The Schedule Dependent Combination of Bortezomib (Bor) with Rituximab (R), Cyclophosphamide (C) and Prednisone (P) Produces Minimal Toxicity, Even at Relatively High Doses of Proteasome Inhibitor, in Patients with Relapsed/Refractory Indolent B-Cell Lymphomproliferative Disorders.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2759-2759 ◽  
Author(s):  
John Gerecitano ◽  
Carol Portlock ◽  
Ariela Noy ◽  
Paul Hamlin ◽  
Craig Moskowitz ◽  
...  
Keyword(s):  
B Cell ◽  
Phase Ii ◽  
Single Agent ◽  
Optimal Dose ◽  
Complete Response ◽  
Weekly Schedule ◽  
Acquired Drug Resistance ◽  
Phase Ii Studies ◽  
High Doses ◽  
Grade 3

Abstract Phase II studies have established the efficacy of single agent Bor in patients with B-cell non-Hodgkin’s Lymphoma (NHL). We sought to determine the safety and efficacy of combining Bor with a modified R-CVP chemotherapy regimen (omitting vincristine). The rationale for this regimen includes: Vincristine has marginal single agent activity in indolent NHL; The optimal dose and schedule for Bor in combination with R, C and P is unknown; and Preclinical data suggests that Bor given after chemotherapy may be synergistic and overcome acquired drug resistance. Patients were enrolled in a traditional 3 by 3 phase I trial. Bor and C were alternately escalated in subsequent cohorts from 1.3 mg/m2 to 1.8 mg/m2 (Bor) and from 750 mg/m2 to 1000 mg/m2 (C). R (375 mg/m2) and P (100 mg per day orally) were fixed. R and C were dosed on day one, followed by Bor on days 2 and 8. P was given on days 2–6. Interim staging was performed after 4 cycles, with additional cycles given to patients with partial response (PR) or stable disease (SD) (4 cycles), and complete response (CR)(2 cycles). Toxicity was assessed using NCI-CTC, v. 3.0. Dose-limiting toxicity (DLT) was defined as the following during cycle 1: grade ≥ 3 nonhematologic toxicity (NHT); grade 4 neutropenia (NTP) lasting ≥ 7 days and/or neutropenic fever (NTPF); a platelet count ≤ 25,000/mm3 for 7 days or associated with bleeding requiring transfusion, or <10,000/mm3 for 1 day. Modified Cheson criteria were used to define responses. Accrual on this schedule is complete with 16 patients. No DLT was seen at maximum doses of Bor (1.8 mg/m2) and C (1000 mg/m2). One patient is excluded from analysis because of withdrawal from study prior to Bor administration. The only cohort expansion was triggered by a grade 3 diarrhea in cohort 2. The most frequent hematologic toxicities (HTs) and NHTs across all dose levels and cycles were grade 1–2. Grade 3–4 HTs included lymphopenia (n=9), thrombocytopenia (n=3), leukopenia (n=9), and neutropenia (n=9, 3 with NTPF). Grade 3–4 NHTs included grade 3 diarrhea (n=1, as mentioned above), hypophosphatemia (n=3), dehydration (n=1), hypomagnesemia (n=1), and anal incontinence (n=1, due to an unrelated rectal prolapse). Of 9 patients assessable for response to date (all of whom had received prior R and CVP- or CHOP-based regimens), 2 achieved PR, 4 minor responses, 1 had no change, and 2 progressed. R-CBorP is well-tolerated in patients with NHL when Bor is dosed on a weekly schedule up to 1.8 mg/m2. We have begun to accrue a second group of patients using this combination treatment with a traditional biweekly Bor administration. A phase II study is planned using the most promising dosing schedule based on the results of this study and emerging data from NHL patients treated with weekly single-agent Bor.

Results of a Phase II Study of 506U78 (Nelarabine) in Refractory Indolent B-Cell or Peripheral T-Cell Lymphoma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2681-2681 ◽  
Author(s):  
Michael A. Thompson ◽  
Barbara Pro ◽  
Andreas Sarris ◽  
Fredrick B. Hagemeister ◽  
Andre Goy ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Study ◽  
Single Agent ◽  
Complete Response ◽  
Water Soluble ◽  
Adult T Cell Leukemia ◽  
Grade 3

Abstract BACKGROUND: Compound 506U78 (Nelarabine), a water soluble pro-drug of 9-β-d-arabinofuranosyl-guanine, is demethoxylated by adenosine deaminase to ara-G in lymphoblasts. Intracellular ara-G is then phosphorylated via deoxycytidine kinase and mitochondrial deoxyguanosine kinase to its active 5′-triphosphate, ara-GTP. Ara-GTP, a potent inhibitor of DNA polymerase, also incorporates into DNA resulting in cell death. Studies in children and adult T-cell leukemia and non-Hodgkin’s lymphoma (NHL) have shown activity, but with reversible neurotoxicity as the most prominent adverse event. METHODS: We report here the results of a phase II study with 506U78 in adults (median age 64, range 33–81) with relapsed or refractory indolent B-cell or peripheral T-cell NHL. Patients had received a median of 2 prior courses of chemotherapy. 506U78 was given at 1.5 g/m2/day IV on days 1, 3, and 5 every 28 days to a maximum of 6 cycles unless toxicity or progressive disease. If after 4 cycles a complete response (CR) or partial response (PR) was not achieved, then treatment was discontinued. RESULTS: There were 23 patients enrolled including 13 with T-cell and 10 with indolent B-cell NHL. Among 19 assessable for response, the overall response rate (ORR) in T-cell NHL was 4/9 (44%) with 2 CR and 2 PR, while in indolent B-cell NHL the PR was 3/9 (33%) with no CR. In responders, the median time to progression (TTP) was 8 months (range 2–22 months). Sixteen of 22 (73%) patients evaluable for toxicity had grade 3 or 4 adverse events. Neurotoxicity included one grade 3 and one grade 4 event. CONCLUSION: Compound 506U78 is active as a single agent in T-cell and B-cell NHL. Our response rate was higher than the ORR of 10.5% reported previously in the Czuczman et al. (2004) Blood 104(11) abstract in adults with T-cell NHL and there was less neurotoxicity in our study. This may be related to different dosing regimens (every 28 days vs. every 21 days). Compound 506U78 should be further evaluated in clinical trials.

Pilot study of fixed-dose bevacizumab (200 mg) for solid malignancies

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14600-e14600
Author(s):  
S. K. Reddy ◽  
M. Curti ◽  
M. Janis ◽  
R. Minow
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Optimal Dose ◽  
Median Number ◽  
Fixed Dose ◽  
Phase I Studies ◽  
Phase Ii Studies ◽  
Prospective Phase ◽  
Grade 3 ◽  
Grade Iii

e14600 Background: We report our initial experience with fixed dose bevacizumab at 200mg (approximately 3mg/kg). Phase I studies suggested that an optimal dose for phase II studies with bevacizumab is 3mg/kg and that circulating VEGF was undetectable at 0.3mg/kg. (Gordon et al. JCO 2001) We proposed a fixed-dose regimen of bevacizumab which we hypothesized would yield equivalent response rates with reduced toxicities and cost versus higher-dose regimens. Patients with advanced malignancies for whom bevacizumab would be indicated were analyzed. Methods: 15 patients were treated with 200mg bevacizumab in combination with antineoplastic therapy. 6 patients had NSCLCa, 8 patients had Colorectal cancer, and 1 patient had BRCA. Results: 15 patients are evaulable for response and have completed a total of 234 doses of bevacizumab (median number of doses =13) with no grade III/IV toxicity, or bevacizumab associated toxicities seen. No grade III or greater hypertension was observed. Proteinuria was not formally assessed, but no grade 3 or greater proteinuria was reported. All patients are evaluable for response with overall response rate of 33% (5/15). With a median follow-up (from the start of bevacizumab) of 452 days (222–1,699 days), median survival has not been reached with only 2 deaths. Conclusions: Fixed dose bevacizumab appears to be effective, less toxic, significantly less expensive and supported by biologic rationale and prior phase I studies and warrants further investigation. Additional patients will be accrued in a prospective phase II trial. [Table: see text]

Phase II study of bortezomib with cisplatin as first-line treatment of malignant pleural mesothelioma (MPM): EORTC 08052.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7081-7081 ◽  
Author(s):  
Mary O'Brien ◽  
Rabab Mohamed Gaafar ◽  
Sanjaykumar Popat ◽  
Francesco Grossi ◽  
Allan Price ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Performance Status ◽  
Single Agent ◽  
Dose Intensity ◽  
Line Treatment ◽  
First Line ◽  
Phase Ii Studies ◽  
Grade 3 ◽  
First Line Treatment

7081 Background: Cisplatin is one of the most active drugs available in MPM while bortezomib has shown some activity in single agent phase II studies against MPM. This was a prospective phase II study of cisplatin and bortezomib (CB) in the first line treatment of MPM. Methods: Patients with histological proven MPM, with performance status (PS) 0/1, were eligible. The doses were cisplatin 75mg/m2 /3 wks and bortezomib 1.3mg/m2 day 1, 4, 8, 11 every 3 wks. The primary end-point was progression free survival rate at 18 wks (PFSR=18). The 2-stage Simon design (a=0.1; b = 0.05, P0=0.50 and P1=0.675) was used. In the first step of the study 37 eligible patients were planned. If more than 19 patients were alive and free of progression at 18 wks the total sample size was increased to 76 eligible patients. Results: Between 2007 and 2010 82 patients were entered. The median follow-up time is 32.3 months The median age was 55 years (range: 22-77yrs), male/female: 55/27 , PS 0/1: 9/73, Stage T1: 10%; T2: 42%, T3: 25%; T4: 23% and N0: 57%; N1: 4%; N2: 33%; N3: 6%. The median number of cycles received was 4 and 38% received 6 cycles. Cisplatin/ bortezomib dose intensity was 98/ 80%. Toxicity (grade 3/4): neutropenia 10%, thrombocytopenia 11%, anaemia 1%. Grade 3-4 hyponatraemia/ hypokalaemia occurred in 46/ and 17%. Grade 2 tinnitus, grade 3 fatigue occurred in 16%, and 12%, of patients. Motor/sensory/other neurotoxicity was grade 1: 6/28/7%, grade 2: 2/26/2% and grade 3: 1/7/2% respectively. There were 2 toxic deaths at 32 and 74 days due to acute pneumonitis and cardiac arrest. The PFRS-18 (including symptomatic progression) was 53% (80% confidence intervals, CI, 42-64%). The overall survival was 13.5 months (95% CI 10.5-15) with 56% (95% CI 44-66%) alive at 1 year. The PFS was 5.1 months (95% CI 3.3-6.5). Conclusions: On the basis of the PFRS-18, the null hypothesis could not be rejected, although CB gave predictable toxicity and was as active as other reported regimens in MPM.

Trabectedin (T) in relapsed advanced ovarian cancer (ROC): A pooled analysis of three phase II studies

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5579-5579 ◽  
Author(s):  
S. McMeekin ◽  
J. M. del Campo ◽  
N. Colombo ◽  
C. Krasner ◽  
A. Roszak ◽  
...  
Keyword(s):  
Phase Ii ◽  
Single Agent ◽  
Advanced Ovarian Cancer ◽  
Dose Intensity ◽  
Pooled Analysis ◽  
Phase Iii ◽  
Clinical Activity ◽  
Weekly Schedule ◽  
Phase Ii Trials ◽  
Phase Ii Studies

5579 Introduction: Trabectedin is a DNA minor groove binding drug with a distinct MoA under development in sarcoma, prostate, breast and ROC. We have performed a pooled analysis of efficacy and tolerability of all phase II trials with T as 2nd - 3rd line in ROC. Methods: Three Trabectedin schedules were investigated: two every 3weeks (q3w; A: 1.3 mg/m2 3-h or B: 1.5 mg/m2 24-h) and one weekly (C: 0.58 mg/m2 3-h ×3 q4w). Endpoints were response rate (RR), time to progression (TTP), response duration (RD) and safety. 294 patients from 3 phase II (one randomized A vs B) trials were included: 108 were resistant (R) and 186 sensitive (S) to last platinum, based on progression-free interval <6 months or longer.Results: Overall RR and median TTP were 8% and 2.1mo in R and 34% and 5.8 mo in S patients. Median RD was 5.8 m. Schedules A & B q3w showed significant better RR (33% vs 16%, p=<0.0001) and median TTP (5.8 vs 2.8 m, p=0.0001) than the weekly schedule C. No efficacy difference was seen between 3-h and 24-h q3wk. In patients with = 2 prior platinum-based regimens, RR (R:7% and S:37%) and median TTP (R: 2.5 m and S:6.3 m) were similar than patients with only 1 prior platinum [RR (R:9%; S:33%) and TTP (R: 2 m; S: 5.5 m)]. 1,404 cycles were delivered [median A: 5(1–23), B: 5(1–19), C: 3(1–22)], with similar dose intensity (mg/m2/wk) across regimens (0.38, 0.42, 0.39). Most common drug-related AEs of any grade by cycle were (A, B, C) fatigue: 38, 35, 63% and vomiting: 16, 27, 21%. Grade 3/4 lab abnormalities were non-cumulative neutropenia: 21, 28, 1% and ALT increase: 32, 26, 3%. Low incidence of febrile neutropenia, neurotoxicity, stomatitis and alopecia was seen regardless of schedule. Conclusions: Trabectedin as single agent has shown clinical activity in both R and, particularly in S ROC. Activity was fully retained in patients with =2 prior platinum lines. Trabectedin q3w schedules (with no difference between 3 and 24-h) showed higher efficacy than T weekly. Toxicities were manageable and non-cumulative. Trabectedin is a promising new drug for the treatment of ROC and is under evaluation in a phase III trial. No significant financial relationships to disclose.

Phase II study of NGR-hTNF, a selective vascular targeting agent (VTA), in previously treated patients with malignant pleural mesothelioma (MPM)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 7582-7582
Author(s):  
V. Gregorc ◽  
G. L. Ceresoli ◽  
P. A. Zucali ◽  
F. G. De Braud ◽  
E. Bajetta ◽  
...  
Keyword(s):  
Phase Ii ◽  
Median Duration ◽  
Stable Disease ◽  
Progression Free Survival ◽  
Patient Characteristics ◽  
Weekly Schedule ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
High Doses ◽  
Grade 3

7582 Background: NGR-hTNF is a VTA exploiting a tumor-homing peptide (NGR) that selectively binds to an aminopeptidase N (CD13) overexpressed on tumor blood vessels. In preclinical models, NGR-hTNF has shown potent anti-vascular and antitumor activity, both at low and at high doses. Methods: Patients with advanced MPM were treated with a low-dose of NGR-hTNF given intravenously at 0.8 μg/m2 as 1-hour infusion every 3 weeks (q3w). This phase II trial had a 2-stage design with 16 and a total of 27 patients to be enrolled after first and second stage, respectively. Primary endpoint was progression-free survival (PFS) with restaging performed q6w according to MPM-modified RECIST criteria. Results: From May 2007 to January 2008, forty-three patients with radiologically-documented progressive disease after a pemetrexed-based regimen were evaluated over 167 cycles (range, 1 to 17). Patient characteristics were: median age 64 years (range, 54 to 80); male/female 27/16; epithelial/non-epithelial histology 34/9; PS 0/1/2 24/10/9; EORTC score good/poor 34/9. Main grade 1–2 toxicity was chills (71%), transiently occurring after the first infusions. Only one grade 3 treatment-related toxicity was observed. One patient (2%) had a partial response lasting 7.1+ months and 17 patients (40%) maintained stable disease for a median duration of 4.4 months (range, 1.3 to 12.4+ months). The median and 3-month PFS were 2.8 months and 43%, respectively, whereas the median and 1-year overall survival were 11.6 months and 48%, respectively. In an additional 14 patients treated at same dose with a weekly schedule, there was any suggestion of toxicity exacerbation. In this cohort, the PFS rate at 6 months was 36%, with 7 patients (50%) experiencing stable disease for a median duration of 6.9 months (range, 2.4 to 9.3+ months). Conclusions: NGR-hTNF 0.8 μg/m2 weekly is well tolerated, showing prolonged disease control in previously treated MPM patients, and will be further developed in this setting. [Table: see text]

Phase II trial of sorafenib in esophageal (E) and gastroesophageal junction (GEJ) cancer: Response observed in adenocarcinoma.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 41-41 ◽  
Author(s):  
D. Ilson ◽  
Y. Y. Janjigian ◽  
M. A. Shah ◽  
L. H. Tang ◽  
D. P. Kelsen ◽  
...  
Keyword(s):  
Phase Ii ◽  
Stable Disease ◽  
Kinase Inhibitor ◽  
Phase Ii Trial ◽  
Gastroesophageal Junction ◽  
Single Agent ◽  
Progression Free Survival ◽  
Complete Response ◽  
Node Disease ◽  
Grade 3

41 Background: Sorafenib is a tyrosine kinase inhibitor targeting VEGFr, PDGFr, Raf and other pathways. Encouraging response and survival were observed in a phase II trial combining sorafenib with chemotherapy in GE cancer (J Clin Oncol 27:2947;2010). We are studying single agent sorafenib in a phase II trial with the primary endpoint to assess progression free survival (PFS). Secondary endpoints include response and therapy tolerance. Methods: Patients (pts) with measurable metastatic E and GEJ cancer with no more than 3 prior chemotherapy regimens were treated with sorafenib 400 mg BID. CT scans were performed monthly for the first 2 months, then every 2 months. Results: Sixteen of 35 pts have been accrued and 14 are currently evaluable. 13 male, 3 female, median KPS 80%, age 58, GEJ 7, E 9, squamous 2, adenocarcinoma (AC)14. An ongoing complete response (11+ months) was observed in a pt with biopsy proven metastatic neck lymphadenopathy (E primary AC, recurrence after prior chemoradiotherapy and surgery). A second pt (GEJ AC) had protracted stable disease in bulky celiac node disease (15+ months). Grade 3 toxicity was limited to skin rash (1 pt), hand foot reaction (1 pt), and fatigue (1 pt). Only 3 of 14 pts (21%) had early disease progression at 2 months or less. Median PFS 4 mos, 4 patients (29%) continue on therapy for more than 7 months. The majority of tumors tested positive for phospho-erk by immunohistochemistry (11/14, 79%). Conclusions: The observation of a durable complete response and protracted stable disease to sorafenib in E cancer is remarkable. Further accrual continues to define PFS. Supported by a grant from Bayer. [Table: see text]

Phase II Trial of Irinotecan in Children With Refractory Solid Tumors: A Children's Oncology Group Study

2007 ◽  
Vol 25 (29) ◽  
pp. 4622-4627 ◽  
Author(s):  
Lisa R. Bomgaars ◽  
Mark Bernstein ◽  
Mark Krailo ◽  
Richard Kadota ◽  
Soma Das ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Phase Ii ◽  
Response Rate ◽  
Single Agent ◽  
Complete Response ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Relative Extent ◽  
Grade 3 ◽  
Ugt1a1 Genotype

Purpose A phase II study was performed to determine the efficacy of irinotecan (IRN) in children with refractory solid tumors. Secondary objectives were to evaluate toxicity, pharmacokinetics, pharmacodynamics, and UGT1A1 genotype. Patients and Methods A total of 181 patients were enrolled, of whom 171 were eligible. Patients received IRN 50 mg/m2/d for 5 days repeated every 3 weeks. Pharmacokinetic studies and UGT1A1 genotyping were performed. Results Of 161 patients assessable for response, one patient with hepatoblastoma had a complete response, with partial responses observed in patients with medulloblastoma (n = 4), rhabdomyosarcoma (n = 1), neuroblastoma (n = 1), and germinoma (n = 1), for an overall response rate of 5%. Grade 4 neutropenia and grade 3 to 4 diarrhea occurred in less than 7% of the courses administered. Pharmacokinetic studies were available for 79 patients. The mean ± standard deviation IRN plasma clearance was 374 ± 148 mL/min/m2, with median relative extent of conversion and relative extent of glucuronidation of 0.05 (range, 0.01 to 0.25) and 2.24 (range, 0.39 to 9.6), respectively. No association between UGT1A1 genotype (n = 61) and toxicity or pharmacokinetic parameters was observed. Conclusion IRN 50 mg/m2/d for 5 days every 21 days is well tolerated, but was not effective as a single agent in a spectrum of solid tumors, with the possible exception of patients with medulloblastoma (16% response rate). There was no association between UGT1A1*28 genotype and toxicity or pharmacokinetic parameters.

Gemcitabine in Combination With Doxorubicin in Advanced Breast Cancer: Final Results of a Phase II Pharmacokinetic Trial

2000 ◽  
Vol 18 (13) ◽  
pp. 2545-2552 ◽  
Author(s):  
G. Pérez-Manga ◽  
A. Lluch ◽  
E. Alba ◽  
J.A. Moreno-Nogueira ◽  
M. Palomero ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Phase Ii ◽  
Response Rate ◽  
Single Agent ◽  
Metastatic Breast ◽  
Complete Response ◽  
Breast Disease ◽  
Advanced Breast ◽  
Weekly Schedule

PURPOSE: Gemcitabine has promising single-agent activity in advanced breast disease. The aim of this phase II study was to determine the efficacy, toxicity, and pharmacokinetic profile of gemcitabine administered with doxorubicin as first-line treatment in patients with metastatic breast cancer. PATIENTS AND METHODS: Of the 42 women with metastatic breast cancer (age 33 to 74 years; mean age, 55 years), 13 were chemotherapy-naive and 29 had received adjuvant chemotherapy. Gemcitabine (800 or 1,000 mg/m2) and doxorubicin (25 mg/m2) were administered intravenously on days 1, 8, and 15 of each 28-day cycle. Blood samples were drawn on day 8 of cycles 1, 2, and 3 and of subsequent odd cycles for gemcitabine pharmacokinetic determinations and before and after the first dose of cycle 1 or 2 for doxorubicin determinations. RESULTS: There were three complete and 20 partial responses, for an overall response rate of 55% (95% confidence interval [CI], 40% to 70%) and a complete response rate of 7%. The median survival time for all 42 patients was 27 months (95% CI, 13.4 to 30.0 months) and the 1-year survival rate was 80%. Toxicity was mainly hematologic. The disposition of both drugs was unchanged when they were administered on the same day compared with when they were given singly. CONCLUSION: The combination of gemcitabine (800 mg/m2) and doxorubicin (25 mg/m2) can be safely administered using a weekly schedule. The disposition of both drugs is unchanged when they are administered on the same day. This combination shows promising activity with acceptable toxicity compared with other combination therapies.

Phase II Trial of Cetuximab in Patients With Refractory Colorectal Cancer That Expresses the Epidermal Growth Factor Receptor

2004 ◽  
Vol 22 (7) ◽  
pp. 1201-1208 ◽  
Author(s):  
Leonard B. Saltz ◽  
Neal J. Meropol ◽  
Patrick J. Loehrer ◽  
Michael N. Needle ◽  
Justin Kopit ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Phase Ii ◽  
Single Agent ◽  
Growth Factor Receptor ◽  
Weekly Schedule ◽  
Epidermal Growth ◽  
Grade 3

Purpose To evaluate the antitumor activity and toxicity of single-agent cetuximab in patients with chemotherapy-refractory colorectal cancer whose tumors express the epidermal growth factor receptor. Patients and Methods Phase II, open-label clinical trial. Patients were required to have EGFr expression demonstrated on formalin-fixed paraffin-embedded tumor tissue by immunohistochemical staining before study participation. Patients were required to have received irinotecan, either alone or in a combination regimen, and to have demonstrated clinical failure on this regimen before study entry. Cetuximab was administered weekly by intravenous infusion. The first dose of 400 mg/m2 was given during the course of 2 hours. Subsequent weekly treatments were given at a dose of 250 mg/m2 during the course of 1 hour. Results Fifty-seven eligible patients were treated. All were assessable for toxicity and response. The most commonly encountered grade 3 to 4 adverse events, regardless of relationship to study drug, were an acne-like skin rash, predominantly on the face and upper torso (86% with any grade; 18% with grade 3), and a composite of asthenia, fatigue, malaise, or lethargy (56% with any grade, 9% with grade 3). Two patients (3.5%) experienced grade 3 allergic reactions requiring discontinuation of study treatment. A third patient experienced a grade 3 allergic reaction that resolved, and the patient continued on the study. Neither diarrhea nor neutropenia were dose limiting in any of the 57 patients treated. Five patients (9%; 95% CI, 3% to 19%) achieved a partial response. Twenty-one additional patients had stable disease or minor responses. The median survival in these previously treated patients with chemotherapy-refractory colorectal cancer is 6.4 months. Conclusion Cetuximab on this once-weekly schedule has modest activity and is well-tolerated as a single agent in patients with chemotherapy-refractory colorectal cancer whose tumors express the epidermal growth factor receptor. Further studies of cetuximab will evaluate the use of cetuximab in conjunction with first-line and adjuvant treatments for this disease.

Increased Dose Rituximab Followed by Maintenance Rituximab As Initial Therapy for Indolent B Cell Lymphomas: A Phase II Trial,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3716-3716
Author(s):  
Jeffrey A. Barnes ◽  
Kristen Stevenson ◽  
Ephraim P. Hochberg ◽  
Tak Takvorian ◽  
David C. Fisher ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
B Cell ◽  
Phase Ii ◽  
Progressive Disease ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Complete Response ◽  
Low Grade ◽  
B Cell Lymphomas ◽  
Grade 3

Abstract Abstract 3716 Background: Rituximab monotherapy as initial treatment for low-grade B-cell lymphomas produces responses in approximately 70% of patients with one third achieving a complete response, and progression-free survival (PFS) of approximately 2 years. Maintenance rituximab appears to prolong initial remissions after rituximab alone. Current dosing for rituximab is largely empiric, so we sought to investigate whether increased doses of rituximab induction would increase the complete response rate (CRR) over that expected from standard dose rituximab. We also sought to assess whether high-dose induction followed by standard maintenance would produce a PFS comparable with that of combination chemoimmunotherapy strategies. Methods: We conducted a phase II trial of increased-dose rituximab monotherapy induction, followed by a standard maintenance schedule. Eligible patients were adults with previously untreated low-grade B-cell lymphomas with measurable disease >2cm and were not candidates for potentially curative radiotherapy to localized disease. Subjects were treated with induction rituximab at a dose of 750 mg/m2 on days 1,8,15, and 22. Patients without progressive disease were then treated with maintenance rituximab at 375mg/m2 every 3 months for 8 doses or until disease progression. The primary end point was CRR as defined by the International Workshop Response Criteria (1999). Secondary endpoints included overall response rate (ORR), PFS, and toxicity. The study was designed with 90% power to show a 50% CRR, with a 30% CRR considered unworthy of further study. Results: Between August 2009 and August 2010, 40 eligible subjects were enrolled (31 grade 1–2 follicular lymphomas, 4 marginal zone lymphomas, 3 small lymphocytic lymphomas, and 2 indolent B cell lymphoma not otherwise specified). The median age was 60 (range 36–88) All subjects had advanced Ann Arbor stage disease. Twenty-two subjects (55%) had involvement of >4 nodal sites, 6 (15%) had a Hgb <12 and 9 (23%) had an elevated LDH. Six subjects (15%) were low risk by the follicular lymphoma prognostic index(FLIPI), 15 (38%) were intermediate risk, and 17 (43%) were high risk. The FLIPI was not available for 2 patients. One patient was not evaluable for the 4 week response assessment in induction due to withdrawal of consent after 3 weeks of therapy. After induction therapy, 1 subject had a CR (3%), 18 had a PR (46%), and 20 had SD (51%). No subjects had progressive disease after induction and all evaluable patients had a reduction in tumor size. With a median number of 4 (range 1–6) maintenance cycles, the CRR increased to 30%, with PRR of 38% and SD in 15% (fig. 1). The PFS at 12 months was 89% [95% CI, 73– 96]. A total of 5 subjects progressed during maintenance therapy, 2 subjects after 3 cycles, 1 after 2 cycles and 2 after 1 cycle. Treatment was well tolerated with only 3 cases (7.5%) of grade 3/4 neutropenia. Twenty three (58%) subjects had allergic reactions with infusions but only 2 (5%) were grade 3 reactions. Conclusions: Increased dose rituximab monotherapy is well tolerated, but does not improve the CRR compared to what would be expected from rituximab at standard doses. Significant improvement in the CRR occurred with ongoing maintenance therapy, and the vast majority of patients remain in remission after 1 year. Ongoing follow-up will determine whether this approach produces a PFS comparable to a chemoimmunotherapy treatment program. Disclosures: Hochberg: Genentech: Consultancy. Fisher:Genentech: Consultancy. Abramson:Genentech: Consultancy.

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