Clinical Trial Results:
CD20-Immunotargeting in Stage IV Melanoma Patients - A Prospective, Open Label, Two-Period Pilot Study to Evaluate Overall Tumor Responsive Rate
Summary
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EudraCT number |
2010-023277-19 |
Trial protocol |
AT |
Global end of trial date |
28 Jan 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
24 Jul 2016
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First version publication date |
24 Jul 2016
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
CD20 Immunotargeting of Melanoma
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01376713 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Medical University of Vienna
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Sponsor organisation address |
Waehringer Guertel 18-20, Vienna, Austria,
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Public contact |
UD Dr. Stephan Wagner, Medical University of Vienna, Department of Dermatology , 0043 14040077050, stephan.wagner@meduniwien.ac.at
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Scientific contact |
UD Dr. Stephan Wagner, Medical University of Vienna, Department of Dermatology , 0043 14040077050, stephan.wagner@meduniwien.ac.at
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
01 Feb 2015
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
19 Sep 2013
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Global end of trial reached? |
Yes
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Global end of trial date |
28 Jan 2015
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objective of this study was to evaluate the overall disease control rate according to criteria of RECIST v. 1.1
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Protection of trial subjects |
Exclusion of:
Subjects who have current active hepatic or biliary disease (with exception of patients with
Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease
per investigator assessment)
• Other past or current malignancy.
• Chronic or current infectious disease requiring systemic antibiotics, antifungal, or antiviral
treatment
• History of significant cerebrovascular disease in the past 6 months or ongoing event with
active symptoms or sequelae
• HIV positive
• Clinically significant cardiac disease including unstable angina, acute myocardial infarction
within six months prior to enrolement, congestive heart failure (NYHA III-IV), and arrhythmia
unless controlled by therapy, with the exception of extra systoles or minor conduction
abnormalities.
• Significant concurrent, uncontrolled medical condition
• Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg. In addition, if
negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HB DNA test will be
performed and if positive the subject will be excluded.
• Positive serology for hepatitis C (HC) defined as a positive test for HCAb, in which case reflexively
perform a HC RIBA immunoblot assay on the same sample to confirm the result
• Screening laboratory values:
hemoglobin < 8g/dL
platelets <70 x 109/L
leukocytes <1.5 x 109/L
creatinine >2.0 times upper normal limit
total bilirubin >1.5 times uppertotal bilirubin >1.5 times upper normal limit
ALT >2.5 times upper normal limit
alkaline phosphatase >2.5 times upper normal limit
• Pregnant or lactating women.
Efficacy, safety and laboratory assessments on a regular basis:
MRI/CT, physical examination, ECOG, weight, 12-lead ECG, adverse events and concomitant therapy evaluation, hematology (hemoglobin, hematocrit, RBC, WBC + differentials), chemistry (ASAT, ALAT, alkaline phosphatase, total bilirubin, creatinine), serum pregnancy testing;
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Background therapy |
In this study, all concomitant medications were allowed, with the exception of: • treatment with any known marketed drug substance or experimental therapy within 5 terminal half lives or 4 weeks prior to enrollment, whichever is longer; • currently participating in any other interventional trials; | ||
Evidence for comparator |
not applicable | ||
Actual start date of recruitment |
21 Jun 2011
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety, Efficacy | ||
Long term follow-up duration |
1 Years | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Austria: 10
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Worldwide total number of subjects |
10
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EEA total number of subjects |
10
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
5
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From 65 to 84 years |
5
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85 years and over |
0
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Recruitment
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Recruitment details |
Patients were recruited from the population that is routinely treated for melanoma at the study sites. | ||||||||||||||
Pre-assignment
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Screening details |
Screening procedures for the study were performed from day -28 until day 0 before administration of study medication. Screening assessments were performed only after the patient has signed the informed consent form. Inclusion and exclusion criteria were checked accordingly at the screening visit. | ||||||||||||||
Period 1
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Period 1 title |
Arm A (Monotherapy) - Stage 1
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Is this the baseline period? |
Yes | ||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||
Blinding implementation details |
not applicable
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Arms
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Arm title
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Arm A - Stage 1 | ||||||||||||||
Arm description |
Initially, 10 eligible patients will be treated with ofatumumab (1000 mg) alone. Tumor imaging is planned at wk 4 (screening for rapid disease progression), 8, 16 and 24. Follow-up starts at wk 24. If interim analysis shows that at least 1 confirmed overall response (CR, PR) occurs, the study will proceed to Arm A stage 2. If ofatumumab at the 1000 mg dose is well tolerated, patients with disease progression will have the opportunity to receive at least 3 cycles of ofatumumab q4w at an increased dose of 2000 mg in combination with 1000 mg DTIC (Arm A - Rescue Arm) | ||||||||||||||
Arm type |
Experimental | ||||||||||||||
Investigational medicinal product name |
Arzerra
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Investigational medicinal product code |
Ofatumumab
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Other name |
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Ofatumumab will be administered at a dose of 1000mg iv weekly (+/- 2 days) for 8 weeks and q4w (+/- 1 week) for another 16 weeks.
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Notes [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: Sequential study design - no patient enroled. For saving the xml-file, a number has to be entered. The information of no enrolment is given under non-completion reason. |
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Period 2
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Period 2 title |
Arm A - Stage 1 - Rescue Arm
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Is this the baseline period? |
No | ||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||
Blinding implementation details |
not applicable
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Arms
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Arm title
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Arm A - Stage 1 Rescue Arm | ||||||||||||||
Arm description |
If ofatumumab at the 1000 mg dose is well tolerated, patients with disease progression will have the opportunity to receive at least 3 cycles of ofatumumab q4w at an increased dose of 2000 mg in combination with 1000 mg DTIC. | ||||||||||||||
Arm type |
Experimental | ||||||||||||||
Investigational medicinal product name |
Arzerra
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Investigational medicinal product code |
Ofatumumab
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Other name |
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Patients with disease progression received at least three cycles of Ofatumumab q4w at an increased dose of 2000 mg in combination with 1000 mg Dacarbazine.
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Investigational medicinal product name |
Dacarbazine medac
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Investigational medicinal product code |
Dacarbazine
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Other name |
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Patients with disease progression received at least three cycles of Ofatumumab q4w at an increased dose of 2000 mg in combination with 1000 mg Dacarbazine.
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Baseline characteristics reporting groups
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Reporting group title |
Arm A (Monotherapy) - Stage 1
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Reporting group description |
Initially, 10 eligible patients shall be treated with ofatumumab (1000 mg) alone. Tumor imaging was planned at wk 4 (screening for rapid disease progression), 8, 16 and 24. Follow-up started at wk 24. If interim analysis shows that at least 1 confirmed overall response oc-curs, the study should proceed to Arm A stage 2. If ofatumumab at the 1000 mg dose is well tolerated, patients with disease progression should have the opportunity to receive at least 3 cycles of ofatumumab q4w at an increased dose of 2000 mg in combination with 1000 mg DTIC. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Arm A - Stage 1
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Reporting group description |
Initially, 10 eligible patients will be treated with ofatumumab (1000 mg) alone. Tumor imaging is planned at wk 4 (screening for rapid disease progression), 8, 16 and 24. Follow-up starts at wk 24. If interim analysis shows that at least 1 confirmed overall response (CR, PR) occurs, the study will proceed to Arm A stage 2. If ofatumumab at the 1000 mg dose is well tolerated, patients with disease progression will have the opportunity to receive at least 3 cycles of ofatumumab q4w at an increased dose of 2000 mg in combination with 1000 mg DTIC (Arm A - Rescue Arm) | ||
Reporting group title |
Arm A - Stage 1 Rescue Arm
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Reporting group description |
If ofatumumab at the 1000 mg dose is well tolerated, patients with disease progression will have the opportunity to receive at least 3 cycles of ofatumumab q4w at an increased dose of 2000 mg in combination with 1000 mg DTIC. |
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End point title |
Evaluation of overall disease control rate according to criteria of RECIST v. 1.1 (measurable disease)) [1] | |||||||||||||||
End point description |
Efficacy criterion.
The primary objective of this study is to evaluate the overall disease control rate according to criteria of RECIST v. 1.1. The primary endpoint disease control, is tested with Simon Two Stage Designs. The primary analysis is based on the full analysis set comprising all patients that received at least one dose of the study drug. Patients for which the primary endpoint is not available will be considered as treatment failures in this analysis. The one sided type I error rate for each of the hypothesis tests (H0A , H0B ) is set to 0.05.
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End point type |
Primary
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End point timeframe |
Disease control according to RECIST v. 1.1 criteria until week 24 (measurable disease).
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Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: no further statistical sub-analysis |
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Notes [2] - please see data below, subject analysis sets [3] - 1 patient not analyzable |
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No statistical analyses for this end point |
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End point title |
Evaluation of overall disease control rate according to ir-RC (overall response) [4] | |||||||||||||||
End point description |
The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). Evaluation by immune-related response criteria (ir-RC). This method of evaluation of the overall response is referred to in the Guidelines for the Evaluation of Immune Therapy Activity in Solid Tumors: Immune-Related Response Criteria (Clin Cancer Res 2009;15(26) December 1, 2009. The ir-RC evaluation was not implemented in the clinical study protocol issued in 2010.
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End point type |
Primary
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End point timeframe |
Disease control according to immune-related response criteria until week 24 (overall response).
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Notes [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: no further statistical sub-analysis |
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Notes [5] - SD in 2 patients |
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No statistical analyses for this end point |
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End point title |
Evaluation of overall disease control rate according to criteria of RECIST v. 1.1 (overall response) [6] | |||||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Disease control according to RECIST v. 1.1 criteria until week 24 (overall response).
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Notes [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: no further statistical sub-analysis |
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Notes [7] - SD in 1 patient [8] - SD in 1 patient |
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No statistical analyses for this end point |
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End point title |
Assessment of progression-free survival (PFS) - RECIST v1.1 (overall response) | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
First day of treatment until first documentation of disease progression or death, whichever occurs first.
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Notes [9] - for patients with disease control only [10] - for patients with disease control only |
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No statistical analyses for this end point |
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End point title |
Overall survival (OS) - RECIST v1.1 (overall response) | |||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Every three months (+/- 1 month) until all patients have died or are lost to follow up.
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Notes [11] - given as mean value in months [12] - given as mean value in months |
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No statistical analyses for this end point |
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End point title |
Assessment of progression-free survival (PFS) - ir-RC (overall response) | ||||||||||||
End point description |
Efficacy endpoint
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End point type |
Secondary
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End point timeframe |
First day of treatment until first documentation of disease progression or death, whichever occurs first.
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No statistical analyses for this end point |
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End point title |
Overall survival (OS) - ir-RC (overall response) | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Every three months (+/- 1 month) until all patients have died or are lost to follow up.
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
Induction (week 1-8 qw) until Follow-up visit (3 months post treatment)
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
19.0
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Reporting groups
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Reporting group title |
Arm A (Monotherapy) - Stage 1
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Reporting group description |
Stage 1: Treatment with Ofatumumab (1000 mg) only. Tumor imaging is planned at wk 4 (screening for rapid disease progression), 8, 16 and 24. Follow-up starts at wk 24. If interim analysis shows that at least 1 confirmed overall response occurs, the study will proceed to Arm A stage 2. If ofatumumab at the 1000 mg dose is well tolerated, patients with disease progression will have the opportunity to receive at least 3 cycles of ofatumumab q4w at an increased dose of 2000 mg in combination with 1000 mg DTIC. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Arm A - Stage 1 - Rescue Arm
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Reporting group description |
Patients with disease progression who have well tolerated the Ofatumumab treatment well, had the opportunity to receive at least 3 cycles of ofatumumab q4w at an increased dose (2000 mg) in combination with DTIC (1000mg). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 0% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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15 Apr 2011 |
Addition of clinical trial site:
Prof.Dr.Klemens Rappersberger
Rudolfstiftung, Department for Dermatology and Venerology |
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13 Mar 2014 |
Release of safety warning by GSK Pharma GmbH with respect to risk of HBV reactivation after administration of Arzerra.
The warning states that HBV reactivation can occur in patients receiving CD20-directed cytolytic antibodies (including Arzerra), resulting in some cases in fulminant hepatitis, hepatic failure, and death.
As a consequence GSK recommends the screening of all patients for HBV infection prior starting Arzerra i.v treatment by measuring HBsAg and HBcAb. Moreover patients with a prior HBV infection who are at risk of HBV reactivation shall be monitored properly.
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
not applicable |