tbuckley/cabot-search huggingface dataset:
Combinatorial effect of dabrafenib, trametinib, and adoptive cell transfer (ACT) in an immune-competent murine model of BRAF<i><sup>V600E</sup></i> mutant melanoma.
Authors: Siwen Hu-Lieskovan, Stephen Mok, Lidia Robert Faja, Lucas Goedert, Begonya Comin-Anduix, Richard C. Koya, Antoni Ribas
Journal: Journal of Clinical Oncology (2014)

2512 Background: The first clinical trial testing the combination of BRAF targeted therapy with vemurafenib and immunotherapy with ipilimumab was terminated early due to significant liver toxicities, possibly due to paradoxical activation of cells with wild type BRAF. MEK inhibitors can potentiate the MAPK inhibition in tumor, while alleviating the unwanted paradoxical MAPK activation. We hypothesized that addition of a MEK inhibitor would enhance the immunosensitization effects of BRAF inhibition, with decreased toxicity. Methods: A mouse model of syngeneic BRAFV600E driven melanoma (SM1) was developed. C57BL/6 mice treated with myeloid-depleting total body irradiation and bone marrow transplantation, were implanted SM1 tumors subcutaneously, followed by iv injection of 3x106gp100 peptide-activated pmel-1 splenocytes when tumors reach 4-5mm. For bioluminescent imaging (BLI), splenocytes were transduced with luciferase-transfected retrovirus. Activated splenocytes from wild type C57 BL/6 mice were controls. BRAF inhibitor dabrafenib (D), MEK inhibitor trametinib (T), vehicle (V), or D+T, were given daily by oral gavage from the day of ACT. Results: Combination of D+T with pmel-1 ACT showed complete tumor regression, not observed in any other groups, including D+T with control ACT (mean volume of 0 mm2 pmel+D+T, vs 30 C57+D+T, 118 pmel +D on day 20, P<0.0001 by one way ANOVA). BLI showed increased T cell infiltration to tumors with the triple combination, compared to ACT with D, or V. Intracellular IFNr staining of the tumor infiltrating T cells did not show significant difference among groups, indicating trametinib is not detrimental to the effector functions. No significant toxicity observed with the triple combination by weight. Conclusions: The MEK inhibitor trametinib, when combined with the BRAF inhibitor dabrafenib and ACT immunotherapy, enhances the antitumor effect, with increased infiltration and preserved function of effectors. Our findings support the testing of this combination in patients with BRAFV600E mutant metastatic melanoma.
Aerosolized pentamidine for the prevention of Pneumocystis carinii pneumonia in children with cancer intolerant or allergic to trimethoprim/sulfamethoxazole.
Authors: M M Mustafa, A Pappo, J Cash, N J Winick, G R Buchanan
Journal: Journal of Clinical Oncology (1994)

Trimethoprim/sulfamethoxazole (TMP/SMX) is the drug of choice for Pneumocystis carinii pneumonia (PCP) prophylaxis in immunocompromised patients. In children with malignancy, TMP/SMX is well tolerated, but adverse reactions that necessitate discontinuation can occur. We evaluated the safety and efficacy of aerosolized pentamidine (AP) as an alternative prophylaxis modality in children with malignancy who are intolerant of or allergic to TMP/SMX.AP (200 mg/m2 every 4 weeks) was administered to 60 children with malignancy receiving chemotherapy who had experienced severe adverse reactions to TMP/SMX. Seven hundred twenty doses of AP have been administered during a 3 1/2-year period (21,600 patient-days), with 30 patients treated for > or = 12 months (range, 12 to 25).Adverse reactions occurred during 79 (10%) of the 720 treatments and included bronchospasm in 23, cough in 40, vomiting in 10, and nausea in six. Only two patients had severe bronchospasm. AP was discontinued due to toxicity in three patients (5%). None of the patients (upper 95% confidence limit, 0.049) have developed PCP.AP appears to be well tolerated and effective in the prevention of PCP in children with malignancy.
Latina patient perspectives about informed decision making for surgical breast cancer treatment
Authors: S. Hawley, N. Janz, A. Hamilton, S. J. Katz
Journal: Journal of Clinical Oncology (2007)

6544 Background: Although increasing informed decision making has been identified as a mechanism for reducing disparities in breast cancer treatment outcomes, little is known about these issues from the Latina perspective. Methods: 2,030 women with non- metastatic breast cancer diagnosed from 8/05–5/06 and reported to the Los Angeles County SEER registry were identified and mailed a survey shortly after receipt of surgical treatment. Latina and African American women were over-sampled. Survey data were merged to SEER clinical data. We report results on a 50% respondent sample (N=742) which will be updated based on a final respondent sample of 1,400 patients (projected response rate, 72%). Dependent variables were patient reports of how decisions were made (doctor-based, shared, patient-based); their preferred amount of decisional involvement; and two 5-item scales measuring satisfaction with decision-making and decisional regret. Results: 32% of women were white, 28% African American (AA), 20% Latina-English speaking (L-E), and 20% Latina-Spanish speaking (L- SP). About 28% of women in each ethnic group reported a surgeon-based, 33% a shared, and 38% a patient-based surgical treatment decision. L- SP women reported wanting more involvement in decision making more often than white, AA or L-E women (16% vs. 4%, 5%, 5%, respectively, p&lt;0.001). All minority groups were less likely than white women to have high decisional satisfaction with L-SP women having the lowest satisfaction (w-74%, AA-63%, L-E-56%, L-SP-31%, p&lt;0.001). L-SP women were more likely than white, AA or L-E women to have decisional regret (35% vs. 7%, 15%, 16%, respectively, p&lt;0.001). Multivariate regression showed that Latina ethnicity and low literacy were independently associated with both low decisional satisfaction and high decisional regret (p&lt;0.001). Conclusions: Latina women, especially Spanish speakers, report more dissatisfaction with the breast cancer surgical treatment decision-making process than other racial/ethnic groups. These results highlight the challenges to improving breast cancer treatment informed decision making for Latina women. Future interventions to improve satisfaction with the decision process should be tailored to ethnicity and acculturation. No significant financial relationships to disclose.
Outcomes of Advanced Renal Cell Carcinoma Patients (Arcc) Treated with First-Line Pazopanib (Paz) in a Us Community Oncology Setting
Authors: N. Vogelzang, M.D. Hackshaw, T. Hutson, D. Bhowmik, M. Yap, D. Rembert, E. Jonasch
Journal: Annals of Oncology (2014)
A dose attenuated schedule of irinotecan and capecitabine in combination with celecoxib in advanced colorectal cancer
Authors: B. F. El-Rayes, A. F. Shields, U. Vaishampayan, L. K. Heilbrun, M. M. Zalupski, P. A. Philip
Journal: Journal of Clinical Oncology (2006)

3584 Background: The cyclooxygenase-2 (COX-2) enzyme is overexpressed in the majority of colorectal cancers. Inhibition of the COX-2 enzyme can sensitize colorectal cancer cells to the apoptotic effects of chemotherapeutic agents and block angiogenesis. This phase II study was undertaken to determine the effects of adding celecoxib to a dose attenuated irinotecan and capecitabine regimen. Methods: The primary objective was to estimate the objective response rate of patients with metastatic colorectal cancer treated with irinotecan, capecitabine, and celecoxib. Previously untreated patients, except for adjuvant therapy, with metastatic colorectal adenocarcinoma were eligible for this study. Patients received irinotecan 70 mg/m 2 (over 30 minutes) on days 1 and 8, and capecitabine 2,000 mg/m 2 /day from day 1 to 14 of a 21-day cycle. Celecoxib was administered at a dose of 400 mg twice-daily starting on day -7 until termination from study. Results: A total of 51 patients (median age 58 years) have been enrolled on the study. The results presented are for the first 48 patients registered to the study. Median performance status was 1. A median number of 5.5 cycles (range 0- 18) were administered. In an intention to treat analysis, objective response rate was 50%. The median progression free survival was 6.9 months (90%CI; 4.7–8.2). Median survival is ≥19.4 months. No treatment related deaths were observed. The only grade 4 toxicity was diarrhea in 2 (4%) patients. Grade 3 toxicities were diarrhea (33%), hand-foot syndrome (8%), nausea (13%), vomiting (8%) and neutropenia (12%). Conclusion: Lowering the dose intensity of irinotecan in this study did not appear to compromise the treatment outcome and markedly improved the therapeutic index of this combination. Celecoxib can be safely administered in combination with irinotecan and capecitabine. Based on the observed progression free survival and response rate, the regimen has promising activity. No significant financial relationships to disclose.
A phase I/II trial of combination of PKC412 and 5-azacytidine (AZA) for the treatment of patients with refractory or relapsed (R/R) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).
Authors: Aziz Nazha, Hagop Kantarjian, Gautam Borthakur, Tapan M. Kadia, Stefan Faderl, Farhad Ravandi, Zeev Estrov, Elias Jabbour, Alfonso Quintas-Cardama, Jorge E. Cortes
Journal: Journal of Clinical Oncology (2012)

6589 Background: Midostaurin (PKC412) is a FLT3 kinase inhibitor with activity in acute myeloid leukemia (AML). Hypomethylating agents play an important role in the treatment of AML and MDS. We investigated the safety (phase I) and clinical activity (phase II) of combination of 5-azacytidine (AZA) and PKC412 in pts with R/R AML and MDS. Method: Pts ≥18 years with MDS, CMML or AML, who failed prior therapies with performance status &lt;2, adequate liver (bilirubin &lt; 2x ULN, ALT ≤ 2.5x ULN) and renal (creatinine &lt; 2x ULN) functions were eligible. Pts received AZA 75 mg/m 2 subcutaneously or intravenously for 7 days of each cycle (Days 1-7) and PKC412 at 25 mg (cohort 1) and 50 mg (cohort 2; target dose) orally twice daily for 14 days (Days 8-21). Pts were to receive up to 12 cycles if benefit from treatment. Supportive care was standard. Results: 14 pts were included in phase I. 1 pt was inevaluable for DLT (withdrawal before completing cycle#1). 6 pts treated in cohort 1 and 7 in cohort 2. 1 pt in cohort 2 received PKC412 dose as per cohort 1 dose by pt error. Pt characteristics and responses are summarized in the Table. The overall response rate (ORR) was 3/13(21%) (2 with CRi, 1 pt dropped BM blasts form 27% to 7% after 2 cycles and went to transplant. 1/4 with FLT3-ITD achieved CRi, 2 of the non-responders received prior FLT3 inhibitors (1 had developed FLT3 D835). All toxicities were grade 1 (nausea 1 pt, vomiting 1 pt, dry skin 1 pt, and rash 1 pt) with no difference between the 2 groups. No DLT was identified. Conclusions: PKC412+AZA is safe and well tolerated at the intended doses with good ORR in high risk pts with R/R AML. Phase II study is enrolling pts with FLT3-ITD. Updated result will be presented. [Table: see text]
A phase II trial of docetaxel and samarium in patients with bone metastases from castration-refractory prostate cancer (CRPC)
Authors: A. Laplanche, P. Beuzeboc, J. Lumbroso, C. Massard, A. Plantade, B. Escudier, M. Di Palma, J. Bouzy, V. Haddad, K. Fizazi
Journal: Journal of Clinical Oncology (2007)

5122 Background: Most patients (pts) with disseminated CRPC have bone metastases. Docetaxel is the current standard of care in CRPC. We assessed the association of docetaxel and samarium, a radio-pharmaceutical with a high affinity to bone, as consolidation treatment after docetaxel-estramustine. Methods: This is a prospective, bi-center phase II trial. Pts with bone metastases from CRPC received docetaxel 70 mg/m 2 day 2 + estramustine 10 mg/Kg/day, day 1–5 (1 cycle/ 3 weeks). Pts with a response or stabilization after 4 cycles were given consolidation therapy: docetaxel 20 mg/m 2 /week × 6 weeks + samarium 37 MBq/Kg during week 1. Zoledronic acid was routinely used and was stopped 1 month before samarium infusion. A Simon design was used with a target of 39 pts receiving consolidation treatment. Response was defined according to the working group criteria (Bubley, J Clin Oncol 1999). The primary endpoint was progression-free survival (PFS). Results: From 01/04 to 12/05, 43 pts were included in the trial: 31 (72%), 11 (26%) and 1 (3%) achieved a PSA response, stabilization, and progression, respectively. After induction therapy, a pain response (defined as a decrease in pain intensity by at least 2/10 on a pain visual analog scale (VAS) in pts with a baseline pain level = 2/10) was achieved in 60% (18/30) and was confirmed in 69% (20/29) after consolidation therapy. Consolidation docetaxel-samarium was feasible with most pts experiencing a mild (grade 1–2) and rapidly reversible thrombocytopenia at week 5. The 7 months PSA-PFS rate was 48% (33–62%). While PSA relapse eventually occurred in all cases, this strategy resulted in an excellent long-term control of pain, with a median pain level on the VAS of 4/10, 1/10, and 0.5/10 at baseline, 12, and 18 months, respectively. With a median follow-up of 14 months, the median survival has not been reached and the 1-year survival rate is 71% (55–84%). Conclusions: Combining docetaxel and samarium is feasible and well-tolerated. It yields a major pain improvement that lasts long after consolidation therapy in pts with bone metastases from CRPC. Survival data are promising in this population of symptomatic metastatic CRPC. This approach should be tested in phase III trials. No significant financial relationships to disclose.
CFU-GM content of bone marrow graft correlates with time to hematologic reconstitution following autologous bone marrow transplantation with 4- hydroperoxycyclophosphamide-purged bone marrow
Authors: SD Rowley, M Zuehlsdorf, HG Braine, OM Colvin, J Davis, RJ Jones, R Saral, LL Sensenbrenner, A Yeager, GW Santos
Journal: Blood (1987)
Evaluation of protocol mandated testing in E4A03, a randomized phase III study of CC-5013 plus dexamethasone versus CC-5013 plus low-dose dexamethasone in multiple myeloma (MM).
Authors: Natalie Scott Callander, Susanna J. Jacobus, Matthias Weiss, Shaji Kumar, Rafael Fonseca, David Samuel DiCapua Siegel, Michael S. Katz, Rafat Abonour, Michael E. Williams, Philip R. Greipp, Vincent Rajkumar
Journal: Journal of Clinical Oncology (2013)

e19517 Background: Investigators cite complicated test (T) schedules as barriers to the conduct of clinical trials, especially T that do not contribute to outcome or pt safety. In MM protocols, some T are prone to being done inaccurately (e.g. UPEP, 24 hour urine collections), or are not useful (e.g. uric acid, AST/ALT) in determination of response (R) or safety. These T lead to increased cost, protocol violations, and do not enhance outcome. Methods: We analyzed data submitted for pts on E4A03 to examine frequency of missing data for R T: serum and urine (U) PEP, immunofixation (IFE) bone surveys (BS), and safety labs for C1-4. Results: Table outlines % pts with completed T. Most had T for serum M protein, as well as heme T but serum and U PEP, and IFE dropped off by C4. Other T e.g. uric acid were completed in 77%. Only 79% of pts had a BS repeated at C4. Incorrect or missing U data led to categorization of 16/445 (3.6%) pts as ineligible and was most frequent reason for ineligibility (69%). Missing U data led to 13/26 pts not evaluable. Analysis of SAE during the C1-4 revealed no SAE for hyperuricemia and &lt; 5 SAE for AST/ALT. Only 5% of pts had lab-based SAE filed in 4 C. Conclusions: Required U T and BS to assess R in E4A03 were missing or completed inadequately and caused pts to be ineligible and or not evaluable. Such T need to be eliminated or replaced. Strategies to monitor data submission in real time may reduce subject loss due to T error. The requirement for routine T should be reassessed to create simpler trial design. Clinical trial information: NCT00098475. [Table: see text]
An update of a phase I/II study of the VEGF receptor tyrosine kinase inhibitor vatalanib and gemcitabine in patients with advanced pancreatic cancer
Authors: T. Kuo, E. C. Cabebe, A. Koong, J. A. Norton, P. L. Kunz, J. M. Ford, H. L. Kaiser, J. Rogers, B. I. Sikic, G. A. Fisher
Journal: Journal of Clinical Oncology (2008)

15571 Background: The VEGF pathway is the predominant mediator of angiogenesis in pancreatic cancer. Vatalanib is a small molecule tyrosine kinase inhibitor of all known VEGF receptors. We initiated a phase I/II study of vatalanib and gemcitabine for advanced pancreatic cancer. Methods: Patients with newly diagnosed unresectable or metastatic pancreatic adenocarcinoma were enrolled. Gemcitabine was given by fixed-dose rate infusion weekly × 3 in a 28-day cycle. Vatalanib was initially given orally 1250 mg once daily, then the protocol was amended to 500 mg twice daily for the phase II portion of the trial. Gemcitabine was escalated from 700 mg/m2 to the final phase II dose of 850 mg/m2. Results: To date, twenty-six patients are evaluable for toxicity and response (14M/12F; median age 62 years, range 40–82 years; median KPS 90%). Sixteen patients were enrolled in phase I and ten patients have been enrolled in phase II. Phase I dose limiting toxicities include: diarrhea, hypokalemia, neutropenia, fatigue, and thrombosis. Common grade 1/2 toxicities include: fatigue, anorexia, thrombocytopenia, anemia, neutropenia, nausea, and hypertension. Beyond the first cycle, grade 3/4 toxicities included neutropenia (6), thrombocytopenia (4), anemia (3), thrombosis (3), hypertension (2), diarrhea (2), hypokalemia (2), colitis (1), febrile neutropenia (1), and proteinuria (1). Three of twenty- six patients (12%) had a partial response by RECIST. Seven patients were withdrawn from study prior to or at the first CT evaluation due to: thrombosis requiring coumadin (2), leukoencephalopathy (1), fatigue (1), patient self-withdrawn (1), and progression of disease (2). The remaining patients had stable disease as the best response (62%) for a period ranging from 2–6 months. Conclusions: The combination of gemcitabine and vatalanib is generally well-tolerated. Adverse effects associated with VEGF inhibition were commonly seen. Antitumor responses have been observed with a majority of patients having stable disease. No significant financial relationships to disclose.
Clinical results of continuous intrathecal or intracavitary administration of sodium butyrate for patients with recurrent and progressive malignant glioma: Experience with 23 cases
Authors: H. Nakagawa, M. Yoshida, T. Motozaki, K. Yoshioka, K. Itoh
Journal: Journal of Clinical Oncology (2007)

2040 Background: We evaluated the clinical potential of intrathecal use of sodium butyrate (NaB) for malignant glioma in experimental research. Based on the results of experimental research, continuous intrathecal or intracavitary administration of NaB for recurrent and progressive malignant glioma was clinically attempted. We evaluated the efficacy and therapeutic safety of this treatment. Methods: A total of 23 patients (pts)(glioblastoma:GB,19; anaplastic astrocytoma: AN, 4) were enrolled in this study between Oct. 2001 and Feb. 2006 and followed until Oct. 2006. Five patients showed CSF dissemination of tumor cells. Sixty milimolar NaB was administered to all pts after dose-escalation study using a simple balloon pump system and continued as long as possible by changing the pump containing NaB weekly. The primary end point was radiographic response, and the secondary end points were progression-free survival (PFS), overall survival, and therapeutic safety. Results: Nineteen of 23 pts (GB, 16; AN,3) were evaluable. Nine pts showed regression of the tumor, 5 showed stable disease, and 5 showed growth of the tumor. The overall median PFS of the pts was 6.0 months (mos) and that of pts with GB was 5.5 mos, while the 6-month PFS was 53.3.% and that of GB was 50%. The overall median survival time was 11.0 mos and that of GB was also 11.0 mos. The overall 1-year survival rate was 42 % and that of GB was 29.4%. Four of 5 pts with CSF tumor cell dissemination showed therapeutic response, including temporary negative cytological conversion. Various adverse effects and complications have been encountered to date, including bacterial meningitis, temporary bradycardia and convulsions. Conclusions: The present therapy was well tolerated and resulted in long-term inhibition of the growth of the tumor in some pts, and showed therapeutic safety. No significant financial relationships to disclose.
Molecular correlates of the EGFR signaling pathway in association with SWOG S0218: a phase II study of oral EGFR tyrosine kinase inhibitor OSI-774 (NSC-718781) in patients with malignant pleural mesothelioma (MPM)
Authors: L. Garland, C. Rankin, K. Scott, R. Nagle, M. Lobell, D. Gandara, S. Rivkin, W. Samlowski, J. Atkins, E. Borden
Journal: Journal of Clinical Oncology (2004)

3007
Decrease of VEGF within malignant ascites during catumaxomab treatment: Results from a pivotal phase II/III study
Authors: M. Jäger, A. Schoberth, B. Theissen, J. Hess, H. Friccius-Quecke, H. Lindhofer
Journal: Journal of Clinical Oncology (2009)

3029 Background: Treatment with the trifunctional anti-EpCAM x anti-CD3 antibody catumaxomab efficiently eliminates tumor cells from the peritoneal cavity (Jäger et al., ASCO 2007) and led to clinically relevant prolongation of puncture-free survival (PuFS) in patients with malignant ascites (MA) in a pivotal phase II/III trial (Parsons et al., ASCO 2008). As vascular endothelial growth factor (VEGF) levels are markedly elevated in MA in comparison to cirrhotic ascites the question was addressed whether catumaxomab treatment impacts the expression or accumulation of VEGF within MA. Here we report that in addition to tumor cell depletion, VEGF protein levels in MA significantly decreased upon catumaxomab therapy. We propose that the strongly correlated tumor cell elimination and reduced VEGF protein levels are causative for the prolonged PuFS of patients suffering from MA. Methods: VEGF and total protein levels were measured by ELISA and BCA from MA supernatants before catumaxomab therapy, after the 1st infusion (10μg; day 3) and after the 4th infusion (150μg; day 11). Data were statistically analysed for the ratio of the VEGF protein concentration versus the total protein concentration for the MA treatment groups with ovarian (OC) or nonovarian cancer (NC) as underlying disease and the corresponding control groups that received paracentesis only. Results: One day after the last catumaxomab infusion 46 or 47 patients analysed in the OC or NC treatment group showed a statistically significant decrease in VEGF to total protein ratio when compared to the measurement before catumaxomab therapy (ANOVA p=0.034 for OC and p&lt;0.001 for NC). These results are consistent with the tumor cell elimination previously assessed in these patients. In contrast, the OC control group showed a statistically significant increase of VEGF to total protein ratio (p=0.009), which is accompanied by an increase in tumor cell numbers. In the NC control group VEGF to total protein ratio remained unaffected (p=0.096). Conclusions: Catumaxomab therapy significantly reduced VEGF protein levels correlating with tumor cell elimination in MA, which in turn led to the prevention of fluid accumulation in the peritoneal cavity and finally to prolonged PuFS of patients suffering from MA. [Table: see text]
Deposition of Lambda Chain Constant Region within AL-Amyloid Lesion
Authors: Hiroyuki Hata, Masayoshi Tasaki, Konen Obayashi, Taro Yamashita, Yukio Ando, Shinya Endo, Nao Nishimura, Yutaka Okuno, Shiho Fujiwara, Naoko Wada, Eri Fujii, Kennichi Iyama, Hiroaki Mitsuya
Journal: Blood (2014)