Clinical Trial Result Information
Title of Study:
MARCH study: Management of Anemia Under Radiochemotherapy : an Open, Randomized, Multi-Center Study of the Effect of NeoRecormon on Treatment Outcome in Patients With Advanced Cervical Cancer Stage IIB-IVA Treated With Primary Simultaneous Radiochemotherapy (Radiotherapy Plus Cisplatin).
Fast Facts:
| Protocol number: | MO16375 |
| Sponsor: | F. Hoffmann-La Roche Ltd. |
| Company division: | Pharmaceutical |
| Product name: | NeoRecormon |
| Generic name: | epoetin beta |
| Phase of development: | IV |
| Therapeutic area, approved indication: | Anemia |
| Date of report: | 3/31/2005 |
Clinical study summary:
This open-label, randomized, 2-arm, parallel-group 2 stage adaptive study was designed to examine the effect of NeoRecormon (epoetin beta) on the outcome of radiochemotherapy (RCT) treatment in patients with advanced cervical cancer. Patients were randomized to receive radiochemotherapy (radiotherapy plus cisplatin) alone, or with Neorecormon. Weekly hemoglobin determinations were performed, and patients were monitored for safety and iron parameters. NB This study was completed in the first stage.
Study center(s) :
Multi-center study in Germany.
Objectives:
Primary: To investigate whether the effectiveness and eventual outcome of radiochemotherapy (RCT) in patients with cervical cancer could be positively influenced by treatment with NeoRecormon.
Methodology:
All eligible patients received radiotherapy over a 6-week period (to a maximum duration of 50 days) plus concomitant chemotherapy with cisplatin (40 mg/m2 iv once weekly) starting on Day 1 of radiotherapy. Total duration of cisplatin therapy was 6 weeks. In those patients randomized to receive NeoRecormon, treatment at a starting dose 150 IU/kg subcutaneous (sc) three times a week was initiated 2 weeks prior to radiotherapy and continued for the entire period during which radiotherapy was administered. During the RCT treatment period, patients reported to the clinic weekly for hemoglobin determinations. Safety laboratory determinations and monitoring of iron parameters were performed during the treatment period. The Functional Assessment of Cancer Therapy Anemia (FACT-An) Quality of Life questionnaire was completed at screening, the end of RCT, and the first follow-up visit. Administration of study medication, iron supplementation, transfusions, concomitant medications, and adverse events (AEs) was recorded throughout the treatment period.
Number of patients (planned/analyzed):
80 planned; 74 treated.
Diagnosis and main criteria for inclusion:
adult patients >18 years of age with previously untreated cervical cancer, Federation of Gynecology and Obstetrics (FIGO) Stage IIB-IVA (except chorion carcinoma and neuroendocrine small cell carcinoma), who were scheduled to undergo primary RCT.
Test product, dose and mode of administration or test procedure:
NeoRecormon (lyophilized in 60,000-IU cartridges for Reco-Pen) ~150 IU/kg sc injection three times weekly.
Duration of treatment:
8–14 weeks
Reference therapy, dose and mode of administration or reference procedure:
Transfusion, as required.
Criteria for evaluation (efficacy, safety):
Primary efficacy parameter: (1) Number of treatment failures, ie, patients without complete response or relapsing within 6 months of RCT initiation, including correlation with change from baseline in hemoglobin at end of treatment period.
Secondary efficacy parameters: (1) Progression-free survival; (2) Overall response rate to RCT; (3) Overall survival following RCT; (4) Frequency and localization of relapses and metastases; (5) Hemoglobin change from baseline during therapy; and (6) FACT-An Quality of Life assessment.
Safety parameters: (1) AEs; (2) Laboratory test parameters; and (3) Vital signs.
Statistical methods:
Primary variable: Logistic regression on failure of treatment at 6 months and change from baseline in hemoglobin levels at end of treatment period.
Secondary variables: Log-rank test for difference in progression-free survival; chi-squared test with Schouten correction for overall complete response rates; log-rank test for survival; descriptive statistics for frequency and localization of relapses and metastases; analysis of covariance for hemoglobin change from baseline; and analysis of covariance for total FACT-An score.
Summary (efficacy, safety, other results):
Efficacy – At the end of 6 months, there were no significant differences between the NeoRecormon and standard treatment arms with respect to treatment failure. No correlation could be found between the change in hemoglobin levels from baseline to end of treatment period and treatment failure. Therefore, as per protocol, the study did not proceed to the second stage of the study. Although no correlation between change in hemoglobin levels and outcome of RCT was found, the study demonstrated a statistically significant difference in the hemoglobin change from baseline to end of treatment between the NeoRecormon and standard treatment groups (P<0.0001). A mean increase of 1.2 g/dL in hemoglobin levels between baseline and the last value was observed in patients receiving NeoRecormon compared with a mean decrease of 0.8 g/dL in hemoglobin levels for patients on standard therapy. In addition, 71% of patients (24/34) in the NeoRecormon arm achieved the target hemoglobin level (ie, ≥13 g/dL) compared with only 25% of patients (10/40) on standard therapy. Between the NeoRecormon and standard treatment arms, there was no significant difference with respect to the number of complete responses (or partial responses), no evidence that the increase in hemoglobin levels may promote tumor relapse, and no significant difference with regard to either the time to progression or death or to overall survival. Furthermore, there was no significant difference in terms of overall FACT-An Quality of Life scores.
Safety – A total of 58% of patients (19/33) in the NeoRecormon group and 68% of patients (26/38) in the standard therapy group experienced AEs during the study. Gastrointestinal events, such as diarrhea (27% vs 26%), nausea (24% vs 26%), and vomiting (21% vs 18%), and leukopenia (21% vs 34%) were the most frequently reported AEs in patients receiving NeoRecormon therapy compared with patients receiving standard therapy. Diarrhea was the most frequently reported AE in patients receiving NeoRecormon (27%), and leukopenia was the most frequently recorded AE in patients receiving standard therapy (34%). The majority of AEs recorded by patients in the NeoRecormon treatment arm were mild in intensity, whereas the majority of AEs in the standard therapy group were of moderate intensity. In the NeoRecormon group, 2 patients experienced AEs considered at least remotely related to treatment; 1 patient experienced an erythematous rash and another deep vein thrombosis (also recorded as a serious adverse event [SAE]). No patient on standard therapy experienced an AE considered related to treatment. Five patients (15%) in the NeoRecormon arm recorded 7 SAEs; 2 patients (5%) receiving standard therapy recorded 2 SAEs. No individual SAE was recorded by >1 patient in either treatment group. The only SAE related to treatment was deep vein thrombosis recorded by a patient in the NeoRecormon arm. No patient was withdrawn prematurely as a result of an AE. In total, 13 patients (8 NeoRecormon and 5 standard therapy) died during the study period, but no death was considered related to study treatment. No clinically relevant differences between treatment groups with respect to abnormalities of laboratory test parameter values, marked abnormalities, or vital signs were seen during the study.
Conclusions:
There was a statistically significant difference in the change in hemoglobin levels from baseline to the end of treatment between the NeoRecormon and standard therapy arms. However, there was no significant correlation between the increase in hemoglobin levels and rate of treatment failure at Month 6. There also was no significant difference with respect to treatment failure between the NeoRecormon and standard treatment arms. NeoRecormon therapy was well tolerated. There were no significant difference in survival or progression-free survival between patients treated with NeoRecormon and those on standard therapy.
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