A Study to Evaluate Pertuzumab + Trastuzumab + Docetaxel vs. Placebo + Trastuzumab + Docetaxel in Previously Untreated HER2-positive Metastatic Breast Cancer (CLEOPATRA) (CLEOPATRA)

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Hoffmann-La Roche
Information provided by (Responsible Party):
Genentech, Inc.
ClinicalTrials.gov Identifier:
NCT00567190
First received: December 3, 2007
Last updated: April 6, 2016
Last verified: April 2016
Results First Received: August 14, 2012  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition: Metastatic Breast Cancer
Interventions: Drug: Pertuzumab
Drug: Placebo
Drug: Trastuzumab
Drug: Docetaxel

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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Reporting Groups
  Description
Pertuzumab + Trastuzumab + Docetaxel Patients received pertuzumab 420 mg intravenously (IV) every 3 weeks (q3w) plus trastuzumab 6 mg/kg IV q3w plus docetaxel 75 mg/m^2 IV q3w for at least 6 cycles.
Placebo + Trastuzumab + Docetaxel Patients received placebo IV q3w plus trastuzumab 6 mg/kg IV q3w plus docetaxel 75 mg/m^2 IV q3w for at least 6 cycles.

Participant Flow:   Overall Study
    Pertuzumab + Trastuzumab + Docetaxel     Placebo + Trastuzumab + Docetaxel  
STARTED     402 [1]   406 [1]
COMPLETED     192 [2]   142 [3]
NOT COMPLETED     210     264  
Death                 168                 221  
Withdrew Consent or Lost to Follow-up                 42                 43  
[1] All randomized patients (Intent-to-Treat [ITT]) population
[2] On 11 February 2014, 67 were alive and on study treatment; 125 were alive and in survival follow-up
[3] On 11 February 2014, 37 were alive and on study treatment; 105 were alive and in survival follow-up



  Baseline Characteristics


  Outcome Measures
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1.  Primary:   Progression-free Survival (PFS) Determined by an Independent Review Facility   [ Time Frame: Baseline to primary data cut-off on 13 May 2011 (up to 3 years, 3 months) ]

2.  Secondary:   Overall Survival   [ Time Frame: Baseline to the third data cut-off (11 February 2014) at 389 deaths (approximately 43 months after enrollment of the last patient, up to 6 years overall) ]

3.  Secondary:   Progression-free Survival (PFS) Determined by the Investigator   [ Time Frame: Baseline to the third data cut-off (11 February 2014) at 389 deaths (approximately 43 months after enrollment of the last patient, up to 6 years overall) ]

4.  Secondary:   Objective Response Determined by an Independent Review Facility   [ Time Frame: Baseline to primary data cut-off on 13 May 2011 (up to 3 years, 3 months) ]

5.  Secondary:   Duration of Objective Response Determined by an Independent Review Facility   [ Time Frame: Baseline to primary data cut-off on 13 May 2011 (up to 3 years, 3 months) ]

6.  Secondary:   Time to Symptom Progression   [ Time Frame: Baseline to primary data cut-off on 13 May 2011 (up to 3 years, 3 months) ]


  Serious Adverse Events


  Other Adverse Events
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Time Frame First treatment dose (12 February 2008) through final data analysis cut-off (11 February 2014) for a total safety analysis time frame of 6 years. The AE data derived from a snapshot taken on 24 March 2014 of the final analysis dataset (11 February 2014).
Additional Description Of those who started the study (pertuzumab [Ptz]=402, placebo[Pla]=406), 2 patients in each group received no treatment (total of 4), 9 Pla patients received at least 1 dose of Ptz, 1 Ptz patient received Pla at every cycle; resulting in Ptz=408 (402-2+9-1) and Pla=396 (406-2-9+1)

Frequency Threshold
Threshold above which other adverse events are reported   5%  

Reporting Groups
  Description
Placebo + Trastuzumab + Docetaxel Patients received placebo IV q3w plus trastuzumab 6 mg/kg IV q3w plus docetaxel 75 mg/m^2 IV q3w for at least 6 cycles. For the 48 patients that crossed over to the pertuzumab treatment group, AEs were analyzed from the day of their first placebo dose (Day 1) through the day just prior to their first pertuzumab dose. Any AEs occurring on, or after, the day of their first dose of pertuzumab were included in the Crossover treatment group analysis.
Pertuzumab + Trastuzumab + Docetaxel Patients received pertuzumab 420 mg intravenously (IV) every 3 weeks (q3w) plus trastuzumab 6 mg/kg IV q3w plus docetaxel 75 mg/m^2 IV q3w for at least 6 cycles.
Crossover From Placebo to Pertuzumab Forty-eight of 406 patients (11.8%) randomized to the placebo treatment group whose disease had not progressed crossed over to an open-label pertuzumab treatment group between July 2012 and November 2012. Patients received pertuzumab administered as an IV loading dose of 840 mg at cycle 1 then 420 mg IV every q3w until investigator-assessed radiographic or clinical evidence of PD, unacceptable toxicity, or withdrawal of consent. Trastuzumab and docetaxel doses continued in accordance with the pre-crossover placebo treatment regimens and according to dosing specifications indicated in the study protocol.

Other Adverse Events
    Placebo + Trastuzumab + Docetaxel     Pertuzumab + Trastuzumab + Docetaxel     Crossover From Placebo to Pertuzumab  
Total, other (not including serious) adverse events        
# participants affected / at risk     386/396 (97.47%)     400/408 (98.04%)     39/48 (81.25%)  
Blood and lymphatic system disorders        
Neutropenia † 1      
# participants affected / at risk     191/396 (48.23%)     209/408 (51.23%)     0/48 (0.00%)  
Anaemia † 1      
# participants affected / at risk     77/396 (19.44%)     96/408 (23.53%)     5/48 (10.42%)  
Leukopenia † 1      
# participants affected / at risk     82/396 (20.71%)     75/408 (18.38%)     0/48 (0.00%)  
Cardiac disorders        
Left ventricular dysfunction † 1      
# participants affected / at risk     27/396 (6.82%)     22/408 (5.39%)     0/48 (0.00%)  
Eye disorders        
Lacrimation increased † 1      
# participants affected / at risk     55/396 (13.89%)     60/408 (14.71%)     0/48 (0.00%)  
Conjunctivitis † 1      
# participants affected / at risk     17/396 (4.29%)     31/408 (7.60%)     0/48 (0.00%)  
Dry eye † 1      
# participants affected / at risk     8/396 (2.02%)     23/408 (5.64%)     0/48 (0.00%)  
Gastrointestinal disorders        
Diarrhoea † 1      
# participants affected / at risk     193/396 (48.74%)     277/408 (67.89%)     22/48 (45.83%)  
Nausea † 1      
# participants affected / at risk     168/396 (42.42%)     183/408 (44.85%)     4/48 (8.33%)  
Vomiting † 1      
# participants affected / at risk     96/396 (24.24%)     105/408 (25.74%)     5/48 (10.42%)  
Constipation † 1      
# participants affected / at risk     100/396 (25.25%)     65/408 (15.93%)     0/48 (0.00%)  
Stomatitis † 1      
# participants affected / at risk     63/396 (15.91%)     81/408 (19.85%)     3/48 (6.25%)  
Abdominal pain † 1      
# participants affected / at risk     48/396 (12.12%)     62/408 (15.20%)     0/48 (0.00%)  
Dyspepsia † 1      
# participants affected / at risk     48/396 (12.12%)     54/408 (13.24%)     3/48 (6.25%)  
Abdominal pain upper † 1      
# participants affected / at risk     43/396 (10.86%)     43/408 (10.54%)     0/48 (0.00%)  
General disorders        
Fatigue † 1      
# participants affected / at risk     148/396 (37.37%)     154/408 (37.75%)     4/48 (8.33%)  
Asthenia † 1      
# participants affected / at risk     122/396 (30.81%)     112/408 (27.45%)     0/48 (0.00%)  
Oedema peripheral † 1      
# participants affected / at risk     111/396 (28.03%)     98/408 (24.02%)     0/48 (0.00%)  
Mucosal inflammation † 1      
# participants affected / at risk     78/396 (19.70%)     111/408 (27.21%)     0/48 (0.00%)  
Pyrexia † 1      
# participants affected / at risk     72/396 (18.18%)     78/408 (19.12%)     3/48 (6.25%)  
Oedema † 1      
# participants affected / at risk     49/396 (12.37%)     48/408 (11.76%)     0/48 (0.00%)  
Chills † 1      
# participants affected / at risk     15/396 (3.79%)     34/408 (8.33%)     0/48 (0.00%)  
Pain † 1      
# participants affected / at risk     22/396 (5.56%)     26/408 (6.37%)     0/48 (0.00%)  
Chest pain † 1      
# participants affected / at risk     21/396 (5.30%)     14/408 (3.43%)     0/48 (0.00%)  
Influenza like illness † 1      
# participants affected / at risk     9/396 (2.27%)     22/408 (5.39%)     0/48 (0.00%)  
Immune system disorders        
Hypersensitivity † 1      
# participants affected / at risk     21/396 (5.30%)     26/408 (6.37%)     0/48 (0.00%)  
Infections and infestations        
Upper respiratory tract infection † 1      
# participants affected / at risk     57/396 (14.39%)     85/408 (20.83%)     5/48 (10.42%)  
Nasopharyngitis † 1      
# participants affected / at risk     59/396 (14.90%)     69/408 (16.91%)     11/48 (22.92%)  
Urinary tract infection † 1      
# participants affected / at risk     29/396 (7.32%)     36/408 (8.82%)     0/48 (0.00%)  
Paronychia † 1      
# participants affected / at risk     16/396 (4.04%)     31/408 (7.60%)     0/48 (0.00%)  
Influenza † 1      
# participants affected / at risk     22/396 (5.56%)     26/408 (6.37%)     4/48 (8.33%)  
Rhinitis † 1      
# participants affected / at risk     22/396 (5.56%)     20/408 (4.90%)     3/48 (6.25%)  
Investigations        
Weight decreased † 1      
# participants affected / at risk     19/396 (4.80%)     36/408 (8.82%)     0/48 (0.00%)  
Weight increased † 1      
# participants affected / at risk     22/396 (5.56%)     16/408 (3.92%)     0/48 (0.00%)  
Metabolism and nutrition disorders        
Decreased appetite † 1      
# participants affected / at risk     106/396 (26.77%)     120/408 (29.41%)     0/48 (0.00%)  
Hypokalaemia † 1      
# participants affected / at risk     21/396 (5.30%)     37/408 (9.07%)     0/48 (0.00%)  
Musculoskeletal and connective tissue disorders        
Myalgia † 1      
# participants affected / at risk     98/396 (24.75%)     98/408 (24.02%)     0/48 (0.00%)  
Arthralgia † 1      
# participants affected / at risk     69/396 (17.42%)     79/408 (19.36%)     3/48 (6.25%)  
Pain in extremity † 1      
# participants affected / at risk     53/396 (13.38%)     73/408 (17.89%)     0/48 (0.00%)  
Back pain † 1      
# participants affected / at risk     48/396 (12.12%)     65/408 (15.93%)     3/48 (6.25%)  
Bone pain † 1      
# participants affected / at risk     34/396 (8.59%)     37/408 (9.07%)     0/48 (0.00%)  
Musculoskeletal pain † 1      
# participants affected / at risk     38/396 (9.60%)     38/408 (9.31%)     0/48 (0.00%)  
Muscle spasms † 1      
# participants affected / at risk     20/396 (5.05%)     42/408 (10.29%)     0/48 (0.00%)  
Nervous system disorders        
Neuropathy peripheral † 1      
# participants affected / at risk     79/396 (19.95%)     91/408 (22.30%)     0/48 (0.00%)  
Headache † 1      
# participants affected / at risk     76/396 (19.19%)     105/408 (25.74%)     6/48 (12.50%)  
Dysgeusia † 1      
# participants affected / at risk     62/396 (15.66%)     75/408 (18.38%)     0/48 (0.00%)  
Peripheral sensory neuropathy † 1      
# participants affected / at risk     59/396 (14.90%)     50/408 (12.25%)     0/48 (0.00%)  
Dizziness † 1      
# participants affected / at risk     53/396 (13.38%)     61/408 (14.95%)     0/48 (0.00%)  
Paraesthesia † 1      
# participants affected / at risk     41/396 (10.35%)     40/408 (9.80%)     0/48 (0.00%)  
Psychiatric disorders        
Insomnia † 1      
# participants affected / at risk     55/396 (13.89%)     64/408 (15.69%)     0/48 (0.00%)  
Depression † 1      
# participants affected / at risk     20/396 (5.05%)     26/408 (6.37%)     0/48 (0.00%)  
Anxiety † 1      
# participants affected / at risk     20/396 (5.05%)     16/408 (3.92%)     0/48 (0.00%)  
Renal and urinary disorders        
Dysuria † 1      
# participants affected / at risk     11/396 (2.78%)     23/408 (5.64%)     0/48 (0.00%)  
Respiratory, thoracic and mediastinal disorders        
Cough † 1      
# participants affected / at risk     79/396 (19.95%)     96/408 (23.53%)     3/48 (6.25%)  
Dyspnoea † 1      
# participants affected / at risk     62/396 (15.66%)     61/408 (14.95%)     0/48 (0.00%)  
Epistaxis † 1      
# participants affected / at risk     35/396 (8.84%)     41/408 (10.05%)     0/48 (0.00%)  
Oropharyngeal pain † 1      
# participants affected / at risk     27/396 (6.82%)     32/408 (7.84%)     0/48 (0.00%)  
Rhinorrhoea † 1      
# participants affected / at risk     23/396 (5.81%)     32/408 (7.84%)     0/48 (0.00%)  
Skin and subcutaneous tissue disorders        
Alopecia † 1      
# participants affected / at risk     240/396 (60.61%)     248/408 (60.78%)     0/48 (0.00%)  
Rash † 1      
# participants affected / at risk     95/396 (23.99%)     153/408 (37.50%)     8/48 (16.67%)  
Nail disorder † 1      
# participants affected / at risk     92/396 (23.23%)     96/408 (23.53%)     0/48 (0.00%)  
Pruritus † 1      
# participants affected / at risk     40/396 (10.10%)     72/408 (17.65%)     0/48 (0.00%)  
Dry skin † 1      
# participants affected / at risk     24/396 (6.06%)     46/408 (11.27%)     3/48 (6.25%)  
Palmar-Plantar erythrodysaesthesia syndrome † 1      
# participants affected / at risk     22/396 (5.56%)     28/408 (6.86%)     0/48 (0.00%)  
Erythema † 1      
# participants affected / at risk     20/396 (5.05%)     24/408 (5.88%)     0/48 (0.00%)  
Vascular disorders        
Hypertension † 1      
# participants affected / at risk     32/396 (8.08%)     45/408 (11.03%)     0/48 (0.00%)  
Hot flush † 1      
# participants affected / at risk     21/396 (5.30%)     23/408 (5.64%)     0/48 (0.00%)  
Lymphoedema † 1      
# participants affected / at risk     16/396 (4.04%)     24/408 (5.88%)     0/48 (0.00%)  
Events were collected by systematic assessment
1 Term from vocabulary, MedDRA 16.1



  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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