tbuckley/cabot-search huggingface dataset:
A phase II study of S-1 for previously treated small cell lung cancer (SCLC)
Authors: K. Kudo, F. Ohyanagi, A. Horiike, E. Miyauchi, I. Motokawa, T. Horai, M. Mun, Y. Sakao, S. Okumura, K. Nakagawa, M. Nishio
Journal: Journal of Clinical Oncology (2009)

e19074 Background: S-1 is a novel oral 5-fluorouracil derivative that exhibits obvious activity against various tumor types including NSCLC. However, the effects of S-1 against SCLC have not been reported. The present phase II trial assesses the efficacy and safety of S-1 in previously treated SCLC patients. Methods: Eligible patients had pathologically documented SCLC that relapsed after platinum-based chemotherapy, ECOG performance status (PS) 0–2, and adequate bone marrow, kidney and liver function. Patients with untreated or symptomatic brain metastasis were excluded. Treatment comprised the oral administration of S-1 at 40 mg/m 2 twice each day for 28 days every 6 weeks. The primary end point was the objective tumor response rate (RECIST). Secondary endpoints included progression-free survival and overall survival. Results: Twenty-six evaluable patients were enrolled (Simon's two-stage optimal design; α = 0.1; β = 0.1; P 0 = 0.05; P 1 = 0.25) with the following characteristics: male: female, 22/4; median age, 68 (33 - 79) y; PS0–1, n = 21; PS2, n = 5. The median number of prior treatment regimens was 2 (1–3). S-1 was administered for a mean of 1.3 cycles (1 - 5). One patient (3.8%) partially responded, 10 (38.5%) had stable and 15 (57.7%) had progressive disease. The overall response rate was 3.8% and the disease control rate was 42.3%. The median time to progression was 33 days. The median survival time was 8.0 months and the 1-year survival rate was 23%. This regimen was well tolerated. The common grade 3/4 toxicities included neutropenia (7.7%), leukopenia (7.7%), anemia (7.7%), hyponatremia (7.7%), rush (7.7%), infection (7.7%), and diarrhea (3.8%). None of the patients developed febrile neutropenia and no deaths were attributed to treatment. Conclusions: S-1 is well tolerated but has low activity as a single agent in previously treated patients with SCLC. No significant financial relationships to disclose.
WR-2721 and high-dose cisplatin: an active combination in the treatment of metastatic melanoma.
Authors: D Glover, J H Glick, C Weiler, K Fox, D Guerry
Journal: Journal of Clinical Oncology (1987)

Cisplatin, alone or in combination with other chemotherapeutic agents, is relatively inactive against metastatic melanoma. Prior trials have demonstrated partial response (PR) rates of less than 10% with cisplatin alone. WR-2721 is an organic thiophosphate compound, which in the animal model, selectively protects normal tissues against the toxicity of cisplatin chemotherapy. During the course of a phase I trial of WR-2721 and cisplatin, objective PRs were noted in patients with far advanced metastatic melanoma. These observations led us to perform a phase II trial of WR-2721 and cisplatin. Thirty-six patients received 128 courses of WR-2721 before cisplatin (60 to 150 mg/m2). All patients had progressive disease before treatment. Objective PRs were observed in 19 of 36 evaluable patients (53%). Three additional patients had minor responses (MRs). PRs occurred in 53% of patients with prior chemotherapy (ten of 19). Sites of responding metastases were subcutaneous disease (15 of 19 patients), lymph nodes (16 of 21 patients), lung (four of ten patients), and liver (eight of 17 patients). The median duration of response was 4 months, with a mean of 4.5 months (range, 1 to 8 months). Transient nephrotoxicity was observed in less than 5% of courses. In all cases, renal function returned to normal within 1 to 2 weeks. Hematologic toxicity was mild and infrequent. Nine patients developed peripheral neuropathy following a median cisplatin dose of 670 mg/m2. Twenty patients experienced mild clinical hearing loss. These data suggest that WR-2721 may potentiate the antitumor activity of cisplatin in metastatic melanoma.
Phase 1 and pharmacokinetic study of AI-850, a novel microparticle hydrophobic drug delivery system (HDDS) for paclitaxel
Authors: A. J. Olszanski, L. D. Lewis, C. Mita, R. C. Walovitch, R. P. Perez, D. P. Tuck, E. K. Rowinsky
Journal: Journal of Clinical Oncology (2004)

2048 Background: AI-850 is a novel, rapidly dissolving, cremophor-free microparticle formulation of the hydrophobic drug paclitaxel (PCTX). Preclinical studies demonstrated that AI-850 can be administered quickly and safely at higher doses with improved efficacy in xenograft models as compared to cremophor paclitaxel formulations. The principle study objectives were to define the dose-limiting toxicity (DLT) and maximally tolerated dose (MTD) of AI-850 and to study the pharmacokinetics (PK) of PCTX. Methods: AI-850 was administered by rapid intravenous infusion (<30 minutes), without corticosteroid pretreatment, every 3 weeks to patients (pts) with solid tumors in cohorts of 3–6. Total and free plasma PCTX concentrations were measured by LC/MS/MS, up to 168h post dose. Results: 22 pts (13M:9F) median age 58 yrs (range 38–76) have been enrolled at doses of 36–250 mg/m2. Tumor types; 8 colorectal, 3 melanoma, 2 each of pancreatic, head & neck, gynecological cancers and 5 other. At the current dose of 250mg/m2, 3/6 pts had grade IV neutropenia, one of these pts had a DLT with grade 3 mucositis and neutropenic sepsis. Total and free PCTX PK parameters (mean ± SD) are shown in the table. The PK data suggest some degree of saturable elimination. One head & neck cancer patient (non-measurable disease) had durable radiographic resolution of pleural disease after 4 cycles at 205 mg/m2. Conclusions: Administration of AI-850 by short infusion was generally well tolerated and the study is ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Acusphere, Inc. Acusphere, Inc. Acusphere, Inc. Accusphere Pharmaceutical Company
Phase I Study of PSMA-Targeted Docetaxel-Containing Nanoparticle BIND-014 in Patients with Advanced Solid Tumors
Authors: Daniel D. Von Hoff, Monica M. Mita, Ramesh K. Ramanathan, Glen J. Weiss, Alain C. Mita, Patricia M. LoRusso, Howard A. Burris, Lowell L. Hart, Susan C. Low, Donald M. Parsons, Stephen E. Zale, Jason M. Summa, Hagop Youssoufian, Jasgit C. Sachdev
Journal: Clinical Cancer Research (2016)

Abstract Purpose: First-in-human phase I trial to determine the safety, pharmacokinetics, and antitumor activity of BIND-014, a novel, tumor prostate-specific membrane antigen (PSMA)–targeted nanoparticle, containing docetaxel. Experimental Design: Patients with advanced solid tumors received BIND-014 every three weeks (n = 28) or weekly (n = 27), with dose levels ranging from 3.5 to 75 mg/m2 and 15 to 45 mg/m2, respectively. Results: BIND-014 was generally well tolerated, with no unexpected toxicities. The most common drug-related toxicities (&amp;gt;20% of patients) on either schedule included neutropenia, fatigue, anemia, alopecia, and diarrhea. BIND-014 demonstrated a dose-linear pharmacokinetic profile, distinct from docetaxel, with prolonged persistence of docetaxel-encapsulated circulating nanoparticles. Of the 52 patients evaluable for response, one had a complete response (cervical cancer on the every three week schedule) and five had partial responses (ampullary adenocarcinoma, non–small cell lung, and prostate cancers on the every-three-week schedule, and breast and gastroesophageal cancers on the weekly schedule). Responses were noted in both PSMA-detectable and -undetectable tumors. Conclusions: BIND-014 was generally well tolerated, with predictable and manageable toxicity and a unique pharmacokinetic profile compared with conventional docetaxel. Clinical activity was noted in multiple tumor types. The recommended phase II dose of BIND-014 is 60 mg/m2 every three weeks or 40 mg/m2 weekly. Clin Cancer Res; 22(13); 3157–63. ©2016 AACR.
Long-term impact of chemotherapy on early stage ovarian cancer patients
Authors: U. A. Matulonis, A. Kornblith, H. Lee, J. Bryan, C. Gibson, C. Wells, J. Lee, L. Sullivan, R. T. Penson
Journal: Journal of Clinical Oncology (2006)

5024 Background: Quality of life (QOL) assessments in early stage (stage I and II) ovarian cancer survivors (CS) are limited and have to date not focused on CS who have received adjuvant platinum- and taxane-based chemotherapy (CT). Methods: 55 early stage ovarian patients (pts) were identified from patient logs from the Dana-Farber Cancer Institute and Massachusetts General Hospital. 54 pts. received CT. QOL and long-term medical sequelae were measured in pts who were &gt; 3 years from diagnosis and had no evidence of recurrent cancer. Pts were interviewed by phone, and the following surveys were administered: EORTC QLQ-C30 (EORTC) and QLQ-OV28 (OV-28), MHI-17, CALGB sexual functioning, GOG Neuropathy, FACT Fatigue, Beck’s Hopelessness, Fear of Recurrence (FOR), Dyadic Adjustment Scale (DAS), PCL-C post-traumatic stress disorder (PTSD), Unmet Needs, FACT-Spirituality (FACT-Sp), complementary therapy use, and MOS Social Support (MOS). Results: 55 pts were interviewed (mean age 58 yrs, range 34 to 77 yrs). Mean time between diagnosis and interview was 5.6 yrs. CS reported significantly higher MHI-17 scores than the population norm, and higher MHI-17 scores were associated with better overall QOL (EORTC, r = 0.57, p &lt; 0.0001), increased social support (MOS, r = 0.54, p &lt; 0.0001), and better marital relationships (DAS, r = 0.42, p &lt; 0.001). Sexual problems (1.57 out of 6) and unmet needs (1.5 out of 14) were minimal. FOR was correlated with lowered overall QOL (EORTC, r = −0.63, p &lt; 0.0001), increased abdominal symptoms (OV-28 abdominal scale, r = 0.48, p &lt; 0.0002), increased hopelessness (Beck’s, r = 0.46, p &lt; 0.0005), and increased spirituality (FACT-Sp, r = −0.57, p &lt; 0.0001). CS were using 5.4 complementary therapies for QOL purposes and 5.8 for cancer treatment. Minimal negative socioeconomic impact was observed in CS (0.16 out of 4). However, 12.5% of pts had scores indicative of a diagnosis of PTSD. Conclusions: Long-term QOL follow-up of early stage ovarian cancer survivors demonstrated minimal long-term symptoms, excellent mental health, minimal unmet needs, and minimal socioeconomic impact. No significant financial relationships to disclose.
Increased Erythropoietin Sensitivity After In Vitro Transformation of Hematopoietic Precursors by RNA Tumor Viruses&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="fn3"&gt;3&lt;/xref&gt;
Authors: W D Hankins
Journal: JNCI Journal of the National Cancer Institute (1983)

Two strains of Friend virus differ in their in vivo actions in that one strain induces anemia (FVA), while the other induces polycythemia (FVP). This study characterizes differences in the in vitro effects of these viruses on hematopoietic cells of (BALB/c x DBA/2)F1 mice. Both variants induced erythroid bursts that proliferated and differentiated without added erythropoietin (EPO). However, while the bursts induced by FVP were well "hemoglobinized" (i.e., most cells contained hemoglobin), the cells of FVA-induced bursts contained little or no hemoglobin. The nonhemoglobinized bursts, induced by FVA, were established to be erythroid by cytochemistry, electron microscopy, and hormone sensitivity. FVA-induced cells appeared to be hypersensitive to EPO, since small concentrations of the hormone produced marked increases in hemoglobin production--even when the hormone was added to the culture 3 days post infection. Time-lapse photography documented that EPO stimulated hemoglobin synthesis in virally transformed cells rather than uninfected erythroid precursors. This observation of FVA-induced hypersensitivity prompted the reexamination of the hormone requirements of FVP-induced bursts--previously considered to be EPO-independent. Reduction of the serum in the cultures allowed the demonstration that FVP-induced erythroid cells also were hypersensitive to EPO. Thus FVA and FVP can be readily distinguished in vitro by the relative EPO sensitivity of virus-induced bursts. From these findings, a hypothesis is drawn: i.e., oncogenic transformation may result from increased sensitivity of progenitor cells for natural, physiologic regulators, and transformation is not necessarily accompanied by a block in differentiation. In addition, since hypersensitive virus-induced bursts could be recognized and picked from the cultures, these studies provide a method for obtaining highly purified erythroid precursors for the study of the regulation of terminal differentiation by EPO and other regulatory factors.
Survival outcome of metastatic adenocarcinoma patients after patient-tailored outpatient chemotherapy guided by fusion imaging
Authors: F. Uckun, S. Morar, J. Larson, S. Qazi
Journal: Journal of Clinical Oncology (2006)

13145 Background: We treated 173 patients with metastatic Stage IV adenocarcinoma, including 65 patients with metastatic colorectal cancer (MCRC), 22 patients with metastatic pancreas cancer (MPC), and 86 patients with metastatic breast cancer (MBC) in an outpatient setting. The metastatic sites included liver (49% of patients), bone (39%), lung (36%), brain (16%), peritoneum (16%), lymph node (14%) and chest wall (8%). Methods: MCRC patients received multiple cycles of Xeloda-based empirical chemotherapy regimens: alone or in combination with Irinotecan, Oxaliplatin or Mitomycin. MPC patients were given cycles of Gemcitabine-based empirical chemotherapy regimens: alone or with Cisplatin, 5-FU or Xeloda. MBC patients received cycles of Taxol-based chemotherapy: alone or with Adriamycin, Carboplatin or Gemcitabine; Xeloda plus Taxotere or Vinorelbine; Gemcitabine plus Taxotere or Vinorelbine; and Adriamycin plus Taxotere. Anatomic imaging/fusion technology with combined anatomic and functional imaging (CT/MRI fused with whole body PET scans) plus serial cancer marker level measurements monitored response to therapy and in patients showing evidence of progression on a given regimen were switched to a different treatment regimen. Results: Kaplan Meier calculated median survival time for all 173 metastatic adenocarcinoma patients was 17 mo (95% CI 13–19 mo); for subgroups medians were 12 mo (9–16 mo), 16 (8–22 mo) and 22 mo (18–42 mo) for MCRC, MPC and MBC patients respectively. The probability of living at 1 yr after initiation of therapy was 61 ± 6% for all patients, 47 ± 6% for MCRC, 59 ± 10% for MPC and 72 ± 5% for MBC patients. Our results indicate that a significant portion of previously treated patients with MCRC, MPC and MBC with liver, lung, and/or brain metastases can achieve objective responses and long-term progression-free survival with an excellent quality of life on patient tailored outpatient treatments guided by fusion imaging. Conclusions: Fusion technology provides a powerful diagnostic tool for timely termination or modification of ineffective treatments. Empirical patient-tailored chemotherapy should be offered to metastatic adenocarcinoma patients as an alternative to the clinical trial and hospice options. No significant financial relationships to disclose.
Comparative effectiveness of first-line (1<sup>st</sup>) VEGF TKI followed by second-line (2<sup>nd</sup>) therapy with either a VEGF TKI or an mTOR inhibitor in patients (pts) with metastatic renal cell carcinoma (mRCC).
Authors: Shiven B. Patel, David D. Stenehjem, JoAnn Hsu, Srinivas Kiran Tantravahi, David Gill, Archana M. Agarwal, Julia A. Batten, Neeraj Agarwal, Sumanta Kumar Pal
Journal: Journal of Clinical Oncology (2015)

e15589 Background: In the INTORSECT trial, not progression-free (PFS), but overall survival (OS) was higher with sorafenib vs. temsirolimus in 2nd setting after 1st sunitinib therapy in mRCC pts. Here, we compare the PFS and OS between any VEGF TKI and mTOR inhibitors (mTORi) in 2nd setting in mRCC after progression on 1st VEGF TKI. Methods: Pts were identified from two institutional databases. Survival estimates of PFS and OS were assessed from initiation of 2nd therapy by Kaplan-Meier methodology and stratified by the median PFS of the 1st therapy. Results: Of 125 pts treated with a 1st VEGFR-TKI, 46 received a 2nd VEGFR-TKI (37%) and 79 received a 2nd mTORi (63%). Baseline variables such as age, race, gender, histology, MSKCC and IMDC criteria did not differ by 2nd therapy (Table). Table presents survival estimates in months (mos) by 2nd therapy. Conclusions: Improved PFS (7.4 vs 4.5 mos, p= 0.026), and a trend for improved OS was observed with 2nd line VEGFR TKI vs mTORi. Improved PFS was more pronounced with 2nd VEGFR TKI if 1stVEFGR TKI usage >8 mos (11.3 vs 5.1 mos, p=0.009), suggesting continued VEGF inhibition may be a pertinent strategy in this subset of patients. VEGFR-TKI (n=46) mTORi (n=79) P-value Survival from 2nd tx, mos Median OS 26.9 15.4 0.053 1st VEGFR-TKI ≥8 mos 28.6 24.2 0.700 1st VEGFR-TKI <8 mos 22.1 7.0 0.058 Median PFS 7.4 4.5 0.026 1st VEGFR-TKI ≥8 mos 11.3 5.1 0.009 1st VEGFR-TKI <8 mos 5.5 3.7 0.461 Age, y (%) Median (IQR) 58 (52-66) 60 (53-69) 0.085 Gender, n (%) Male 28 (61) 60 (76) 0.077 Race, n (%) White 40 (87) 62 (78) 0.408 Hispanic 4 (9) 9 (11) Other 2 (4) 8 (10) Histology subtype, n (%) Clear cell 35 (76) 65 (82) 0.221 Papillary 7 (15) 7 (6) Chromophobe 3 (7) 3 (4) Other 1 (2) 6 (8) MSKCC, n (%) Favorable 11 (34) 26 (36) 0.263 Intermediate 21 (66) 40 (56) Poor 0 (0) 6 (8) IMDC, n (%) Favorable 0 (0) 4 (5) 0.079 Intermediate 25 (78) 41 (56) Poor 7 (22) 28 (38) 1st VEGFR-TKI, n (%) Sunitinib 33 (72) 75 (95) Sorafenib 10 (22) 2 (3) Pazopanib 3 (7) 2 (3) 2nd line, n (%) Pazopanib 13 (28) - Sorafenib 16 (35) - Axitinib 4 (9) - Sunitinib 12 (26) - Cabozantinib 1 (2) - Temsirolimus - 30 (38) Everolimus - 49 (62) *SBP and DDS: Equal contribution.
Re-challenge with temozolomide (TMZ) at recurrence in high-grade gliomas (HGG)
Authors: T. Jauch, P. Hau, U. Bogdahn
Journal: Journal of Clinical Oncology (2007)

2034 Background: TMZ is standard therapy for patients (pts) with HGG. Recent data suggest potentially enhanced efficacy of alternative schedules of TMZ administration based on optimizing depletion of MGMT. However, no prospective data have been published on the efficacy of TMZ regimens after failure of first-line TMZ (FL-TMZ). We therefore assessed the outcome of rechallenge with TMZ in pts with HGG. Methods: A retrospective review of pt with recurrent HGG who were rechallenged with TMZ between Jan 2000 and Oct 2006 was conducted. Standard criteria for rechallenge were as follows: if pts relapsed=8 wks after discontinuation of FL-TMZ, they were treated with the same or an alternative regimen of TMZ; however, if they progressed while still receiving TMZ, they were treated with an alternative regimen. Results: Of a total 81 pts identified, 54 intra-institutional pts were evaluable, 23 glioblastoma (GBM), 22 anaplastic glioma (AG). Median age was 44 yr with median KPS of 80. The response rate (RR) to FL-TMZ was 65% in GBM and 95% in AG using Macdonald criteria. At rechallenge, pts received one of four TMZ regimens: 150–200 mg/m 2 /d for 5/28 days (n=35), 150 mg/m 2 /d for 7/14 days (n=7), 75 mg/m 2 /d for 21/28 days (n=4), or continuous 50 mg/m 2 /d (n=7). All pts had progressed during FL-TMZ or after initial discontinuation of TMZ. Discontinuation during rechallenge TMZ was due to progressive disease in 36 pts and patient request in 6 pts. None of the pts discontinued due to toxicity. The response rates were 66% and 70% in GBM and AG, respectively. 8/12 non-responders to FL-TMZ responded to alternate regimens of TMZ. Median time to progression (TTP) was 20 weeks and 22 weeks, respectively. Six-month progression-free survival was 41% in GBM and 43% in AG. Conclusions: TMZ was well tolerated without major toxicities and had a good RR in pts who had previously failed TMZ. Durable responses were observed in patients who had not initially responded to front-line TMZ. These data suggest that rechallenge with TMZ in previous responders and non-responders warrants further investigation in a prospective study. No significant financial relationships to disclose.
Pharmacokinetics of irinotecan: Comparison of intravenous and intra-arterial administration in patients with liver metastases
Authors: A. Mambrini, A. Di Paolo, P. Pacetti, M. P. Muttini, M. Orlandi, R. Danesi, G. Fiorentini, M. Cantore
Journal: Journal of Clinical Oncology (2008)

14608 Background: To determine and to compare the plasma pharmacokinetics of irinotecan when administered intravenously and in hepatic artery to the same patient with liver metastases; to evaluate the toxicity of both kinds of infusion. Methods: In 10 enrolled patients, plasma levels of irinotecan and its metabolites SN-38 and SN-38 glucuronide were measured by HPLC after a loco-regional and a systemic infusion, and main pharmacokinetic parameters were calculated, including area under the time-concentration curve (AUC) and clearance. Irinotecan infusion was followed by De Gramont regimen given systemically (folinic acid, 5-fluorouracil bolus and continuous infusion). Results: The pharmacokinetic data provided evidence that the intra-arterial (IA) infusion increased the conversion of irinotecan to SN-38 with respect to standard intra-venous (IV) infusion. In fact, the AUC of irinotecan, SN-38 and SN-38 glucuronide were 5462.2±696.7, 87.5±29.9 and 904.7±150.9 h×ng/ml, respectively, after IA administration, and 6799.2±1055.7, 60.9±24.1 and 460.8±136.1 h×ng/ml, respectively, for IV infusion. The IA infusion was characterized by lower biliary index and greater glucuronidation ratio and relative extent of conversion than the IV administration, despite a more frequent occurrence of moderate-to- severe toxicity after IA infusion. Nine heavily pretreated patients who received at least 2 cycles were evaluable for response, and we observed 4 stable disease and 5 progressions. Conclusions: The comparison of the IA and IV infusion of irinotecan in the same patient demonstrates that the IA route improves the transformation of irinotecan to SN-38 and also results in increased glucuronidation of the active metabolite. Then, the administration of irinotecan as a IA infusion is feasible despite higher incidence of toxicity in comparison to IV infusion. No significant financial relationships to disclose.