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    Clinical Trial Results:
    A Phase 1/3, Randomised, Parallel-Group, Active-Controlled, Double-Blind Study to Demonstrate Equivalence of Pharmacokinetics and Noninferiority of Efficacy for CT-P10 in Comparison With Rituxan, Each Administered in Combination With Cyclophosphamide, Vincristine, and Prednisone (CVP) in Patients With Advanced Follicular Lymphoma

    Summary
    EudraCT number
    		 2013-004493-96
    Trial protocol
    		 NL   ES   GR   IT   PT   BG  
    Global end of trial date
    29 Dec 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Dec 2019
    First version publication date
    27 Dec 2019
    Other versions
    Summary report(s)
    		 American Society of Hematology (ASH) 2016
    International Conference on Malignant Lymphoma (ICML) 2017
    European Hematology Association (EHA) 2017
    American Society of Clinical Oncology (ASCO) 2017
    European Society for Medical Oncology (ESMO) Asia 2017
    American Society of Hematology (ASH) 2017
    American Society of Hematology (ASH) 2018
    Lancet Hematology

    Trial information

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    Trial identification
    Sponsor protocol code
    CT-P10-3.3
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02162771
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    CELLTRION, Inc
    Sponsor organisation address
    23 Academy-ro, Yeonsu-gu , Incheon Metropolitan City , Korea, Republic of,
    Public contact
    Clinical Operation, CELLTRION, Inc, +82 328505776, sueun.song@celltrion.com
    Scientific contact
    Clinical Planning, CELLTRION, Inc, +82 328505778, sunghyun.kim@celltrion.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    28 Dec 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Dec 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study will be divided into 2 parts, each of which will assess one of its 2 primary endpoints (pharmacokinetics and efficacy of CT-P10 compared to Rituxan). The primary objective of Part 1 of this study is: • To demonstrate that CT-P10 is similar to Rituxan in terms of pharmacokinetics as determined by AUCtau and CmaxSS at Cycle 4. The primary objective of Part 2 of this study is: • To demonstrate that CT-P10 is noninferior to Rituxan in terms of efficacy as determined by overall response rate (CR + CRu + PR) over Cycle 8 (Core Study Period) according to the 1999 International Working Group (IWG) criteria in previously untreated patients with advanced (stage III-IV) CD20+ FL.
    Protection of trial subjects
    Hypersensitivity will be assessed by vital sign monitoring (including systolic and diastolic blood pressure (BP), heart rate, respiratory rate, and temperature) on each dosing day and recorded on each dosing day at the following time points: • Before beginning the study drug infusion on Day 1 of each cycle (within 15 minutes before the beginning of the study drug infusion) • At the end of the study drug infusion (within 15 minutes after the end of the study drug infusion) • At 60 minutes (±15 minutes) after the end of the study drug infusion In addition, hypersensitivity should be monitored by routine continuous clinical monitoring including ECG monitoring at 60 minutes (±15 minutes) after the end of the study drug infusion. Emergency equipment, such as adrenaline, antihistamines, corticosteroids, and respiratory support (including inhalational therapy, oxygen, and artificial ventilator), must be available. For patients who experience or develop life-threatening infusion-related anaphylactic reactions, rituximab treatment must be stopped immediately and the patient withdrawn from the study.
    Background therapy
    		 CT-P10 or Rituxan will be administered with standard premedication during the Core Study Period, followed by CVP chemotherapy, constituting 1 cycle of therapy. The sequence of the study treatment will be as follows: prednisone, study drug, and CVP chemotherapy. • Prednisone (40 mg/m2, oral) • Cyclophosphamide (750 mg/m2, IV) • Vincristine (1.4 mg/m2 - maximum 2 mg, IV) Premedication consisting of an antipyretic, an antihistamine, and a glucocorticoid must be administered 30 minutes before each infusion of CT P10 or Rituxan during the Core Study Period (in all combination treatment cycles) and during the Maintenance Study Period. The following recommended premedications can be given: • Paracetamol (500 mg, oral) • H1 antihistamine (oral or IV) • Prednisone (40 mg/m2, oral)
    Evidence for comparator
    		 CT P10 is being developed as a proposed biosimilar product of Rituxan (rituximab), a compound with established efficacy in the treatment of NHL. The purpose of this study is to determine whether CT-P10 is similar to Rituxan with respect to pharmacokinetics and noninferior to Rituxan with respect to efficacy and to assess efficacy and safety in patients with advanced FL.
    Actual start date of recruitment
    14 Jul 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Belarus: 14
    Country: Number of subjects enrolled
    Brazil: 12
    Country: Number of subjects enrolled
    Chile: 2
    Country: Number of subjects enrolled
    Georgia: 4
    Country: Number of subjects enrolled
    India: 12
    Country: Number of subjects enrolled
    Korea, Republic of: 8
    Country: Number of subjects enrolled
    Mexico: 1
    Country: Number of subjects enrolled
    Philippines: 3
    Country: Number of subjects enrolled
    Russian Federation: 10
    Country: Number of subjects enrolled
    South Africa: 4
    Country: Number of subjects enrolled
    Turkey: 2
    Country: Number of subjects enrolled
    Ukraine: 8
    Country: Number of subjects enrolled
    Poland: 17
    Country: Number of subjects enrolled
    Portugal: 2
    Country: Number of subjects enrolled
    Romania: 6
    Country: Number of subjects enrolled
    Spain: 24
    Country: Number of subjects enrolled
    Bulgaria: 1
    Country: Number of subjects enrolled
    Greece: 4
    Country: Number of subjects enrolled
    Italy: 4
    Worldwide total number of subjects
    140
    EEA total number of subjects
    60
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    100
    From 65 to 84 years
    39
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 First patient randomly assigned to treatment: 28 July 2014 A total of 64 study centers were initiated in Europe, Africa, Asia Pacific, and Latin America.

    Pre-assignment
    Screening details
    		 Key Inclusion Criteria 1. Patient is male or female 18 years or older. 2. Patient has histologically confirmed CD20+ FL according to the WHO 2008 classification; grades 1 to 3a based on local laboratory review. 3. Patient has at least 1 measurable tumour mass that has not previously been irradiated. 4. Patient has Ann Arbor stage III or IV.

    Pre-assignment period milestones
    Number of subjects started
    		 184 [1]
    Intermediate milestone: Number of subjects
    Enrolled: 140
    Number of subjects completed
    		 140

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Screening Failure: 44
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The number of subjects reported to have started the pre-assignment period, 184, represents the number of subjects screened for this study. Of those, 44 failed screening and 140 patients were randomised.
    Period 1
    Period 1 title
    Core Study Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor
    Blinding implementation details
    This study was double-blinded. The study blind was not to be broken except in either a medical emergency (where knowledge of the study drug received was able to affect the treatment of the emergency) or a regulatory requirement, and the overall randomization code will be broken only for reporting purpose. Sponsor and CRO will predefine unblinded team and run them separately to maintain blinding throughout the study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 CT-P10
    Arm description
    		 Patient treated with CT-P10 (375 mg/m2, IV) in combination with cyclophosphamide (750 mg/m2 IV), vincristine (1.4 mg/m2 [up to a maximum of 2 mg] IV), and prednisolone (40 mg/m2 orally) up to 8 cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CT-P10
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    CT-P10 375 mg/m2 diluted in 500 mL of normal saline administered as an IV infusion.

    Arm title
    		 Rituxan
    Arm description
    		 US-licensed product. Patient treated with Rituxan (375 mg/m2, IV) in combination with cyclophosphamide (750 mg/m2 IV), vincristine (1.4 mg/m2 [up to a maximum of 2 mg] IV), and prednisolone (40 mg/m2 orally) up to 8 cycles.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Rituxan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituxan 375 mg/m2 diluted in 500 mL of normal saline administered as an IV infusion.

    Number of subjects in period 1
    		CT-P10 Rituxan
    Started
    70
    70
    Completed
    62
    62
    Not completed
    8
    8
         Consent withdrawn by subject
    1
    2
         Physician decision
    -
    2
         Adverse event, non-fatal
    4
    1
         Death
    1
    -
         Progressive disease
    2
    3
    Period 2
    Period 2 title
    Maintenance Study Period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor
    Blinding implementation details
    This study was double-blinded. The study blind was not to be broken except in either a medical emergency (where knowledge of the study drug received was able to affect the treatment of the emergency) or a regulatory requirement, and the overall randomization code will be broken only for reporting purpose. Sponsor and CRO will predefine unblinded team and run them separately to maintain blinding throughout the study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 CT-P10
    Arm description
    		 Patients having responses during Period 1 (Core Study Period) were treated with CT-P10 (375 mg/m2, IV) monotherapy up to 12 cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CT-P10
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    CT-P10 375 mg/m2 diluted in 500 mL of normal saline administered as an IV infusion.

    Arm title
    		 Rituxan
    Arm description
    		 US-licensed product. Patients having responses during Period 1 (Core Study Period) were treated with Rituxan (375 mg/m2, IV) monotherapy up to 12 cycles.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Rituxan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituxan 375 mg/m2 diluted in 500 mL of normal saline administered as an IV infusion.

    Number of subjects in period 2 [2]
    		CT-P10 Rituxan
    Started
    62
    60
    Completed
    46
    38
    Not completed
    16
    22
         Adverse event, serious fatal
    1
    -
         Consent withdrawn by subject
    -
    3
         Adverse event, non-fatal
    2
    3
         Death
    2
    1
         Stable disease
    -
    1
         Progressive disease
    11
    13
         Protocol deviation
    -
    1
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Two subjects did not enter the Maintenance Study Period due to a withdrawal by subject and a non-responder, respectively. Patients having responses (CR, CRu or PR) during the Core Study Period were allowed to proceed with the Maintenance Study Period after completion of the Core Study Period as per protocol.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CT-P10
    Reporting group description
    		 Patient treated with CT-P10 (375 mg/m2, IV) in combination with cyclophosphamide (750 mg/m2 IV), vincristine (1.4 mg/m2 [up to a maximum of 2 mg] IV), and prednisolone (40 mg/m2 orally) up to 8 cycles.

    Reporting group title
    Rituxan
    Reporting group description
    		 US-licensed product. Patient treated with Rituxan (375 mg/m2, IV) in combination with cyclophosphamide (750 mg/m2 IV), vincristine (1.4 mg/m2 [up to a maximum of 2 mg] IV), and prednisolone (40 mg/m2 orally) up to 8 cycles.

    Reporting group values
    		 CT-P10 Rituxan Total
    Number of subjects
    		 70 70 140
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 51 49 100
        From 65-84 years
    		 18 21 39
        85 years and over
    		 1 0 1
    Age continuous
    Units: years
        median (full range (min-max))
    		 57.0 (30 to 85) 58.5 (26 to 84) -
    Gender categorical
    Units: Subjects
        Female
    		 40 37 77
        Male
    		 30 33 63

    End points

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    End points reporting groups
    Reporting group title
    CT-P10
    Reporting group description
    		 Patient treated with CT-P10 (375 mg/m2, IV) in combination with cyclophosphamide (750 mg/m2 IV), vincristine (1.4 mg/m2 [up to a maximum of 2 mg] IV), and prednisolone (40 mg/m2 orally) up to 8 cycles.

    Reporting group title
    Rituxan
    Reporting group description
    		 US-licensed product. Patient treated with Rituxan (375 mg/m2, IV) in combination with cyclophosphamide (750 mg/m2 IV), vincristine (1.4 mg/m2 [up to a maximum of 2 mg] IV), and prednisolone (40 mg/m2 orally) up to 8 cycles.
    Reporting group title
    CT-P10
    Reporting group description
    		 Patients having responses during Period 1 (Core Study Period) were treated with CT-P10 (375 mg/m2, IV) monotherapy up to 12 cycles.

    Reporting group title
    Rituxan
    Reporting group description
    		 US-licensed product. Patients having responses during Period 1 (Core Study Period) were treated with Rituxan (375 mg/m2, IV) monotherapy up to 12 cycles.

    Subject analysis set title
    Pharmacokinetic Population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The PK population was defined as all patients who receive at least 1 dose (full) of study drug (CT-P10 or Rituxan) and who had at least 1 posttreatment PK concentration result. The PK population was the primary population for the summary of PK data.

    Subject analysis set title
    Efficacy Population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The per-protocol (PP) population in this study was defined for the principle of efficacy population. The PP population was defined as all randomly assigned patients who had at least 1 response evaluation after receiving at least 1 treatment cycle (full) in the Core Study Period and who did not have any major protocol deviation that were relevant to the efficacy endpoint.

    Subject analysis set title
    Pharmacodynamic Population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The pharmacodynamic (PD) population was defined as all patients who received at least 1 dose (full) of study drug (CT-P10 or Rituxan) and who had at least 1 posttreatment PD result and who did not have any major protocol deviation that was relevant to the PD endpoint. The PD population was the primary population for the summary of PD data.

    Primary: AUCtau

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    End point title
    		 AUCtau
    End point description
    Area under the serum concentration-time curve at steady state. Measure type is geometric least squares mean.
    End point type
    Primary
    End point timeframe
    Core Cycle 4 at Steady State
    End point values
    		 CT-P10 Rituxan
    Number of subjects analysed
    50 [1]
    56 [2]
    Units: h•µg/mL
        geometric mean (standard error)
    41002.43 ± 1.136
    40099.08 ± 1.143
    Notes
    [1] - Patients who did not receive full dose of study drug up to Core Cycle 4 and outliers were excluded.
    [2] - Patients who did not receive full dose of study drug up to Core Cycle 4 and outliers were excluded.
    Statistical analysis title
    		 Co-primary Pharmacokinetic Endpoints - AUCtau
    Statistical analysis description
    The primary PK endpoints of the AUCtau between patients treated with CT-P10 and Rituxan reference product at steady state were analyzed using an analysis of covariance with treatment as a fixed effect and country, gender, race, the value of ECOG status, and the FLIPI Score (0 to 2 vs. 3 to 5) at baseline fitted as covariates. Point estimates and 90% CIs for differences on the log scale were exponentiated to obtain estimates for ratios of geometric least square means on the original scale.
    Comparison groups
    CT-P10 v Rituxan
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [3]
    Method
    		 ANCOVA
    Parameter type
    		 Ratio of geometric least square means
    Point estimate
    102.25
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 94.05
         upper limit
    		 111.17
    Notes
    [3] - Equivalence margin: 80%-125%

    Primary: CmaxSS

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    End point title
    		 CmaxSS
    End point description
    Maximum serum concentration at steady state. Measure type is geometric least square means.
    End point type
    Primary
    End point timeframe
    Core Cycle 4 at Steady State
    End point values
    		 CT-P10 Rituxan
    Number of subjects analysed
    53 [4]
    56 [5]
    Units: μg/mL
        geometric mean (standard error)
    256.19 ± 1.115
    254.49 ± 1.120
    Notes
    [4] - Patients who did not receive full dose of study drug up to Core Cycle 4 and outliers were excluded.
    [5] - Patients who did not receive full dose of study drug up to Core Cycle 4 and outliers were excluded.
    Statistical analysis title
    		 Co-primary Pharmacokinetic Endpoints - CmaxSS
    Statistical analysis description
    The primary PK endpoints of the CmaxSS between patients treated with CT-P10 and Rituxan reference product at steady state were analyzed using an analysis of covariance with treatment as a fixed effect and country, gender, race, the value of ECOG status, and the FLIPI Score (0 to 2 vs. 3 to 5) at baseline fitted as covariates. Point estimates and 90% CIs for differences on the log scale were exponentiated to obtain estimates for ratios of geometric least square means on the original scale.
    Comparison groups
    CT-P10 v Rituxan
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [6]
    Method
    		 ANCOVA
    Parameter type
    		 Ratio of geometric least square means
    Point estimate
    100.67
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 93.84
         upper limit
    		 108
    Notes
    [6] - Equivalence margin: 80%-125%

    Primary: ORR (CR + CRu + PR) during the Core Study Period

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    End point title
    		 ORR (CR + CRu + PR) during the Core Study Period
    End point description
    Overall response rate (CR + CRu + PR) according to the 1999 IWG criteria during the Core Study Period by central review.
    End point type
    Primary
    End point timeframe
    During the Core Study Period (up to 8 cycles)
    End point values
    		 CT-P10 Rituxan
    Number of subjects analysed
    66 [7]
    68 [8]
    Units: Number of Patients
        ORR (CR+CRu+PR)
    64
    63
        Complete Response (CR)
    20
    15
        Unconfirmed CR (CRu)
    6
    8
        Partial Response (PR)
    38
    40
        Stable disease
    1
    2
        Relapse/Progressive disease
    1
    2
        Unable to assess
    0
    1
    Notes
    [7] - Four patients with major protocol deviations or no posttreatment efficacy results were excluded.
    [8] - Two patients with no posttreatment efficacy results were excluded.
    Statistical analysis title
    		 Co-primary Efficacy Endpoint - ORR
    Statistical analysis description
    The point estimate difference of the ORR between the CT-P10 and Rituxan.
    Comparison groups
    CT-P10 v Rituxan
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [9]
    Method
    Parameter type
    		 Point estimate difference
    Point estimate
    4.3
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 -4.25
         upper limit
    		 -
    Notes
    [9] - Non-inferiority margin : -7%

    Secondary: B-cell kinetics (B-cell depletion and recovery) during the Core Study Period

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    End point title
    		 B-cell kinetics (B-cell depletion and recovery) during the Core Study Period
    End point description
    Pharmacodynamics (B-cell counts) of rituximab during the Core Study Period
    End point type
    Secondary
    End point timeframe
    During the Core Study Period (up to 8 cycles)
    End point values
    		 CT-P10 Rituxan
    Number of subjects analysed
    70
    70
    Units: cells/μL
    median (full range (min-max))
        Core Cycle 1 (Predose)
    92.5 (20 to 2890)
    62.0 (20 to 2890)
        Core Cycle 1 (1Hr after End of Infusion)
    20.0 (20 to 1108)
    20.0 (20 to 51)
        Core Cycle 2 (Predose)
    20.0 (20 to 1750)
    20.0 (20 to 2890)
        Core Cycle 3 (Predose)
    20.0 (20 to 231)
    20.0 (20 to 35)
        Core Cycle 4 (Predose)
    20.0 (20 to 51)
    20.0 (20 to 20)
        Core Cycle 5 (Predose)
    20.0 (20 to 20)
    20.0 (20 to 20)
        Core Cycle 6 (Predose)
    20.0 (20 to 33)
    20.0 (20 to 20)
        Core Cycle 7 (Predose)
    20.0 (20 to 24)
    20.0 (20 to 20)
        Core Cycle 8 (Predose)
    20.0 (20 to 20)
    20.0 (20 to 20)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Overall study period
    Adverse event reporting additional description
    All TESAEs and non-serious AEs reported for more than 5% of the patients in either treatment group are summarized for the safety population.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    CT-P10
    Reporting group description
    		 All randomly assigned patients who received at least 1 dose (full or partial) of CT-P10.

    Reporting group title
    Rituxan
    Reporting group description
    		 All randomly assigned patients who received at least 1 dose (full or partial) of Rituxan.

    Serious adverse events
    		 CT-P10 Rituxan
    Total subjects affected by serious adverse events
         subjects affected / exposed
    24 / 70 (34.29%)
    13 / 70 (18.57%)
         number of deaths (all causes)
    8
    4
         number of deaths resulting from adverse events
    4
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma gastric
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hepatocellular carcinoma
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Invasive lobular breast carcinoma
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer metastatic
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic shock
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 70 (2.86%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Investigations
    Liver function test abnormal
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fracture
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural fistula
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    2 / 70 (2.86%)
    3 / 70 (4.29%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal perforation
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal infection
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Campylobacter gastroenteritis
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes virus infection
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 70 (1.43%)
    2 / 70 (2.86%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 70 (5.71%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sialoadenitis
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 70 (0.00%)
    2 / 70 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 CT-P10 Rituxan
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    58 / 70 (82.86%)
    57 / 70 (81.43%)
    Injury, poisoning and procedural complications
    Fracture
         subjects affected / exposed
    4 / 70 (5.71%)
    1 / 70 (1.43%)
         occurrences all number
    5
    1
    Infusion related reaction
         subjects affected / exposed
    16 / 70 (22.86%)
    19 / 70 (27.14%)
         occurrences all number
    24
    25
    Vascular disorders
    Hypertension
         subjects affected / exposed
    6 / 70 (8.57%)
    3 / 70 (4.29%)
         occurrences all number
    6
    3
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    4 / 70 (5.71%)
    5 / 70 (7.14%)
         occurrences all number
    4
    5
    Headache
         subjects affected / exposed
    4 / 70 (5.71%)
    6 / 70 (8.57%)
         occurrences all number
    4
    6
    Hypoaesthesia
         subjects affected / exposed
    6 / 70 (8.57%)
    2 / 70 (2.86%)
         occurrences all number
    6
    3
    Neuropathy peripheral
         subjects affected / exposed
    10 / 70 (14.29%)
    12 / 70 (17.14%)
         occurrences all number
    12
    15
    Paraesthesia
         subjects affected / exposed
    3 / 70 (4.29%)
    8 / 70 (11.43%)
         occurrences all number
    7
    9
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    6 / 70 (8.57%)
    5 / 70 (7.14%)
         occurrences all number
    6
    6
    Neutropenia
         subjects affected / exposed
    27 / 70 (38.57%)
    20 / 70 (28.57%)
         occurrences all number
    60
    37
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    5 / 70 (7.14%)
    8 / 70 (11.43%)
         occurrences all number
    5
    12
    Fatigue
         subjects affected / exposed
    6 / 70 (8.57%)
    8 / 70 (11.43%)
         occurrences all number
    7
    12
    Oedema
         subjects affected / exposed
    5 / 70 (7.14%)
    3 / 70 (4.29%)
         occurrences all number
    6
    3
    Pyrexia
         subjects affected / exposed
    3 / 70 (4.29%)
    6 / 70 (8.57%)
         occurrences all number
    5
    10
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    8 / 70 (11.43%)
    11 / 70 (15.71%)
         occurrences all number
    8
    12
    Constipation
         subjects affected / exposed
    12 / 70 (17.14%)
    10 / 70 (14.29%)
         occurrences all number
    13
    12
    Diarrhoea
         subjects affected / exposed
    6 / 70 (8.57%)
    7 / 70 (10.00%)
         occurrences all number
    8
    8
    Nausea
         subjects affected / exposed
    9 / 70 (12.86%)
    7 / 70 (10.00%)
         occurrences all number
    11
    7
    Stomatitis
         subjects affected / exposed
    2 / 70 (2.86%)
    4 / 70 (5.71%)
         occurrences all number
    2
    6
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    6 / 70 (8.57%)
    5 / 70 (7.14%)
         occurrences all number
    6
    10
    Dyspnoea
         subjects affected / exposed
    4 / 70 (5.71%)
    1 / 70 (1.43%)
         occurrences all number
    4
    1
    Oropharyngeal pain
         subjects affected / exposed
    1 / 70 (1.43%)
    4 / 70 (5.71%)
         occurrences all number
    1
    4
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    10 / 70 (14.29%)
    5 / 70 (7.14%)
         occurrences all number
    10
    5
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    2 / 70 (2.86%)
    6 / 70 (8.57%)
         occurrences all number
    2
    9
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    7 / 70 (10.00%)
    4 / 70 (5.71%)
         occurrences all number
    8
    7
    Back pain
         subjects affected / exposed
    2 / 70 (2.86%)
    12 / 70 (17.14%)
         occurrences all number
    2
    15
    Myalgia
         subjects affected / exposed
    6 / 70 (8.57%)
    2 / 70 (2.86%)
         occurrences all number
    7
    2
    Infections and infestations
    Fungal infection
         subjects affected / exposed
    4 / 70 (5.71%)
    4 / 70 (5.71%)
         occurrences all number
    4
    4
    Influenza
         subjects affected / exposed
    2 / 70 (2.86%)
    4 / 70 (5.71%)
         occurrences all number
    2
    4
    Lower respiratory tract infection
         subjects affected / exposed
    7 / 70 (10.00%)
    1 / 70 (1.43%)
         occurrences all number
    12
    1
    Sinusitis
         subjects affected / exposed
    5 / 70 (7.14%)
    2 / 70 (2.86%)
         occurrences all number
    5
    6
    Upper respiratory tract infection
         subjects affected / exposed
    14 / 70 (20.00%)
    18 / 70 (25.71%)
         occurrences all number
    21
    31
    Urinary tract infection
         subjects affected / exposed
    6 / 70 (8.57%)
    6 / 70 (8.57%)
         occurrences all number
    9
    15
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 70 (0.00%)
    6 / 70 (8.57%)
         occurrences all number
    0
    7
    Hyperglycaemia
         subjects affected / exposed
    2 / 70 (2.86%)
    5 / 70 (7.14%)
         occurrences all number
    2
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Jul 2014
    Summary of significant change included the following: -Acceptance of patients aged 18 years to enroll. -Clarification of nodal and extranodal lesions, and dimensions. -Acceptance of previous radiotherapy under specific circumstances. -Providing flexibility in the acceptable methods for diagnosis of active TB. -The reduced number of blood samples for PK and PD analyses. -Sample size recalculation after expansion of research into randomized controlled trials with R-CVP. -Changes of analysis method from exact binomial approach to descriptive analysis, and clarification of Cox's proportional hazard model not used in this study. -Reduced freqeuncy of folow-up visits upon the information available in the phase 3 PRIMA study. -Revised definitions of some efficacy analyses based on the 2007 IWG criteria and the 1999 IWG criteria.
    16 Mar 2016
    Summary of significant changes included the following: -Reflection of changed covariates for PK analysis. -Deletion of sensitivity analysis in efficacy considered irrelevant. -Specification of how to maintain blinding. -Addition of evaluation variables other than pharmacokinetics for the first CSR.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/28712940
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