Survey of Modalities of Toxicity Assessment and Reporting in Noncomparative Prospective Studies of Chemotherapy in Breast Cancer

2002 ◽  
Vol 20 (1) ◽  
pp. 52-57 ◽  
Author(s):  
Francesco Perrone ◽  
Ermelinda De Maio ◽  
Paolo Maione ◽  
Massimo Di Maio ◽  
Alessandro Ottaiano ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase Ii ◽  
Ad Hoc ◽  
Statistical Design ◽  
Toxicity Assessment ◽  
The Body ◽  
World Health ◽  
Published Data ◽  
Hematologic Toxicity ◽  
Phase Ii Studies

PURPOSE: To review how toxicity, a main end point of phase II studies, is assessed and reported in published phase II chemotherapy trials in breast cancer. METHODS: A survey was performed by hand-searching studies published in seven distinguished journals between 1995 and 1999. All selected articles were independently evaluated by two investigators using an ad hoc study report form. Descriptive statistics, contingency tables, and the χ2 test were applied. RESULTS: Overall, 122 articles were found; 65.6% lacked a statistical study design. Planned modalities for assessment of toxicity were inadequately reported in 20.5% of the studies. The scheduling of assessment of hematologic toxicity varied greatly. Toxicity was predominantly summarized per patient (69.7%). Although overall the World Health Organization scale was adopted more frequently (45.9%), the Common Toxicity Criteria (in different versions) were used more frequently in studies published in journals with a high impact factor (P = .001), in more recently initiated studies (P = .03), in sponsored studies (P = .0006), and in studies with an identifiable statistical design (P = .006). CONCLUSION: The wide diversity in modalities of toxicity assessment and reporting observed in this study suggests that the reliability of the body of published data on the toxicity of chemotherapy in breast cancer may be questionable. Current standards should be revised and harmonized to improve the reliability of such data. A checklist is proposed to help editorial evaluation of assessment and reporting of toxicity in phase II studies.

Advanced breast cancer: a phase II trial with gemcitabine.

1995 ◽  
Vol 13 (11) ◽  
pp. 2731-2736 ◽  
Author(s):  
J Carmichael ◽  
K Possinger ◽  
P Phillip ◽  
M Beykirch ◽  
H Kerr ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Phase Ii ◽  
Single Agent ◽  
Advanced Breast ◽  
World Health ◽  
Survival Duration ◽  
Hematologic Toxicity ◽  
Who Grade ◽  
The Mean

PURPOSE In this phase II study, the efficacy and tolerability of gemcitabine were studied in 44 patients with locally advanced or metastatic breast cancer. PATIENTS AND METHODS Of 40 patients assessable for response, 14 were chemotherapy-naive, seven had received adjuvant chemotherapy, and 19 had received one prior chemotherapy regimen for metastatic disease. Gemcitabine was administered as a 30-minute intravenous infusion once a week for 3 weeks followed by a 1-week rest every 4 weeks. The mean number of completed cycles administered was 2.7 and the mean dosage delivered was 725 mg/m2 per injection. Eighty-one percent of doses were delivered as scheduled. RESULTS There were three complete responses and seven partial responses, for an overall response rate of 25.0% (95% confidence interval [CI], 12.7% to 41.2%). Four patients were not assessable for efficacy (one had insufficient therapy, two had no bidimensionally measurable disease, and one had neither). All responses were independently validated by an external oncology review board. Responses were observed early in treatment, with a median time to response of 1.9 months. The median survival duration for all 40 assessable patients was 11.5 months. Hematologic toxicity was generally mild, with World Health Organization (WHO) grade 3 and 4 leukopenia occurring in 6.8% and 2.3% of patients and neutropenia in 23.3% and 7.0%, of patients, respectively. The only other grade 4 toxicities were infection and nausea and vomiting in one patient each. One patient was withdrawn due to shortness of breath, possibly drug-related. Flu-like symptoms, which were mild, transient, and treatable with acetominophen, were reported in 6.8% of patients. Only one patient developed alopecia of severity greater than WHO grade 2. CONCLUSION In view of the single-agent activity seen in advanced breast cancer, modest toxicity profile, and novel mechanism of action, gemcitabine deserves evaluation in breast cancer and is an ideal candidate for combination therapy.

Phase II trial of gemcitabine and carboplatin, plus trastuzumab in HER2+ patients as first line therapy in metastatic breast cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10590-10590
Author(s):  
D. A. Yardley ◽  
N. W. Peacock ◽  
D. Shipley ◽  
D. Waterhouse ◽  
R. Landgdon ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Single Agent ◽  
Metastatic Breast ◽  
Toxicity Assessment ◽  
Hematologic Toxicity ◽  
Line Therapy ◽  
Carboplatin Auc

10590 Background: Gemcitabine (G) and carboplatin (C) demonstrate significant preclinical synergy together as well as in combination with trastuzumab (H) in metastatic breast cancer (MBC) pts. This multicenter phase II trial evaluates the efficacy and safety of G + C with trastuzumab in HER2 + pts as 1st line therapy in MBC. Methods: Eligibility requirements: females > 18 with no prior regimens for MBC, ECOG 0–2, RECIST bidimensional disease, and adequate organ function. FISH HER2 + pts received H with GC. Treatment: G 1,000 mg/m2 D1& 8 with C AUC 5 D1 in the first 20 pts. Following a toxicity assessment revealing significant myelosuppression, C was administered in subsequent pts at AUC 4. 14 HER2+ pts received H 8 mg/kg loading dose followed by 6 mg/kg q21 days. Pts were evaluated for response after 9 weeks; treatment continued until progression or toxicity except in HER2+ pts who received up to 6 cycles GCH followed by single agent H. Results: Between 11/03 & 11/05, 45 pts have been treated: median age 55 for GC, 65 for GCH, ECOG 0/1 22/23. 19 pts were chemonaive. 26 pts received prior adjuvant chemotherapy: 20 pts adjuvant anthracyclines (A) & taxanes (T), 3 only prior A and 3 prior T. 73% had 2 or more metastatic sites of disease. 31 pts received GC & 14 pts received GCH. 18 of 41 evaluable pts (44%) had objective responses (PR 16, CR 2) with 17 pts (42%) exhibiting SD & 6 pts PD (15%). 91% of AT pretreated pts demonstrated SD or better. 9 remain on study. 6 went off study due to heme related toxicities and 9 due to MD discretion [4 max benefit, 3 XRT]. Median # of cycles was 5. Combined G3/4 hematologic toxicity was notable for 66% neutropenia (only 1 FN), 55% thrombocytopenia, and 32% anemia, predominately occurring at the carboplatin AUC 5 dose level. Transfusions of PRBCs and plts were administered in 14 and 8 pts respectively. Nonhematologic toxicity was minimal and remarkable for G3/4 fatigue in 20%. Conclusions: In FISH HER2+ pts, the addition of trastuzumab to GC yielded a 50% RR, with no evident cardiotoxicity. The combination of gemcitabine with carboplatin AUC 4 is active, albeit with moderate hematologic toxicity, warranting further exploration of alternate GC ± H schedules in breast cancer. [Table: see text]

Population pharmacokinetics/pharmacodynamics of docetaxel in phase II studies in patients with cancer.

1998 ◽  
Vol 16 (1) ◽  
pp. 187-196 ◽  
Author(s):  
R Bruno ◽  
D Hille ◽  
A Riva ◽  
N Vivier ◽  
W W ten Bokkel Huinnink ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Phase Ii ◽  
Independent Predictor ◽  
Large Population ◽  
Systemic Exposure ◽  
Fluid Retention ◽  
Population Pharmacokinetic ◽  
Hematologic Toxicity ◽  
Phase Ii Studies ◽  
Time To Onset

PURPOSE The population pharmacokinetic/pharmacodynamic (PK/PD) approach was prospectively integrated in the clinical development of docetaxel to assess the PK profile in a large population of patients and investigate systemic exposure as a prognostic factor for clinical outcome. PATIENTS AND METHODS PK analysis was performed at first course in 24 phase II studies of docetaxel monotherapy using four randomized limited-sampling schedules. Bayesian estimates of clearance (CL), area under the concentration-time curve (AUC), and peak and duration of plasma levels greater than threshold levels were used as measures of exposure. PD data included for efficacy, response rate, time to first response, and time to progression (TTP) in breast cancer and non-small-cell lung cancer (NSCLC), and for toxicity, grade 4 neutropenia, and febrile neutropenia at first course and time to onset of fluid retention. PK/PD analysis was conducted using logistic and Cox multivariate regression models. RESULTS PK protocol implementation was successful. Most of the patients registered (721 of 936, 77%) were sampled and 68% were assessable for PK (640 patients). First-course docetaxel AUC was a significant predictor (P = .0232) of TTP in NSCLC (n = 151). Docetaxel CL was a strong independent predictor (P < .0001) of both grade 4 neutropenia and febrile neutropenia (n = 582). Cumulative dose was the strongest predictor (P < .0001) of the time to onset of fluid retention (n = 631). However, the duration of exposure over 0.20 micromol/L (0.16 microg/mL) at first course was an independent predictor (P = .0029). Few patients (n = 25, 4%) received the recommended dexamethasone premedication. CONCLUSION First-course docetaxel PK is a predictor of first-course hematologic toxicity, but also of fluid retention, which is cumulative in nature. Patients with elevated hepatic enzymes have a 27% reduction in docetaxel CL and are at a higher risk of toxicity. A starting dose of 75 mg/m2 is currently being evaluated in this population. Prospective implementation of large-scale population PK/PD evaluation is feasible in early drug development and this approach generates clinically relevant findings.

Multicenter Phase II Study of a 28-Day Regimen of Orally Administered Eniluracil and Fluorouracil in the Treatment of Patients With Anthracycline- and Taxane-Resistant Advanced Breast Cancer

2002 ◽  
Vol 20 (4) ◽  
pp. 987-993 ◽  
Author(s):  
Edgardo Rivera ◽  
Linda Sutton ◽  
Bruce Colwell ◽  
Mark Graham ◽  
Debra Frye ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Adverse Events ◽  
Advanced Breast Cancer ◽  
Phase Ii ◽  
Median Duration ◽  
Dihydropyrimidine Dehydrogenase ◽  
Advanced Breast ◽  
Hematologic Toxicity ◽  
Low Grade ◽  
Grade 3

PURPOSE: Eniluracil (776C85), a potent inactivator of dihydropyrimidine dehydrogenase, allows fluorouracil (5-FU) to be administered orally on a schedule that simulates continuous-infusion 5-FU. The primary objective of this study was to estimate the objective tumor response rate of orally administered eniluracil and 5-FU in the treatment of anthracycline- and taxane-resistant advanced breast cancer. PATIENTS AND METHODS: Patients with anthracycline- and taxane-resistant advanced breast cancer were enrolled onto this open-label, phase II, multicenter study. Patients received orally administered 5-FU 1.0 mg/m2 with eniluracil given in a 10:1 ratio (eniluracil:5-FU) twice daily for the first 28 days of each 35-day cycle. RESULTS: Eighty-four patients were enrolled. Eight partial responses were observed in 84 patients (10%; 95% confidence interval [CI], 4.2% to 17.9%), and 20 patients (24%) had stable disease. The median duration of partial response was 20.1 weeks (95% CI, 12 to 26.7 weeks). The median duration of progression-free survival and overall survival for all patients was 9.9 weeks and 40.4 weeks, respectively. Most adverse events were grade 1 or 2 in intensity. Diarrhea, nausea, malaise/fatigue, vomiting, and mucositis were the most common treatment-related nonhematologic adverse events. The most frequently occurring grade 3 or 4 treatment-related adverse events were malaise/fatigue and diarrhea, occurring in 17% and 7% of patients, respectively. The incidence of grade 3 or 4 hematologic toxicity was low. Grade 3 or 4 hyperbilirubinemia occurred in 17% of patients. CONCLUSION: Eniluracil–5-FU has modest antitumor activity and an acceptable safety profile in anthracycline- and taxane-resistant breast cancer. Treatment was convenient, and patient compliance was high.

Suramin in Non-small Cell Lung Cancer and Advanced Breast Cancer: Two Parallel Phase II Studies

1997 ◽  
Vol 36 (2) ◽  
pp. 171-174 ◽  
Author(s):  
Mansoor R. Mirza ◽  
Erik Jakobsen ◽  
Per Pfeiffer ◽  
Bente Lindebjerg-Clasen ◽  
Jonas Bergh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Advanced Breast Cancer ◽  
Phase Ii ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Advanced Breast ◽  
Small Cell Lung ◽  
Phase Ii Studies

Phase II pilot trial of imatinib mesylate with weekly docetaxel in metastatic breast cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10716-10716
Author(s):  
J. H. Barton ◽  
W. Liggett ◽  
M. Mainwaring ◽  
J. D. Hainsworth ◽  
L. Simons ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Imatinib Mesylate ◽  
Phase Ii ◽  
Metastatic Breast ◽  
Hematologic Toxicity ◽  
Antitumor Effects ◽  
Weekly Docetaxel ◽  
Gi Toxicity ◽  
Ecog Ps

10716 Background: Overexpression of platelet derived growth factor receptor (PDGFR) has been associated with breast cancer tumor progression and may serve as a potential target for therapy. Inhibition of PDGFR signaling in tumor stroma represents a novel strategy that has demonstrated enhanced chemotherapy antitumor effects, decreased tumor interstitial fluid pressure as well as increased tumor transcapillary transport. Imatinib mesylate (G) is a potent PDGFR tyrosine kinase antagonist. This phase II pilot study evaluates the feasibility, toxicity, and efficacy of imatinib administered with docetaxel as a strategy to enhance docetaxel’s chemotherapeutic effects in metastatic breast cancer (MBC). Methods: Eligibility requirements: 0–1 prior regimens for MBC, > 6 months from prior adjuvant taxanes, RECIST measurable disease, ECOG PS 0–2, adequate organ function, < G2 neuropathy. Treatment: docetaxel 30 mg/m2 IV weekly 3 of 4 weeks. Imatinib mesylate 600 mg po QD. Pts were evaluated for response every 8 weeks; treatment continued until progression or toxicity. Results: 7 pts have been enrolled to date. Median age is 61, all with ECOG PS 0. 5 pts received prior adjuvant therapy; 2 pts received prior taxanes. 43% received prior hormonal therapy. Only 1 pt was ER+/PR+. Hematologic toxicity was mild, consisting only of G3/4 anemia in 2 pts and G3 thrombocytopenia in 1. No febrile neutropenia was noted. Nonhematologic toxicity was characterized primarily by G3 GI toxicity: 4 pts diarrhea, 3 N, V, 1 anorexia, 1 abdominal pain. This was attributed to imatinib in all but 1 pt, in whom both drugs were implicated. 2 pts were removed from treatment and 3 pts required dose reductions, all due to GI toxicity consisting of N, V, and diarrhea. 3 pts experienced dose interruptions and 2 pts exhibited disease progression. Conclusion: These early preliminary results demonstrate imatinib mesylate, in combination with weekly docetaxel as a strategy to inhibit breast cancer PDGFR signaling, is feasible. GI toxicity with this combination was prominent and warrants dose modifications. Updated toxicity and efficacy data will be presented. [Table: see text]

Amrubicin as second- or third-line treatment for patients with HER2-negative metastatic breast cancer (MBC): A phase II trial of the Sarah Cannon Research Institute (SCRI).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 1086-1086
Author(s):  
John H. Barton ◽  
Eric Raefsky ◽  
William N. Harwin ◽  
Alejandro A. Inclan ◽  
Gerald Miletello ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Adjuvant Therapy ◽  
Phase Ii ◽  
Hematologic Toxicity ◽  
Significant Activity ◽  
Line Treatment ◽  
Prior Chemotherapy ◽  
Third Line ◽  
Grade 3 ◽  
Third Line Treatment

1086 Background: Anthracyclines demonstrate significant activity in breast cancer, but the potential for cardiotoxicity is dose-limiting. Amrubicin is a novel anthracycline with broad-spectrum preclinical activity and low potential for cardiotoxicity. We present phase II results from a phase I/II trial of amrubicin as second/third- line therapy for HER2- negative MBC. Methods: Women with measurable HER2-negative MBC with 1 or 2 prior chemotherapy regimens for metastatic disease and normal LVEF were eligible. Prior anthracycline- containing adjuvant therapy was allowed. Amrubicin 110 mg/ m2 IV every 3 weeks was administered until disease progression or intolerable toxicity. Tumor assessments were performed every 6 weeks and LVEF assessments every 12 weeks. The primary endpoint was progression free survival (PFS); a median PFS ≥ 4.5 months was considered a study result meriting further development of amrubicin. Results: 48 evaluable patients (pts) were treated from 1/2010 to 9/2011. Baseline characteristics included median age 57; 23% were triple-negative; 33% had 2 prior chemotherapy regimens for MBC; 38% had anthracycline- containing adjuvant therapy. Median treatment duration was 6 weeks (2 cycles), range 1- 12+ cycles. 8 pts (17%) had objective RECIST responses (1 CR, 7 PR); 5 of the 8 responders had received anthracycline-containing adjuvant therapy. 24 additional pts (50%) had stable disease at first reevaluation. The median PFS for all patients was 2.8 months (95% CI 1.6- 4.0 months); median PFS was similar for pts with 1 vs 2 previous regimens for MBC (95% CI 2.5 vs 4.0 months). 24% of pts were progression-free at 6 months. Neutropenia was the most common grade 3/4 toxicity (63%; 6% febrile neutropenia). No grade 3/4 non- hematologic toxicity occurred in > 5% pts. No cardiotoxicity occurred. Only 1 pt discontinued amrubicin due to toxicity (grade 2 fatigue). Conclusions: Amrubicin had good tolerability, no cardiotoxicity and was active as a second/third-line treatment for HER2- negative MBC, including pts previously treated with adjuvant anthracyclines. The median PFS was comparable to other standard single agents in the MBC setting.

Phase II randomized study of the EGFR, HER2, HER3 signaling inhibitor AZD8931 in combination with anastrozole (A) in women with endocrine therapy (ET) naive advanced breast cancer (MINT).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 531-531 ◽  
Author(s):  
Stephen R. D. Johnston ◽  
Mark Basik ◽  
Roberto Hegg ◽  
Wirote Lausoontornsiri ◽  
Lukasz Grzeda ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase Ii ◽  
Interim Analysis ◽  
Randomized Study ◽  
Acquired Resistance ◽  
Endocrine Resistance ◽  
Population Data ◽  
Double Blind ◽  
Egfr Inhibition ◽  
Phase Ii Studies

531 Background: Preclinical data suggest a key role for EGFR inhibition in delaying acquired resistance to ET in ER+ breast cancer (BC). Retrospective analyses of 2 Phase II studies suggested adding gefitinib to ET delayed PFS in ET naive (ETN) BC. This randomized, double-blind, placebo-controlled multi-center study (NCT01151215) was conducted to prospectively test the hypothesis that adding AZD8931, an inhibitor of EGFR, HER2 and HER3 signaling, to A would be beneficial in delaying endocrine resistance in an advanced ETN BC population. Methods: Post-menopausal women with ER+ and/or PR+, ETN, HER2-negative, advanced BC were randomized (1:1:1) to receive A (1 mg od) plus AZD8931 20 or 40 mg bd or placebo (P). The primary endpoint was PFS (ITT population). Data presented are from an interim analysis (data cutoff 31 Aug 2012; 39% pts had a progression event). Results: Between Jun 2010 and Jun 2012, 359 pts (median age 61 years) were randomized to A combined with AZD8931 20 mg (n=118), 40 mg (n=120) or P (n=121). At the interim analysis, median PFS in the AZD8931 20 mg, 40 mg and P arms was 10.9, 13.8 and 14.0 months, respectively; PFS HR (95% CI) for AZD8931 20 mg:P was 1.37 (0.91–2.06, P=0.135) and for AZD8931 40 mg:P was 1.16 (0.77–1.75, P=0.485). Deaths were reported for 20 (17%), 16 (13%) and 12 pts (10%) in the AZD8931 20 mg, 40 mg and P arms, respectively. Grade ≥3 AEs were reported for 22 (19%), 44 (37%) and 18 (15%) pts in the AZD8931 20 mg, 40 mg, and P arms, respectively, the most frequent being rash (0% vs 8% vs 2%), acneiform dermatitis (0% vs 7% vs 0%) and hypertension (3% vs 3% vs 2%). Serious AEs were reported for 12%, 14% and 9% pts in the AZD8931 20 mg, 40 mg and P arms, respectively, and discontinuation (of AZD8931 or P) due to an AE in 5%, 8% and 2% pts, respectively. Conclusions: Co-blockade of EGFR, HER2, HER3 in combination with aromatase inhibition does not appear to delay endocrine resistance to ETN BC. Based on the low probability of demonstrating superior efficacy with addition of AZD8931 to A and the overall risk/benefit, the study was closed at the recommendation of the IDMC and pts discontinued AZD8931. Clinical trial information: NCT01151215.

Phase II studies of two trial regimens of topotecan as second-line single agent therapy in advanced breast cancer

1997 ◽  
Vol 33 ◽  
pp. S158 ◽  
Author(s):  
D. Spaëth ◽  
J. Bonneterre ◽  
M. Marty ◽  
D. Khayat ◽  
T. Facchini ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Phase Ii ◽  
Single Agent ◽  
Advanced Breast ◽  
Second Line ◽  
Single Agent Therapy ◽  
Phase Ii Studies
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