tbuckley/cabot-search huggingface dataset:
Therapeutic potential of AGS-PSCA: A fully human monoclonal antibody to prostate stem cell antigen (PSCA) for the treatment of prostate and pancreatic cancers
Authors: A. Jakobovits, J. M. Gudas, X. Jia, K. Morrison, Z. An, H. Shao, A. B. Raitano, K. J. Morrison, P. Challita, S. B. Kanner
Journal: Journal of Clinical Oncology (2005)

4722 Background: PSCA is a 123 amino acid GPI-linked surface antigen that is expressed in approximately 80% of prostate cancers and 50% of pancreatic and bladder cancers (Reiter et al., PNAS, 95:1753, 1998; Amara et. al., Cancer Res. 61: 4660, 2001; Argani et. al., Cancer Res. 61: 4320, 2001). In human prostate cancers elevated PSCA levels are correlated with advanced disease and androgen independence, including high expression in bone metastases (Gu et al., Oncogene 19: 1288, 2000). Previous studies with a murine monoclonal antibody (MAb) demonstrated the therapeutic potential of PSCA MAbs in prostate cancer xenograft models and provided the rationale for developing fully human MAb to treat localized and metastatic prostate cancers in man (Saffran et. al. PNAS 98: 2658, 2001). Methods and Results: XenoMouse technology was employed to identify a therapeutic antibody product candidate, AGS-PSCA, a high affinity (Kd = 1.6 x 10-10M) fully human IgG1κ antibody. Our studies show that AGS-PSCA can significantly inhibit the growth of established LAPC9 androgen-independent tumors grown subcutaneously and established LAPC9 androgen-dependent tumors grown orthotopically. In the orthotopic models, AGS-PSCA significantly increased the lifespan and cured tumors in a subset of mice. To further evaluate the efficacy of AGS-PSCA in a clinically relevant setting, experiments were performed with AGS-PSCA in combination with Docetaxol using patient-derived prostate tumor xenografts. Enhanced activity was demonstrated when AGS-PSCA was administered in combination with Docetaxol to established LAPC9 androgen-independent prostate tumors. In addition, AGS-PSCA significantly inhibited the growth of pancreatic tumors grown subcutaneously and orthotopically. Conclusions: These data provide strong evidence for the anti-tumor activity of AGS-PSCA as a monotherapy and in combination with an approved chemotherapeutic agent for the treatment of recurrent and metastatic prostate and pancreatic cancers. Activities are underway to progress this promising antibody product candidate into human clinical trials. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Agensys Agensys
A randomized multicenter phase II trial on efficacy of high-slip skin care pad for hand-foot skin reaction caused by sorafenib in patients with renal cell carcinoma.
Authors: N. Shinohara, N. Nonomura, G. Kimura, M. Eto, H. Minami, N. Yamazaki, S. Naito
Journal: Journal of Clinical Oncology (2011)

TPS233 Background: Hand-foot skin reaction (HFSR) is the most clinically significant dermatologic toxicity in patients (pts) with metastatic renal cell carcinoma (mRCC) who receive sorafenib. HFSR was found to occur in 72 of 131 Japanese pts (Akaza et al, JJCO, 2007). Since HFSR is reported to be associated with significant tenderness affecting function and quality of life (especially difficulty in walking), prevention and management of HFSR would be mandatory. Although treatment with topical urea cream is frequently performed, the control of pain is not completely established. HFSR may be attributed to keratinous disorders of the skin and tends to develop in particular in areas on the soles of the feet subject for strong pressure. Since high-slip skin care pad (Remois pad) is a protective dressing on pressure ulcer to reduce surface pressure and to result in the prevention of skin damage, the characteristics of this material may prevent the development and worsening of HFSR. The purpose of the study is to investigate the usefulness of a high-slip skin care pad for HFSR on the soles. Methods: This randomized, prospective, open-label trial intends to enroll 100 pts with mRCC who received 400 mg bid of sorafenib. Eligibility criteria include pts with confirmed RCC, within 8 weeks after the initiation of sorafenib treatment, with ECOG-PS 0 or 1, and with grade 1 HFSR on their sole. Exclusion criteria are pts who had previously treated with other molecular targeted drugs, with a systemic dermatological disease, or with > grade 3 adverse events other than HFSR. Pts are randomized into two groups: high-slip skin care pad group versus 10% urea cream group. High slip skin care pad is recommended to change every 2-3 days, and 10% urea cream is ordered to apply and rub to affected sites 2 or 3 times per day. Their subsequent progress will be monitored every 2 weeks by 4 weeks after the initiation of these supportive therapy. Primary endpoint is incidence of Grade 2 or 3 HFSR during these supportive therapy. Secondary endpoints are treatment compliance (dose reduction/discontinuation of sorafenib), pain assessment (visual analogue scale), and safety. Currently 19 pts have enrolled.
Effect of age on treatment outcome to palonosetron (PALO) plus 1-day dexamethasone (DEX) for the prevention of nausea and vomiting in women receiving anthracycline plus cyclophosphamide (AC)-based chemotherapy: A meta-analysis of two phase III trials.
Authors: L. Celio, E. Bonizzoni, E. Bajetta, S. Sebastiani, T. Perrone, M. S. Aapro
Journal: Journal of Clinical Oncology (2011)

e19536 Background: Women receiving AC-based chemotherapy represent a situation with a particularly high risk of developing chemotherapy-induced nausea and vomiting (CINV). Age younger than 50 years has also been identified as a risk factor for developing CINV. Combined data from two phase III trials evaluating a DEX-sparing regimen against CINV due to moderately emetogenic chemotherapy were assessed for potential effect of age on treatment outcome. Methods: A total of 405 chemo-naïve women with breast cancer who underwent AC-based chemotherapy were randomized to receive a single IV dose of PALO 0.25 mg plus DEX 8 mg IV on day 1 of chemotherapy (1-day regimen; n=200) or the same regimen followed by DEX 8 mg orally on days 2 and 3 (3-day regimen; n=205). The primary endpoint was complete response (CR; no emesis, and no rescue anti-emetics) in the 5-day study period. The effect of the 1-day regimen and age (<50 and ≥50 years) was investigated by a modified intention-to-treat approach. Meta-analysis of individual patient data was performed using the CR in the overall study period as dependent variable. A generalized mixed linear model with study and treatment group as dummy fixed effect was used for the analysis. Results: Patients under the age of 50 years comprised 43.5% and 49.3% of the 1-day and 3-day regimen groups, respectively. Among women receiving the 1-day regimen, 55.2% of younger patients achieved overall CR compared with 54% of older patients. In the 3-day regimen group, 51.5% of younger patients achieved overall CR compared with 58.7% of older patients. In the adjusted analysis, younger age was not associated with CR to anti-emetic treatment (risk difference, -3.1%; 95% CI, -13 to 6.7%; P=0.533). Conclusions: These findings provide evidence that younger age does not predict for worse outcome in terms of overall CR to anti-emetic coverage with PALO plus single-dose DEX in women receiving AC-based chemotherapy.
Predictive value of RRM1 and ERCC1 protein levels in a prospective community-based trial of gemcitabine/carboplatin (GC) vs gemcitabine (G) alone
Authors: G. Bepler, X. Li, M. Schell, Z. Zheng, D. Boulware, C. K. Obasaju, C. Reynolds
Journal: Journal of Clinical Oncology (2008)

8033 Background: RRM1 and ERCC1 mRNA and/or protein levels are molecular predictors of G and C efficacy. Prior studies had been performed under highly controlled conditions in tertiary referral centers. We prospectively assessed if RRM1 and ERCC1 protein levels are predictive of response in a community-based randomized phase III trial of GC vs G. Patients and Methods: 170 pts with NSCLC were enrolled from 3/04–12/06. All had IIIB/IV, PS 2, and no prior therapy. Routine diagnostic pretreatment tumor specimens were collected a priori and shipped to a single laboratory for blinded determination of in situ RRM1 and ERCC1 protein expression by an automated quantitative immunofluorescence-based technology (AQUA, HistoRx). Full section specimens were analyzed individually, and expression data were adjusted by using a standardized control TMA that was included in each analysis. Results: Tumor specimens were received from 91 pts. 69 were of sufficient quality for expression analysis (76% of specimens, 41% of all pts). These pts included 34 treated with GC, 35 with G; 34 women, 35 men; age 49–85 y; 5 stage IIIB, 64 stage IV; 43 adeno-, 13 squamous, 13 other cas. Adjusted RRM1 values ranged from 5.3- 105.6 (median 34.1). Adjusted ERCC1 values ranged from 10.4 -262.6 (median 69.4). RRM1 and ERCC1 expression levels were significantly correlated (p=0.001, r=0.39). They were marginally associated with pts’ age (p=0.05 and p=0.11). Neither was significantly associated with gender (p=0.73 and p=0.39) or histology (p=0.77 and p=0.91). RRM1 and ERCC1 protein values were significantly and inversely correlated with disease response (p=0.001, r=0.41 for RRM1; p=0.003, r=0.39 for ERCC1) in all pts; i.e., response was better for pts with low levels of expression. There was no significant interaction between either RRM1 or ERCC1 and best response by treatment arm. Conclusion: Quantitative analysis of RRM1 and ERCC1 protein expression in routinely collected tumor specimens from pts with advanced NSCLC is possible in most cases in a community setting. RRM1 and ERCC1 expression are predictive of response to G and GC. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Eli Lilly Eli Lilly Eli Lilly Eli Lilly Eli Lilly, sanofi-aventis
Feasibility phase II study of pegylated liposomal doxorubicin (PLD) and weekly paclitaxel-carboplatin (wTC), as first line therapy for patients with advanced ovarian carcinoma suboptimally debulked
Authors: J. A. Arranz Arija, R. González Beca, A. Velasco, P. Borrega, I. Siso, G. Abad, V. Pachon, L. Iglesias
Journal: Journal of Clinical Oncology (2005)

5139 Background: This is a pilot study to evaluate the feasibility of the combination of PLD (Caelyx) and wTC, as first line therapy in patients (p) with advanced ovarian cancer suboptimally debulked (FIGO III-IV with residual disease (RD) > 1 cm). This study is a part of a whole phase II study planned to test if this regimen could achieve a pathologic complete response (pCR) rate of 25%, and a clinical overall response (cOR) rate of 80%. Methods: PLD-wTC consisted of 6 courses every 28 days of PLD 30 mg/m2 d1, Paclitaxel 60 mg/m2 d1,8,15 and Carboplatin AUC 2, d1,8,15. In addition to antiemetics, corticoids, antihistaminics and ranitidine, a single daily dose of dexametasone 8 mg p.o. d2–4 was added to reduce the risk of palmar-plantar erythrodysesthesia (PPE). Response was assessed after 6 courses or earlier in case of progressive disease. A laparotomy after PLD-wTC was planned for p with clinical complete response (cCR), and allowed in selected cases of partial response (cPR). Results: Sixteen p have been included in this feasibility part of the study. Mean age was 55 y (39–74). There were 81.2% FIGO stages IIIc and 18.8% stages IV. Debulking surgery was possible in 75% of p (in 25% only biopsy could be done), and RD larger than 2 cm was left in 81.3% of p. Histology was serous in 43.8%, mucinous 12.5% and 6.3% endometrioid. Grade 3–4 toxicities were anemia 6.3%, neutropenia 80.3% (mainly during the last 2 courses), thrombocytopenia 18.8%%, mucositis 12.5%, alopecia 62.5% and PPE 12.5%. There were no toxic deaths. Other toxicities were G1–2 or absent. After PLD-wTC, cOR was 81.3% (cCR: 31.3%, cPR: 50%). Surgery was performed in 5 p with cCR, and also in 6 p with cPR. A pCR was obtained in 2 p (12.5%, 95% CI: 1.5 - 38.3%). With a median follow-up of 25 months, 5 p have died due to their tumor, 4 p remain alive in cCR and 7 p have active disease. Median time to progression was 16 months (95% CI: 2 - 30 m). Median overall survival (OS) has not been reached; 2-year OS was 74.5% (95% CI: 52% - 97%). Conclusions: PLD-wTC is a feasible regimen. After this pilot phase, we can not yet accept or reject the planned hypothesis of efficacy (pCR and cOR rates) of the whole phase II study. No significant financial relationships to disclose.
Monocytosis Is a Powerful and Independent Predictor of Shortened Overall and Leukemia-Free Survival in Primary Myelofibrosis
Authors: Sahrish Shah, Mythri Mudireddy, Terra L. Lasho, Daniela Barraco, Curtis A. Hanson, Rhett P. Ketterling, Naseema Gangat, Michelle Elliott, Animesh Pardanani, Ayalew Tefferi
Journal: Blood (2016)
Phase II study of granulocyte-macrophage colony stimulating factor (GM-CSF) plus thalidomide in patients (pts) with hormone naïve adenocarcinoma of the prostate
Authors: J. Hernandez, R. J. Amato
Journal: Journal of Clinical Oncology (2005)

4743 Background: A subset of men post definitive local therapy (radical prostatectomy or radiation therapy) with no evidence of metastatic disease but rising prostate specific antigen (PSA) exists. Androgen ablation is palliative and effective in most men, but this population is hesitant to begin due to adverse effects. GM-CSF is a cytokine for the generation of antigen-presenting cells and priming of cellular immune responses. Thalidomide is an agent augmenting the immune system and inhibiting angiogenesis. Correlation of antitumor activity to the immune modulation and angiogenic growth factor inhibition is being investigated. Methods: Eligibility:pts who are hormone naïve, failed local therapy, no evidence of radiographic involvement; evidence of progression demonstrated by at least 3 consecutive rises in PSA by intervals of at least 4 wks. (Absolute change of at least 1 ng/mL). Adequate marrow/renal/hepatic functions. GM-CSF is given at 250μg/m2 3 days/wk by subcutaneous injection 24 hours apart. Thalidomide administered orally with an initial dose of 100mg daily for 1 wk. Wks 2–4 doses escalated every 7 days by 100mg/individual tolerance with maximum of 400mg. Men who didn’t tolerate 100mg, dose reduction to 50mg occurred. The maximum dose of thalidomide tolerated continued without break. A cycle is 12 wks. Results: Sixteen men enrolled, median age: 71 (60–83) yrs. Ten had RP, 4 had RT, and 2 had RP/RT. All pts had rising PSAs with no evidence of metastatic disease. Baseline PSA ranged from 1.8–20.4. A median of 33 wks (1–58+) of therapy has been completed. Three pts are off study at 48, 48 and 36 wks, secondary to individual tolerance and second primary. Dose levels ranged from 4 pts at 50mg, 11 pts at 100mg, and 1 pt at 300mg. Six men are too early for PSA evaluation. Ten men had a PSA reduction of 48% or greater. The median response is 63%. Grade 1–2 toxicity included: skin rash, fatigue, peripheral neuropathy and constipation. One pt had a DVT/PE. Hematologic changes noted: leukocytosis with an associated lymphocytosis and eosinophilia. Conclusion: Enrollment is ongoing. Further data regarding PSA reduction, time to progression, and toxicity will be presented No significant financial relationships to disclose.
Catumaxomab administered as a 3-hour intraperitoneal infusion: Results from an integrated safety analysis.
Authors: B. Schmalfeldt, D. Finas, J. Schilling, H. Oettle, H. Gamperl, M. Hennig, T. Ligensa, D. Seimetz, A. Kainz
Journal: Journal of Clinical Oncology (2011)

e13058 Background: Catumaxomab (anti-EpCAM x anti-CD3) is approved in the EU for the intraperitoneal treatment of malignant ascites with an infusion time of 6 hours (h), as used in the pivotal phase II/III clinical study. Experience with a 3-h infusion has grown substantially as all studies conducted thereafter used a reduced 3-h infusion time. Methods: An integrated safety analysis (ISA) comprising 5 completed studies of patients with ovarian or gastric cancer and without malignant ascites treated with a 3-h catumaxomab infusion was conducted. In 4 of 5 studies, catumaxomab was administered in a perioperative setting. This 3-h database (ISA-3 h) was compared with the reference database (ISA-6 h) of the 6-h catumaxomab infusion, which mainly includes patients with malignant ascites. Symptomatic adverse drug reactions (ADRs) of intensity grade ≥3 occurring in ≥1% of patients were used to describe the safety profiles derived from the ISA-6 h (N=258) and ISA-3 h (N=125) databases. Results: The nature of these ADRs was comparable between both databases. The frequency of ADRs of intensity grade ≥3 was comparable for reactions such as abdominal pain, pyrexia and vomiting. Increased occurrence rates were observed for specific ADRs with the 3-h vs the 6-h infusion, e.g. diarrhea (5.6% vs 1.6% of patients) and nausea (4.8% vs 2.3% of patients). For ADRs of intensity grade 1 or 2, a higher occurrence rate was observed in the ISA-3 h data set for a few ADRs, e.g. chills, fatigue and diarrhea. Cytokine release related symptoms were largely comparable. The observed ADRs are expected due to catumaxomab’s mechanism of action and can be well controlled with pre- and/or concomitant medication. Conclusions: The available safety data support the reduction of the catumaxomab infusion time from 6 h to 3 h. The reduction of the infusion time represents a significant advance in terms of the time spent at a healthcare facility. A variation of the approved product information is under preparation.
Iron deficiency anemia related to hereditary hemorrhagic telangiectasia: Response to treatment with bevacizumab.
Authors: J. M. Fleagle, R. K. Bobba, R. F. Khozouz, P. Garg, C. G. Kardinal, C. Freter
Journal: Journal of Clinical Oncology (2011)

e13521 Background: Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant condition associated with arteriovenous malformations or telangiectasia’s of the pulmonary (15-30%), gastrointestinal (~30%) or hepatic (~30%) circulations. Methods: A 52-year-old female with a known diagnosis of HHT presented for evaluation of anemia. She had a prior history of iron sucrose infusions, frequent blood transfusions and hospitalizations for anemia related to gastrointestinal bleeding and epistaxis. After presenting to our center, she was hospitalized for epistaxis once, and twice for gastrointestinal bleeding. Her nadir for hemoglobin in our center was 6.4 g/dL. Despite the maximal treatment of her disease with iron infusions, she required repeated blood transfusions and cauterization of the ectasias, and risked at any time of a fatal hemorrhage. The patient was treated with bevacizumab at a dose of 5mg/kg infusion every 2 weeks. Results: Within one month of the infusions, her hemoglobin reached 11 g/dL, the highest on record including outside hospital records even with no transfusion. In the next four months her hemoglobin improved to 13.7g/dL and she had not presented to an emergency room or was hospitalized for bleeding and did not require iron infusions or transfusions. Conclusions: Abnormal angiogenesis primarily due to mutations in the transforming growth factor β receptors endoglin and the activin receptor-like kinases is a central contributor to the formation of AVMs in HHT. Since bevacizumab is a monoclonal antibody against VEGF and therefore may be a useful treatment against AVM formation in patients with HHT. In conclusion, bevacizumab could be an alternative in patients with HHT with uncontrolled gastrointestinal bleeding, but should be individualized as there are no major randomized trials regarding its usage in patients with HHT.
An evaluation of PI3K pathway activation on the efficacy of both trastuzumab and lapatinib.
Authors: X. Hu, L. P. Wang, Q. L. Zhang, J. Zhang, H. Y. Guo, S. Sun, B. Y. Wang, Z. Jia, Z. M. Shao, Z. H. Wang
Journal: Journal of Clinical Oncology (2011)

541 Background: PI3K pathway activation is associated with primary resistance of trastuzumab in patients with HER2-positive metastatic breast cancer. It remains to be not fully understood how this pathway activation correlates with sensitivity and resistance to lapatinib in patients pretreated with anthracyclins, taxanes, and trastuzumab. Methods: Sixty-seven HER2-positive metastatic breast cancer patients were recruited into a global lapatinib Expanded Access Program and 57 patients have primary tumor specimens available for determination of PI3K pathway status. PTEN status was determined by immunohistochemical staining and PIK3CA mutations were detected via PCR sequencing. All patients were treated with lapatinib 1,250 mg/day continuously and capecitabine 1,000 mg/m2 twice daily on a 2-week-on and 1-week-off schedule until disease progression, death, withdrawal of informed consent, or intolerable toxicity. Results: PIK3CA mutations and PTEN loss were detected in 12.3% (7/57) and 31.6% (18/57) of the patients, respectively. Twenty-two patients with PI3K pathway activation (defined as PIK3CA mutation and/or PTEN expression loss) had a lower clinical benefit rate (36.4% versus 68.6%, p = 0.017) and a lower overall response rate (9.1% versus 31.4%, p = 0.05), when compared with the 35 patients with no activation. A retrospective analysis of first trastuzumab-containing regimen treatment data showed that PI3K pathway activation correlated with a shorter median progression-free survival (4.5 versus 9.0 months, p = 0.013). Conclusions: PIK3CA mutations occur more frequently in elder patients for HER2-positive breast cancer. PIK3CA mutations and PTEN loss are not mutually exclusive. PI3K pathway activation resulting from PTEN loss or PIK3CA mutations may lead to drug resistance to lapatinib as well as trastuzumab.