tbuckley/cabot-search huggingface dataset:
RTOG 0315: A randomized, double-blind, placebo-controlled phase III study to determine the efficacy of octreotide acetate in preventing or reducing the severity of chemoradiation-induced diarrhea in patients with anal or rectal cancer
Authors: B. Zachariah, J. James, C. K. Gwede, J. Ajani, L. Chin, D. Donath, B. L. Kane, M. Rotman, L. Berk
Journal: Journal of Clinical Oncology (2007)

4032 Background: Diarrhea is a common side effect of chemoradiation for pelvic malignancies. Octreotide acetate has been shown to control grade 3–4 chemotherapy-induced diarrhea in &gt;90% of patients. The primary objective of this randomized placebo-controlled phase III study was to determine the efficacy of long acting octreotide acetate in preventing the onset of grade 2–4 diarrhea. Secondary objectives were to assess the impact of diarrhea on chemoradiation delivery and medical resource utilization. Methods: Eligible patients (pts) with primary anal or rectal cancer, and scheduled to receive concurrent chemoradiation to a minimum dose of 45 Gy using pelvic field sizes greater than 10x10cm, were enrolled. Pts with history of pelvic radiotherapy, chronic bowel disease, diarrhea of grade ≥2, or colostomy were excluded from the study. Pts were stratified by RT dose (&lt;50 Gy and ≥50 Gy), chemotherapy (bolus and continuous) and gender. Pts were randomized to receive two 30 mg intramuscular injections of octreotide acetate (Sandostatin LAR® Depot) or placebo. Injections were given between day -7 and day -4 and on day 22 (± 3 days) of RT. The primary endpoint was incidence of grade 2, 3, or 4 diarrhea (CTCAE v3.0). Assuming a 45% placebo incidence rate, a one-sided chi-square test (alpha 0.05) would require 226 pts to detect a 42% reduction in incidence due to octreotide acetate. Results: The study accrued 233 pts (215 analyzable), 106 pts in the placebo arm and 109 pts in the octreotide acetate arm. The majority of pts (80%) on each arm had rectal cancer. There was no statistically significant difference in incidence of grade 2+ diarrhea (p=0.21) with 52 (49%) and 48 (44%) in the placebo and octreotide acetate treatment arms, respectively. There was also no statistically significant difference between the treatment arms in chemoradiation delivery or medical resource utilization. Conclusions: Prophylactic use of octreotide acetate was not shown to significantly reduce the incidence of mild, moderate or severe diarrhea. No significant financial relationships to disclose.
Phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of LBH589A: A novel histone deacetylase inhibitor
Authors: J. Beck, T. Fischer, E. Rowinsky, C. Huber, M. Mita, P. Atadja, B. Peng, C. Kwong, M. Dugan, A. Patnaik
Journal: Journal of Clinical Oncology (2004)

3025 Background: LBH589A is a novel histone deacetylase inhibitor which inhibits HDAC enzyme activity, activates p21 and inhibits proliferation of tumor cell lines at nanomolar concentrations. Methods: In this phase I trial, LBH589A was administered IV as a 30-minute infusion either on days 1–3 and 8–10 of a 21 day cycle (arm 1) or on days 1–3 and 15–17 of a 28 day cycle (arm 2). Results: Thirteen pts. (median age: 64.3 years; 10M, 3F) have been treated. Tumor types: renal cell (4 pts), NSCLC (2 pts), sarcoma (2 pts), hepatocellular (1 pt), colon (1 pt), others (3 pts). In arm 1, 11 pts. have been treated at dose levels (mg/m2): 1.2 (2 pts), 2.4 (3 pts), 4.8 (3 pts), 7.2 (3 pts). In arm 2, two pts. have been treated at dose levels: 2.4 (1 pt), 4.8 (1 pt). Performance status: 0 (3 pts), 1 (10 pts). One DLT (prolonged G2 thrombocytopenia) has been observed at the 7.2 mg/m2 dose level in arm 1. Other toxicities (all cycles): G3 neutropenia (1 pt), G3 hypoglycemia (1 pt), G2 thrombocytopenia (2 pts), and G2 anemia (2 pts). No abnormalities observed in >100 ECGs. Six of 13 pts. have exhibited stable disease (range 2–8 cycles, tumors: renal (3 pts), sarcoma (1 pt), NSCLC (1 pt), hepatocellular (1 pt)). To determine if LBH589A increases histone acetylation, Western blots were performed on total cell lysates from peripheral blood lymphocytes. Increased acetylation was observed in 1 of 2 pts. at 2.4 mg/m2 and in 2 of 3 pts. at 4.8 mg/m2 up to 24 hrs after the third dose. Onset of acetylation was rapid (1h) and, in 1 patient at 4.8 mg/m2 dose, lasted up to 7 days after the first dose. PK samples were collected on days 1 and 3 of cycle 1 and analyzed using a noncompartmental analysis. Plasma LBH589A concentrations were determined using HPLC/MS/MS assay. AUC increased proportionally with dose and mean AUCs (0–24h) were 37.7, 85.8 and 151.1 ng.h/mL, respectively, for 1.2, 2.4 and 4.8 mg/M2 dose levels on Day 3. Terminal half-life was approximately 15–20 hrs. Conclusions: In this phase I study, LBH589A given IV appears to be well tolerated with consistent PD effects. Additional evaluation is continuing at the 7.2 mg/m2 dose level for arm 1 and at the 9.6 mg/m2 dose level a for arm 2. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis; Novartis Germany Novartis Novartis Novartis
Patterns of PET/CT-assessed bone-marrow involvement and prognosis in newly diagnosed Hodgkin lymphoma: A detailed review of 122 treated patients treated with ABVD
Authors: C Zwarthoed, John Ouvier Matthieu, Anna Borra, F. Bergesio, S. Chauvie, A. Biggi, Martin Hutchings, Tarec El-Galaly, A. Gallamini
Journal: American Journal of Hematology (2015)
Dose-escalation trial of milatuzumab (humanized anti-CD74 monoclonal antibody) in multiple myeloma
Authors: J. L. Kaufman, R. Niesvizky, E. A. Stadtmauer, A. Chanan-Khan, D. Siegel, H. Horne, N. Teoh, W. A. Wegener, D. M. Goldenberg
Journal: Journal of Clinical Oncology (2009)

8593 Background: CD74 (HLA-DR-associated invariant chain) is highly expressed in multiple myeloma (MM), rapidly internalized, and a promising target for immunotherapy. Methods: A multicenter dose-escalation study was initiated in patients (pts) with relapsed/refractory MM who had failed at least 2 standard therapies. Pts received milatuzumab IV twice-weekly for 4 wks, with doses escalated by a 3+3 cohort design. Pts were evaluated over 12 wks, with responding pts continuing follow-up. AEs and safety laboratories were evaluated by NCI CTC v3 grades, with any treatment-related Grade 3–4 events considered dose-limiting toxicity (DLT). Responses were classified by EBMT criteria, with PK and immunogenicity evaluated by serum milatuzumab levels and human anti-milatuzumab antibody (HAHA) titers, respectively. Results: Twenty-one pts (12M/9F, median age 63) have now received 1.5 (n=8), 4.0 (n=9) or 8.0 mg/kg (n=4) doses twice weekly. They had MM for 0.9–16.8 years (median 5.4), predominantly IgG subtype, were heavily pretreated (4 median prior treatments), and were Durie-Salmon stage II (n=13) or III (n=8). After increasing premedications and slowing administration, infusions were well tolerated (Grade 1–2). There was 1 DLT (infusion reaction) and 3 SAEs (bact. meningitis, confusion/hypercalcemia, fever post demerol) at 1.5 mg/kg, 1 DLT (unexplained anemia) and 2 SAEs (cord compression, epistaxis/thrombocytopenia), at 4.0 mg/kg, but no DLTs or SAEs at 8.0 mg/kg. There has been no pattern of other AEs nor effects on routine laboratories, including serum chemistries, CBC, serum immunoglobulins, B- or T-cells, and no cases of HAHA. At current doses, milatuzumab is rapidly cleared from serum, with little accumulation and low trough levels across infusions. There have been no objective responses so far, but 4 pts have had stable disease by EBMT criteria for at least 3 months post-treatment, occurring with a possible trend towards higher milatuzumab serum levels than pts with earlier disease progression. Conclusions: Milatuzumab doses up to 8.0 mg/kg may be given safely twice-weekly for 4 weeks. In spite of rapid clearance, several patients have had disease stabilization at 4.0 and 8.0 mg/kg doses, which is encouraging. Accrual of the next cohort receiving 16.0 mg/kg is ongoing. [Table: see text]
A phase II trial of carboplatin and ABI-007 in patients with unresectable stage IV melanoma, N057E
Authors: L. A. Kottschade, V. J. Suman, T. Amatruda, R. R. McWilliams, S. R. Dakhil, D. A. Nikcevich, R. F. Morton, T. R. Fitch, A. J. Jaslowski, S. N. Markovic
Journal: Journal of Clinical Oncology (2008)

9044 Background: There has been evidence to show that the combination of paclitaxel and carboplatin is clinically active in the treatment of metastatic melanoma. ABI-007 is a unique protein formulation of paclitaxel which was developed primarily to reduce the toxicities associated with paclitaxel and the Cremophor-EL/ethanol vehicle while maintaining or improving chemotherapeutic effect. ABI-007 demonstrates single agent activity in the treatment of metastatic melanoma. The current study explores the clinical activity of the combination of ABI-007 and carboplatin. Methods: A one stage phase II clinical trial was conducted in patients with unresectable stage IV melanoma, who were chemotherapy naive. A treatment regimen consisting of ABI-007 (100 mg/m2) and carboplatin (AUC 2) was administered on days 1, 8, and 15 of a 28 day cycle. The primary aim of this study was to assess whether tumor response rate (CR + PR by RECIST) was ≤15% vs. ≥35% with this combination. With α=β=0.10, we reject CR + PR ≤ 15% if ≥ 9 responses among first 35 patients enrolled. Eligible patients, were at least 18 years of age, with ECOG PS of 0–2 and adequate organ function. Exclusion criteria included: any chemotherapy in the metastatic setting, any prior treatment with a platinum or taxane agent, uncontrolled infection or CHF, existence of peripheral neuropathy ≥ grade 2, history of malignancy within the last 5 years, or prior untreated brain metastasis. Pregnant or nursing women were not eligible. Results: Forty patients were enrolled from November 2006 thru June 2007, one patient cancelled prior to starting treatment. Among the 39 evaluable patients, 56% were male, median age was 58 years (range: 23–91), 49% had M1c disease and 62% had a PS of 0. The median number of cycles administered was 3 (range 1–11). Nine partial responses (25.7%) were seen among the first 35 patients enrolled (90% CI: 14.1–40.6%). Among all 39 evaluable patients the median PFS was 4.3 months. The median overall survival was 10.1 months. The most common severe toxicities (CTCAE ≥ grade 3) included neutropenia (27%), thrombocytopenia (5%) and neuro-sensory (5%). Conclusions: This weekly combination of ABI-007 and carboplatin appears to be well tolerated with promising clinical activity as first-line therapy in patients with metastatic melanoma. No significant financial relationships to disclose.
Impact of disease progression (DP) date determination method on post progression survival (PPS) and DP metrics in advanced lung cancer.
Authors: Sumithra J. Mandrekar, Nathan R. Foster, Yingwei Qi, Grace K. Dy, Aminah Jatoi, Julian R. Molina, James R. Jett, Philip J. Stella, Steven E. Schild, Alex A. Adjei
Journal: Journal of Clinical Oncology (2012)

7605 Background: Overall survival (OS) can be partitioned into progression-free survival (PFS) and PPS. PPS helps to understand trial results, especially when PFS and OS data on trial treatment effects are discordant. At ASCO 2011, we reported that the magnitude of difference in the PFS estimates using different DP date methods was large enough to alter trial conclusions. Here, we investigate the impact of the DP date method on 1) PPS estimates, and 2) predictive utility of DP metrics on subsequent OS (SOS). Methods: Individual patient (pt) data from 14 trials were pooled. DP date was determined using: reported progression date (RPD) (method 1, M1), one day after last progression-free (PF) scan (M2), and midpoint between last PF scan and RPD (M3). PPS was estimated using the method of Kaplan-Meier for the 3 DP date methods. A flexible landmark analysis at 2, 4, and 6 months (mos) using Cox proportional hazards model was used to assess the impact of DP status (progression versus no-progression) on SOS (using M1, M2, or M3). Results: Among NSCLC (SCLC), 87% (91%) of pts reported DP. As expected, the PPS estimates were the lowest for RPD, highest for M2, and in-between for M3 (a direct consequence of the DP date method); with no difference by arm for the randomized trials. Regardless of the DP date method, patients who were progression-free had improved SOS (NSCLC: Hazard ratio, HR&lt;=0.33; p &lt; 0.0001; SCLC: HR&lt;=0.48; p &lt; 0.002) at each landmark time point, with comparable concordance index (SCLC: 0.57-0.65; NSCLC: 0.63-0.67), i.e., ability to discriminate patients with different SOS outcomes. Conclusions: While the DP date methods do not impact the predictive utility of the DP metrics, they significantly impact PPS estimates. The translation of a significant treatment effect on PFS to an effect on OS is influenced by PPS (longer PPS dilutes effect on OS). Standards for declaring DP date are thus critical to trial design and for trial go/no-go decisions. [Table: see text]
Plerixafor (AMD3100) in myeloma and lymphoma patients undergoing autologous stem cell transplantation
Authors: J. S. Moreb, D. Salmasinia, C. Cline, E. Rosenau
Journal: Journal of Clinical Oncology (2009)

7100 Background: Poor peripheral blood stem cell (PBSC) mobilization has been reported as an obstacle to autologous stem cell transplant (ASCT). Plerixafor (AMD3100) has been recently approved as a mobilization agent for PBSC in the setting of ASCT. Methods: We retrospectively analyzed the data on patients who received plerixafor in our institution over two-year period. Four lymphoma patients received the drug in their first cycle of mobilization and 17 patients (hard to mobilize, HTM) as a rescue after failing to achieve cell target using G-CSF alone. These patients include 8 multiple myeloma (MM) and 9 lymphoma patients. A control group of 26 randomly picked MM and lymphoma patients who were good mobilizers and received ASCT during the same period were used for comparison. Results: Sixteen of the 17 HTM patients proceeded to ASCT with median CD34+ cell dose of 3.68 X 10 6 /kg (range, 1.88–5.01 X 10 6 ), and two of them had tandem transplants. All MM patients achieved minimum cell dose for two ASCTs. One MM patient died of progressive disease prior to ASCT. In comparison to the control group, plerixafor patients tended to have lower median CD34+ cell dose/kg collected and higher number of apheresis days, however the content of CFU-GM/kg on 1 st day of apheresis was either equal or higher in the plerixafor group versus the control. The length of hospital stay, number of serious bacterial infection, time to granulocyte engraftment (AGC &gt; 500) and long-term hematopoietic recovery at ≥ 12 mo post ASCT were not different among the two groups. Time to platelet recovery &gt; 20,000/mm 3 was similar for the MM patients, while more delayed for the plerixafor mobilized lymphoma patients (24 versus 12 days in the control group). One lymphoma patient in the control died of transplant-related complications before engraftment and none in the plerixafor group. Disease relapse at 12 months post ASCT was 0 and 10 % for plerixafor and control MM patients, respectively, and 46 and 20 % for lymphoma patients. However, the overall survival for both groups was not significantly different. Conclusions: all poor mobilizers were able to obtain adequate transplant CD34+ cell dose by using plerixafor and G-CSF. In general, patients mobilized with plerixafor had similar post transplant course and long-term outcome. [Table: see text]
Phase 1 study of CPX-1, a fixed ratio formulation of irinotecan (IRI) and floxuridine (FLOX), in patients with advanced solid tumors
Authors: G. Batist, K. Chi, W. Miller, S. Chia, F. Hasanbasic, A. Fisic, L. Mayer, C. Swenson, A. Janoff, K. Gelmon
Journal: Journal of Clinical Oncology (2006)

2014 Background: In vitro studies have shown that varying the ratio of individual agents in drug combinations can result in synergistic, additive or antagonistic activity against tumor cells. CPX-1 is a liposomal formulation of IRI and FLOX in a fixed 1:1 molar ratio which was selected as optimal in vitro and confirmed to be synergistic in vivo in preclinical tumor models. CPX-1 overcomes the dissimilar pharmacokinetics (PK) of the individual drugs, enables sustained maintenance of this ratio after IV administration, and was evaluated in a Phase I open-label, dose-escalation study. Methods: Starting dose was 30 U/m 2 (1 Unit of CPX-1 contains 1 mg IRI + 0.36 mg FLOX) given on day 1 and 15 of each 28-day cycle. Dose escalation was by modified Fibonacci with 4 subjects/cohort. Eligibility included: ≥ 18 yo; advanced solid tumor; ECOG PS ≤ 2; adequate bone marrow/liver/renal function. PK analysis was done on day 1 and 15 of the first cycle. Results: 26 subjects (16M:10F), median age 54.5 y (21–72), all with prior therapy, enrolled in 6 cohorts with the 5th cohort expanded to 6 subjects. Diagnoses: 8 colorectal, 3 pancreatic, 3 ovarian, 2 breast, 2 gastric, 2 esophageal, 2 sarcomas, 1 renal cell, 1 prostate, 1 NSCLC and 1 sphenoid sinus. Response: 20 subjects evaluable: 2 confirmed PRs (NSCLC 8+ wks; Colon 13+ wks, in a patient with prior IRI exposure) and 13 with SD (8–24+wks). Safety: DLTs were observed at the 6 th dose level: 4 subjects with DLTs: 3 diarrhea (one resulting in death due to dehydration/ARF) and one neutropenia. Other possibly related grade 3 and 4 events included one each of: grade 3 diarrhea, grade 3 vomiting, grade 3 neutropenia, grade 3 fatigue, grade 3 compression fracture and arthralgia and pulmonary embolism grade 4. PK: In all 14 subjects analyzed to date the 1:1 molar ratio of IRI to FLOX was maintained for 24 hours and metabolites 5-FU and SN-38 were present in the plasma. Conclusions: CPX-1 represents a new approach to developing drug combinations in which drug ratios are pre-selected in vitro based on optimal antitumor activity and maintained systemically through pharmacokinetic control. Phase 2 studies are planned with a recommended dose of 210U/m 2 of CPX-1. [Table: see text]
Escalating doses of hepatic arterial oxaliplatin in combination with docetaxel and capecitabine in patients with liver metastases from non-colorectal gastrointestinal malignancies
Authors: S. De La Cruz, J. Rodriguez, J. De La Cámara, G. Nagore, S. Viteri, C. Reyna, A. Chopitea, A. Viúdez, A. Gúrpide, J. García-Foncillas
Journal: Journal of Clinical Oncology (2006)

14110 Background: Docetaxel (T), oxaliplatin (O) and capecitabine (C) are active agents in gastrointestinal (g.i.) tumors. Synergism has been reported in several preclinical studies. The purpose of this study was to assess the maximum tolerated dose of hepatic arterial oxaliplatin in combination with docetaxel and capecitabine in patients (pts) with hepatic metastases from non-colorectal g.i. tumors. Preliminary evidence of activity was also evaluated. Methods: Patients with liver metastases from gastric (n=3), pancreas (n=6), esophageal (n=2) and cholangiocarcinoma (n=1) were treated with fixed doses of docetaxel (60 mg/m 2 ), capecitabine (650 mg/m 2 bid on days 1–14) and escalating doses of hepatic intraarterial oxaliplatin. Oxaliplatin dose was escalated according to the following schedule: level 1, 100 mg/m 2 ; level 2, 110 mg/m 2 ; level 3, 120 mg/m 2 . The cycle was repeated every 3 weeks. A CT scan or MRI was performed to evaluate response. Liver function tests were performed the day after and before the hepatic arterial infusion. Results: The median number of cycles was 5. At first dose level, 1 pt showed grade 3 mucositis and capecitabine intolerance that required treatment discontinuation. Three pts were later included in the same level with no further toxicity. At dose level 3, grade 3 vomiting was recorded in 1 pt and subsequently this level is now being expanded. Liver function tests on day 2 were elevated over baseline in 10 pts (83%). Seven pts (58%) required morphine due to pain associated with intraarterial infusion. Among 11 evaluable pts, 10 (83%) PRs have been confirmed. Conclusions: Accrual is ongoing at dose level 3. Preliminary data on efficacy seems promising. No significant financial relationships to disclose.
Estimation of the U.S. rate of neutropenic complications for cancer hospital discharges.
Authors: M. Dickson, C. M. Kozma, R. Barron, V. M. Chia, J. C. Legg, J. Malin
Journal: Journal of Clinical Oncology (2010)

6027 Background: To estimate US rates of neutropenic complications per annum in inpatient settings over time, among discharges of all patients, patients with any cancer diagnosis, and patients with lung cancer, non-Hodgkin lymphoma (NHL), and female breast cancer. Methods: This descriptive, cross-sectional analysis used data from 1989-2007 from the Agency for Healthcare Research and Quality Healthcare Cost and Utilization Project Nationwide Inpatient Sample (NIS). Neutropenic complications were defined by a neutropenia diagnosis code (ICD-9- CM=288.0X) only, or the combination of neutropenia and infection diagnosis codes. Rates of neutropenic complications per 10,000 discharges were calculated for all discharges, cancer discharges (140.XX-208.XX), lung cancer (162.XX), NHL (NHL, 201.XX and 202.XX) and female breast cancer (174.XX). Discharges for patients < 18 years of age and for patients receiving therapeutic radiology (92.2X) or stereotactic radiosurgery (92.3X) were excluded. Results: The estimated annual number of U.S. hospital discharges ranged from 28 to 33 million from 1989-2007. Cancer discharges accounted for 2.3-2.7 million discharges per year. The rates of neutropenic complications per 10,000 cancer discharges increased through 1999 and stabilized or declined after 1999. The rate of neutropenia discharges per 10,000 cancer (female breast cancer, lung cancer, and NHL only) discharges was 288.9 (95% CI 265.7-312.1) in 1989. The rate increased to 560.4 (95% CI 533.3-581.4) by 1999, and then declined to 495.0 (95% CI 469.4-520.7) in 2007. Trends of neutropenic complications within cancer types were similar. Neutropenia complication rates in patients with lung cancer and NHL peaked in 1997 and then declined through 2007; however, neutropenia rates in female breast cancer did not decline as much as in NHL or lung cancer in the more recent years. Conclusions: After 1999, rates of neutropenic complications among breast cancer, lung cancer, and NHL patients stabilized or declined. Further research is needed to understand whether this is the result of policy changes influencing hospitalization decisions or changing treatment patterns for cancer and the management of treatment toxicity. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen Amgen Amgen Amgen