bluuebunny/crossref_metadata_2025 huggingface dataset:
Update of a phase II trial of bevacizumab in combination with hormonal therapy to reverse acquired estrogen independence in metastatic breast cancer patients
Authors: Falkson C. , Rossman J. , Nabell L. , Carpenter J. , Forero A. , Kim Y. , Saleh M.
Published: August 2020

e12027

Background: Metastatic breast cancer (MBC) remains the second most common cause of cancer death in women in the US. More than 80% of breast cancers are potentially hormone responsive, but resistance eventually precludes cure. Various mechanisms of acquired hormone resistance have been postulated. Our Breast Cancer SPORE showed that increased expression of VEGF caused acquired tamoxifen resistance in MCF-7 xenografts. VEGF over-expressing MCF-7 cells displayed increased tumor growth rates and estrogen independence in vivo, and reversal of VEGF over-expression in vivo returned tumors to estrogen dependent growth. Methods: We hypothesized that adding the anti-VEGF monoclonal antibody, bevacizumab, to hormonal therapy would result in reversal of acquired hormone resistance. This multi-center, open-label, single arm phase II study was designed to evaluate safety and efficacy of this combination. Primary end point was time to progression (TTP), and the secondary endpoints were response rate and toxicity. Eligible patients had MBC and had progressed on hormonal therapy after previously responding for at least 6 months.Results: We previously reported a planned interim analysis. Results of further analysis after completion of accrual will be reported here. All 27 patients were female with median age of 63 years, and all had ER and/or PR positive MBC. Patients were continued on the same hormonal therapy to which they had become refractory, and bevacizumab (15mg/kg IV every 3 weeks) was added. Treatment was stopped early in 3 patients due to a grade 3 leg ulcer, grade 3 hypertension, and grade 3 fatigue, respectively. Overall, the therapy was tolerated well, and no treatment related deaths or thromboembolic events were seen. Stable disease was documented in 18 (66%) patients. There were no complete or partial responses. Updated median TTP will be reported. Conclusions: The combination of bevacizumab plus hormonal therapy is well tolerated in patients with metastatic breast cancer. This combination may prolong the TTP with acceptable toxicity. Further investigation utilizing this combination in metastatic breast cancer are ongoing.

[Table: see text]
Patterns of care and outcomes in patients with intracranial hemangiopericytomas: The Memorial Sloan-Kettering Cancer Center (MSKCC) experience
Authors: Dankwah-Quansah M. A. , Gutin P. , Bilsky M. , Huse J. , Rosenblum M. , Abrey L. E. , DeAngelis L. , Omuro A.
Published: August 2020

e13011

Background: Intracranial hemangiopericytomas are rare primary brain tumors with a tendency to metastasize. Available literature is restricted to small series of patients, and little is known regarding optimal clinical management and disease course, particularly in the targeted therapy era. Methods: Retrospective review of all patients with intracranial hemangiopericytoma seen at MSKCC from January 1, 1990 to December 31, 2008. Patients were included if histology was reviewed at MSKCC, and if clinical information was deemed sufficient for the analysis. Results: A total of 32 patients met inclusion criteria. The median age was 43 (range 24–68), median KPS was 80 (range 70–100), 17 were women. Disease was metastatic at presentation in only one patient. Initial treatment consisted of surgical resection in all patients (gross total resection: 14 patients, partial resection: 7, equivocal/unknown extent of surgery: 11). Adjuvant radiotherapy following surgery was given to 21 patients. The median progression-free survival was 65 months; median overall survival was 153 months and the 15-year survival was 48%. Treatment for recurrence included re-resection in 19 patients, additional radiotherapy in 17, and chemotherapy in 10. Regimens used included cytotoxic chemotherapy (6 patients) and targeted therapy (sorafenib: 3 patients; sunitinib: 3; imatinib: 2; erlotinib: 1; sirolimus: 1; bevacizumab: 1). Stable disease was the best observed response to these agents. Metastatic sites throughout disease course included lungs in 7 patients, bone in 10, liver in 3 and chest wall in 2. Immunohistochemistry and molecular analyses are ongoing and updated results will be presented. Conclusions: Hemangiopericytomas can be associated with late recurrences, even in patients completely resected and irradiated. Salvage treatment with surgery and radiotherapy seems effective, although the efficacy of chemotherapy remains to be determined. Given the slow growth rates, the meaning of stable disease while on chemotherapy is uncertain. Several patients in this series received agents targeting PDGFR or VGFR pathways, but such strategies need to be investigated further.

No significant financial relationships to disclose.
Extended exposure to alkylator chemotherapy: Delayed appearance of myelodysplasia
Authors: Chamberlain M. C. , Raizer J.
Published: August 2020

e13030

Background: Alkylator-based chemotherapy is recognized to be leukemogenic, however, it is infrequently described as a delayed consequence of anti-glioma treatment. Objective: A case series of gliomas treated with alkylator-based chemotherapy who subsequently developed myelodysplastic syndrome (tMDS) or acute myelocytic leukemia (AML). Methods: Seven patients (4 men; 3 women) ages 34–69 years (median 44), with gliomas (3 Grade 2; 4 Grade 3) were treated with surgery, all but one with involved-field radiotherapy and all with alkylator-based chemotherapy (temozolomide; 6 patients, nitrosoureas; 5 patients, both agents; 5 patients). Results: Exposure to alkylator-based chemotherapy ranged from 8 months to 30 months (median 24). The diagnosis of tMDS was determined by bone marrow biopsy in seven patients. Seven patients showed chromosomal abnormalities consistent with chemotherapy induced MDS. Three patients were diagnosed with AML as well (in two determined by bone marrow and one at autopsy). Interval from last chemotherapy exposure to diagnosis of tMDS/AML ranged from 3 months to 31 months (median 24 months). Two patients were treated with bone marrow transplantation and five received supportive care only. Five patients have died, two as a consequence of recurrent brain tumor, one as a complication of transplantation, and due due to AML. Conclusions: Although rare, induction of tMDS/AML following extended use of alkylator-based chemotherapy may become more relevant with the evolving practice to treat gliomas for protracted periods. Future work to determine at-risk patients would be important.

No significant financial relationships to disclose.
HER-2/neu expression in glioblastoma multiforme (GBM)
Authors: Gupta S. , Sheikh H. , Schneider C. , Zhang X. , Padmanabhan A. , Ali A.
Published: August 2020

e13035

Background: Glioblastoma multiforme (GBM) is a disease in which very few cytotoxic chemotherapy agents have been shown to have activity. This is partly due to their inability to cross the blood brain barrier. Trials with bevacizumab, a VEGF inhibitor that disrupts tumor angiogenesis, have demonstrated activity against this otherwise chemotherapy resistant disease. This has led to interest in other biologic agents that target angiogenic pathways for the treatment of GBM. Over-expression of HER-2/neu by human tumor cells is closely associated with increased angiogenesis and expression of VEGF. Lapatinib is a recently available low molecular weight immunotherapeutic agent that targets HER-2/neu proteins. In a recent study, breast cancer patients treated with lapatinib and capcitabine had decreased brain metastases indicating that lapatinib may cross the blood brain barrier and thus have potential in the treatment of malignant gliomas. Limited studies have evaluated HER-2/neu gene expression in GBM and the results are inconsistent. We evaluated the expression of Her-2/neu protein in 41 consecutive GBM cases to explore the potential utility of targeting this pathway. Methods: Archival histopathologic sections from 41 patients (age 26–89 years) with a diagnosis of GBM from 2004–2008 were reviewed. The diagnosis was confirmed and optimal sections were selected. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded tissue sections using the primary antibody against HER-2/neu (clone 4B5, Ventana). The results were evaluated by three independent investigators. Interpretation was performed using the semi-quantitative criteria (Score 0 to 3+) currently used for primary breast carcinomas. Results: 38 out of 41 cases showed no immunohistochemical staining with HER-2/neu antibody (score 0). Three cases demonstrated weak, incomplete membrane staining of rare tumor cells (score 1+) and were interpreted as negative. The positive and negative controls worked properly. Conclusions: Our study indicates that there is no significant immunohistochemical over-expression of HER-2/neu protein in GBM. This suggests that HER-2/neu over-expression is not a significant oncogenic pathway in GBM, and therefore may not be a potential therapeutic target in this disease.

No significant financial relationships to disclose.
Treatment of glioblastoma in Venezuela: Limitations using the current standard of care
Authors: Arbona-Roche E. I. , Sucre C. , Vera-Gimón R. , Vera-Gimón A. , Vera-Vera R. , Gutierrez E. , Urdaneta N. , Gutierrez M. , Somaza S. , Tremont-Lukats I. W.
Published: August 2020

e13036

Background: The EORTC/NCIC phase III clinical trial using chemoirradiation with temozolomide (TMZ) 75 mg m-2 x 42d, followed by adyuvant TMZ 150–200 mg m-2 daily x 5d q28d x six cycles set a new standard of care for newly diagnosed glioblastoma (GBM). The applicability of this regimen in developing countries can be problematic. Objectives: To review our experience in Venezuela, contrasting overall survival (OS), 6-month progression-free survival (6PFS), and toxicity in our patients with corresponding outcomes from the EORTC/NCIC trial. Methods: We treated 30 patients with this regimen from March 2001 through July 2004. Results: The median age was 51 years; 17 (60%) were men; 27 (90%) had biopsy or partial resection; 27 (90%) took prophylactic anticonvulsants; and 23 (77%) had prophylaxis against P. jiroveci. Most patients (83%) took the full TMZ treatment during radiation, 7% interrupted TMZ during RT, and 10% could not afford the drug. One patient had Stevens-Johnson syndrome and did not complete RT. Twelve (40%) patients had stereotactic radiosurgery for recurrent disease during the adjuvant phase. The 24-month OS was 30%, median OS was 7.5 months, median PFS was 5 months, and 6PFS was 41%. SRS did not have any effect on OS (p = 0.17, logrank). Grade 3–4 hematologic toxicity was seen in two patients (7%). Conclusions: Except for differences in median OS (7.1 mo) and in 6-PFS (12.6 percentage points) all other measures were reasonably close to the EORTC/NCIC trial. Of concern is the high rate of anticonvulsant prophylaxis using enzyme-inducing drugs and the difficult access to TMZ.

No significant financial relationships to disclose.
Preliminary results of a phase I trial of sorafenib combined with cisplatin/etoposide (CE) or carboplatin/pemetrexed (CbP) in solid tumor patients (pts)
Authors: Dhruva N. S. , Stinchcombe T. E. , Walko C. M. , Socinski M. A. , Bernard S. , Kim W. Y. , Keller K. , Hilbun L. R. , Dees E. C.
Published: August 2020

e13521

Background: Sorafenib had demonstrated single agent activity in non-small cell and small cell lung cancer. Methods: A non-comparative, two arm phase I trial escalating sorafenib in combination with fixed doses of CE or CbP was performed. A 3-patient cohort design was utilized to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT). Dose level 0 for all pts was a sorafenib dose of 200 mg po BID continuously. Pts on arm A received C (60 mg/m2) on day 1 and E 120 mg/m2 on days 1,2,3 every 3 weeks with escalating doses of sorafenib. On arm B, pts received treatment with Cb (AUC=6) and P 500 mg/m2 every 3 weeks with escalating doses of sorafenib. However, excessive toxicity was observed on arm B, therefore the trial was amended such that Cb dose was lowered to AUC=5 (arm C). DLT were assessed in the 1st cycle and defined as grade (gr.) 4 anemia or thrombocytopenia, gr. 4 neutropenia lasting > 7 days, gr. ≥ 3 non-hematologic toxicity (except nausea, vomiting, and alopecia) and > 2 week dose delay. Response was assessed every 2 cycles according to RECIST, and best response was recorded. Results: Between 9/2007 and 9/2008, 20 pts were treated on the trial; median age 62 (range 47–73), male/female: 12/8, PS of 0/1: 6/14, and median number of prior therapies 2 (range 1–4). The most common tumor types were NSCLC (n=8), SCLC (n=4) and head/neck (n=2). At dose level 0 arm A (200 mg BID), 2 of 4 patients experienced DLT (gr.4 thrombocytopenia, gr.3 fatigue, febrile neutropenia and gr.4 neutropenia for > 7 days, gr.3 febrile neutropenia, diarrhea, hypokalemia, hyponatremia); 2 pts have been enrolled at dose level -1 (200 mg po QD) without DLT. Two of 3 patients enrolled on arm B at dose level 0 had gr.4 thrombocytopenia. On arm C at dose level 0 (200 mg po BID), 1/6 pts experienced DLT (gr.3 hyponatremia, dehydration, hypoglycemia). Enrollment continued at dose level 1 (400 mg po BID), but 2/5 pts experienced a DLT (both gr. 3 fatigue/anorexia). Responses observed were: PR (n=3) (all arm C), and SD (n=6). Conclusions: The MTD of sorafenib in combination with carboplatin (AUC=5) and pemetrexed 500 mg every 3 weeks is 200 mg po BID. The MTD of sorafenib in combination with cisplatin/etoposide has yet to be determined and is currently accruing at dose level -1.

[Table: see text]
Antitumor activity of NK012 combined with cisplatin against small-cell lung cancer and intestinal mucosal changes in tumor-bearing mouse after treatment
Authors: Nagano T. , Yasunaga M. , Goto K. , Koga Y. , Kuroda J. , Nishimura Y. , Sugino T. , Nishiwaki Y. , Matsumura Y.
Published: August 2020

e13522

Background: The novel SN-38-incorporating polymeric micelles NK012 has been shown to have significant antitumor activity against several cancer mouse models compared with CPT-11. The phase I study demonstrated that patients treated with NK012 did not develop grade 3/4 diarrhea, one of the major adverse effects of CPT-11. The aim of this study is to investigate the advantages of NK012 combined with cisplatin (cis-dichlorodiammineplatinum (II): CDDP) over CPT-11/CDDP, one of the most active regimens against small-cell and non-small-cell lung cancers in the clinic, in mice bearing a small-cell lung cancer (SCLC) xenograft in terms of antitumor activity and toxicity, particularly intestinal toxicity. Methods: Cytotoxic effects were evaluated in human SCLC cell lines (H69, H82, vascular endothelial growth factor [VEGF]-secreting cells, SBC-3/VEGF and its mock transfectant SBC-3/Neo). In vivo antitumor effects were evaluated in SBC-3/Neo-and SBC-3/VEGF-bearing mice after NK012/CDDP or CPT-11/CDDP administration on days 0, 7, and 14. Drug distribution was analyzed by high-performance liquid chromatography or fluorescence microscopy, and the small intestine was pathologically examined. Results: The in vitro growth inhibitory effects of NK012 were 198- to 532-fold more potent than those of CPT-11. A significant difference in the relative tumor volume on day 30 was found between NK012/CDDP and CPT- 11/CDDP treatments (P=0.0058). Inflammatory changes in the small intestinal mucosa were rare in all NK012-treated mice, but were commonly observed in CPT-11-treated mice. Moreover, a large amount of CPT-11 was excreted into the feces and high CPT-11 concentration was detected in the small intestinal epithelium. On the other hand, a small amount of NK012 was found in the feces and NK012 was weakly and uniformly distributed in the mucosal interstitium. Conclusions: NK012/CDDP combination may be a promising candidate regimen against lung cancer without severe diarrhea toxicity, and therefore warrants further clinical evaluation.

No significant financial relationships to disclose.
Phase I study of imatinib in combination with gemcitabine and capecitabine
Authors: Ramaekers R. C. , Elkahwaji J. , Reed E. , Ganti A. , Wang J. , Grem J. , Baranowska-Kortylewicz J. , Hauke R.
Published: August 2020

e13523

Background: Imatinib-mediated inhibition of platelet-derived growth factor receptor lowers tumor interstitial pressure allowing for improved intratumoral antineoplastic drug concentration. A phase I study of imatinib (Im) with the synergistic combination of gemcitabine (Gem) and capecitabine (Cape) was undertaken. Methods: Eligibility requirements included refractory solid tumors, ECOG 0/1 and adequate organ function. A 3-week treatment cycle was used with the dose levels (DL) 0 and -1 as outlined in the table. Dose limiting toxicity (DLT) was defined as occurring within the first 2 cycles of therapy. Patients remained on therapy unless DLT occurred or disease progression. Results: Twelve patients with a median age of 59.5 (range 44 - 77) were evaluable. Baseline characteristics included ECOG PS 0/1: 6/6; prior systemic therapies: median 3 (range 1–6); tumor types: renal (4), melanoma (2), prostate, esophageal, pancreatic, small cell lung, breast, unknown primary. At DL 0, 2 of 6 patients experienced DLT (gr. 3 thrombocytopenia; gr. 4 leucopenia). At DL -1, 1 of 6 patients experienced DLT (gr. 3 thrombocytopenia). No patient missed a dose; one patient in DL -1 completed only 1 cycle. Median cycles administered was 2 (range, 1 - 19). At cycle 2 evaluation, 7 pts had stable disease, 4 had progressive disease and 1 was not evaluable. Grade 3 or 4 toxicity included thrombocytopenia, leucopenia, hyperglycemia and weakness. All hematologic grade 3/4 toxicity was seen in patients having received ≥3 cytotoxic regimens previously. Most common grade 1/2 toxicities included anemia, nausea/emesis and fatigue. One patient with renal cell had stable disease (SD) for 15 cycles and one patient with melanoma had SD for 19 cycles. Conclusions: Im in combination with Gem and Cape is well tolerated in patients without extensive exposure to cytotoxic therapy. Activity is seen in various tumor types particularly melanoma and renal cell. The suggested dose for phase II studies is Im 400 mg/d, Gem 400 mg/m2 and Cape 400 mg/m2 in the dose schedule as described above.

[Table: see text]

[Table: see text]
Tolerability and efficacy of indigenously developed nanoparticle paclitaxel in Indian patients
Authors: Deshmukh C. D. , Hingmire S. S. , Bakshi A. V. , Kelkar D. S.
Published: August 2020

e13533

Background: Nanoparticle paclitaxel ([N]), India's first cremaphor free water-soluble paclitaxel is based on the principles of nanotechnology. The present study evaluates the safety and efficacy of this formulation in an Indian population. Methods: A prospective observational study over 18 months between April 2007 and December 2008 was done using N in a dose of 220 mg/m2 infused over 1 hour. Safety parameters were based on self reported adverse events while efficacy was monitored as per the RECIST criteria. Results: Fifty-four patients were included. The average age was 56 years (21–72 years). Ten patients (18.52%) had stage III and 23 (42.59%) had stage IV disease. Over 70% of patients were suffering from ovarian cancer, gastric cancer and non small-cell lung cancer (39 of 54 patients). The overall efficacy results across all tumour types were comparable to the published literature with 19 (35.19%) patients showing partial response, 3 (5.56%) showing complete response, stable disease in 11 (20.37%) patients while progressive disease in 12 (22.22%) patients. The efficacy results in the 3 most common tumour types are shown in the table below. In the cohort, 22 (40.74%) patients did not experience any side effects. The most common side effect was body ache (Grade III-NCI CTC v3.0) in 17 (31.5%) patients, neutropenia (Grade II -7, grade III and grade IV -1 each) in 9 (16.67%) cases, 3 (5.56%) cases each experienced neuropathy (Grade III -2 and grade IV-1), nausea, and weakness. Two patients (3.70%) experienced grade III thrombocytopenia and 1 (1.85%) patient developed grade II anemia. Conclusions: Our observations confirm the safety of nanoparticle paclitaxel (N) in an Indian population. This formulation obviates the need for cremaphor thereby allowing shorter infusion duration and eradicating the need of premedication, reduced incidence and severity of adverse effects. Nanoparticle based paclitaxel offers a major advancement in paclitaxel administration.

[Table: see text]

No significant financial relationships to disclose.
Reduced folat carrier gene status in colorectal, gastric, and pancreatic cancer
Authors: Cil T. , Tuzun A. Y. , Altintas A. , Batum S. , Isikdogan A. , Yurt M.
Published: August 2020

e13540

Background: Folates play a key role in one-carbon metabolism essential for the biosynthesis of purines, thymidylate and hence DNA replication. Folates and antifolates which cannot traverse membranes must use specific transport systems for their cellular uptake. Antifolates such as raltitrexed and pemetrexed which will be used for gastrointestinal system cancer patients treatment are divalent anions which predominantly use the reduced folate carrier (RFC) for their cellular uptake. The aim of this prospective study; was documenting RFC gene status in gastric, colorectal and pancreatic cancers in southeast region of Turkey. Methods: We were evaluated homozygote, heterozygote mutations of RFC (SLC19A1) and wild type of RFC in new diagnosis gastric, colorectal and pancreas cancer patients who presented at the medical oncology and gastroenterology divisions of the Dicle University Hospital in Turkey between the dates August 2007 and October 2008 in southeast region of Turkey. Results: We were evaluated gene status of RFC in 62 (50%) colorectal, 45 (36.3%) gastric and 17 (13.7%) pancreatic cancer patients. In colorectal cancer patients group; 28 (45.9%), 19 (31.1%), 14 (23%), in gastric cancer 29 (64.4%), 7 (15.6%), 9 (20%), in pancreatic cancer 11 (64.7%), 2 (11.8%), 4 (23.5%) heterozygote, homozygote and wild type gene status, respectively. These results have no statistically significant (p=0.209) in three different gastrointestinal cancer types. Conclusions: New generation antifolat chemotherapeutic drugs such as pemetrexed which is multitargeted antifolat and enters the cells via the RFC system has demonstrated activity in gastrointestinal cancers. We think that antifolat drugs will be used in colorectal, gastric and pancreatic cancer patients in standard treatment protocols and RFC gene status will be an important of antifolat drugs activity in these tumors.

No significant financial relationships to disclose.
Paclitaxel and cisplatin versus paclitaxel and cisplatin plus all-trans retinoic acid for the prevention of chemotherapy-induced neuropathy: A randomized phase II trial
Authors: Rios Trejo M. A. , Ceron Lizarraga T. , Fernández González M. C. , Ordoñez G. , Martinez Barrera L. , Astorga Ramos A. , Mendoza D. , Sotelo J. , Arrieta O.
Published: August 2020

e14506

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse event, similar to that of diabetes where there is reduction of the expression and transport of Neural Growth Factor (NGF). Retinoic acid regulates genes related to cellular proliferation and NGF expression. We conducted this clinical trial to determine the effect of all-trans retinoic acid (ATRA) on the development of CIPN with paclitaxel and cisplatin in patients with advanced non-small cell lung cancer (NSCLC). Methods: Ninety five patients with advanced NSCLC were included to receive chemotherapy based on paclitaxel 175 mg/m2 and cisplatin 80 mg/m2 every 3 weeks for a maximum of 6 cycles. The patients were randomized to receive ATRA 20 mg/day or placebo 1 week before treatment until after completing 2 cycles. Prior to chemotherapy and after 2 cycles of treatment neurophysiology tests, clinical exam and serum NGF levels (34 patients) were performed. Results: There were no differences in general characteristics of the patients between groups. NGF serum levels were lower in the placebo group 4.89 pg/ml baseline and 4.6 pg/ml 2C (p = 0.007) versus ATRA 4.8 pg/ml and 4.7 pg/ml (p=0.107). The electrophysiological studies showed a greater degree of motor axonal damage in the right (p=0.003) and left (p=0.013) tibial nerves in the placebo group after 2C. In the ATRA group there were no significant differences baseline and after chemotherapy. Conclusions: ATRA might have a neuroprotective effect in patients with NSCLC treated with paclitaxel and cisplatin. A phase III trial is needed to confirm these findings.

No significant financial relationships to disclose.
A pilot study evaluating surrogates of response to short-term vorinostat in women with newly diagnosed breast cancer
Authors: Stearns V. , Jacobs L. K. , Tsangaris T. N. , Briest S. , Lange J. R. , Slater S. , Fackler M. , Sugar E. , Gabrielson E. , Davidson N. E.
Published: August 2020

e14508

Background: Epigenetic modifications contribute to breast cancer initiation and progression and may be reversible, thus representing an attractive area for new drug investigation. In preclinical breast cancer models, the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA, vorinostat) induces cell cycle arrest, apoptosis and differentiation. Methods: We evaluated the safety and tolerability of short term vorinostat in women with a primary clinical stage I-III histologically confirmed carcinoma of the breast on a core needle biopsy. Participants received vorinostat 300 mg PO bid for a total of 6 doses, the last dose 2 hours prior to surgery or biopsy. Peripheral blood mononuclear cells were collected at baseline and following the last vorinostat dose to determine histone acetylation. Baseline and post-treatment tumor specimens were collected for analysis of histone acetylation, candidate gene methylation and expression. Tissues were also collected from untreated controls. Paired t-tests and Fisher's exact tests were used to evaluate changes from baseline for continuous and categorical data, respectively. Results: From March 2006 to October 2008, 25 women signed an informed consent and initiated study drug. Median age was 55 and 80% had hormone receptor positive tumors. Twenty-two women took all 6 prescribed doses. One participant took 4 and one 5 doses due to insurance clearance delay; one received a single dose due to fatigue and abdominal pain. Study-related surgical delays did not occur. Grade 1 toxicities included diarrhea (28%), low white blood cell count (24%), and fatigue, taste alterations and nausea (16% each). Tissue and blood samples were successfully collected. Tissue was also collected from 25 untreated controls. No significant change was observed in the proliferation marker Ki67 following 3 days of agent administration. Modulation of apoptosis, histone acetylation and gene methylation will be presented. Conclusions: Short-term administration of vorinostat is feasible, safe, and allows for studies of biomarker modulation. The results will be used to design future studies in which vorinostat will be administered in combination with other targeted therapies or with other epigenetic modifiers.

[Table: see text]
Midostaurin: Review of pharmacokinetics (PK) and PK/pharmacodynamic (PD) relationship in AML/MDS patients
Authors: Dutreix C. , Huntsman Labed A. , Roesel J. , Lanza C. , Wang Y.
Published: August 2020

e14540

Background: Midostaurin is a multi-tyrosine-kinases inhibitor targeting class III tyrosine-protein-kinases, including Fms-like tyrosine kinase-3 (FLT3), involved in hematopoiesis and leukemia. Oral midostaurin has been tested as a single agent and in combination therapy in >800 subjects. Methods: The two studies presented here involved patients with wild-type or FLT3-mutated de novo (phase Ib) or relapsed (phase II) AML or MDS. They covered a wide range of doses, given as monotherapy or in combination. Results: PK studies demonstrated that midostaurin was rapidly absorbed and metabolized into two major active metabolites: the demethylated compound, CGP62221 and the hydroxylated compound, CGP52421 . The relative potency of these metabolites (Midostaurin: CGP62221 : CGP52421 ) is approximately 1 : 1.4 : 0.1 in FLT3-based cellular assays. Following multiple oral daily single-agent doses, midostaurin and CGP62221 concentrations accumulated significantly in the first 3–5 days then declined by 40- 80% prior to a new steady state 2–3 weeks post-dose. CGP52421 concentrations accumulated continuously through day 28 and remained stable thereafter, roughly 7-times higher than the parent drug or CGP62221 . The time-dependent kinetics of midostaurin may reflect an induction of CYP3A4 by midostaurin and/or its metabolites, as already demonstrated in vitro, or alternatively a protein binding displacement mechanism. The blast response with monotherapy appeared to be correlated both with midostaurin plasma levels alone and summed together with its two major metabolites, corrected for their in vitro potency differences. PK/PD analyses showed sustained reduction (>90% from baseline) in peripheral blast (PB) counts in patients with a higher midostaurin plasma exposure at steady state (>2–3 μg/mL). However, evaluation of available bone marrow blast (BM) response data revealed that a much higher midostaurin plasma would be needed for a satisfactory BM response. Conclusions: Additional chemotherapy was required to achieve a clinical response, with particularly promising results for the FLT3-mutated patients. These results support the ongoing phase III AML study in AML FLT3-mutated patients with midostaurin given in combination with chemotherapy.

No significant financial relationships to disclose.
Bioavailability of sorafenib tablets administered as a liquid suspension
Authors: Lettieri J. T. , Dubowy R. , Xia C. , Rotolo C. , Zinny M. A.
Published: August 2020

e14549

Background: Sorafenib is a multikinase inhibitor currently approved by the FDA for the treatment of advanced renal-cell carcinoma (RCC) and unresectable hepatocellular carcinoma (HCC), and by the EMEA for the treatment of HCC and advanced RCC. Sorafenib is available as a tablet formulation. Some patients who are unable to swallow tablets have suspended sorafenib tablets in a liquid for ease of administration. We performed a study to assess whether this process alters the bioavailability of sorafenib. Methods: Twenty-six healthy male volunteers were enrolled. Utilizing a randomized, crossover design, subjects received either two 200-mg intact tablets (IT) with 8 ounces water, or two 200-mg tablets disintegrated over 10 minutes in 2 ounces of water (ST), with an additional 6 ounces of water swallowed as a rinse of the dosing vessel. Doses were separated by a 10- to 14-day washout period. Following each dose, blood samples were collected at designated times up to 144 hours after dosing for measurement of sorafenib plasma concentrations. Sorafenib was assayed by a validated liquid chromatography/mass spectrometry method. The pharmacokinetic parameters area under the curve (AUC), maximum concentration (Cmax) and time to Cmax (Tmax) were assessed by noncompartmental analysis. Results: Geometric mean (percentage coefficient of variation) or median results for these pharmacokinetic assessments are shown in the table. Conclusions: The pharmacokinetics of sorafenib, when administered as a liquid suspension of tablets in water, were similar to the pharmacokinetics of tablets swallowed whole.

[Table: see text]

[Table: see text]
Correlation of immunological effects of anti-VEGF therapy with progression-free survival of advanced colorectal cancer patients
Authors: Manzoni M. , Rovati B. , Delfanti S. , Bencardino K. , Chatzileontiadou S. , Brugnatelli S. , Loupakis F. , Villa E. , Falcone A. , Danova M.
Published: August 2020

e14559

Background: The clinical efficacy of Bevacizumab (BEV) in advanced colorectal cancer (mCRC) could be related not only to its well-established effect on tumor neoangiogenesis but also to a counteraction of VEGF-mediated dendritic cell (DC) abnormalities. The addition of BEV to chemotherapy (CT) may improve the number and function of blood DCs in cancer pts. We have focused on the correlation between this effect and the clinical efficacy of a BEV-based, 1st-line treatment for mCRC. Methods: Starting from January 2007 we performed a flow cytometric analysis of PB lymphocytes and DC subsets in 53 mCRC pts who had not received prior CT for metastatic disease or for whom 6 months had elapsed since adjuvant CT (M/F: 31/22, median age: 59yrs; range 32–75; ECOG PS <2), before and every 3 courses of a BEV+CT (5-FU± CPT11± Oxaliplatin) program. Biological data of the 42 evaluable pts that received all the planned treatment were correlated to both tumor response (OR) and progression free survival (PFS). Results: During treatment, DCs and their subsets showed a progressive, significant increase in absolute number, with respect to baseline, both in responder (CR,PR,SD) (67%) and in non responder pts. This effect on the DC profile was evidenced in responder pts up to 4 weeks since the last treatment course. After therapy completion, pts with PFS > 15 months (58%) showed DC and DC1 absolute number significantly higher with respect to pts with shorter PFS (p< .02). Conclusions: The recovery of blood DCs induced by 1st- line, BEV-based therapy in mCRC pts indicates a potential additional anticancer mechanism of this drug. The improvement of DC number does not influence OR but correlates with longer PFS. This suggests that BEV can influence tumor regrowth by contributing to overcome the impairement of the host immune surveillance induced by VEGF.

No significant financial relationships to disclose.
A prospective PGx and PK/PD dose-finding study of irinotecan based on UGT1A1*6 and *28 genotyping (UGT0601)
Authors: Esaki T. , Satoh T. , Ura T. , Tsujinaka T. , Sasaki Y. , Yamazaki K. , Yamada Y. , Ishizuka N. , Hyodo I. , Sakata Y.
Published: August 2020

e14560

Background: UGT1A1*6 as well as UGT1A1*28 polymorphisms is associated with decreased glucuronidation of SN-38, the active metabolite of irinotecan (CPT-11). Although the maximum tolerated dose (MTD) and the recommended dose (RD) in Hetero was determined 150 mg/m2 (approval dose in Japan), those of Homo were unknown. Methods: Pts received prior chemotherapies except for CPT-11 for metastatic gastrointestinal cancer were enrolled. UGT1A1 polymorphisms were categorized into Wild(*1/*1), Hetero(*1/*28, *1/*6), and Homo(*28/*28, *6/*6, *28/*6). CPT-11 was administered biweekly. Starting doses were 150 mg/m2 in Wild, 100 mg/m2 in Hetero, and 75 mg/m2 in Homo. DLT was defined as grade 4 hematological, or grade 3 non-hematological toxicity. MTD closest to dose-limiting toxicity (DLT) appearance of 30% was guided by the continual reassessment method in the cohort of Hetero and Homo. DLT and pharmacokinetic (PK) sampling was evaluated during the 1st cycle. Results: Eighty-two pts were enrolled from November 2006 to November 2008 (Wild, Hetero, Homo: 41, 20, and 21, respectively). The dose level reached at 150 mg/m2 in Homo. At 150 mg/m2, DLT was observed in six pts of Homo (grade 4 neutropenia, grade 3 diarrhea: 6 and 1, respectively). The probability of DLTs were 22.2% at 125 mg/m2, and 37.4% at 150 mg/m2. The MTD was determined 150 mg/m2 in pts with Homo group. However, the incidences of grade 3/4 neutropenia at 150 mg/m2 during the 1st cycle were 9.8% (4/41), 18.8% (3/16), and 62.5% (10/16) in Wild, Hetero, and Homo, respectively. And the second administration was delayed 7 days or more in most pts in Homo (63% at 150 mg/m2). In one pt of Homo for *28/*28 died of septic shock during the 2nd cycle. SN-38 AUC (0–24h, ng*hr/mL, median) was 239 in Wild, 237 in Hetero, and 410 in Homo. Pts with Homo showed the different trend of PK/PD compared to those with Wild and Hetero. Conclusions: The MTD was 150 mg/m2 in pts with Homo group and the most frequent DLT was grade 4 neutropenia. However, our findings suggest that 150 mg/m2 q2w is difficult to recommend and the initial dosage and administration should be considered carefully for pts with Homo.

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Synergistic effect of SNDX-275 with lapatinib or erlotinib in breast, lung, or head and neck cancer cell lines expressing HER- 2
Authors: Witta S. E. , Franekova V. , Yoshida K. , Igolnikov I. , Frederick B. , Varella-Garcia M. , Bunn P. A. , Hirsch F. R.
Published: August 2020

e14566

Background: We previously demonstrated the synergistic effect of the histone deacetylase inhibitor SNDX-275 and gefitinib in non-small cell lung cancer (NSCLC) cell lines lacking E-cadherin expression. We evaluated the combination effect of SNDX- 275 with erlotinib or lapatinib in lung, head and neck (H&N) and breast cancer cell lines resistant to erlotinib or lapatinib(IC50> 1uM) and expressing Her2. Methods: This study included 10 H&N and 17 NSCLC cell lines, 2 breast cancer cell lines with expressing Her2 (SK BR3, MCF7) and one lacking Her2 expression, MDA-MB231. Cell lines were incubated for 5 days with increasing concentrations (0.16, 1 and 6μM) of SNDX-275, lapatinib and erlotinib alone or in combination. The growth inhibitory effect was analyzed with MTT assay. The combination drug effect was evaluated using CalcuSyn (Cambridge, UK). E-cadherin and Her2 expression was evaluated using microarray analysis and RT-PCR. Her2 was considered positive if the relative expression was >300 by RT-PCR. Protein expression was analyzed with western blots. Results: Among the 17 NSCLC and 10 H&N cell lines 16 (12 NSCLC and 4 H&N) had positive Her2 RNA expression. 2 NSCLC (A549, H1703) and 2 H&N (UMSCC10, UMSCC19) were resistant to erlotinib or lapatinib (IC50>1μM). The 2 breast cancer cell lines 2, MCF7 and MDA-MB-321, were resistant to erlotinib and lapatinib. SNDX-275 increased the expression of E-cadherin in 5 of the 6 cell lines selected (A549, H1703, UMSCC19, MCF7 and MDA- MB-321). Synergistic effect of SNDX-275 1μM and lapatinib 1μM was detected in the MCF7, UMSCC10, UMSCC19 cell lines (Combination Index, CI: 0.09, 0.9, 0.67; respectively), while SNDX-275 1μM and erlotinib 1μM were synergistic in MCF7, MDA-MB-321, H1703 and A549 (CI: 0.2, 0.95, 0.58, 0.32; respectively). Conclusions: The combination of SNDX-275 and erlotinib or lapatinib is active in breast, NSCLC, H&N cell lines resistant to either drug alone.

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Phase I study of nimotuzumab, a humanized anti-epidermal growth factor receptor (EGFR) IgG1 monoclonal antibody in patients with solid tumors in Japan
Authors: Boku N. , Yamazaki K. , Yamamoto N. , Takahashi T. , Fukutomi A. , Miyazaki M. , Satoh T. , Okamoto I. , Nakagawa K. , Fukuoka M.
Published: August 2020

e14574

Background: Nimotuzumab, a humanized IgG1 monoclonal antibody targeting EGFR, has been used in head & neck cancer or malignant glioma outside Japan, and MTD including severe skin rash were not observed up to 800mg/body. This phase I study of nimotuzumab was conducted to investigate the safety profile, MTD, DLT, PK, human antibody against nimotuzumab (HAHA) in Japanese patients (pts), and PD analysis (activation of EGFR, Akt, MAPK, Ki67) was done. Methods: Pts with advanced solid tumors having no available standard therapy were enrolled. Nimotuzumab was given intravenously at dose levels of nimotumumab 100, 200 and 400mg/body, weekly. Blood, skin samples before treatment and after 4th infusion and pre-treatment tumor were collected for PD analysis. Results: 4 pts were enrolled in each level (total 12 pts). Pt characteristics were M/F 5/7, median age 57 years, ECOG PS 0/1 7/5. No grade 3 or 4 toxicities and no DLT were observed, and MTD was not determined. The major adverse event was grade 1 or 2 skin rash (58%, 7/12). Neither infusion reaction nor HAHA was observed. AUC0-inf, Cmax and t1/2 increased and CL deceased by dose dependent manner, indicating nonlinear PK characteristic. SD and PD were observed in 8 patients (67%) and4 patients (33%), without objective responses. Median time to progression was 4 months. Time to progression seemed to be longer in the pts with amplified gene copy number of EGFR though the number of pts was limited. Conclusions: Weekly infusion of nimotuzumab was well tolerated up to 400 mg/body in Japanese pts. A correlation between anti-tumor activity and EGFR amplification was speculated. Additional PD analysis is currently ongoing.

No significant financial relationships to disclose.
Prediction of the benefit of trastuzumab (T)-based therapy by the change of gene expression of peripheral blood mononuclear cells (PBMC)
Authors: Shimizu C. , Tamura K. , Koizumi F. , Komori O. , Pritchard M. , Mollah M. H. , Eguchi S. , Fujiwara Y.
Published: August 2020

e14578

Background: Identification of molecular predictors of response is important in the aspect of personalization of treatment, especially in the era of molecular targeted drugs. Antibody-dependent cell-mediated cytotoxicity (ADCC) is suggested as one of the main mechanism of action of T. Moreover, PBMC specimens can securely be obtained with minimal invasion. We therefore hypothesized that gene expression changes induced by T of PBMC may be useful for prediction of response of T. Methods: 36 HER2-positive metastatic breast cancer (BC) patients were enrolled in this prospective biomarker study. The patients were treated with single-agent T (q1w) for chemotherapy-naïve, hormone refractory metastatic disease. The clinical response was measured after 8 cycles of single-agent T. PBMC were collected prior to and 1-week after the first administration of T. Gene expressions of PBMC were measured using Affimetrix GeneChip Human Genome U133 Plus 2.0 array. Change of gene expressions before and after T was correlated with clinical response using Wilcoxon rank sum test. A multi-gene predictor of response to T was generated using the highly ranked genes. The performance of the predictor was then assessed in patients prospectively treated with neoadjuvant chemotherapy (NAC): HER2- positive BC patients recieved NAC containing T. PBMC were collected prior to NAC and 1-week after the first administration of T. Results: 34 patients were evaluable for clinical outcome. 15 and 19 patients were classified as responders and non- responders, respectively. The top 4 genes differentially regulated by T between responders and non-responders were selected for development of a predictor by leave-one-out cross validation. The 4-gene predictor correctly predicted the pathological complete response (pCR) in 5 out of 5 patients who achieved pCR and residual disease (RD) in 10 out of 12 patients with RD (error rate 12 %) in HER2-positive breast BC patients treated with NAC containing T. However, it was not associated with pathological response in 19 HER2- negative patients treated with NAC without T (error rate 39 %). Conclusions: Change in PBMC gene expression after single dosage of T may be useful as a predictor of response to T-based therapy.

No significant financial relationships to disclose.
Cetuximab-mediated antibody-dependent cellular cytotoxicity (ADCC) against tumor cell lines characterized for EGFR expression and K-ras mutation
Authors: Barriere J. , Fischel J. , Formento P. , Renée N. , Francoual M. , Formento J. , Chefrour M. , Etienne-Grimaldi M. , François E. , Milano G.
Published: August 2020

e14583

Background: Mutated K-ras protein is a strong predictive factor of cetuximab resistance, bypassing the classical direct inhibitory effect on epidermal growth factor receptor (EGFR) signaling. However, cetuximab is also able to mediate ADCC, which may be part of the clinical response. The aim of this ex-vivo study was to quantify cetuximab-mediated ADCC on various human cancer cell lines characterized for EGFR-expression and K-ras mutation. Methods: Two K-ras mutated cell lines over-expressing EGFR and resistant to anti-EGFR tyrosine kinase inhibitor were tested (Capan-1 and Capan-2, pancreatic), along with 2 K-ras wild-type cell lines over- expressing EGFR (CAL166, head and neck; A431, epidermoid carcinoma) and an EGFR-negative cell line (OCM1, uveal melanoma). The tested monoclonal antibodies (mAbs) were: cetuximab (Merck, anti-EGFR IgG1 mAb), panitumumab (Amgen, anti-EGFR IgG2 mAb), and as a negative control, rituximab (Roche, IgG1 anti-CD20 mAb). ADCC (51Cr release assay) was performed using freshly- isolated peripheral blood mononuclear cells from a healthy donor. Results were expressed as % of potentially maximum 51Cr release. Results: Cetuximab mediates ADCC against EGFR-over-expressing cell lines CAL166 (38.4 ± 3.1 %), A431 (13.5 ± 1.7 %), Capan-1 (31.2 ± 0.8 %) and Capan-2 (27.8 ± 8.6 %) irrespective of the K-ras mutational status, but not against EGFR-negative OCM-1 (6.2 ± 1 %). Conversely, unlike IgG1 cetuximab, the anti-EGFR IgG2 panitumumab and the irrelevant antibody rituximab were both unable to induce significant ADCC (< 10 % on all tested cell lines). Conclusions: Cetuximab-mediated ADCC is independent of the K-ras mutational status of the tumor cell lines. Present data suggest that cetuximab may remain of clinical interest in K-ras-mutated patients. Immunostimulation, as well as new generation anti-EGFR mAbs with improved ability to induce ADCC, may be promising in the management of K-ras-mutated patients.

No significant financial relationships to disclose.
A three-part, phase I, dose-escalation study of GSK1120212, a potent MEK inhibitor, administered orally to subjects with solid tumors or lymphoma
Authors: Thompson D. S. , Flaherty K. , Messersmith W. , Harlacker K. , Nallapareddy S. , Vincent C. , DeMarini D. J. , Cox D. S. , O'Neill V. J. , Burris H. A.
Published: August 2020

e14584

Background: GSK1120212 is a potent and highly selective inhibitor of MEK1, a component of the MAP kinase pathway. GSK1120212 demonstrates efficient inhibition of p-ERK which correlates with inhibition of cell proliferation and induction of apoptosis. PO administration of GSK1120212 achieved tumor regression in multiple mouse xenograft models. The objectives of this study are to define the maximum tolerated dose (MTD) and to evaluate the pharmacokinetics (PK) and pharmacodynamic (PD) effects of GSK1120212. Methods: In Part 1, patients (pts) with solid tumors or lymphoma are enrolled in successive cohorts and receive a single PO dose of GSK1120212 followed by QD doses on days 1 - 21 of each 28-day cycle. Tumor response is assessed Q 8 weeks. PK blood samples are collected from all pts. Ophthalmic exams are administered at baseline and as clinically warranted. Dose escalation occurs via an accelerated titration followed by a standard 3+3 escalation. In Part 2, pts with pancreatic or K-Ras mutant CRC will be enrolled at the MTD. In Part 3, pts with biopsiable tumors will enroll at MTD and sub-MTD doses. Tumor biopsies will be taken pre- and post-dose to measure pERK and other markers of cell proliferation. Results: Six pts with advanced malignancies (neuroendocrine, thyroid, colorectal (n=2), melanoma (n=2) have been treated with tablets at four dose levels: 0.125 (n=2), 0.25 (n=1), 0.5 (n=2), and 1.0 mg (n=1). No DLTs or grade 2 toxicities have been reported. One patient was on study for over 17 weeks. Based on mean AUC and Cmax, GSK1120212 exposures following 15 days of repeat-dose administration were approximately dose proportional across the dose range (0.125–0.5 mg) with a median Tmax of approximately 1.5 hours. Conclusions: GSK1120212 has been well tolerated to date. Dose escalation is ongoing.

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