 4 or more pts experienced a DLT during cycle 1. Ten additional pts were entered at the highest dose achieved. Results: Disease sites: lung 6, pancreas 3, breast 3, renal 2, sarcoma 2, other 5. The median age was 61 (range 29–82); 11 pts were male and median ECOG performance status was 1 (range 0–2). All pts had received prior chemotherapy (median 3, range 1–4) & 6 had received prior G. 10 pts had received prior radiotherapy. The grade 3/4 non hematologic toxicities for each cohort are given in the table below: One pt on cohort 3 died from pneumonia and sepsis unrelated to therapy after cycle 1. A median of 4 cycles (range 1 - 18) were delivered. At each dose 50% of pts had no G dose reductions. P doses were reduced in 7% of cycles (50 mg - 5%, 100 mg - 15%, 150 mg - 7%). Fifteen pts were evaluable & 4 partial responses (lung, breast, pancreas and unknown primary) were seen; 6 pts had stable disease (renal (2), sarcoma (2), liver and head/neck) for a median of 6 (range 3 - 9) months. No responder had received prior G. Pharmacokinetic (PK) studies showed that the steady state level at 150 mg was 9.47 ± 4.56 μM compared to 10.14 ± 2.02 μM in an earlier study (Crul, Eur. J. Cancer 38: 1615–21, 2002) when this dose of perifosine was used alone. Conclusions: It is concluded that full dose G can be safely administered with perifosine doses up to 150 mg with manageable toxicity and without affecting the PK of P. Phase II studies are warranted to further define the activity of the combination and the contribution of P.

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Her2-targeted pegylated stealth liposomal doxorubicin (PLD) retains its specific targeting ability to Her2-expressing tumor cells after in vivo circulation and extravasation to mouse malignant ascites
Authors: Shmeeda H. , Tzemach D. , Mac L. , Najafi A. , Hjortsvang K. , Gabizon A.
Published: March 2020

13097

Background: Receptor-directed targeting of ligand-bearing liposomes to tumor cells may enhance therapeutic efficacy by intracellular delivery of a concentrated payload of liposomal drug. The goal of this study was to assess whether Her2-targeted PLD retains its binding ability to Her2-expressing target cells through circulation in the blood and extravasation to the ascitic fluid of mice with malignant ascites. Methods: PLD was grafted with a pegylated lipophilic conjugate of an anti-Her2 scFv antibody fragment (F5) at a ratio of 15 ligands per liposome. BALB/c mice were injected with J6456 lymphoma cells into the peritoneal cavity to generate malignant ascites. When abdominal swelling developed, Her2-targeted PLD and nontargeted PLD were injected into the mice i.v. at a dose of 15 mg/kg. The ascitic fluid was collected 48 hr later, ascitic tumor cells were removed, and the doxorubicin levels in the cell-free ascitic fluid and plasma were determined. Binding of the liposome-containing ascitic fluid was tested in vitro against Her2-expressing human tumor cell lines (N87, SKBR-3) and compared to the binding of shelf formulations (not passaged in vivo) of Her2-PLD and PLD, using as parameter the amount of cell-associated doxorubicin. Results: Plasma and ascitic fluid levels of Her2-PLD were only slightly below those of PLD indicating that the Her2 ligand did not cause any significant change in the clearance rate of PLD. Her2-PLD and PLD bound to an equal extent to J6456 cells in vivo. The in vitro binding of Her2-PLD from ascites to Her2- expressing cells was increased 10 to 20-fold above that of PLD from ascites, similarly to the 20-fold difference in binding between shelf Her2-PLD and PLD. Conclusions: Her2-targeted PLD demonstrates similar circulation time to that of nontargeted PLD. After in vivo passage, the targeted liposome retains most of its original binding capacity to Her2 expressing cells indicating that the ligand is stably maintained in association with the doxorubicin liposomal carrier. Targeting of PLD using this Her2 antibody fragment should provide an important means of selective drug delivery to tumors expressing the Her2 receptor.

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Phase I study of RX-0201 in patients with advanced or metastatic solid tumors
Authors: Malik S. M. , Hwang J. , Marshall J. , Ramzi P. , Posey J. A. , Ahn C. , Lee Y.
Published: March 2020

13102

Background: RX-0201 is a 20-mer oligonucleotide that is complementary to Akt-1 mRNA. Strong evidence exists that Akt plays a very important role in cancer progression by stimulating cell proliferation and inhibiting apoptosis. Over-expression of constitutively activated Akt in many cell types promotes cellular transformation. In addition to reducing Akt mRNA levels and inhibiting the expression of Akt protein, in vitro pharmacology studies have demonstrated that RX-0201 suppressed cell proliferation in carcinomas of the brain, breast, cervix, colon, head & neck, kidney, liver, lung, ovary, pancreas, prostate, stomach and melanoma. In vivo studies have also shown that RX-0201 significantly inhibits the growth of tumor in human prostate and brain cancer of nude mice models. This study is designed to determine the maximum tolerated RX-0201 dose in patients with advanced malignancies. Methods: Patients with solid tumors for whom no standard therapies exist, Karnofsky PS>70, adequate hepatic and renal function and normal coagulation parameters were eligible. Eligible patients were scheduled to receive 2 treatment cycles with RX-0201 via continuous infusion for 14 days with 7 days off q 21 days. Dose escalation was based on observed treatment-related toxicities. One patient was enrolled at each dose level (6 mg/m2/day - 315mg/m2/day). Tumor measurements were performed at screening and at the completion of treatment cycle 2. Tumor biopsies were obtained at screening and at the completion of treatment cycle 2 to look for inhibition of AKT in tumor cells. Plasma samples for pharmacokinetic analyses were collected. Results: To date 9 patients have been enrolled, 4 with GI malignancies, 1 with small cell lung cancer, 2 with breast cancer and 1 with locally advanced Basal Cell carcinoma. 6/9 patients were able to complete the 2 cycles.1/9 patients were taken off study because of withdrawal of consent due to grade 1 vomiting. 8 patients were taken off for disease progression. Drug related toxicities were Grade 1 and included fatigue, dizziness, cough vomiting and myalgia. Conclusions: While enrolment is still ongoing, the RX-0201 has been well tolerated upto 315mg/m2 in this previously heavily treated patient population. Once MTD is reached phase II trials will be planned. PK and PD data will be presented.

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Effect of simultaneous or sequential treatment with Imatinib mesylate on the radiosensitivity of U343MG glioblastoma cells in vitro
Authors: Herskind C. , Körschgen T. , Lohr F. , Hochhaus A. , Vajkoczy P. , Wenz F.
Published: March 2020

13125

Background: In a current clinical study, the tyrosine kinase (TK) inhibitor, imatinib mesylate, is given alternately with radiotherapy in inoperable glioblastoma patients. Imatinib inhibits phosphorylation of certain protein TKs including activated Bcr-Abl, c-kit, and the PDGF receptor. To study the interaction between imatinib and irradiation, a translational study on glioblastoma cells in vitro was conducted in parallel with the clinical study. The purpose of the present work was to study the effect of simultaneous or sequential treatment of the two agents. Methods: U343MG glioblastoma cells were grown in medium supplemented with 10% foetal bovine serum (FBS) or 5% platelet poor plasma (PPP). The colony formation assay was used to test the cytostatic effect of imatinib alone and clonogenic cell survival after irradiation. The surviving fraction as function of dose was fitted by the linear-quadratic model. Results: Irradiation in dilute culture conditions showed a moderate enhancement of radiation-induced cell inactivation by 3–10 μM imatinib. The sensitising effect was similar when the medium was supplemented with PPP instead of FBS. The inhibitory effect on colony formation was the same whether imatinib was added before or after irradiation. However, the inhibitor was required to be present during colony formation since no significant effect was observed when the inhibitor was present only during irradiation and repair. Pretreatment of mass cultures with imatinib for 2–5 days had no effect on the radiosensitivity in delayed plating experiments where imatinib was absent during colony formation. Conclusions: Imatinib showed a synergistic effect in combination with radiation but did not act as a classical radiosensitiser. We suggest that the interaction of imatinib with radiation may be associated with an inhibitory effect on cell proliferation.

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Apoptosis signal ceramide c6 synergizes anti-tumor effects of paclitaxel oxaliplatin & cisplatin on growth of pancreatic cancer in SCID mice
Authors: Shrayer D. , Wanebo H. J. , Resnick M.
Published: March 2020

13135

Background: Ceramide (C6) is an analog of endogenous ceramides, which are a major signaling pathway for apoptosis in cells undergoing stress, exposure to chemotherapy. Current report documents in vivo anti tumor effects combining C6 with oxaliplatin & cisplatin on L3.6 human pancreatic adenocarcinoma implanted in the SCID mouse. Correlative histologic studies provide additional mechanistic insights. Methods: SCID/Beige/ Taconicmale mice were inoculated subcutaneously (S.C.) w/2×106 L3.6 pancreatic cells. Chemotherapy doses were based on clinical & in vitro data. Treatment began 4 days post tumor implant with 3 weekly 3×/wk) intraperitoneal (IP) injections of Paclitaxel (P) 3.0 m/kg, oxaliplatin (OX) 2.5 mg/kg, cisplatin (CP) 2.5 mg/kg, with/without ceramide 10 mg/kg. Mice were observed for 6 weeks & were autopsied when near death, or at 6 week level. (All controls died by 3rd week). Data recovered included maximum tumor volume, tumor weight, body weight & survival. Histopathology studies were carried out in a separate group of 40 mice treated by the same drug dose levels & autopsied at 4 hours & 24 hours. Tumors were bi-valved & fixed in buffered formalin or frozen in hexane/acetone bath. Major focus was effects on tumor necrosis, apoptosis, mitotic index & Apoptosis (caspase 3 expression) index. Results: Combination w/C6 ceramide augmented the tumor reduction obtained by chemotherapy alone by 57% (while preserving body weight), & increased 6 wk survival from 0% (Chemotherapy alone) to 60% w/combined therapy. Mean survival was increased from 25 to 37 days. Preliminary short term immunohisto chemical studies showed enhancement of apoptotic index by increased and caspase 3 expression at 4 & 24 hr by ceramide combinations. Conclusion: Combination therapy w/C6 Ceramide significantly enhanced anti tumor response to Paclitaxel, Oxaliplatin & Cisplatin in SCID Mice bearing L3.6 pancreatic tumor implants. Early development of enhanced apoptosis by caspase 3 expressions was shown in preliminary short term exposure experiments.

No significant financial relationships to disclose.